Asymmetric catalysis with bifunctional cinchona alkaloid-based
Application of asymmetric catalysis for the synthesis and medicinal chemistry study …... ·...
Transcript of Application of asymmetric catalysis for the synthesis and medicinal chemistry study …... ·...
Application of Asymmetric Catalysis for the Synthesis and Medicinal
Chemistry Study of Polyketide Natural Products
by Yanping Wang
B. Eng. in Polymer, Shandong Institute of Light Industry
M.S. in Chemistry, Wuhan University
M.S. in Chemistry, University of Pittsburgh
A dissertation submitted to
The Faculty of
the College of Science of
Northeastern University
in partial fulfillment of the requirements
for the degree of Doctor of Philosophy
June 24, 2014
Dissertation directed by
George A. O’Doherty
Professor of Chemistry and Chemical Biology
ii
ACKNOWLEDGEMENTS
I would like to thank my research advisor, Professor George O’Doherty for the opportunities
to work in his group, for the broad knowledge and sharp insight for chemistry he had taught me
patiently. I also gave my great appreciation to Prof. Geoffrey Coates and Brandon Tiegs, who
helped me to finish and discuss the carbonylation of epoxides for tetrahydrolipstatin project. I
would like to give my thanks to my committee, Professors Graham Jones, Michael Pollastri and
Zhaohui Sunny Zhou for their advice and guidance. Without their help, I could not complete my
dissertation.
I would also like to show my appreciation to my group colleagues, especially Dr. Qian Chen
for his discussion of chemistry with me, and Drs. Huayu Leo Wang and Mike Cuccarese for their
teaching me biological assays. I would like to give my great gratitude to Dr. Roger Kautz, who
taught most knowledge about NMR I had learned.
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ABSTRACT
Most polyketide natural products are chiral and exist in enantiomerically pure form, often
containing more than one stereogenic centers. During synthesis of the polyketide natural
products, these centers can be either derived from nature’s chiral pools or from resolution of
racemic mixtures. Alternatively, the chiral center can be installed using asymmetric catalysis.
The asymmetric catalysis approach has the potential to be the most efficient strategy for the
construction of libraries of stereochemical polyketide natural products by the installation
stereochemistry into the achiral starting materials.
Asymmetric catalysis was used to synthesize two categories of polyketide natural products,
cryptocaryols and tetrahydrolipstatin, in 25 and 10 longest linear steps, respectively. In addition,
five cryptocaryol and eight tetrahydrolipstatin stereochemical analogues were also accessed,
which demonstrated the versatility of the catalytic asymmetric approach. The asymmetric
catalysis strategy is also applied to an ongoing project the total synthesis of EBC-23.
These stereochemical analogues were used to develop structure activity relationship profiles
for cryptocaryols and tetrahydrolipstatin cytotoxicity against cancer cell lines (e.g. MCF-7 and
H460).
iv
Table of Contents
Acknowledgements ii
Abstract iii
Table of Contents iv
List of Figures vi
List of Schemes vii
List of Tables viii
List of Abbreviations x
Chapter 1. Cryptocaryol A and B: Total Syntheses, Stereochemical Revision, Structure
Elucidation, Structure-Activity Relationship and Ability to Stabilize PDCD4
1
1.1 Introduction of PDCD4 and cryptocaryols 1
1.2 Restrosynthetic analysis 4
1.3 Synthesis of pseudo-Cs symmetric intermediate 4
1.4 Synthesis of 6-epi-ent-cryptocaryol B 5
1.5 Synthesis of ent-cryptocaryol A and B 8
1.6 Synthesis of cryptocaryol A and B 10
1.7 Synthesis of cryptocaryol analogues 11
1.8 Biological evaluation of cryptocaryol analogues 12
Chapter 2. Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio-
and Diastereoselective Carbonylation of Epoxyhomoallylic Alcohols
20
2.1 Introduction of tetrahydrolipstatin 20
2.2 Retrosynthetic analysis 22
2.3 Formal synthesis of tetrahydrolipstatin 23
2.4 Asymmetric synthesis of cis-epoxyhomoallylic alcohol 24
v
2.5 Total synthesis of tetrahydrolipstatin 25
2.6 Alternative approach to THL 26
2.7 Examination of late stage of carbonylation of epoxides 29
2.8 Syntheis of other THL stereoisomers 35
Chapter 3. Total Synthesis of EBC-23 37
3.1 Introduction of EBC-23 37
3.2 Restrosynthetic analysis of EBC-23 39
3.3 Synthesis of protected diol methyl ketone 40
3.4 Synthesis of acyl chloride 40
3.5 End game of synthesis of EBC-23 41
Experimental Section 43
References 184
vi
Lists of Figures
Figure 1. Tumor-suppressive effects of PDCD4/inhibition of eIF4A 2
Figure 2. Purported structures of cryptocaryols A–H (I-1–I-8) and revised structures of
cryptocaryol A (I-9) and B (I-10)
3
Figure 3. 1H NMR of reported cryptocaryol B and synthesized I-2 7
Figure 4. 13
C NMR comparison of reported cryptocaryol B and synthesized I-2 8
Figure 5. 1H NMR of reported cryptocaryol A and synthesized I-42 9
Figure 6. 13
C NMR comparison of reported cryptocaryol A and synthesized I-42 10
Figure 7. PDCD4 stabilization by cryptocaryol analogues 14
Figure 8. Effect of cryptocaryol A and cryptocaryol B on the cytotoxicity of
camptothecin and digitoxin against MCF-7 cells
15
Figure 9. Changes in CTC/anticancer drug profiles depending on the presence of 20
nM of TPA
17
Figure 10. HT-29 cells were pretreated with PDCD4 stabilizers CTCA, CTCB (1 µM)
and rapamycin (10 nM) followed by DIG or CPT
18
Figure 11. Tetrahydrolipstatin (THL, II-1), lipstatin (II-2) and analogues (II-3) 20
Figure 12. Rationale for loss of regiocontrol for epoxides II-33 and II-35 34
Figure 13. Structures of EBC family members 37
vii
Lists of Schemes
Scheme 1. Retrosynthetic analysis of cryptocaryol A and B 4
Scheme 2. Synthesis of pseudo-Cs symmetric intermediate I-13 5
Scheme 3. Synthesis of 6-epi-ent-cryptocaryol B (I-2) 6
Scheme 4. Synthesis of ent-cryptocaryol A and B (I-42 and I-46) 9
Scheme 5. Synthesis of cryptocaryol A and B (I-9 and I-10) 11
Scheme 6. Synthesis of cryptocaryol analogues for SAR 12
Scheme 7. Regioselective carbonylation of protected cis-epoxyhomoallylic alcohols 21
Scheme 8. Retrosynthetic analysis of THL (II-1) 23
Scheme 9. Formal synthesis of THL (II-1) 24
Scheme 10. Synthesis of cis-epoxyhomoallylic alcohol II-23 25
Scheme 11. Synthesis of THL (II-1): carbonylation of MOM-protected epoxide II-6b 26
Scheme 12. Synthesis of THL (II-1): a late-stage carbonylation of epoxide 29
Scheme 13. Synthesis of diastereomer II-31 30
Scheme 14. Synthesis of stereoisomeric epoxides from II-23 31
Scheme 15. Synthesis of stereoisomeric epoxides from ent-II-23 31
Scheme 16. Synthesis of β-lactones II-40 and II-41 from known β-lactone II-4b 34
Scheme 17. Evidence for minor regioisomer II-40a by thermolysis 35
Scheme 18. Synthesis of THL stereoisomers 36
Scheme 19. Williams’ restrosynthetic analysis of EBC-23 38
Scheme 20. Restrosynthetic analysis of EBC-23 by Yamamoto 39
Scheme 21. Our de novo retrosynthetic analysis of EBC-23 39
Scheme 22. Synthesis of protected diol ketone III-16 40
Scheme 23. Synthesis of acyl chloride III-17 41
Scheme 24. End game of synthesis of EBC-23 41
viii
Lists of Tables
Table 1. Cryptocaryols cytotoxicity data 13
Table 2. Co-dosing effects of the cryptocaryols in MCF-7 cells 16
Table 3. Co-dosing effect of cryptocaryol B and CPT in the presence of TPA in
MCF-7
17
Table 4. Perturbation in IC50 for CPT and DIG in the presence of CTCA, CTCB or
rapamycin against HT-29 cells.
18
Table 5. 1H NMR assignments of THL. 27
Table 6. 1H NMR assignments of THL. 28
Table 7. Stereochemical scope of regioselective carbonylation 33
ix
List of Abbreviations
5FU 5-fluorouracil
[] specific rotation
Ac acetyl
br broad
Boc tert-butoxycarbonyl
calc calculated
CI chemical ionization
CPT camptothecin
CTC cryptocaryol
δ chemical shift
d doublet
DBU 1,8-Diazabicyclo[5.4.0]
DCC Dicyclohexyl Carbodiimide
DIBALH diisobutylaluminium hydride
DIG digitoxin
DIPEA N,N-diisopropylethylamine
DMAP 4-(dimethylamino)pyridine
DMF dimethylformamide
DMSO dimethylsulfoxide
dr diastereomeric ratio
ee enantiomeric excess
equiv equivalent
ESI electrospray ionization
Et ethyl
x
ETO etoposide
FBS fetal bovine serum
g gram
IC50 half maximal inhibitory concentration
h hour(s)
HRMS high resolution mass spectrometry
Hz Hertz
IR infra red
J coupling constant
k kilo-
L liter
LAH lithium aluminum hydride
m milli; multiplet
M molar
Me methyl
Mes 2,4,6-trimethylphenyl (mesityl)
MHz megahertz
min minute(s)
mol mole
MOM methoxymethyl
mp melting point
MW molecular weight
MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
NBS N-iodosuccinimide
NMR nuclear magnetic resonance
xi
OXA oxaliplatin
Ph phenyl
PKC protein kinase C
PMB para-methoxybenzyl
Pr propyl
PVDF polyvinylidene fluoride
q quartet
rt room temperature
Rf retention factor
s second; singlet
SiO2 silica gel
sp species
t ,t tert, triplet
TBAF tetrabutylammonium fluoride
TBS t-butyldimethylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TPA 12-O-tetradecanoylphorbol-13-acetate
TsOH para-toluenesulfonic acid
1
Chapter 1
Cryptocaryol A and B: Total Syntheses, Stereochemical Revision, Structure
Elucidation, Structure-Activity Relationship and Ability to Stabilize PDCD4*
1.1 Introduction of PDCD4 and cryptocaryols
The early success and subsequent limitation found with the development of protein kinase C
(PKC) as a target for cancer and other diseases, have led to the search for alternative downstream
kinase targets for development (e.g., mTOR, Akt).1 It is believed that the regulation of these
new targets will selectively produce all the desired outcomes (e.g., tumor suppression) without
side effects (e.g., non-cancer cell toxicity).2 Programmed cell death 4 (PDCD4), a downstream
target of Akt, is a novel tumor suppressor protein (Figure 1).3 PDCD4 interaction with eukaryotic
initiation factor 4A (eIF4A) inhibits protein synthesis.4 In addition, PDCD4 suppresses the
activation of activator protein-1 (AP-1) through c-Jun.5 Not surprisingly, the stabilization of
PDCD4 is linked to the induction of apoptosis.6 Also, expression of PDCD4 has been shown to
confer increased sensitivity to some anti-cancer drugs and reduce the malignancy of ovarian
cancer cells.7 Conversely, its low expression levels are linked with the progression of several
cancers (e.g., lung, liver, ovary and brain).8 Loss of PDCD4 is observed in lung, breast, colon
and prostate cancers.4d
Similarly, in a panel of 124 lung cancer patients, expression of PDCD4 in
tumor cells was inversely related to poor prognosis.9 Thus, PDCD4 is a target for the
development of novel antineoplastic agents.10
* Wang, Y.; O’Doherty, G. A. J. Am. Chem. Soc. 2013, 135, 9334-9337. Cuccarese, M. F.; Wang, Y.; Beuning, P.
J.; O’Doherty, G. A. ACS Med. Chem. Lett. 2014, 5, 522-526. (The synthetic work and cytotoxicity assays were
carried out by YW; and the immunoblot experiment by MFC). Reproduced by permission of American Chemical
Society.
2
PDCD4 is degraded within the cell via a discrete pathway. Phosphorylation of PDCD4 by
PI3K/Akt leads to ubiquitination and proteasomal degradation.11
This degradation (aka,
destabilization) appears to be increased in some tumors.3 Given the benefits of PDCD4
expression, stabilization of PDCD4 is an attractive way to elevate PDCD4 levels, and holds the
potential to increase cancer cell sensitivity to chemotherapy. Rapamycin (RAP) is known to both
stabilize PDCD4 and synergize with anticancer drugs;12
unfortunately, the use of rapamycin in
cancer treatment is hindered by its immunosuppressive effects.13
Figure 1. Tumor-suppressive effects of PDCD4/inhibition of eIF4A.a
a PDCD4 is an inhibitor of protein synthesis via inhibition of initiation factor eIF4A. The E3 ubiquitin ligase -TrCP
binds to phosphorylated PDCD4, targeting it for ubiquitination and degradation via the 26S proteasome. TPA
activates PKC, which initiates phosphorylation and degradation of PDCD4 via PI3K, Akt or mTOR. Stabilizers of
PDCD4 interfere with the degradation of PDCD4 (i.e., rapamycin inhibits mTOR, reducing PDCD4
phosphorylation).
In an effort to find natural products that stabilize levels of PDCD4, Gustafson et al.
developed a high-throughput in vivo cell-based assay that identified cryptocaryols A–H (I-1–I-8)
(Figure 2).14
This class of natural products isolated from Cryptocarya spp. shares a 5,6-dihydro-
α-pyranone and a 1,3-polyol segment. In addition, the eight cryptocaryols stablized PDCD4 in
3
12-O-tetradecanoylphorbol-13-acetate (TPA) challenged cells with EC50 ranging from 1.3 to 4.9
µM. The structures of these compounds were elucidated by a combination of NMR, HRMS and
CD analyses. The all syn-tetraol relative configuration was assigned using Kishi's 13
C NMR
database,15
and the absolute configuration of pyranone at C-6 was assigned as R from its Cotton
effect.16
Unfortunately, the development and interpretation of structure-activity relationship
(SAR) data was limited by the ambiguities associated with the absolute and relative
stereochemistry of these structures.17
Figure 2. Purported structures of cryptocaryols A–H (I-1–I-8) and revised structures of cryptocaryol A
(I-9) and B (I-10).
aEC50 = µM concentration for recovery of 50% PDCD4 concentration from TPA-induced degradation in
HEK293 cell lines. bIC50 = µM concentration for cytotoxicity activity against MCF-7 cell lines.
1.2 Restrosynthetic analysis
Thus, we devised a plan for the synthesis of cryptocaryol A and B with the aims of
establishing the 3D structure and providing material for SAR studies (Scheme 1). In particular,
we envisioned an approach that would take advantage of the pseudo-Cs symmetry of a tetraol
fragment in I-13,18
which would be amenable for the synthesis of the purported structures of
these natural products (I-1 and I-2), along with their enantiomers (I-12) and C-6/16-
diastereomers (e.g., I-9, I-10 and I-11). Recently, we developed an iterative hydration of polyene
4
strategy to build 1,3-polyols,19
which has proved to be extremely successful for the syntheses of
related 1,3-polyol natural products20
as well as more complicated variants.21
Scheme 1. Retrosynthetic analysis of cryptocaryol A and B
1.3 Synthesis of pseudo-Cs symmetric intermediate
Towards this end, we began with the synthesis of orthogonally protected pentaol I-13 from
commercially available 5-hexyn-1-ol (I-16) (Scheme 2). The primary alcohol was protected as a
PMB ether I-17, and the terminal alkyne in I-17 was homologated (n-BuLi/methyl
chloroformate, I-17 to I-18) and then subsequently isomerized (PPh3/PhOH)22
to give dienoate I-
19 in an excellent overall yield for three steps (88%). The distal double bond of dienoate I-19
was asymmetrically oxidized under the Sharpless conditions ((DHQ)2PHAL) to give a 2-enoate-
4,5-diol I-20,23
which upon treatment with triphosgene and pyridine gave carbonate I-21. A Pd-
catalyzed regioselective reduction of I-21 with (Et3N/HCO2H, catalytic Pd/PPh3) produced δ-
hydroxy enoate I-22. Acetal formation using the Evans’ conditions (benzaldehyde/KOt-Bu)
diastereoselectively transformed I-22 into benzylidene protected syn-1,3-diol I-23.24
Thus in
four steps, the initial protected diol fragment of I-13 was installed in I-23 from I-19.
The installation of the second protected diol fragment of I-13 began with an ester to aldehyde
reduction of I-23 (DIBALH) followed by Leighton allylation to give homoallylic alcohol I-25.25
5
The homoallylic alcohol stereochemistry of I-25 was used to stereospecifically install the final
benzylidene protected diol fragment. This was accomplished with a two-step cross metathesis
(ethyl acrylate/Grubbs II) and Evans’ acetal formation sequence to furnish the pentaol I-13 via δ-
hydroxy enoate I-26.26
Scheme 2. Synthesis of pseudo-Cs symmetric intermediate I-13
1.4 Synthesis of 6-epi-ent-cryptocaryol B
With the key pentaol I-13 in hand, our efforts were turned to the synthesis of the purported
cryptocaryol A (I-1) and B (I-2). The PMB group in I-13 was deprotected with DDQ to release
the primary alcohol I-27, which then was oxidized with DMP to afford aldehyde I-28 (Scheme
3). Nucleophilic alkyne addition (1-pentadecyne/n-BuLi, –78 °C) to aldehyde I-28 gave a
propargyl alcohol, which upon oxidation (Dess–Martin) and asymmetric reduction (Noyori)
diastereoselectively gave propargyl alcohol I-30 via ynone I-29.27
The alkyne in I-30 was
reduced to alkane I-31 with excess diimide (NBSH/Et3N). A two-step DIBALH reduction and
alcohol acylation procedure on ester I-31 produced aldehyde I-33 via alcohol I-32. The final
stereocenter in I-2 was installed to afford homoallylic alcohol I-34 with the use of a second
6
Leighton allylation, which after acylation (acrylic acid/DCC) was then converted into diene I-35.
A ring closing metathesis (Grubbs I) installed the desired pyranone to give I-36, which after
benzylidene deprotection (AcOH/H2O) furnished the structure purported to be cryptocaryol B (I-
2).17
Scheme 3. Synthesis of 6-epi-ent-cryptocaryol B (I-2)
Although great similarities existed between the 1H and
13C NMR spectra of I-2 and the data
reported for cryptocaryol B,14
our analysis led us to conclude that they did not match (Figure 3
and Figure 4).17
This included discrepancies in the 1H NMR (e.g., H-5a/H-5b, H-7a/H-7b, and H-
8) and the 13
C NMR (C-6, C-7 and C-8), with the variances (0.6 to 0.9 ppm) in the 13
C NMR
values being the hardest to reconcile. In order to gain a locus for further comparison, we
attempted to convert I-2 into the structure reported for cryptocaryol A (I-1). Unfortunately, we
were unable to find conditions to selectively hydrolyze the C-16 acetate without concomitant
hydrolysis of the pyranone ring. Next, we targeted the C-6 diastereomers of I-1 and I-2 (I-42 and
7
I-46, respectively), as the stereochemical relationship between the C-6 and C-8 positions was
ambiguously assigned by Gustafson.14
Moreover, we found the greatest variance in the C-5 to C-
9 positions in our comparison of the 1H and
13C NMR.
Figure 3. 1H NMR of reported cryptocaryol B and synthesized I-2
1H NMR of reported cryptocaryol B
1H NMR of synthesized I-2
8 5 7
8 5
7
8
Figure 4. 13
C NMR comparison of reported cryptocaryol B and synthesized I-2
Difference of chemical shift between reportedcryptocaryol B (I) and synthesized I-2 (II)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
-2
-1
0
1
2II-I
Carbon Number
1.5 Synthesis of ent-cryptocaryol A and B
These revised efforts returned to alcohol I-31 and involved the use of the enantiomeric (R,R)-
Leighton reagent (Scheme 4). In practice, we protected the secondary alcohol in I-31 as a TBS
ether I-37 and reduced the ester to aldehyde I-38. Application of the diasteromeric Leighton
allylation, acylation (acrylic acid/DCC) gave diene I-40 via homoallylic alcohol I-39, which in
two steps (Grubbs I; AcOH/H2O) was converted into I-42. The 1H NMR and
13C NMR spectral
data (Figure 5 and Figure 6) for synthetic I-42 were found to be identical to the data reported for
cryptocaryol A, with the exception of optical rotation (reported: [α]D = +12 (c = 0.1, MeOH);
synthetic: [α]D21
= –13.4 (c = 0.1, MeOH)). Replacing the TBS group in I-40 with an acetate
group (TBAF; Ac2O/Et3N) gave I-44 via alcohol I-43, the precursor for ent-cryptocaryol B,
which in two steps (Grubbs I; AcOH/H2O) was converted into I-46. Once again, the spectral data
for synthetic I-46 was identical to the data reported for cryptocaryol B.14
Thus the structures for
cryptocaryol A and B should be reassigned to I-9 and I-10, respectively.
9
Scheme 4. Synthesis of ent-cryptocaryol A and B (I-42 and I-46)
Figure 5. 1H NMR of reported cryptocaryol A and synthesized I-42
1H NMR of reported cryptocaryol A
1H NMR of synthesized of I-42
10
Figure 6. 13
C NMR comparison of reported cryptocaryol A and synthesized I-42
Difference of chemical shift between reportedcryptocaryol A (I) and synthesized I-42 (II)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
-1.0
-0.5
0.0
0.5
1.0 II-I
Carbon Number
1.6 Synthesis of cryptocaryol A and B
With the elucidation of the structures for the cryptocaryol A and B, we set out to undertake
their enantioselective synthesis and biological evaluation as anticancer agents. This effort began
with pseudo-Cs symmetric protected pentaol I-13, and requires the reversal in the order of
pyranone and side chain installation (Scheme 5). The revised route begins with the conversion of
ester I-13 into ynone I-48 (DIBALH; 1-pentadecyne; Dess–Martin). The C-16 stereochemistry
was installed in alcohol I-50 by a two-step Noyori asymmetric and diimide reduction procedure.
Adjustments of the protecting groups involved the protection of the C-16 alcohol of I-50 as a
TBS group (TBSCl) followed by PMB deprotection (DDQ) to give I-52. Oxidation of the
primary alcohol in I-52 (Dess–Martin) followed by Leighton allylation and acrylate acylation
(acrylic acid/DCC) provided diene I-55, from which I-58 was prepared with the required C-16
acetate group. Using the same ring closing metathesis/deprotection sequence, the dienes I-55 and
I-58 were uneventfully converted into cryptocaryol A (I-9) and B (I-10). The 1H and
13C NMR
data for the synthetic material were identical to the data reported for the isolated material.
11
Scheme 5. Synthesis of cryptocaryol A and B (I-9 and I-10)
1.7 Synthesis of cryptocaryol analogues
In addition to providing ample material (>5 mg/each) for structural elucidation, the route also
provided enough material for the cancer cell cytotoxicity studies. As part of these SAR studies,
additional analogues (hexaol I-60, hexaol acetate I-63 and saturated pyranone compound I-64)
were required for evaluation. These analogues were readily prepared from intermediates I-50 and
I-52, and cryptocaryol B (I-10) by deprotection of benzylidene and hydrogenation of alkene,
respectively (Scheme 6).
12
Scheme 6. Synthesis of cryptocaryol analogues for SAR
1.8 Biological evaluation of cryptocaryol analogues
While other PDCD4 stabilizers are known to be cytotoxic, there is very little data to correlate
their cytotoxicity to PDCD4 stabilization.28
We chose three cancer cell lines to evaluate
cytotoxicity for the eight polyols. Three cell lines selected for study were chosen based on their
basal PDCD4 contents as measured by RNA microarray and protein content analysis by
immunoblot. The first cell line studied was MCF-7, which has been shown to have high
expression levels of PDCD4. The second cell line chosen was HT-29, which has a medium
expression level of PDCD4. The third cell line studied was H460, which has very low expression
levels of PDCD4.7
Both cryptocaryols A and B possessed growth inhibitory activity against the three cell lines
in the micromolar range (Table 1). The relative cytotoxicity of the cryptocaryols was consistent
with their PDCD4 stabilizing activity (i.e., I-10 slightly more active than I-9) for each cell line;
however, the cell line sensitivity to a given compound did not correlate with the cell line’s
PDCD4 expression levels. That is to say, HT-29 cell lines, with the medium level of PDCD4
13
expression, were the most sensitive (e.g., 4.2 µM for I-9); whereas, MCF-7 cells, with the
highest level of PDCD4 expression were the least sensitive (e.g., 8.1 µM for I-9). This trend held
true for cryptocaryols A and B (I-9/I-10) as well as the diastereomers I-2, I-42 and I-46. The
pyranone functionality was identified to be an important pharmacophore, as the two analogues,
I-53 and I-56, without a pyranone ring and the one without the double bond I-57 were least
active. The stereochemistry of the pyranone ring has some importance for cytotoxicity, as the
diastereomer I-2 (with only the C-6 pyrano-stereocenter retained) had a small loss in cytotoxicity
(~2 fold). The effect of C-16 acylation could be seen in the comparison between cryptocaryols A
and B (I-9/I-10), as well as, I-60/I-63, which lacked the pyranone ring. Surprisingly, the
stereochemistry of natural products did not have a significant effect on cytotoxicity as ent-
cryptocaryol B (I-46) and ent-cryptocaryol A (I-42) had only a 2- to 3- fold loss in cytotoxicity.
Table 1. Cryptocaryols cytotoxicity data
Compound (1 µM) Cell Line, IC50 (µM)
a [rel.]
MCF-7 HT-29 H460 PDCD4b
cryptocaryol A (I-9) 8.1 4.2 5.4 3.6
cryptocaryol B (I-10) 5.8 2.9 3.8 4.5
ent-cryptocaryol A (I-42) 25.8 4.1 7.9 3.8
ent-cryptocaryol B (I-46) 9.0 2.4 4.0 3.6
6-epi-ent-cryptocaryol B (I-2) 13.3 4.9 7.8 1.9
hexaol (I-60) 162 1278 >1000 1.8
hexaol Ac (I-63) 133 108 >1000 2.8
2H-cryptocaryol B (I-64) >500 >1500 >1500 N/A aIC50 was determined via MTT colorimetric analysis and curve fitting in Graphpad
® Prism.
bPDCD4 stabilization is
presented as a relative value over cells treated only with TPA (see Figure 7).
In addition, seven compounds were evaluated for their ability to stabilize PDCD4 (The
experiment was carried out by Dr. Mike Cuccarese). This analysis by immunoblot followed the
protocol described by Tobias Schmid,28
which useed the TPA to initiate PDCD4 degradation,
with the known PDCD4 stabilizer, rapamycin, as the positive control. The high expression level
of MCF-79 made it the ideal cell line for PDCD4 stabilization studies. These results are outlined
in Table 1 and Figure 7. Cryptocaryols A and B both showed significant ability to stabilize
14
PDCD4 levels, with cryptocaryol B being a slightly better stabilizer than A, which was in line
with the results found by Gustafson’s high throughput screen.14
To our surprise, the cryptocaryol
diastereomers also showed the ability to stabilize PDCD4 levels. It is also noteworthy that both
hexaol I-60 and hexaol acetate I-63, which lack of the pyranone ring retained significant PDCD4
stabilizing ability, while essentially losing all cytotoxicity (>10 fold). As with the cytotoxicity,
the polyol with the C-16 acetate was a better stabilizer than the one without the acetate.
Figure 7. PDCD4 stabilization by cryptocaryol analogues
Pdcd4 L
evel
NT
TPARAP
CTC
A
CTC
B
ent-C
TCA
ent-C
TCB
6-epi-ent
-CTC
B
Hex
aol
Hex
aol-A
c0
2
4
6
8
MCF-7 cells were seeded at 100,000 cells per well in 12-well plates. After 24 h, cells were treated with RAP
(10 nM) or cryptocaryol analogues (1 µM). After 30 min, cells were treated with TPA (20 nM). After an additional 6
h, cells were harvested by scraping and lysed with RIPA buffer. Gel electrophoresis was carried out with 16 µL of
cell lysate on a 12% polyacrylamide gel and transferred to a PVDF membrane. Western analysis was performed
with antibodies for PDCD4 (Abcam ab87678) and β-actin (Abcam ab8226), and visualized with
chemiluminescence. Contrast was adjusted uniformly over the image for clarity. Band density measurements
(Imagestudio) were made prior to contrast-adjustment. Bars are band density relative to TPA only, which was set to
1. (CTC = cryptocaryol. The experiment was carried out by Dr. Mike Cuccarese)
Encouraged by the significant PDCD4 stabilization, we further explored the potential use of
cryptocaryols in combination with other anticancer drugs to determine if PDCD4 stabilization
could result in an enhanced anticancer effect. These studies were carried out in both MCF-7
(Figures 8 and 9) and HT-29 (Figure 10) cell lines. The co-dosing studies were performed first
with just the combination of cryptocaryol and cancer drug and later with the addition of TPA,
which might better mimic the tumor environment where PDCD4 is more rapidly degraded.
15
Figure 8. Effect of cryptocaryol A and cryptocaryol B on the cytotoxicity of camptothecin and digitoxin
against MCF-7 cells.a
Cryptocaryol A with CPT against MCF-7
-2 0 2 4 60
20
40
60
80
100
log(nM)
%v
iab
ility
1 nM
10 nM
100 nM
1 µM
CPT
Cryptocaryol A with DIG against MCF-7
-2 0 2 4 60
20
40
60
80
100
log(nM)
%v
iab
ility
1 nM
10 nM
100 nM
1 µM
DIG
Cryptocaryol B with CPT against MCF-7
-2 0 2 4 60
20
40
60
80
100
log(nM)
%v
iab
ility
1 nM
10 nM
100 nM
1 µM
CPT
-2 0 2 4 60
20
40
60
80
100
Cryptocaryol B with DIG against MCF-7
log(nM)
%v
iab
ility
DIG
1 µM
100 nM
10 nM
1 nM
aCells were pre-treated with 1 nM to 1 µM of CTCA or CTCB followed by CPT or DIG and cytotoxicity was
measured by MTT after 72 h. No enhancement of anticancer activity was observed following treatment with
cryptocaryols.
We initially studied whether simple co-dosing of cryptocaryols A and B would reveal a
synergistic effect in MCF-7 cells. Adopting a drug combination strategy from our gentamicin-
induced sensitization studies,29
our results are outlined in Figure 8 and Table 2. MCF-7 cells
were treated with several concentrations of cryptocaryol A and cryptocaryol B followed by
camptothecin and digitoxin. Similar results were observed with HT-29 cells (Figure 10). No
enhancement of cytotoxicity for either anticancer drug was observed. Chou-Talalay analysis of
this data gave CI @ ED75 values in the range of 1.3 to 0.8, which are consistent with no
synergistic relationship between the two drugs.14
Table 2. Co-dosing effects of the cryptocaryols in MCF-7 cells
IC50 (102 nM)
a
Co-Drug cryptocaryol A cryptocaryol B
16
Drug CPT DIG CPT DIG
0 nM 1.39 3.27 0.99 2.04
1 nM 1.24 4.35 0.86 3.46
10 nM 1.33 3.06 1.05 2.75
100 nM 1.08 4.74 1.38 2.86
1 µM 0.81 4.86 1.13 2.99 bCI @ ED75 0.78 1.34 1.12 1.04
cRel. PDCD4 3.6 4.5
aIC50 for CPT and DIG in combination with cryptocaryols.
bCI @ ED75 was calculated via Chou-Talalay
(Calcusyn). No synergistic relationship was observed. cCryptocaryols with the highest PDCD4 stabilization activity
were chosen. PDCD4 stabilization activity does not enhance the cytotoxicity of CPT or DIG in MCF-7.
To further probe for a sensitization for the PDCD4 stabilizers we decided to perform the co-
dosing studies in the presence of TPA, which reduces PDCD4 levels by interaction with PKC.
This experiment was performed for four cancer drugs (CPT, ETO, 5FU, OXA), but only clean
dose-response curves could be obtained for camptothecin (Figure 9). Thus, MCF-7 cells were
exposed to a range of camptothecin doses in the presence of TPA (20 nM) and cryptocaryol B (1
µM). Using similar conditions to our Western blot studies (i.e., where PDCD4 stabilization was
observed), the cells were dosed with cryptocaryol B 30 minutes prior to addition of TPA. After
an additional 8 h, cells were treated with a range of CPT concentrations. Under these conditions,
no sensitization effect could be seen. In fact, TPA had a larger protective effect than cryptocaryol
B.
Figure 9. Changes in CTC/anticancer drug profiles depending on the presence of 20 nM of TPA.a
17
-2 0 2 4 60
20
40
60
80
100
log(nM)
% v
iab
ility
CTCB/TPA/CPT
TPA/CPT
aWhen MCF-7 cells were treated with 1 µM CTCA or CTCB and anticancer drugs, the presence of TPA had no
effect, indicating that the degradation of PDCD4 with TPA and recovery with CTCB did not play a role in
cytotoxicity.
Table 3. Co-dosing effect of cryptocaryol B and CPT in the presence of TPA in MCF-7
Treatment CPT IC50 (102 nM)
a
No combination 1.41
20 nM TPA 2.14
1 µM CTCB+TPA 2.02
aAn increase in cell viability was observed in the presence of TPA, whereas pretreatment with CTCB had no further
effect on cytotoxicity of CPT. Drugs with lower cytotoxicity (ETO, 5FU, OXA, see SI) were also tested but accurate
IC50 measurements could not be calculated.
Using the optimized conditions we found for MCF-7 (Table 1, entry 5), we also screened for
a sensitizing effect in HT-29 cells. With 12 h pretreatment with PDCD4 stabilizers, sensitivity of
HT-29 cells to 5FU and CPT was unchanged and appeared to have an antagonistic effect with
DIG. The HT-29 cell line was the most sensitive to the cryptocaryols (Figure 10 and Table 4)
and expressed a moderate level of PDCD4. These studies were conducted with 1 µM
cryptocaryols A or B and at a range of cancer drug doses (camptothecin and digitoxin) without
the use of TPA. As was observed for MCF-7, no enhancement in cytotoxicity between
cryptocaryols (CTCA and CTCB) and anticancer drugs (CPT and DIG) could be observed. This
dose-response assay was also performed for CPT with CTCB in the presence of TPA, once again
no significant enhancement in cytotoxicity was observed (see SI). Similar studies were also
carried out with 5FU, but these gave inconclusive dose-response curves without observable
18
IC50s.30
Interestingly, rapamycin, a well-known PDCD4 stabilizer,31
also showed no significant
enhancement in this co-dosing cytotoxicity assay. This result indicated that the PDCD4 levels in
these cells tested did not necessarily function as the apoptosis factor as expected, or the low level
of PDCD4 did not sensiticize the cancer cells to the cancer drugs.
Figure 10. HT-29 cells were pretreated with PDCD4 stabilizers CTCA, CTCB (1 µM) and rapamycin (10
nM) followed by DIG or CPT.
-2 0 2 4 6
0
50
100
CTCA/DIG
DIG
CTCB/DIG
Rapamycin/DIG
log(nM)
% v
iab
ility
-2 0 2 4 6
0
50
100
CTCA/CPT
CPT
CTCB/CPT
Rapamycin/CPT
log(nM)
% v
iab
ility
Table 4. Perturbation in IC50 for CPT and DIG in the presence of CTCA, CTCB or rapamycin against
HT-29 cells. Drug, IC50 (10
2 nM)
a
Co-Drug PDCD4
Stabil. CPT DIG
no co-drug 0 2.07 1.52
1 µM CTCA (1) 3.6 1.87 2.04
1 µM CTCB (2) 4.5 2.14 2.24
10 nM rapamycin 6.6 1.84 2.00 aNo significant change in IC50 was observed.
In conclusion, the first total synthesis, structural elucidation/correction and SAR of
cryptocaryol A and B have been achieved. The enantioselective synthesis was accomplished in
23 and 25-step linear sequence, respectively, from commercially available 5-hexyn-1-ol. The
stereochemically divergent synthesis concisely enabled the exact stereochemical assignment. It is
worth noting that the difficulties in distinguishing between the two diastereomers (e.g., I-2 and I-
10) demonstrate the need for stereochemically divergent approaches for structural determination.
19
We have determined the cytotoxicity of both cryptocaryols A and B in three cell lines as well as
for several analogues. In addition, the ability to stabilize the tumor suppressor PDCD4 was also
determined for these compounds. Rudimentary structure activity relationships could be drawn as
structures with the best PDCD4 stabilizing ability tending to be the most cytotoxic. However,
changes to the structures that removed cytotoxicity (e.g., I-60 and I-63) did not completely
remove the PDCD4 stabilizing activity. To our surprise, both the cytotoxicity and PDCD4
stabilizing ability were tolerant to changes in stereochemistry, as enantiomers (e.g., I-42 and I-
46) and diastereomers (e.g., I-2) retained significant activity in both assays. For the two most
potent PDCD4 stabilizers, cryptocaryols A and B, no sensitization effects could be seen in co-
dosing studies with several cancer drugs (CPT, DIG, 5FU) in two different cancer cell lines
(MCF-7 and HT-29). Further efforts to elucidate the mechanism of action for this class of natural
products are ongoing.
20
Chapter 2
Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio-
and Diastereoselective Carbonylation of Epoxyhomoallylic Alcohols†
2.1 Introduction of tetrahydrolipstatin
Tetrahydrolipstatin (THL, II-1) is an over-the-counter anti-obesity drug that acts by
inhibiting the absorption of dietary fats. THL is the saturated form of lipstatin (II-2), a natural
product isolated from Streptomyces toxytricini in 1987.32
Due to its greater stability, THL was
chosen over lipstatin for pharmaceutical development. Both THL and lipstatin contain an α-
alkylated β,δ-dihydroxy acid which exists in the β-lactone form (Figure 11). The β-lactone in
THL and lipstatin is believed to ring-open and covalently bind to pancreatic lipase, which results
in irreversible inhibition.32a,33
In addition, THL and related β-lactones have been found to inhibit
the thioesterase domain of fatty acid synthase (FAS),34
the inhibition of which has been linked to
anticancer activity.35
More recently, THL has been shown to inhibit the in vitro growth of G.
duodenalis, the causative parasite of the gastrointestinal disease giardiasis.36
Figure 11. Tetrahydrolipstatin (THL, II-1), lipstatin (II-2) and analogues (II-3)
Since the first synthesis of THL by Schneider,37a
there have been numerous total37–43
and
† Portion of the chapter will appear in a manuscript that was submitted for publication. This manuscript was initially
written by Yanping Wang, and further revised and edited by all the coauthors (Michael Mulzer, Brandon J. Tiegs,
Prof. Geoffrey W. Coates, and Prof. George A. O'Doherty). The synthetic work was carried out by YW, and
carbonylation reaction by MM and BJT.
21
formal syntheses of THL,44
which have involved a diverse range of approaches. In terms of how
they derive absolute stereochemistry, these approaches can be classified into the following
categories: 1) chiral auxiliary,37
2) asymmetric aldol,38
3) asymmetric allylation/crotylation,39
4)
asymmetric reductions,40
5) asymmetric resolutions,41
6) asymmetric oxidations,42
and 7) chiron
approach.43
These routes include the elegant use of a chiral phosphate-template,40c
a tandem
Mukaiyama aldol-lactonization,38e,7i
an anti-aldol segment via a non-aldol route,38h
and a Prins
cyclization for stereocontrol.41b
Scheme 7. Regioselective carbonylation of protected cis-epoxyhomoallylic alcohols
As part of a larger effort aimed at the use of catalysis for the asymmetric synthesis and
structure-activity relationship studies of biologically active natural products,45
we became
interested in the synthesis of THL (II-1) and related analogues II-3 (Figure 11). We were
particularly interested in the carbonylation of epoxides using bimetallic [Lewis acid]+[Co(CO)4]
–
catalysts which has recently emerged as a reliable, direct route to β-lactones.46
The O’Doherty
and Coates groups have had success using this type of carbonylation catalyst for the synthesis of
terminal β-lactones en route to natural products.47
However, unsymmetrically disubstituted
22
epoxides are prone to give a mixture of regioisomeric β-lactones. Presumably this is because of
an unselective SN2-ring opening reaction in the case of electronically or sterically unbiased
substrates (Scheme 7).
This problem has recently been addressed by the introduction of catalysts that can carbonylate
racemic and enantioenriched trans-disubstituted epoxides to the corresponding cis-β-lactones
with high and opposing regioselectivities.48
We hypothesized that it would be possible to obtain
the desired β-lactone isomer 3b of THL and its analogues via regioselective carbonylation of
protected cis-epoxyhomoallylic alcohols (Scheme 7). Herein, I disclose a new route for the
synthesis of THL and seven stereoisomers using regioselective carbonylation of an epoxide to
form the β-lactone moiety. The fatty acid lipid portion of THL ( 4b) was prepared from
protected cis-epoxyhomoallylic alcohol 6b with all the lipid stereogenic centers in place via a
de novo asymmetric route (Scheme 8).
2.2 Retrosynthetic analysis
Retrosynthetically, we envisioned preparing THL from its lipid core II-4b and N-formyl-L-
leucine (Scheme 8). Using a regioselective carbonylation reaction, the lipid portion of THL (II-
4b) could be prepared either directly from cis-epoxyalcohol II-6b, or from II-6a after alkylation
of the terminal β-lactone II-4a. Epoxides II-6a/b could be prepared from a highly diastereo-
selective epoxidation of homoallylic alcohol II-7a/b, which in turn could be prepared from II-
8a/b via asymmetric synthesis. Key to the success of this approach is the need for high
regioselectivity in the carbonylation (II-6 to II-4). Presumably, this could be accomplished with
a high degree of confidence using terminal epoxide II-6a.46a
However, the subsequent alkylation
of terminal β-lactones such as II-4a is highly problematic.41a,49
Consequently, a greater degree of
synthetic efficiency would result from a regioselective carbonylation of a 2,3-disubstituted
23
epoxide with all the requisite lipid carbons in place, i.e. II-4b to II-6b. Regioselective
carbonylation of epoxides had very little precedence in the synthesis of complex molecules prior
to our endeavors.50
Scheme 8. Retrosynthetic analysis of THL (II-1)
We anticipated that the precise choice of hydroxyl protecting group in II-6b could be critical
for the control of the carbonylation regioselectivity. At the outset, we chose a methoxymethyl
group (MOM) for its potential to participate in chelated transition states. However, we were also
interested in investigating the use of N-formyl-L-leucine, thus avoiding the need for a protecting
group at this stage. This had the added advantage of testing the compatibility of the [Lewis
acid]+[Co(CO)4]
– carbonylation catalyst with the Lewis basic and Brønsted acidic formamide
functional group as well as the epimerizable α-amino ester group.
2.3 Formal synthesis of tetrahydrolipstatin
To ensure success with this approach, we began our efforts with the synthesis of the
diastereomeric terminal epoxides II-11/ II-14 (Scheme 9). The approach began with a Leighton
allylation25
of dodecanal II-8a to give homoallylic alcohol II-7a. After Boc-protection of alcohol
II-7a the resulting t-butylcarbonate II-9 was treated with iodine to form cyclic carbonate II-10.
Hydrolysis of carbonate II-10 led to in situ epoxidation to form II-11, which was then protected
as a MOM ether II-6a (MOMCl/DIPEA). Alternatively, the stereochemistry at C5 in II-11 was
24
inverted using Mitsunobu conditions to give II-14 after hydrolysis (PNBA/PPh3/DIAD,
K2CO3/MeOH), which was also protected as a MOM ether II-15. Epoxides II-6a/II-15
underwent regioselective carbonylation to give β-hydroxy esters II-12/II-16 when exposed to
carbonylation conditions (CO, 10 mol % Co2(CO)8, 20 mol % 3-hydroxypyridine).51
The
synthesis of β-hydroxy ester II-16 constitutes a formal synthesis of THL (II-1) as II-16 has been
previously transformed into THL via the n-hexyl α-alkylation of a dianion generated from II-
16.43
Scheme 9. Formal synthesis of THL (II-1)
2.4 Asymmetric synthesis of cis-epoxyhomoallylic alcohol II-23
With access to a formal synthesis of THL, we turned our focus to potentially more efficient
approaches to THL, which involved carbonylation of the more challenging 2,3-disubstituted cis-
epoxide II-6b. The synthesis of epoxide II-6b required a practical asymmetric synthesis of
epoxyhomoallylic alcohol II-23 (Scheme 10). Our approach involved the novel construction of
the Z-homoallylic alcohol functionality via a Noyori reduction/alkyne zipper/Lindlar reduction
sequence.52
To establish the absolute stereochemistry for this route, we used a highly
25
enantioselective (95% ee) Noyori asymmetric reduction53
of achiral ynone II-8b, which could be
prepared in one step from a known Weinreb amide II-8c. Using the alkyne zipper reaction,54
the
internal 2-alkyne in II-17 was isomerized into a terminal alkyne and then TBS protected to give
II-19. Alkylation of terminal alkyne II-19 (n-BuLi then n-Hex-I, 88%) and TBAF-promoted
deprotection of the TBS-ether provided the homopropargyl alcohol II-21. Partial hydrogenation
of alkyne II-21 using Lindlar conditions55
(1 atm H2, Pd/CaCO3, quinoline, 96%) cleanly gave
(Z)-olefin II-7b. Finally, a highly diastereoselective hydroxy-directed epoxidation of II-7b
furnished II-23 (t-BuOOH, 2 mol % VO(acac)2, 94%, 92% dr) via putative intermediate II-22.56
Scheme 10. Synthesis of cis-epoxyhomoallylic alcohol II-23
2.5 Total synthesis of tetrahydrolipstatin
With the establishment of a practical and stereocontrolled synthesis of epoxide II-23, we
began our investigation of the regioselectivity of the carbonylation reaction (Scheme 11). This
study began with the protection of the alcohol as a MOM ether II-6b (MOMCl, 85%). To our
delight, when the MOM-protected epoxide II-6b was subjected to carbonylation (1 mol %
[ClTPPAl][Co(CO)4], CO (900 psi)),46f
a single regioisomer β-lactone II-24 was formed which
was obtained in an 81% isolated yield.
26
Scheme 11. Synthesis of THL (II-1): carbonylation of MOM-protected epoxide II-6b
The synthesis of THL was easily finished via a four-step deprotection/acylation/deprotection/
formylation procedure. Thus, the MOM group was removed with BF3 etherate to give II-4b
(83%). A DCC coupling of II-4b with N-Cbz-L-leucine installed the amino acid side chain in II-
25. Finally, a one-pot hydrogenolysis/formylation procedure both removed the Cbz group (1 atm
H2, Pd/C in AcOCHO) and installed the N-formyl group to give THL (II-1) without any
epimerization (vide infra).37f,38h
The synthetic THL produced had spectral (1H,
13C NMR, IR) and
optical properties (reported: [α]D20
= –33 (c = 0.36, CHCl3),37b
synthetic: [α]D23
= –33.7 (c =
0.48, CHCl3)) consistent with what has been reported in the literature. 1H NMR completely
matches the reported in the existing literature, although the coupling constants are slightly
different for several peaks (Table 5). The matching situation also happens to 13
C NMR, except
that two publications reported extra peaks, which might be from unremoved impurities (Table 6).
2.6 Alternative approach to THL
To test the functional group compatibility of the carbonylation catalyst, we explored
alternatives to the MOM protecting group. In this vein, we looked at the use of the N-formyl-L-
leucine ester group (i.e., II-26) (Scheme 12) as a replacement for the MOM ether. Along with
testing the functional group compatibility of the carbonylation conditions, this substitution also
had the advantage of reducing steps.
Table 5. 1H NMR assignments of THL (
1H NMR comparision with existed publications).
27
Position J. Antibiot.
1987, 1086 This Work
J. Org. Chem.
2012, 4885
Org. Lett. 2010,
1556
J. Org. Chem.
2009, 4508
Synthesis
2006, 3888
CHO
(1H) 8.21 (s)
a 8.22 (s) 8.22 (s) 8.22 (s) 8.22 (s) 8.23 (s)
2''-NH
(1H) 6.43 (d, 9) 5.91 (d, 8.5) 5.90 (d, 8.5) 5.96 (d, 8.4) 5.91 (d, 8.1) 6.05 (d, 8.5)
5
(1H) 5.03 (m) 5.03–5.00 (m)
5.03 (dddd, 7.0,
6.5, 5.5, 4.0)
5.06–4.99 (m,
1H) 5.05–5.00 (m) 5.02 (m, 1H)
2''
(1H)
4.68 (ddd, 9, 9,
5)
4.69 (ddd, 9.0, 9.0,
5.0)
4.69 (ddd, 13.0,
8.5, 4.0)
4.68 (td, 8.7,
4.1) 4.71–4.66 (m) 4.68 (m,1H)
3
(1H)
4.32 (ddd, 9, 5,
4)
4.29 (ddd, 7.5, 5.0,
5.0)
4.29 (ddd, 8.0,
4.5, 4.5)
4.32–4.27 (m,
1H)
4.29(dt, 7.3,
4.7) 4.28 (m, 1H)
2
(1H)
3.24 (ddd, 7.5,
7.5, 4)
3.22 (ddd, 7.5, 7.5,
4.0)
3.21 (ddd, 11.5,
4.5, 4.0 )
3.22 (ddd, 7.9,
7.2, 4.1)
3.22 (dt, 7.1,
3.2)
3.22 (dt, 7.6,
3.9)
4, 4a
(2H)
1.9–2.25 (m,
2H)
2.17 (ddd, 15.0,
7.5, 7.5)
2.16 (dt, 15.0,
8.0, 7.0)
2.21–2.12 (m,
1H)
2.15–2.10 (m,
1H)
2.25–2.11 (m,
1H)
2.00 (ddd, 15.0,
4.5, 4.5)
2.01 (dt, 15.0,
4.5, 4.0)
1.99 (ddd, 14.9,
4.7, 4.1)
2.08–2.00 (m,
1H) 2.02 (m, 1H)
CH2
(33H) 1.15–1.85 (m) 1.84–1.78 (m, 1H)
1.85–1.50 (m,
6H)
1.86–1.49 (m,
7H)
1.85–1.51 (m,
7H)
1.80–1.15 (m,
33H)
1.77–1.63 (m, 4H)
1.61–1.53 (m, 2H)
1.47–1.41 (m, 1H) 1.50–1.15 (m,
27H)
1.49–1.03 (m,
26H)
1.41–1.15 (m,
26H)
1.32–1.24 (m,
25H)
5'', 5'''
(6H)
0.97 (d, 6, 6H) 0.972 (d, 6.5, 3H) 1.05–0.82 (m,
12H)
0.97 (dd, 6.1,
2.5, 6H) 0.96 (t, 6.3, 6H)
0.95 (d, 5.2,
6H)
0.967 (d, 6.5, 3H)
16, 6'
(6H) 0.89 (t, 7, 6H) 0.885 (t, 6.5, 3H) 0.89 (t, 6.9, 3H) 0.89 (t, 6.5, 6H)
0.87 (distorted
t, 6H)
0.878 (t, 7.0, 3H) 0.88 (t, 6.9, 3H) a (multiplicity, coupling constant (J) in Hz)
Table 6. 13
C NMR assignments of THL (13
C NMR comparision with existed publications).
28
Position J. Antibiot.
1987, 1086
This
Work
J. Org. Chem.
2012, 4885
Org. Lett.
2010, 1556
J. Org. Chem.
2009, 4508
Synthesis
2006, 3888
1, 1'' 171.93 171.92 171.9 171.9 171.9 171.9
170.73 170.75 170.7 170.7 170.7 170.8
1''' 160.83 160.60 160.6 160.6 160.5 160.7
3, 5 74.74 74.76 74.7 74.7 74.7 74.8
72.63 72.76 72.7 72.7 72.7 72.6
2, 2'' 57.07 57.03 57.0 57.0 57.0 56.9
49.76 49.60 49.6 49.6 49.6 49.7
4, 6, 9
12, 13,
14, 1', 2',
3' 4', 3'',
41.44 41.56 41.5 41.5 41.5 41.4
38.73 38.70 38.7 38.7 38.7 38.7
34.07 34.05 34.0 34.0 34.0 34.0
31.93 31.89 31.9 31.9 31.8 31.9
31.51 31.47 31.4 31.4 31.4 31.2
29.63 29.60 29.6 29.6 29.6 29.6
29.63 29.60
29.57 29.53 29.5 29.5 29.5
29.46 29.42 29.4 29.4 29.4 29.4
29.35 29.33 29.3 29.3 29.3 29.3
29.35 29.29 29.3 29.2 29.2
7, 8, 10,
11
28.99 28.96 28.9 28.9 28.9 28.8
27.67 27.61 27.6 27.6 27.6 27.7
26.73 26.70 26.7 26.7 26.6 26.8
25.12 25.09 25.1 25.0 25.0 25.2
4'' 24.93 24.88 24.9 24.8 24.8 24.9
5'' or 5''' 22.87 22.87 22.8 22.8 22.8 22.8
15, 5' 22.69 22.68 22.7 22.6 22.6 22.7
22.53 22.51 22.5 22.5 22.5 22.5
5'' or 5''' 21.78 21.73 21.7 21.7 21.7 21.7
16, 6' 14.10 14.12 14.1 14.1 14.1 14.1
14.00 14.01 14.0 14.0 14.0 14.0
unknown 21.9 25.8
Notes: 1) Residual solvent signal was used as reference: CDCl3 δc 77.0 ppm. (77.23 ppm for Org. Lett. 2006,
4497)
2) The paper (J. Org. Chem. 2012, 4885) reported one extra peak at 21.9 ppm. The paper (J. Org. Chem.
2009, 4508) reported one extra peak at 25.8 ppm.
We initially investigated the synthesis of epoxide II-26 via the direct DCC coupling of N-
29
formyl-L-leucine with II-23. Unfortunately, we were not able to find conditions under which the
coupling occurred without appreciable amounts of epimerization (i.e., II-26 and II-27 were
isolated as a 6:4 mixture of epimers).37f,38h
To circumvent the epimerization problem, we
returned to the less epimerizable N-Cbz-protected L-leucine (less electron withdrawing property).
Under the same DCC coupling procedure, N-Cbz-L-leucine coupled with II-23 to afford ester II-
28 in 99% yield without any sign of epimerization.37f
Exposure of II-28 to the two-step/one-pot
hydrogenolysis/formylation conditions (1 atm H2, Pd/C then HCO2H/DCC) provided the desired
epoxide II-26 in 79% yield. Gratifyingly, under carbonylation conditions (2 mol %
[ClTPPAl][Co(CO)4], CO (900 psi)), epoxide II-26 with an N-formyl-L-leucine side chain was
cleanly transformed into THL (II-1) as the single regioisomer which was obtained in excellent
yield (80%) without any sign of epimerization.
Scheme 12. Synthesis of THL (II-1): a late-stage carbonylation of epoxide
2.7 Examination of late stage of carbonylation of epoxides
The successful synthesis of THL via late-stage regioselective carbonylation of epoxide II-26
prompted us to explore the scope of this approach. In particular, we were interested in exploring
its utility for the synthesis of various stereoisomers of THL.57
To do this, we required access to a
30
series of stereoisomeric epoxides with various groups at the C5 position. This was carried out
from epoxyalcohol II-23 and its enantiomer ent-II-23, which was synthesized for ynone II-8b
using the same strategy as that for II-23 (Scheme 13). Thus, the C5 diastereomer II-31 with a
MOM-protecting group was easily prepared from ent-II-23 by means of a three-step
Mitsunobu/hydrolysis/protection sequence in a 74% overall yield.
Scheme 13. Synthesis of diastereomer II-31
Using both invertive and retentive acylation chemistry, the three epoxides with an N-formyl
leucine side chain (II-27, II-33, and II-35) were prepared from epoxide II-23 (Scheme 14). To
circumvent the problem associated with epimerization during the DCC coupling with N-formyl
leucine, we resorted to the use of N-Cbz-L-leucine in the coupling to form II-32, which could be
readily converted into N-formyl amide II-27 by hydrogenolysis followed by a DCC coupling
with formic acid. In contrast to the DCC coupling of with N-formyl leucine, the invertive
Mitsunobu acylation of epoxide II-23 with N-formyl leucine occurred with complete
stereocontrol to give II-33. Epoxide II-35 was also made from II-23 via ester II-34 by means of
a two-step Mitsunobu acylation and hydrogenolysis N-Cbz to N-formyl group exchange (1 atm
H2, Pd/C then HCO2H/DCC).
Scheme 14. Synthesis of stereoisomeric epoxides from II-23
31
Using related invertive and retentive acylation chemistry, three stereoisomeric epoxides (ent-
II-28, ent-II-34, and II-37) and their enantiomers were made with N-Cbz leucine side chain from
epoxide ent-II-23 (Scheme 15). To serve as a control group for the amide substitution, epoxide
II-36 with no amino-substitution was prepared by a Mitsunobu acylation with isohexanoic acid.
Scheme 15. Synthesis of stereoisomeric epoxides from ent-23
We next investigated the regioselectivity of the carbonylation with the various epoxide
stereoisomers (Table 7). Exposure of the MOM-protected diastereomeric epoxide II-31 to typical
carbonylation conditions cleanly converted it into β-lactone II-38 (Entry 1, 88%) with complete
32
regioselectivity. Similarly, clean conversion was found for the C2” stereoisomeric epoxide II-27,
which reacted to give β-lactone II-39 as a single regio- and stereoisomer (Entry 2, 77%). In
contrast to changes in stereochemistry at C2”, the inversion of the stereochemistry at C5 had a
significant effect on the regioselectivity of the reaction (Entries 3 and 4). Epoxide II-33 with an
N-formyl amide carbonylated to give β-lactones II-40 in good yields of a 6:1 mixture of
regioisomers. The C2” epimeric epoxide II-35 also carbonylated with lower regioselectivity to
give β-lactones II-41 in good yields of a 5:1 mixture of regioisomers. In addition to poor
regioselectivities, epoxides II-33 and II-35 also required higher catalyst loadings.
We hypothesized that the loss in regioselectivity for substrates II-33 and II-35 could be the
result of hydrogen bonding interactions (Figure 12). This hydrogen bonding interaction in turn
could lower the barrier for pathway a to the regioisomeric β-lactone. To test this hypothesis, we
investigated the carbonylation of epoxides (II-36, ent-II-28, ent-II-34, and II-37). When the N-
formyl group was removed as in epoxide II-36 (Entry 5), the carbonylation occurred to give β-
lactone II-42 with complete control of regioselectivity. Interestingly, when the N-formyl group
was replaced with the less acidic N-Cbz-group the high regioselectivity returned. Thus, epoxides
ent-II-28, ent-II-34, and II-37 carbonylated to form β-lactones ent-II-25, ent-II-43, and ent-II-
44 as single regioisomers (Entries 6–8; 75%, 80%, 74%; respectively).
Table 7. Stereochemical scope of regioselective carbonylationa
33
Entry Epoxide major regioisomer
b
Ratiob
b:a
Isolated
Yield (%)
1
>99:1 88
2
>99:1 77
3
6:1 72
4
5:1 77
5
>99:1 53
6
>99:1 75
7
>99:1 80
8
>99:1 74
aSee Supporting Information for detailed reaction conditions for each entry.
bRatio determined by
1H NMR
spectroscopy; for entries 1–2, 5–8 regioisomer a was not observed.
`
Figure 12. Rationale for loss of regiocontrol for epoxides II-33 and II-35
34
In order to confirm the connectivity of unknown β-lactones II-40, II-41, II-43, and II-44, we
prepared them independently from known β-lactone II-4b (Scheme 16). The β-lactone II-4b was
converted into Cbz-protected leucine esters II-43 and II-44 via a Mitsunobu esterification. A
hydrogenolysis/formylation reaction converted II-43 and II-44 into II-41 and II-40, respectively,
which had identical 1H NMR spectra to the products prepared from the carbonylation reactions.
Scheme 16. Synthesis of β-lactones II-40 and II-41 from known β-lactone II-4b
In support of the structure of the minor isomers formed from the carbonylation of epoxides
II-33 and II-35 (entries 3 and 4; II-40 and II-41), we carried out a thermolytic decarboxylation
reaction on the product mixture II-40 and presumed regioisomer II-40a (Scheme 17).
35
Specifically, a 2:1 mixture of II-40 and hypothesized II-40a was heated to 230 °C in a sealed
tube under argon for 1 hour producing trans-olefin II-45 as the sole product. The identity of
olefin II-45 was confirmed by its synthesis from homoallylic alcohol II-46, which in turn was
made from terminal olefin II-7a using cross metathesis.26
For comparison, cis-olefin II-47 was
prepared from II-7b, which was readily distinguishable from its trans-isomer II-45 by 13
C NMR
spectra.
Scheme 17. Evidence for minor regioisomer II-40a by thermolysis
2.8 Syntheis of other THL stereoisomers
With the route established above, we were able to accomplished the synthesis of the other
THL stereisomers trans-β-lactones ent-II-1, ent-II-39, ent-II-40, and ent-II-41 (Scheme 18).
Taking advantage of the epimerization of DCC coupling of epoxide ent-II-23 and N-formyl-L-
leucine, a mixture of ent-II-26 and ent-II-27 was afforded, which upon carbonylation conditions
was converted into a mixture of two β-lactone ent-II-1 and ent-II-39 smoothly. With preparative
HPLC, ent-II-1 and ent-II-39 were successfully separated with high purity. In this manner, ent-
II-1 and ent-II-39 could be accomplished in two steps and one HPLC purification, which was
slightly more effiecient than synthesizing them independently. The two β-lactone ent-II-43 and
36
ent-II-44 were transformed into THL stereoisomers ent-II-41 and ent-II-40, respectively, by
replacing the Cbz group with formyl group.
Scheme 18. Synthesis of THL stereoisomers
2.9 Conclusions
A concise enantioselective synthesis of THL has been achieved in 10 steps and 31% overall
yield from achiral ynone II-8b. The route is amenable for the production of eight stereoisomers
(only one set of enantiomers were shown). In addition, the route demonstrated the versatility and
regioselectivity of the bimetallic [Lewis acid]+[Co(CO)4]
– catalyzed carbonylation of
enantiomerically pure cis-epoxides to trans-β-lactones. Further application of bimetallic
carbonylation catalysts for the synthesis and medicinal chemistry studies of natural products will
be reported in due course.
37
Chapter 3
Total Synthesis of EBC-23
3.1 Introduction of EBC-23
Nature contains a rich source of chemical compounds, which have the potential to be used to
treat human diseases (e.g., cancers, fungal infection).58
Tremendous efforts have been focused on
the isolation natural product from nature sources (e.g., plants, bacteria) using liquid-solid
chromatographic techniques.59
In an effort to discover new bioactive compounds, Williams et al.
isolated eight novel spiroketal products from the fruit of Cinnamomum laubatii (family
Lauraceae) (Figure 13).60
This family of compounds showed anticancer activity against several
cancer cell lines MM96L, MCF7 and DU145. More importantly, EBC-23 was found to inhibit
the growth of prostate tumor in immunodeficient mice.60
Figure 13. Structures of EBC family members
After elucidation of the structure of this family compounds by a combination of analyses of
NMR and HRMS, the Williams group also completed the first total synthesis of the EBC-23 by
using a linchpin strategy (Scheme 19). In this retrosynthetic analysis, EBC-23 (III-1) was
derived from polyketide III-2 by ring opening of the spiroketal. The protected precursor of III-2,
38
polyol III-3, could be constructed from three fragments epoxide III-4, 1,3-dithianes III-5 and
epoxide III-6 via a Tietze-Smith61
type dithiane linchpin methodology. In turn, the left-hand
fragment III-4 was also assembled using a linchpin strategy again via III-7 form three partners
dithiane III-5, epoxide III-8 and epoxide III-9. In the synthesis, four of the six stereogenic
centers were introduced from enantiopure starting materials.
Scheme 19. Williams’ retrosynthetic analysis of EBC-23
A second EBC-23 total synthesis was accomplished by Yamamoto et al. utilizing their
“supersilyl” chemistry (Scheme 20).62
Similar to Williams’ retrosynthetic analysis, EBC-23 was
envisioned from polyketide III-10, which was constructed from polyhydroxy ketone (±)-III-11
and chiral aldehyde III-12 using an aldol reaction. The racemic intermediate (±)-III-11 was
generated from tetradecanal III-13 and silyl enol ether III-14 applying an iterative
supersilyldirected aldol method. Although the total synthesis was only seven steps in the longest
linear sequence, the absolute stereochemistry of EBC-23 was introduced at late stage by using a
chiral fragment III-12 for differentiation, leading to an inefficient access to the synthetic material
due to the need of separated diasteroisomers.
Scheme 20. Restrosynthetic analysis of EBC-23 by Yamamoto
39
3.2 Restrosynthetic analysis of EBC-23
Intrigued by the unique structure and biological activity of this family products, we decided
to synthesize EBC-23 using an asymmetric synthetic strategy developed in our group (Scheme
21). Retrosynthetically, ring opening of the spiroketal in EBC-23 revealed a diketone
intermediate III-15, which could be derived from protected diol ketone III-16 and acyl chloride
III-17 using lithium mediated coupling.63
The stereochemistry in III-16 was envisioned to be
elucidated from tetradecanal III-13 via III-18 using asymmetric Leighton allylation,25
cross
metathesis26
and Evans’ acetal formation.24
Meanwhile, the chirality of pyranone III-17 could be
introduced utilizing Noyori reduction27
and stereoselective NaBH4 mediated asymmetric
reduction from 2-acetyl furan III-20 via β-hydroxy ester III-19.64
Herein, I will present the
efforts to the total synthesis of EBC-23.
Scheme 21. Our de novo retrosynthetic analysis of EBC-23
3.3 Synthesis of protected diol methyl ketone
40
The efforts to EBC-23 began with the synthesis of protected diol ketone III-16 from
tetradecanal III-13 (Scheme 22). Leighton allylation25
of III-13 gave homoallylic alcohol III-18,
which was converted into δ-hydroxy enoate III-21 using metathesis reaction (Grubbs II) with
ethyl acrylate. Then, III-21 was exposed to Evans’ acetal formation conditions (PhCHO, KOt-
Bu)24
to form benzylidene protected diol III-22. The ester moiety in III-22 was transformed into
methyl ketone III-16 via Weinreb amide III-23 in two steps.
Scheme 22. Synthesis of protected diol ketone III-16
3.4 Synthesis of acyl chloride
With access to the ketone III-16, efforts were turned to the synthesis of acyl chloride III-17
(Scheme 23). The effort started from commercially available 2-acetyl furan III-20, which was
homologated to β-keto ester III-24 using a known procedure (CO(OMe)2, NaH).65
Asymmetric
Noyori reduction condition was used to converted β-keto ester III-24 into β-hydroxy ester III-
19. Then a three-step procedure (Achmatowicz reaction/Jones oxidation/reduction) was applied
on III-19 to result in pyranone III-27 in an high yield (61%). The stereochemistry of C-5 was
inverted under Mitsunobu conditions (p-nitrobenzoic acid, DIAD). The resulting ester III-28 was
hydrolyzed with Et3N in MeOH to give an alcohol III-29, which was then protected as a TBS
ether III-30 (TBSOTf, 2,6-lutidine). Hydrolysis of methyl ester in III-30 with LiOH led to an
acid III-31, which was converted into acyl chloride III-17 with Ghosez reagent III-32 (1-choro-
1-(dimethylamino)-2-methyl-2-propene).66
41
Scheme 23. Synthesis of acyl chloride III-17
3.5 End game of synthesis of EBC-23
With the available ketone III-16 and acyl chloride III-17 in hand, lithium mediated
reaction63
will be used to couple these two fragment to arrive at diketone III-15 (Scheme 24).
Exposure of III-15 to acetic acid in water should supply a global deprotection product, which
can subsequently form spiroketal III-33. The ketone in III-33 is then asymmetrically reduced to
the natural product EBC-23.
Scheme 24. End game of synthesis of EBC-23
In summary, a de novo synthesis of EBC-23 has been investigated. Two key fragments
(methyl ketone III-16 and acyl chloride III-17) have been accessed from achiral starting
materials tetradecanal and 2-acetyl furan, respectively. The syntheses of III-16 and III-17
42
feature asymmetric Leighton allylation, diastereoselective Evans’ acetal formation and
asymmetric Noyori reduction. The end game of synthesis of EBC-23 is ongoing in our group.
43
Experimental section
Section A: General Information
1H and
13C NMR spectra were recorded on a Varian 400 or 500 MHz spectrometer. Chemical
shifts were reported relative to internal tetramethylsilane (δ 0.00 ppm) or CDCl3 (δ 7.26 ppm) or
CD3OD (δ 3.30 ppm) for 1H NMR and CDCl3 (δ 77.2 ppm) or CD3OD (δ 49.05 ppm) for
13C
NMR. Infrared (IR) spectra were obtained on a FT-IR spectrometer. Optical rotations were
measured with a digital polarimeter in the solvent specified. Melting points were determined
with a standard melting point apparatus. Flash column chromatography was performed on 60-
200 or 230-400 mesh silica gel. Analytical thin-layer chromatography was performed with
precoated glass-backed plates and visualized by quenching of fluorescence and by charring after
treatment with p-anisaldehyde or potassium permanganate stain. Rf values were obtained by
elution in the stated solvent ratios. Diethyl ether, tetrahydrofuran, methylene dichloride and
triethylamine were dried by passing through activated alumina column with argon gas pressure.
Commercial reagents were used without purification unless otherwise noted. Air- and/or
moisture-sensitive reactions were carried out under an atmosphere of argon/nitrogen using oven-
or flame-dried glassware and standard syringe/septa techniques.
44
Section B: Experiment Procedures
Chapter 1 Cryptocaryol A and B: Total Syntheses, Stereochemical Revision, Structure
Elucidation, Structure-Activity Relationship and Ability to Stabilize PDCD4
(2S,4S,6R,8R,10R)-2,4,6,8-Tetrahydroxy-1-((R)-6-oxo-3,6-dihydro-2H-pyran-2-yl)pentaco
san-10-yl acetate (I-2):
To a flask with I-36 (17.0 mg, 22.8 µmol) was added a solution of acetic acid (2 mL, 80%) in
water. The resulting mixture was heated to 80 °C and stirred for 1 h. The solvent was removed
under reduced pressure. The crude residue was purified by flash chromatography (2 to 8%
MeOH in EtOAc) on silica gel (10 mL) to afford 2 (29.3 mg, 75%) as a colorless oil.
Data for I-2: Rf = 0.23 (5% MeOH in CH2Cl2); [α]D22
= +10.1 (MeOH, c = 0.72); IR (neat):
3367, 2924, 2854, 1721, 1461, 1377, 1260, 1098, 1028 cm-1
; 1H NMR (400 MHz, CD3OD) δ
7.05 (ddd, J = 9.6, 6.0, 2.4 Hz, 1H), 5.98 (dd, J = 9.6, 2.4 Hz, 1H), 5.08 (dddd, J = 9.6, 6.4, 6.4,
2.8 Hz, 1H), 4.68 (dddd, J = 10.4, 6.8, 6.8, 3.6 Hz, 1H), 4.02–3.92 (m, 3H), 3.81–3.74 (m, 1H),
2.54 (dddd, J = 18.8, 5.6, 4.0, 0.8 Hz, 1H), 2.39 (dddd, J = 18.8, 11.6, 2.4, 2.4 Hz, 1H), 2.04 (s,
3H), 1.97 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.86 (ddd, J = 14.0, 6.4, 5.2 Hz, 1H), 1.75–1.68 (m,
4H), 1.67–1.56 (m, 6H), 1.29–1.27 (m, 26H), 0.90 (t, J = 6.8 Hz, 3H); 13
C NMR (125 MHz,
CD3OD) δ 173.1, 167.0, 148.4, 121.4, 77.4, 72.9, 69.84, 69.77, 67.6, 67.5, 45.9, 45.4, 45.0, 43.3,
43.1, 36.0, 33.1, 30.8, 30.73, 30.69, 30.6, 30.5, 30.2, 26.3, 23.8, 21.2, 14.5; HRMS (ESI) calcd
for C32H58O8Na [M Na]+: 593.4029 Found: 593.4036.
45
(R)-6-((2R,4R,6R,8R,10S)-2,4,6,8,10-pentahydroxypentacosyl)-5,6-dihydro-2H-pyran-2-one
(I-9):
To a flask with I-56 (16.5 mg, 20.1 µmol) was added a solution of acetic acid (2 mL, 80%) in
water. The resulting mixture was heated to 80 °C and stirred for 1 h. The solvent was removed
under reduced pressure. The crude residue was purified by flash chromatography (2 to 8%
MeOH in EtOAc) on silica gel (10 mL) to afford I-9 (7.5 mg, 70%) as a white amorphous solid.
Data for I-9: Rf = 0.44 (10% MeOH in CH2Cl2); [α]D23
= +14.0 (MeOH, c = 0.20); IR (neat):
3304, 2918, 2849, 1719, 1553, 1458, 1378, 1260, 1136, 1096 cm-1
; 1H NMR (400 MHz,
CD3OD) δ 7.04 (ddd, J = 9.6, 6.0, 2.8 Hz, 1H), 5.97 (dd, J = 9.6, 2.5 Hz, 1H), 4.74–4.67 (m,
1H), 4.09 (dddd, J = 8.8, 6.4, 6.4, 2.4 Hz, 1H), 4.04–3.96 (m, 3H), 3.82–3.77 (m, 1H), 2.45 (ddd,
J = 19.2, 5.2, 5.2 Hz, 1H), 2.36 (dddd, J = 19.2, 11.6, 2.8, 2.8 Hz, 1H), 1.94 (ddd, J = 14.8, 9.6,
2.8 Hz, 1H), 1.71–1.55 (m, 7H), 1.52–1.49 (m, 2H), 1.46–1.40 (m, 2H), 1.28–1.25 (m, 26H),
0.89 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CD3OD) δ 167.0, 148.6, 121.4, 76.6, 70.2, 69.9,
69.1, 68.2, 66.6, 46.0, 45.9, 45.8, 45.3, 43.9, 39.3, 33.1, 31.0, 30.9, 30.85, 30.82, 30.5, 26.8, 23.8,
14.5.14
(2R,4R,6S,8S,10S)-2,4,6,8-tetrahydroxy-1-((R)-6-oxo-3,6-dihydro-2H-pyran-2-
yl)pentacosan-10-yl acetate (I-10):
To a flask with I-59 (25.6 mg, 34.3 µmol) was added a solution of acetic acid (2 mL, 80%) in
water. The resulting mixture was heated to 80 °C and stirred for 1 h. The solvent was removed
46
under reduced pressure. The crude residue was purified by flash chromatography (1 to 5%
MeOH in EtOAc) on silica gel (10 mL) to afford I-10 (7.5 mg, 77%) as a white amorphous solid.
Data for I-10: Rf = 0.36 (5% MeOH in EtOAc); [α]D20
= +22.6 (MeOH, c = 0.25); IR (neat):
3391, 2918, 2850, 1709, 1467, 1377, 1324, 1255, 1111, 1049 cm-1
; 1H NMR (400 MHz,
CD3OD) δ 7.04 (ddd, J = 9.6, 5.6, 2.8 Hz, 1H), 5.97 (dd, J = 9.6, 1.6 Hz, 1H), 5.07 (dddd, J =
9.2, 6.4, 6.4, 2.8 Hz, 1H), 4.74–4.67 (m, 1H), 4.08 (dddd, J = 9.2, 6.4, 6.4, 2.4 Hz, 1H), 4.01–
3.92 (m, 2H), 3.81–3.75 (m, 1H), 2.45 (ddd, J = 18.4, 5.2, 5.2 Hz, 1H), 2.36 (dddd, J = 18.4,
11.2, 2.8, 2.8 Hz, 1H), 2.03 (s, 3H), 1.94 (ddd, J = 14.4, 9.6, 2.8 Hz, 1H), 1.72 (ddd, J = 14.4,
9.2, 2.8 Hz, 1H), 1.67–1.54 (m, 10 H), 1.28–1.25 (m, 26H), 0.89 (t, J = 6.8 Hz, 3H); 13
C NMR
(100 MHz, CD3OD) δ 173.1, 167.0, 148.6, 121.4, 76.6, 72.9, 69.91, 69.84, 67.5, 66.6, 45.9, 45.8,
45.3, 43.9, 43.3, 36.0, 33.1, 31.0, 30.8, 30.73, 30.69, 30.62, 30.5, 26.3, 23.8, 21.2, 14.5.14
Ethyl 2-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-
4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-13):
To a stirred solution of I-26 (3.43 g, 7.08 mmol) in tetrahydrofuran (20 mL) at 0 °C was added
benzaldehyde (0.72 mL, 7.08 mmol), followed by potassium tert-butoxide (86.5 mg, 0.708
mmol) under N2. The resulting mixture was stirred for 15 min. Then the addition of
benzaldehyde/potassium tert-butoxide was repeated three more times. The mixture was passed
through a pad of silica gel, and the silica gel was washed with EtOAc (50 mL). The filtrate was
concentrated, and the crude residue was purified by flash chromatography (10 to 30% EtOAc in
hexanes) on silica gel (100 mL) to afford I-13 (3.23 g, 77%) as a colorless oil.
47
Data for I-13: Rf = 0.41 (30% EtOAc in hexanes); [α]D23
= –18.0 (CH2Cl2, c = 1.72); IR (neat):
2918, 2859, 1732, 1512, 1247, 1107, 1010 cm-1
; 1H NMR (400 MHz, CDCl3) δ 7.50–7.45 (m,
4H), 7.39–7.33 (m, 6H), 7.26 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.58 (s, 1H), 5.53 (s,
1H), 4.48 (d, J = 11.2 Hz, 1H), 4.43 (d, J = 11.2 Hz, 1H), 4.34 (dddd, J = 13.2, 6.8, 6.8, 2.0 Hz,
1H), 4.17 (q, J = 7.2 Hz, 2H), 4.15–4.02 (m, 3H), 3.78 (s, 3H), 3.68 (ddd, J = 8.8, 8.8, 5.2 Hz,
1H), 3.58 (ddd, J = 10.8, 5.4, 5.4 Hz, 1H), 2.74 (dd, J = 15.2, 7.6 Hz, 1H), 2.53 (dd, J = 15.4, 6.0
Hz, 1H), 2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.93 (dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.86
(dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.83–1.67 (m, 3H), 1.61–1.46 (m, 2H), 1.27 (t, J = 7.2,
3H); 13
C NMR (100 MHz, CDCl3) δ 171.0, 159.4, 138.9, 138.6, 130.7, 129.6, 129.0, 128.9,
128.5, 128.4, 126.31, 126.28, 114.0, 100.8, 100.7, 74.0, 73.5, 73.26, 73.20, 72.9, 65.9, 60.9, 55.5,
41.9, 41.2, 37.1, 36.6, 36.3, 14.5; HRMS (ESI) calcd for C35H42O8Na [M Na]+: 613.2777
Found: 613.2785.
1-((Hex-5-yn-1-yloxy)methyl)-4-methoxybenzene (I-17):
To a stirred solution of 5-hexyn-1-ol I-16 (45.0 g, 0.459 mol) and 4-methoxybenzyl chloride
(73.2 g, 0.468 mol) in dimethylformamide (500 mL) at 0 °C was added sodium hydride (60%
wt/wt in mineral oil, 36.7 g, 0.917 mol) portionwise, followed by tetra-n-butylammonium
bromide (14.8 g, 45.9 mmol) under N2. The resulting mixture was stirred at 0 °C for 2 h, and
slowly warmed to room temperature. After 16 h, the reaction was quenched by pouring onto ice
slowly, and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
48
residue was purified by flash chromatography (2.5 to 5% EtOAc in hexanes) on silica gel (1000
mL) to afford I-17 (100 g, 99%) as a colorless oil.
Data for I-17: Rf = 0.28 (10% EtOAc in hexanes); IR (neat): 3294, 2938, 2861, 1613, 1586,
1514, 1464, 1361, 1302, 1248, 1173, 1101, 1036 cm-1
; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J
= 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.43 (s, 2H), 3.81 (s, 3H), 3.47 (t, J = 5.6 Hz, 2H), 2.21
(td, J = 7.2, 2.8 Hz, 2H), 1.94 (t, J = 2.8 Hz, 1H), 1.76–1.69 (m, 2H), 1.65–1.56 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 159.4, 130.9, 129.4, 114.0, 84.6, 72.8, 69.7, 68.6, 55.5, 29.0, 25.5,
18.4.67
Methyl 7-((4-methoxybenzyl)oxy)hept-2-ynoate (I-18):
To a stirred solution of I-17 (100 g, 0.458 mol) in tetrahydrofuran (600 mL) at –78 °C was added
n-butyl lithium (250 mL, 2.20 M, 0.550 mol) slowly via syringe under N2. After 1 h at the same
temperature, methyl chloroformate (46.1 mL, 0.596 mol) was added via syringe. The resulting
mixture was stirred at –78 °C for 1 h and then allowed to warm to 0 °C for 1 h. The reaction was
quenched by pouring into ice-cold saturated aqueous ammonium chloride and extracted with
EtOAc (3 × 200 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (2.5 to 20% EtOAc in hexanes) on silica gel (1000 mL) to
afford I-18 (127 g, 99%) as a colorless oil.
Data for I-18: Rf = 0.44 (20% EtOAc in hexanes); IR (neat): 2952, 2863, 2237, 1715, 1613,
1586, 1513, 1435, 1361, 1251, 1173, 1080, 1035 cm-1
; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J
= 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.42 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.46 (t, J = 5.6
49
Hz, 2H), 2.35 (t, J = 6.4 Hz, 2H), 1.73–1.66 (m, 4H); 13
C NMR (100 MHz, CDCl3) δ 159.4,
154.4, 130.8, 129.5, 114.0, 89.8, 73.3, 72.8, 69.4, 55.5, 52.8, 29.0, 24.6, 18.7; HRMS (ESI)
calcd for C16H20O4Na [M Na]+: 299.1259, found 299.1254.
(2E,4E)-Methyl 7-((4-methoxybenzyl)oxy)hepta-2,4-dienoate (I-19):
To a stirred solution of I-18 (126 g, 0.456 mol) in benzene (500 mL) at room temperature was
added triphenylphosphine (120 g, 0.456 mol), followed by phenol (42.6 g, 0.456 mol) under N2.
The resulting mixture was heated to 50 °C and stirred at the same temperature for 4 h. The
mixture was diluted with EtOAc (700 mL), washed with NaOH (1 M, 3 × 330 mL) and brine,
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (1 to 20% EtOAc in hexanes) on silica gel (1000
mL) to afford I-19 (114 g, 90%) as a colorless oil.
Data for I-19: Rf = 0.38 (20% EtOAc in hexanes); IR (neat): 3004, 2951, 2856, 1716, 1644,
1613, 1512, 1435, 1244, 1172, 1140, 1087 cm-1
; 1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J =
15.6, 10.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.23 (dd, J = 15.2, 10.4
Hz, 1H), 6.13 (ddd, J = 15.2, 6.4, 6.4 Hz, 1H), 5.79 (d, J = 15.2 Hz, 1H), 4.44 (s, 2H), 3.80 (s,
3H), 3.74 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.47 (q, J = 6.8 Hz, 2H); 13
C NMR (100 MHz,
CDCl3) δ 167.9, 159.5, 145.2, 141.0, 130.5, 130.1, 129.6, 119.6, 114.0, 72.9, 68.8, 55.5, 51.7,
33.7; HRMS (ESI) calcd for C16H20O4Na [M Na]+: 299.1259 Found: 299.1265.
50
(4S,5S,E)-Methyl 4,5-dihydroxy-7-((4-methoxybenzyl)oxy)hept-2-enoate (I-20):
To a mechanically stirred mixture of tert-butyl alcohol (270 mL) and water (270 mL) at room
temperature was added potassium hexacyanoferrate (265 g, 0.803 mol), potassium carbonate
(111 g, 0.803 mol), methanesulfonamide (25.5 g, 0.258 mol), osmium tetroxide (490 mg, 1.93
mmol) and (DHQ)2PHAL subsequently. The resulting mixture was stirred at the same
temperature for 1 h and cooled to 0 °C. A solution of I-19 (74.0 g, 0.268 mol) in
dichloromethane (20 mL) was added to the mixture. After 6 h, the reaction was diluted with
water (500 mL) and quenched by adding sodium sulfite (101 g, 0.803 mol). The mixture was
stirred at 0 °C for 30 min and filtered through a pad of Celite. The solid residue was washed with
EtOAc (400 mL). The filtrate was separated, and the aqueous layer was extracted with EtOAc (4
× 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude residue was purified by flash
chromatography (30 to 50% EtOAc in hexanes) on silica gel (500 mL) to afford I-20 (70.5 g,
85%) as a colorless oil.
Data for I-20: Rf = 0.26 (50% EtOAc in hexanes); [α]D21
= –40.9 (MeOH, c = 1.75 ); IR (neat):
3423, 2952, 2865, 1721, 1613, 1514, 1438, 1249, 1174, 1089, 1034 cm-1
; 1H NMR (400 MHz,
1% CD3OD in CDCl3) δ 7.22 (d, J = 8.8 Hz, 2H), 6.94 (dd, J = 15.6, 4.4 Hz, 1H), 6.86 (d, J = 8.8
Hz, 2H), 6.12 (dd, J = 15.6, 1.6 Hz, 1H), 4.43 (s, 2H), 4.13 (ddd, J = 4.4, 4.4, 1.6 Hz, 1H), 3.79
(s, 3H), 3.77–3.74 (m, 1H), 3.72 (s, 3H), 3.70–3.60 (m, 2H), 1.86–1.79 (m, 2H); 13
C NMR (100
MHz, CDCl3) δ 167.0, 159.6, 147.3, 129.72, 129.66, 122.1, 114.2, 74.0, 73.8, 73.4, 68.3, 55.5,
51.9, 32.8; HRMS (ESI) calcd for C16H22O6Na [M Na]+: 333.1314 Found: 333.1321.
51
(E)-Methyl 3-((4S,5S)-5-(2-((4-methoxybenzyl)oxy)ethyl)-2-oxo-1,3-dioxolan-4-yl)acrylate
(I-21):
To a stirred solution of I-20 (65.4 g, 0.211 mol) in dichloromethane (500 mL) at –78 °C was
added pyridine (84.9 mL, 1.05 mol), followed by 4-dimethylaminopyridine (0.515 g, 4.22 mmol)
under N2. Then a solution of triphosgene (43.8 g, 0.148 mol) in dichloromethane (200 mL) was
added to the mixture. After 50 min at the same temperature, the reaction was quenched with
saturated aqueous ammonium chloride (200 mL), and extracted with EtOAc (3 × 300 mL). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography
(20 to 40% EtOAc in hexanes) on silica gel (400 mL) to afford I-21 (63.3 g, 89%) as a colorless
oil.
Data for I-21: Rf = 0.28 (40% EtOAc in hexanes); [α]D18
= –40.0 (CH2Cl2, c =1.32); IR (neat):
2954, 2866, 1801, 1723, 1612, 1513, 1437, 1245, 1168, 1028 cm-1
; 1H NMR (400 MHz, CDCl3)
δ 7.22 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.84 (dd, J = 16.0, 5.2 Hz, 1H), 6.14 (dd, J =
16.0, 1.6 Hz, 1H), 5.01 (ddd, J = 6.8, 5.2, 1.6 Hz, 1H), 4.53 (q, J = 6.8, Hz, 1H), 4.42 (d, J = 2.4
Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.65–3.55 (m, 2H), 2.09–2.04 (m, 2H); 13
C NMR (100 MHz,
CDCl3) δ 165.7, 159.7, 153.8, 140.1, 129.8, 129.7, 124.3, 114.2, 80.1, 79.7, 73.4, 65.0, 55.5,
52.3, 33.6; HRMS (ESI) calcd for C17H20O7Na [M Na]+: 359.1107 Found: 359.1102.
52
(R,E)-Methyl 5-hydroxy-7-((4-methoxybenzyl)oxy)hept-2-enoate (I-22):
To a stirred solution of I-21 (33.7 g, 0.100 mol) in tetrahydrofuran (200 mL) at 0 °C was added
triethylamine (69.5 mL, 0.500 mol), followed by formic acid (37.8 mL, 1.00 mol) slowly via
syringe under N2. After the white smoke subsided, tris(dibenzylideneacetone)dipalladium(0)
chloroform complex (0.104 g, 0.100 mmol) was added, followed by triphenylphosphine (26.3
mg, 0.100 mmol). The resulting mixture was heated to reflux and became clear. At the moment a
black color was observed, the reaction was cooled to 0 °C immediately, quenched by adding
water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (20 to 40% EtOAc in
hexanes) on silica gel (300 mL) to afford I-22 (28.1 g, 95%) as a colorless oil.
Data for I-22: Rf = 0.23 (40% EtOAc in hexanes); [α]D20
= +11.4 (CH2Cl2, c = 1.39); IR (neat):
3474, 2948, 2860, 1718, 1657, 1612, 1512, 1436, 1245, 1170, 1084, 1030 cm-1
; 1H NMR (400
MHz, CDCl3) δ 7.24 (d, J = 8.8 Hz, 2H), 6.99 (ddd, J = 15.2, 7.6, 7.6 Hz, 1H), 6.88 (d, J = 8.8
Hz, 2H), 5.88 (ddd, J = 15.2, 1.6, 1.6 Hz, 1H), 4.45 (s, 2H), 3.96 (m, 1H), 3.81 (s, 3H), 3.72 (s,
3H), 3.70 (ddd, J = 8.0, 8.0, 3.2 Hz, 1H), 3.62 (ddd, J = 9.2, 8.4, 4.4 Hz, 1H), 2.44–2.31 (m, 2H),
1.82–1.69 (m, 2H); 13
C NMR (100 MHz, CDCl3) δ 167.0, 159.5, 145.8, 130.0, 129.6, 123.4,
114.1, 73.3, 70.7, 69.0, 55.5, 51.8, 40.3, 36.0; HRMS (ESI) calcd for C16H22O5Na [M Na]+:
317.1365 Found: 317.1368.
53
Methyl 2-((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-yl)acetate
(I-23):
To a stirred solution of I-22 (9.26 g, 31.5 mmol) in tetrahydrofuran (60 mL) at 0 °C was added
benzaldehyde (3.20 mL, 31.5 mmol), followed by potassium tert-butoxide (0.353 g, 3.15 mmol)
under N2. The resulting mixture was stirred for 15 min. Then the addition of benzaldehyde/
potassium tert-butoxide was repeated three more times. The mixture was passed through a pad of
silica gel, and the silica gel was washed with EtOAc (300 mL). The filtrate was concentrated,
and the crude residue was purified by flash chromatography (5 to 40% EtOAc in hexanes) on
silica gel (170 mL) to afford I-23 (8.40 g, 67%) as a colorless oil.
Data for I-23: mp 53-55 °C; Rf = 0.45 (40% EtOAc in hexanes); [α]D23
= –28.2 (CH2Cl2, c =
1.62); IR (neat): 2949, 2862, 1737, 1612, 1512, 1442, 1349, 1245, 1088, 1016 cm-1
; 1H NMR
(400 MHz, CDCl3) δ 7.44 (dd, J = 8.0, 2.4 Hz, 2H), 7.37–7.32 (m, 3H), 7.27 (d, J = 8.8 Hz, 2H),
6.87 (d, J = 8.8 Hz, 2H), 5.55 (s, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.32
(dddd, J = 13.2, 7.2, 7.2, 2.4 Hz, 1H), 4.07 (dddd, J = 10.8, 7.2, 4.4, 2.4 Hz, 1H), 3.79 (s, 3H),
3.71 (s, 3H), 3.69–3.64 (m, 1H), 3.57 (ddd, J = 9.6, 5.2, 5.2 Hz, 1H), 2.74 (dd, J = 15.6, 7.2 Hz,
1H), 2.52 (dd, J = 15.6, 6.0 Hz, 1H), 1.93 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.84 (dddd, J =
14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.72 (ddd, J = 12.8, 2.4, 2.4 Hz, 1H), 1.46 (ddd, J = 12.8, 11.2, 11.2
Hz, 1H); 13
C NMR (100 MHz, CDCl3) δ 171.4, 159.4, 138.7, 130.7, 129.6, 128.9, 128.4, 126.3,
114.0, 100.7, 73.8, 73.4, 72.9, 65.8, 55.5, 52.0, 41.0, 36.8, 36.3; HRMS (ESI) calcd for
C23H28O6Na [M Na]+: 423.1784 Found: 423.1769.
54
2-((2S,4S,6S)-6-(2-((4-Methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-
24):
To a stirred solution of I-23 (15.2 g, 38.0 mmol) in dichloromethane (110 mL) at –78 °C was
added a solution of diisobutylaluminium hydride (1 M, 38.0 mL, 38.0 mmol) in hexane slowly
via syringe under N2. After the starting material was consumed, the reaction mixture was
quenched by adding 1 N hydrochloric acid (100 mL), and stirred at room temperature for 1 h.
The mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was purified by flash chromatography (5 to 20% EtOAc in hexanes) on silica gel
(200 mL) to afford I-24 (11.7 g, 83%) as a colorless oil.
Data for I-24: Rf = 0.30 (20% EtOAc in hexanes); [α]D21
= –30.1 (CH2Cl2, c = 1.07); IR (neat):
2923, 2857, 1724, 1612, 1512, 1245, 1097, 1026 cm-1
; 1H NMR (400 MHz, CDCl3) δ 9.86 (t, J =
2.0 Hz, 1H), 7.44 (dd, J = 8.0, 2.0 Hz, 2H), 7.38–7.32 (m, 3H), 7.27 (d, J = 8.8 Hz, 2H), 6.87 (d,
J = 8.8 Hz, 2H), 5.57 (s, 1H), 4.45 (d, J = 6.0 Hz, 2H), 4.43–4.37 (m, 1H), 4.08 (dddd, J = 13.2,
7.6, 4.4, 3.2 Hz, 1H), 3.79 (s, 3H), 3.67 (ddd, J = 9.6, 9.6, 5.2 Hz, 1H), 3.57 (ddd, J = 9.2, 5.2,
5.2 Hz, 1H), 2.80 (ddd, J = 16.8, 8.4, 2.0 Hz, 1H), 2.61 (ddd, J = 16.8, 4.4, 2.0 Hz, 1H), 1.93
(dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.84 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.69 (ddd, J =
13.2, 2.4, 2.4 Hz, 1H), 1.49 (ddd, J = 13.2, 11.6, 11.6 Hz, 1H); 13
C NMR (100 MHz, CDCl3) δ
200.6, 159.4, 138.5, 130.7, 129.6, 129.0, 128.4, 126.2, 114.0, 100.8, 73.9, 72.9, 72.1, 65.7, 55.5,
49.6, 36.9, 36.2; HRMS (ESI) calcd for C23H30O6Na [M Na + MeOH]+: 425.1940 Found:
425.1952.
55
(R)-1-((2S,4R,6S)-6-(2-((4-Methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-
ol (I-25):
To a stirred solution of I-24 (2.23 g, 6.02 mmol) in dichloromethane (20 mL) at –10 °C was
added a solution of (S,S)-Leighton reagent (5.01 g, 9.03 mmol) in dichloromethane (10 mL)
slowly via syringe, followed by scandium triflate (74.1 mg, 0.151 mmol) under N2. Then the
resulting mixture was transferred to freezer at –10 °C. After 12 h, the reaction was quenched by
adding 1 N hydrochloric acid (20 mL). The formed solid was filtered through a fritted funnel,
and the filtrate was extracted with EtOAc (3 × 50 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 30% EtOAc in
hexanes) on silica gel (50 mL) to afford I-25 (1.79 g, 72%, dr = 8.7:1.0) as a colorless oil.
Data for I-25: Rf = 0.31 (30% EtOAc in hexanes); [α]D21
= –19.2 (CH2Cl2, c = 0.92); IR (neat):
3518, 3069, 2940, 2915, 2861, 1733, 1611, 1512, 1345, 1244, 1092, 1018 cm-1
; 1H NMR (400
MHz, CDCl3) δ 7.42 (dd, J = 7.2, 2.4 Hz, 2H), 7.36–7.32 (m, 3H), 7.26 (d, J = 8.8 Hz, 2H), 6.86
(d, J = 8.8 Hz, 2H), 5.85 (dddd, J = 16.8, 10.0, 6.8, 6.8 Hz, 1H), 5.56 (s, 1H), 5.16–5.10 (m, 2H),
4.47 (d, J = 12.0 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.15–4.02 (m, 2H), 3.97 (dddd, J = 9.2, 6.4,
6.4, 2.8 Hz, 1H), 3.78 (s, 3H), 3.66 (ddd, J = 9.6, 9.6, 5.2 Hz, 1H), 3.56 (ddd, J = 9.6, 5.2, 5.2
Hz, 1H), 2.32–2.21 (m, 2H), 1.92 (dddd, J = 13.6, 8.0, 5.2, 5.2 Hz, 1H), 1.82 (dddd, J = 13.6,
8.0, 5.2, 5.2 Hz, 1H) 1.77–1.75 (m, 1H), 1.69 (ddd, J = 14.8, 2.8, 2.8 Hz, 1H), 1.61 (ddd, J =
13.2, 2.8, 2.8 Hz, 1H), 1.49 (ddd, J = 13.2, 10.8, 10.8 Hz, 1H); 13
C NMR (100 MHz, CDCl3) δ
159.4, 138.5, 135.0, 130.7, 129.6, 129.0, 128.5, 126.2, 117.9, 114.0, 100.8, 77.6, 74.0, 72.9, 70.6,
56
65.7, 55.5, 42.21, 42.19, 37.4, 36.2; HRMS (ESI) calcd for C25H33O5 [M H]+: 413.2328 Found:
413.2327.
(R,E)-Ethyl 5-hydroxy-6-((2S,4R,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-
dioxan-4-yl)hex-2-enoate (I-26):
To a stirred solution of I-25 (2.95 g, 7.15 mmol) in dichloromethane (10 mL) at room
temperature was added ethyl acrylate (30.4 mL, 0.286 mol), followed by the Grubbs second-
generation catalyst (146 mg, 0.179 mmol) under N2. The resulting mixture was degassed by two
freeze−pump−thaw cycles, then warmed to room temperature and stirred at the same
temperature. After 3 h, the mixture was diluted with hexanes (100 mL), and purified by flash
chromatography (20 to 50% EtOAc in hexanes) on silica gel (100 mL) to afford I-26 (3.43 g,
99%) as a colorless oil.
Data for I-26: Rf = 0.34 (50% EtOAc in hexanes); [α]D21
= –10.9 (CH2Cl2, c = 1.26); IR (neat):
3514, 2941, 2914, 2862, 1713, 1654, 1611, 1511, 1244, 1171, 1094, 1021 cm-1
; 1H NMR (400
MHz, CDCl3) δ 7.41 (dd, J = 7.2, 2.4 Hz, 2H), 7.37–7.33 (m, 3H), 7.26 (d, J = 8.8 Hz, 2H), 6.98
(ddd, J = 14.8, 7.2, 7.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 5.91 (d, J = 14.8 Hz, 1H), 5.55 (s, 1H),
4.46 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.18 (q, J = 7.6 Hz, 2H), 4.14–4.02 (m, 3H),
3.78 (s, 3H), 3.65 (ddd, J = 8.8, 8.8, 5.2 Hz, 1H), 3.54 (ddd, J = 10.4, 5.2, 5.2 Hz, 1H), 2.45–2.33
(m, 2H), 1.91 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.80 ( dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H),
1.77–1.75 (m, 1H), 1.67 (ddd, J = 14.0, 2.8, 2.8 Hz, 1H), 1.59 (ddd, J = 13.2, 2.4, 2.4 Hz, 1H),
1.50 (ddd, J = 13.2, 10.8, 10.8 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ
166.6, 159.4, 145.2, 138.3, 130.7, 129.6, 129.1, 128.5, 126.2, 124.0, 114.0, 100.9, 77.8, 74.0,
57
72.9, 70.5, 65.6, 60.5, 55.5, 42.3, 40.4, 37.3, 36.2, 14.5; HRMS (ESI) calcd for C28H36O7Na [M
Na]+: 507.2359 Found: 507.2329.
Ethyl 2-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-hydroxyethyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-2-
phenyl-1,3-dioxan-4-yl)acetate (I-27):
To a stirred solution of I-13 (2.17 g, 3.67 mmol) in dichloromethane (10 mL) at 0 °C was added
water (0.5 mL), followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.50 g, 11.0 mmol)
under N2. The resulting mixture was stirred at the same temperature for 2 h. The reaction was
quenched by adding saturated aqueous sodium bicarbonate (30 mL), and filtered through a pad
of Celite. The filtrate was extracted with EtOAc (3 × 50 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (20 to 50% EtOAc in
hexanes) on silica gel (50 mL) to afford I-27 (1.60 g, 92%) as a colorless oil.
Data for I-27: Rf = 0.23 (50% EtOAc in hexanes); [α]D19
= –2.8 (CH2Cl2, c = 1.68); IR (neat):
3493, 3038, 2946, 2872, 1731, 1452, 1377, 1343, 1214, 1106, 1007 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.49–7.47 (m, 4H), 7.39–7.33 (m, 6H), 5.58 (s, 1H), 5.57 (s, 1H), 4.34 (dddd, J = 13.2,
6.4, 6.4, 2.0 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 4.18–4.10 (m, 3H), 3.90–3.80 (m, 2H), 2.73 (dd, J
= 15.6, 6.8 Hz, 1H), 2.52 (dd, J = 15.6, 6.0 Hz, 1H), 2.15 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.97–
1.90 (m, 1H), 1.88–1.83 (m, 1H), 1.82–1.77 (m, 2H), 1.72–1.50 (m, 3H), 1.26 (t, J = 7.2, 3H);
13C NMR (100 MHz, CDCl3) δ 171.0, 138.63, 138.57, 129.1, 129.0, 128.5, 128.4, 126.30,
126.27, 101.0, 100.8, 76.3, 73.5, 73.3, 73.1, 60.9, 60.5, 41.8, 41.2, 38.3, 36.9, 36.6, 14.5; HRMS
(EI) calcd for C27H34O7 [M]+: 470.2305 Found: 470.2297.
58
Ethyl 2-((2S,4S,6S)-6-(((2R,4R,6R)-6-(2-oxoethyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-2-
phenyl-1,3-dioxan-4-yl)acetate (I-28):
To a stirred solution of I-27 (1.49 g, 3.17 mmol) in dichloromethane (11 mL) at 0 °C was added
Dess–Martin periodinane (1.61 g, 3.80 mmol). After 2 h at the same temperature, the reaction
was quenched by adding saturated aqueous sodium bicarbonate (50 mL) and sodium sulfite
(0.958 g, 7.60 mmol). The mixture was stirred at room temperature for 30 min, and extracted
with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (20 to 30% EtOAc in hexanes) on silica gel (50 mL) to afford
I-28 (1.20 g, 81%) as a colorless oil.
Data for I-28: Rf = 0.33 (40% EtOAc in hexanes); [α]D25
= +2.08 (CH2Cl2, c = 1.21); IR (neat):
3064, 2981, 2948, 2917, 2869, 2733, 1725, 1453, 1390, 1343, 1267, 1214, 1107, 1009 cm-1
; 1H
NMR (400 MHz, CDCl3) δ 9.86 (t, J = 2.0 Hz, 1H), 7.50–7.47 (m, 4H), 7.40–7.34 (m, 6H), 5.60
(s, 1H), 5.59 (s, 1H), 4.43 (dddd, J = 11.6, 7.6, 5.2, 2.4 Hz, 1H), 4.34 (dddd, J = 13.2, 6.4, 6.4,
2.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.17–4.10 (m, 2H), 2.83 (ddd, J = 16.8, 7.6, 2.0 Hz, 1H),
2.74 (dd, J = 15.6, 7.6 Hz, 1H), 2.63 (ddd, J = 16.8, 4.8, 1.2 Hz, 1H), 2.53 (dd, J = 15.6, 6.0 Hz,
1H), 2.16 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.83–1.75 (m, 3H), 1.62–1.51 (m, 2H), 1.27 (t, J = 7.2
Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 200.6, 171.0, 138.5, 138.4, 129.1, 129.0, 128.52,
128.48, 126.30, 126.29, 101.0, 100.9, 73.5, 73.2, 73.1, 72.1, 60.9, 49.6, 41.8, 41.2, 36.6, 36.5,
14.5; HRMS (EI) calcd for C27H32O7 [M]+: 468.2148 Found: 468.2146.
59
Ethyl 2-((2S,4S,6S)-6-(((2R,4R,6R)-6-(2-oxoheptadec-3-yn-1-yl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-29):
To a stirred solution of 1-pentadecyne (0.409 g, 1.96 mmol) in tetrahydrofuran (5 mL) at –78 °C
was added a solution of n-butyllithium (1.82 M, 0.97 mL, 1.77 mmol) in hexane slowly via
syringe under N2. The resulting mixture was stirred at the same temperature for 30 min, and then
transferred to a stirred solution of I-28 (0.460 g, 0.982 mmol) in tetrahydrofuran (5 mL) at –78
°C via syringe under N2. After the addition, the flask was taken out of the dry ice-acetone bath,
kept in the ambient environment for 4 min with stirring, and immersed in the bath again. The
reaction was quenched by adding saturated aqueous ammonium chloride (10 mL), and extracted
with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure.
The crude residue was dissolved in dichloromethane (6 mL). The resulting solution was cooled
to 0 °C, and Dess–Martin periodinane (0.583 g, 1.38 mmol) was added. After 2 h at the same
temperature, the reaction was quenched by adding saturated aqueous sodium bicarbonate (20
mL) and sodium sulfite (0.348 g, 2.76 mmol). The mixture was stirred at room temperature for
30 min, and extracted with Et2O (3 × 40 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (5 to 20% EtOAc in hexanes) on silica gel (30
mL) to afford I-29 (0.443 g, 67%) as a colorless oil.
Data for I-29: Rf = 0.31 (20% EtOAc in hexanes); [α]D18
= –0.53 (CH2Cl2, c = 1.24); IR (neat):
2925, 2854, 2211, 1737, 1674, 1453, 1391, 1346, 1172, 1115, 1027 cm-1
; 1H NMR (400 MHz,
60
CDCl3) δ 7.50–7.48 (m, 4H), 7.39–7.33 (m, 6H), 5.58 (s, 2H), 4.46 (dddd, J = 13.2, 6.8, 6.8, 2.0
Hz, 1H), 4.34 (dddd, J = 13.2, 6.8, 6.8, 2.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.17–4.12 (m, 2H),
3.01 (dd, J = 16.0, 7.2 Hz, 1H), 2.77–2.70 (m, 2H), 2.53 (dd, J = 16.4, 6.8 Hz, 1H), 2.36 (t, J =
7.2 Hz, 2H), 2.16 (ddd, J = 15.2, 7.6, 7.6 Hz, 1H), 1.83–1.75 (m, 3H), 1.61–1.49 (m, 4H), 1.40–
1.36 (m, 2H), 1.33–1.21 (m, 21H), 0.89 (t, J = 6.8 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ
185.0, 170.9, 138.6, 138.5, 129.0, 128.43, 128.42, 126.31, 126.27, 100.85, 100.82, 95.7, 81.3,
73.5, 73.1, 72.8, 60.9, 51.5, 41.9, 41.2, 36.6, 32.2, 29.92, 29.88, 29.85, 29.69, 29.60, 29.27,
29.13, 27.9, 22.9, 19.2, 14.5, 14.4; HRMS (ESI) calcd for C42H59O7 [M H]+: 675.4261 Found:
675.4246.
Ethyl 2-((2S,4S,6S)-6-(((2S,4S,6S)-6-((S)-2-hydroxyheptadec-3-yn-1-yl)-2-phenyl-1,3-
dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-30):
To a stirred solution of I-29 (0.930 g, 1.38 mmol) in triethylamine (7.4 mL, 53.1 mmol) at 0 °C
was added formic acid (2.0 mL, 53.0 mmol) under N2. After the white smoke subsided, (S)-
RuCl[(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2](6-mesitylene) (42.9 mg, 69.0 µmol) was added.
The resulting mixture was stirred at room temperature for 7 h. The reaction was quenched by
adding water (10 mL), and extracted with Et2O (3 × 40 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 30% EtOAc in
hexanes) on silica gel (35 mL) to afford I-30 (0.876 g, 94%) as a colorless oil.
61
Data for I-30: Rf = 0.44 (30% EtOAc in hexanes); [α]D19
= –17.8 (CH2Cl2, c = 1.60); IR (neat):
3499, 2924, 2854, 2230, 1737, 1454, 1393, 1346, 1215, 1115, 1027 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.50–7.47 (m, 4H), 7.39–7.33 (m, 6H), 5.59 (s, 1H), 5.58 (s, 1H), 4.68–4.63 (m, 1H),
4.37–4.31 (m, 2H), 4.17 (q, J = 6.8 Hz, 2H), 4.17–4.10 (m, 2H), 2.73 (dd, J = 15.2, 7.2 Hz, 1H),
2.53 (dd, J = 15.2, 6.0 Hz, 1H), 2.22 (td, J = 7.6, 1.6 Hz, 2H), 2.15 (ddd, J =14.4, 7.2, 7.2 Hz,
1H), 2.07 (ddd, J = 13.6, 9.6, 4.0 Hz, 1H), 1.87 (ddd, J = 14.4, 7.2, 3.2 Hz, 1H), 1.83–1.75 (m,
2H), 1.68 (ddd, J = 13.2, 2.8, 2.8 Hz, 1H), 1.65–1.56 (m, 1H), 1.54–1.48 (m, 2H), 1.40–1.36 (m,
1H), 1.28–1.21 (m, 23H), 0.89 (t, J = 6.8 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 170.9, 138.6,
129.03, 128.96, 128.5, 128.4, 126.30, 126.25, 100.85, 100.83, 86.0, 81.0, 74.5, 73.5, 73.4, 73.2,
60.9, 60.3, 43.3, 41.9, 41.2, 36.8, 36.6, 32.2, 29.93, 29.89, 29.80, 29.6, 29.4, 29.1, 28.9, 22.9,
19.0, 14.5, 14.4; HRMS (ESI) calcd for C42H61O7 [M H]+: 677.4417 Found: 677.4410.
Ethyl 2-((2S,4S,6S)-6-(((2S,4S,6S)-6-((R)-2-hydroxyheptadecyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-31):
To a stirred solution of I-30 (0.871 g, 1.29 mmol) in dichloromethane (5 mL) at room
temperature was added triethylamine (3.59 mL, 25.7 mmol), followed by o-
nitrobenzenesulfonylhydrazide (2.79 g, 12.9 mmol). The resulting mixture was stirred at the
same temperature for 20 h. The reaction was quenched by adding saturated aqueous sodium
bicarbonate, and extracted with Et2O (3 × 40 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
62
crude residue was purified by flash chromatography (10 to 30% EtOAc in hexanes) on silica gel
(35 mL) to afford I-31 (0.875 g, 90%) as a colorless oil.
Data for I-31:Rf = 0.44 (30% EtOAc in hexanes); [α]D19
= –1.30 (CH2Cl2, c = 2.91); IR (neat):
3517, 2924, 2853, 1737, 1454, 1391, 1345, 1215, 1113, 1027 cm-1
; 1H NMR (400 MHz, CDCl3)
δ 7.49–7.47 (m, 4H), 7.38–7.33 (m, 6H), 5.57 (s, 1H), 5.55 (s, 1H), 4.34 (dddd, J = 13.2, 6.4, 6.4,
2.4 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 4.18–4.10 (m, 3H), 3.99–3.94 (m, 1H), 2.73 (dd, J = 15.6,
7.2 Hz, 1H), 2.52 (dd, J = 15.6, 6.8 Hz, 1H), 2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.82–1.74 (m,
3H), 1.71–1.61 (m, 3H), 1.59–1.50 (m, 2H), 1.47–1.43 (m, 1H), 1.28–1.21 (m, 29H), 0.88 (t, J =
6.8 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 170.9, 138.7, 138.6, 128.95, 128.93, 128.5, 128.4,
126.29, 126.25, 100.9, 100.8, 74.6, 73.5, 73.4, 73.2, 68.5, 60.9, 42.7, 41.9, 41.2, 38.0, 36.8, 36.6,
32.2, 29.93, 29.86, 29.85, 29.59, 25.9, 22.9, 14.45, 14.36; HRMS (ESI) calcd for C47H65O7 [M
H]+: 681.4730 Found: 681.4720.
2-((2S,4S,6S)-6-(((2S,4S,6S)-6-((R)-2-Hydroxyheptadecyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-32):
To a stirred solution of I-31 (0.369 g, 0.542 mmol) in dichloromethane (110 mL) at –78 °C was
added a solution of diisobutylaluminum hydride (1 M, 1.1 mL, 1.1 mmol) in hexane slowly via
syringe under N2. After the starting material was consumed, the reaction mixture was quenched
by adding 1 N hydrochloric acid (10 mL), and stirred at room temperature for 1 h. The mixture
was extracted with Et2O (3 × 30 mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
63
residue was purified by flash chromatography (10 to 50% EtOAc in hexanes) on silica gel (25
mL) to afford I-32 (0.301 g, 87%) as a colorless oil.
Data for I-32: Rf = 0.29 (40% EtOAc in hexanes); [α]D21
= –8.15 (CH2Cl2, c = 1.41); IR (neat):
3426, 2924, 2853, 1725, 1641, 1454, 1390, 1343, 1113, 1026 cm-1
; 1H NMR (400 MHz, CDCl3)
δ 9.86 (t, J = 1.6 Hz, 1H), 7.49–7.47 (m, 4H), 7.39–7.34 (m, 6H), 5.59 (s, 1H), 5.55 (s, 1H), 4.43
(dddd, J = 11.2, 7.6, 5.2, 2.4 Hz, 1H), 4.22–4.09 (m, 3H), 3.98–3.94 (m, 1H), 2.83 (ddd, J = 16.8,
7.2, 2.0 Hz, 1H), 2.64 (ddd, J = 16.8, 4.8, 1.2 Hz, 1H), 2.16 (ddd, J = 14.0, 6.8, 6.8 Hz, 1H),
1.81–1.75 (m, 3H), 1.71–1.53 (m, 4H), 1.50–1.43 (m, 2H), 1.30–1.20 (m, 26H), 0.88 (t, J = 6.8
Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 200.6, 138.7, 138.4, 129.1, 129.0, 128.5, 126.28,
126.26, 100.98, 100.95, 74.6, 73.3, 73.2, 72.1, 68.4, 49.6, 42.7, 41.8, 38.0, 36.8, 36.7, 32.2,
29.94, 29.91, 29.88, 29.86, 29.6, 25.9, 22.9, 14.4; HRMS (ESI) calcd for C40H61O6 [M H]+:
637.4468 Found: 637.4470.
(R)-1-((2R,4R,6S)-6-(((2S,4S,6S)-6-(2-Oxoethyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-
1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-33):
To a stirred solution of I-32 (0.301 g, 0.473 mmol) in dichloromethane (2 mL) at 0 °C was added
triethylamine (0.33 mL, 2.36 mmol), followed by 4-dimethylaminopyridine (2.8 mg, 24 µmol)
and acetic anhydride (89 µL, 2.36 mmol). The resulting mixture was stirred at the same
temperature for 20 min. The reaction was quenched by adding methanol (0.1 mL), and diluted
with Et2O (60 mL). The mixture was washed with brine, dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The crude residue was purified by flash
64
chromatography (5 to 30% EtOAc in hexanes) on silica gel (25 mL) to afford I-33 (0.230 g,
72%) as a colorless oil.
Data for I-33: Rf = 0.21 (20% EtOAc in hexanes); [α]D22
= –16.9 (CH2Cl2, c = 0.73); IR (neat):
2924, 2853, 1734, 1453, 1373, 1342, 1242, 1112, 1025 cm-1
; 1H NMR (400 MHz, CDCl3) δ 9.86
(s, 1H), 7.52–7.48 (m, 4H), 7.40–7.32 (m, 6H), 5.60 (s, 1H), 5.50 (s, 1H), 5.21 (dddd, J = 9.2,
6.4, 6.4, 3.6 Hz, 1H), 4.43 (dddd, J = 10.0, 7.2, 4.8, 2.0 Hz, 1H), 4.20–4.14 (m, 1H), 4.12–4.05
(m, 1H), 3.90–3.83 (m, 1H), 2.83 (ddd, J = 16.8, 7.2, 1.6 Hz, 1H), 2.63 (ddd, J = 16.8, 4.8, 1.2
Hz, 1H), 2.17 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 2.05 (s, 3H), 1.88–1.76 (m, 3 H), 1.75–1.69 (m,
1H), 1.64–1.50 (m, 5H), 1.25–1.24 (m, 26H), 0.88 (t, J = 6.8 Hz, 3H); 13
C NMR (100 MHz,
CDCl3) δ 200.6, 170.9, 138.7, 138.4, 129.1, 128.8, 128.5, 128.4, 126.3, 126.2, 101.0, 100.5, 73.7,
73.3, 73.1, 72.1, 71.2, 49.6, 41.8, 40.9, 37.2, 36.6, 35.1, 32.2, 29.95, 29.91, 29.83, 29.78, 29.6,
25.4, 23.0, 21.6, 14.4; HRMS (ESI) calcd for C42H62O7Na [M Na]+: 701.4393 Found:
701.4440.
(R)-1-((2R,4R,6S)-6-(((2R,4R,6R)-6-((R)-2-hydroxypent-4-en-1-yl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-34):
To a stirred solution of I-33 (0.214 g, 0.315 mmol) in dichloromethane (2 mL) at –10 °C was
added a solution of (S,S)-Leighton reagent (0.350 g, 0.620 mmol) in dichloromethane (2 mL)
slowly via syringe, followed by scandium triflate (7.8 mg, 15.8 µmol) under N2. Then the
resulting mixture was transferred to freezer at –10 °C. After 12 h, the reaction was quenched by
adding 1 N hydrochloric acid (10 mL). The formed solid was filtered through a fritted funnel,
65
and the filtrate was extracted with Et2O (3 × 40 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was purified by flash chromatography (5 to 30% EtOAc in hexanes) on silica gel
(30 mL) to afford I-34 (0.170 g, 75%) as a colorless oil.
Data for I-34: Rf = 0.37 (30% EtOAc in hexanes); [α]D20
= –10.5 (CH2Cl2, c = 0.49); IR (neat):
3460, 2329, 2853, 1737, 1453, 1373, 1341, 1240, 1113, 1020 cm-1
; 1H NMR (400 MHz, CDCl3)
δ 7.51–7.45 (m, 4H), 7.38–7.32 (m, 6H), 5.84 (dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H), 5.59 (s,
1H), 5.49 (s, 1H), 5.24–5.18 (m, 1H), 5.14–5.09 (m, 2H), 4.17–4.10 (m, 2H), 4.10–4.04 (m, 1H),
3.98 (dddd, J = 8.4, 6.4, 6.4, 2.4 Hz, 1H), 3.89–3.83 (m, 1H), 2.28–2.24 (m, 2H), 2.16 (ddd, J =
14.8, 7.6, 7.6 Hz, 1H), 2.05 (s, 3H), 1.87–1.69 (m, 6H), 1.64–1.49 (m, 5H), 1.25–1.24 (m, 26H),
0.88 (t, J = 7.2 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 171.0, 138.7, 138.4, 134.9, 129.2, 128.8,
128.6, 128.5, 128.4, 126.3, 126.2, 117.9, 101.0, 100.4, 73.7, 73.4, 73.1, 71.2, 70.6, 42.22,
42.18,41.8, 40.8, 37.2, 37.1, 35.1, 32.2, 30.5, 29.95, 29.91, 29.83, 29.78, 29.6, 25.4, 23.0, 21.6,
14.4; HRMS (ESI) calcd for C45H69O7 [M H]+: 721.5043 Found: 721.5053.
(R)-1-((2S,4S,6R)-6-(((2R,4S,6R)-6-((R)-2-Acetoxyheptadecyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-35):
To a stirred solution of I-34 (71.3 mg, 98.9 µmol) in dichloromethane (0.5 mL) at room
temperature was added N,N'-dicyclohexylcarbodiimide (40.8 mg, 198 µmol), followed by acrylic
acid (10 µL, 148 µmol) and 4-dimethylaminopyridine (0.6 mg, 4.9 µmol). The resulting mixture
was stirred at the same temperature for 20 h, diluted with Et2O (10 mL) and filtered through filter
66
paper. The filtrate was concentrated under reduced pressure. The crude residue was purified by
flash chromatography (5 to 15% EtOAc in hexanes) on silica gel (15 mL) to afford I-35 (47.0
mg, 61%) as a colorless oil.
Data for I-35: Rf = 0.48 (20% EtOAc in hexanes); [α]D21
= –13.1 (CH2Cl2, c = 0.72); IR (neat):
2924, 2853, 1725, 1453, 1405, 1375, 1341, 1241, 1194, 1113, 1021 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.52–7.46 (m, 4H), 7.38–7.31 (m, 6H), 6.35 (dd, J = 17.6, 1.6 Hz, 1H), 6.06 (dd, J =
17.6, 10.4 Hz, 1H), 5.82–5.73 (m, 1H), 5.76 (dd, J = 10.4, 1.6 Hz, 1H), 5.50 (s, 2H), 5.24–5.19
(m, 1H), 5.12 –5.07 (m, 2H), 4.12–4.05 (m, 2H), 3.98–3.92 (m, 1H), 3.89–3.83 (m, 1H), 2.44–
2.39 (m, 2H), 2.18–2.06 (m, 2H), 2.05 (s, 3H), 1.88–1.68 (m, 6H), 1.64–1.47 (m, 5H), 1.25–1.24
(m, 26H), 0.88 (t, J = 6.8 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 170.9, 166.0, 138.82, 138.77,
133.4, 131.0, 128.9, 128.8, 128.7, 128.4, 128.3, 126.4, 126.2, 118.5, 100.9, 100.4, 74.3, 73.7,
73.3, 73.1, 71.2, 70.5, 41.9, 40.9, 40.0, 39.2, 37.3, 36.7, 35.1, 32.2, 29.93, 29.89, 29.82, 29.78,
29.59, 25.4, 22.9, 21.5, 14.4; HRMS (ESI) calcd for C48H71O8 [M H]+: 775.5149 Found:
775.5156.
(R)-1-((2R,4R,6S)-6-(((2S,4R,6S)-6-(((R)-6-Oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-2-
phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-36):
To a stirred solution of I-35 (40.5 mg, 52.3 µmol) in dichloromethane (5 mL) at room
temperature was added the Grubbs first-generation catalyst (2.2 mg, 2.6 µmol) under N2. The
resulting solution was degassed by two freeze−pump−thaw cycles, and then heated to reflux.
After 2 h, the mixture was cooled to room temperature, and dimethyl sulfoxide was added. The
67
stirring was then continued for another 2 h. The mixture was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 40% EtOAc in
hexanes) on silica gel (10 mL) to afford I-36 (29.3 mg, 75%) as a colorless oil.
Data for I-36: Rf = 0.37 (40% EtOAc in hexanes); [α]D22
= +6.04 (CH2Cl2, c = 0.63); IR (neat):
2924, 2853, 1735, 1453, 1377, 1342, 1244, 1113, 1025 cm-1
; 1H NMR (400 MHz, CDCl3) δ
7.51–7.45 (m, 4H), 7.39–7.32 (m, 6H), 6.89 (ddd, J = 9.6, 5.6, 2.0 Hz, 1H), 6.04 (dd, J = 9.6, 2.0
Hz, 1H), 5.55 (s, 1H), 5.50 (s, 1H), 5.23–5.17 (m, 1H), 4.73–4.66 (m, 1H), 4.20–4.05 (m, 3H),
3.89–3.83 (m, 1H), 2.51 (dddd, J = 18.4, 10.8, 2.4, 2.4 Hz, 1H), 2.41 (ddd, J = 18.4, 5.2, 5.2 Hz,
1H), 2.23 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 2.05 (s, 3H),
1.97–1.91 (m, 1H), 1.89–1.82 (m, 1H), 1.79–1.69 (m, 2H), 1.64–1.50 (m, 6H), 1.26–1.25 (m,
26H), 0.88 (t, J = 6.8 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 170.9, 164.6, 145.5, 138.8, 138.7,
129.0, 128.8, 128.5, 128.4, 126.3, 126.2, 121.5, 100.9, 100.5, 74.8, 73.7, 73.4, 73.1, 72.8, 71.2,
41.9, 40.9, 40.6, 37.2, 36.6, 35.1, 32.2, 29.93, 29.89, 29.82, 29.76, 29.6, 29.5, 25.4, 22.9, 21.5,
14.4; HRMS (ESI) calcd for C46H67O8 [M H]+: 747.4836 Found: 747.4833.
Ethyl 2-((2S,4S,6S)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-
phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-37):
To a stirred solution of I-31 (0.785 g, 1.25 mmol) in dimethylformamide (2.5 mL) at room
temperature was added tert-butyldimethylsilyl chloride (0.348 g, 2.31 mmol), followed by
imidazole (0.196 g, 2.88 mmol). The resulting mixture was stirred at the same temperature for 14
h. The reaction was quenched by adding water (10 mL) and extracted with Et2O (3 × 40 mL).
68
The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography (2
to 5% EtOAc in hexanes) on silica gel (35 mL) to afford I-37 (0.880 g, 96%) as a colorless oil.
Data for I-37: Rf = 0.41 (10% EtOAc in hexanes); [α]D20
= –16.9 (CH2Cl2, c = 1.06); IR (neat):
2926, 2855, 1737, 1462, 1388, 1344, 1254, 1112, 1027 cm-1
; 1H NMR (400 MHz, CDCl3) δ
7.50–7.47 (m, 4H), 7.38–7.32 (m, 6H), 5.58 (s, 1H), 5.51 (s, 1H), 4.36–4.31 (m, 1H), 4.17 (q, J =
7.6 Hz, 2H), 4.17–4.13 (m, 1H), 4.13–4.07 (m, 1H), 4.03–3.99 (m, 2H), 2.74 (dd, J = 15.6, 7.2
Hz, 1H), 2.53 (dd, J = 15.6, 6.0 Hz, 1H), 2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.84–1.81 (m,
1H), 1.79–1.69 (m, 2H), 1.65–1.51 (m, 7H), 1.48–1.43 (m, 2H), 1.28–1.25 (m, 26H), 0.90 (s,
9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13
C NMR (100 MHz, CDCl3) δ 171.0, 139.1, 138.6,
128.9, 128.8, 128.42, 128.39, 126.28, 126.27, 100.8, 100.5, 73.5, 73.4, 73.34, 73.27, 68.1, 60.9,
43.6, 42.0, 41.3, 38.5, 37.7, 36.6, 32.2, 30.2, 29.94, 29.91, 29.8, 29.6, 26.2, 24.7, 22.9, 18.4, 14.5,
14.4, –4.0, –4.3; HRMS (ESI) calcd for C48H79O7Si [M H]+: 795.5595 Found: 795.5599.
2-((2S,4S,6S)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-phenyl-
1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-38):
To a stirred solution of I-37 (0.870 g, 1.09 mmol) in dichloromethane (110 mL) at –78 °C was
added a solution of diisobutylaluminum hydride (1 M, 1.1 mL, 1.1 mmol) in hexane slowly via
syringe under N2. After the starting material was consumed, the reaction mixture was quenched
by adding 1 N hydrochloric acid (5 mL), and stirred at room temperature for 1 h. The mixture
was extracted with Et2O (3 × 50 mL). The combined organic layers were washed with brine,
69
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (5 to 25% EtOAc in hexanes) on silica gel (35
mL) to afford I-38 (0.560 g, 68%) as a colorless oil.
Data for I-38: Rf = 0.23 (10% EtOAc in hexanes); [α]D20
= –21.2 (CH2Cl2, c = 1.06); IR (neat):
2926, 2854, 1727, 1459, 1404, 1343, 1254, 1112, 1058, 1027 cm-1
; 1H NMR (400 MHz, CDCl3)
δ 9.86 (s, 1H), 7.50–7.47 (m, 4H), 7.38–7.33 (m, 6H), 5.60 (s, 1H), 5.50 (s, 1H), 4.47–4.41 (m,
1H), 4.19–4.14 (m, 1H), 4.10–4.05 (m, 1H), 4.05–3.98 (m, 2H), 2.83 (ddd, J = 16.8, 7.2, 2.0 Hz,
1H), 2.64 (ddd, J = 16.8, 4.8, 1.6 Hz, 1H), 2.15 (ddd, J = 14.0, 6.8. 6.8 Hz, 1H), 1.83–1.69 (m,
3H), 1.64–1.50 (m, 4H), 1.49–1.43 (m, 2H), 1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6
Hz, 3H), 0.05 (s, 6H); 13
C NMR (100 MHz, CDCl3) δ 200.6, 139.1, 138.4, 129.1, 128.8, 128.5,
128.4, 126.3, 101.0, 100.6, 73.4, 73.34, 73.29, 72.1, 68.1, 49.6, 43.6, 41.9, 38.5, 37.7, 36.7, 32.2,
30.2, 29.95, 29.92, 29.86, 29.6, 26.2, 24.7, 22.9, 18.4, 14.4, –3.9, –4.3; HRMS (ESI) calcd for
C46H75O6Si [M H]+: 751.5333 Found: 751.5338.
(S)-1-((2R,4R,6R)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-
phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-ol (I-39):
To a stirred solution of I-38 (0.264 g, 0.351 mmol) in dichloromethane (2 mL) at –10 °C was
added a solution of (R,R)-Leighton reagent (0.390, 0.703 mmol) in dichloromethane (2 mL)
slowly via syringe, followed by scandium triflate (8.6 mg, 17.6 µmol) under N2. Then the
resulting mixture was transferred to freezer at –10 °C. After 12 h, the reaction was quenched by
adding 1 N hydrochloric acid (10 mL). The formed solid was filtered through a fritted funnel,
70
and the filtrate was extracted with Et2O (3 × 40 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was purified by flash chromatography (5 to 20% EtOAc in hexanes) on silica gel
(20 mL) to afford I-39 (0.265 g, 95%) as a colorless oil.
Data for I-39: Rf = 0.41 (20% EtOAc in hexanes); [α]D22
= –7.9 (CH2Cl2, c = 0.95); IR (neat):
3443, 2926, 2854, 1641, 1461, 1405, 1388, 1342, 1254, 1057, 1027 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.51–7.47 (m, 4H), 7.38–7.32 (m, 6H), 5.83(dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H),
5.56 (s, 1H), 5.50 (s, 1H), 5.16–5.12 (m, 2H), 4.22–4.16 (m, 1H), 4.15–4.10 (m, 1H), 4.09–3.98
(m, 4H), 2.33–2.19 (m, 2H), 2.15 (ddd, J = 14.0, 6.8, 6.8 Hz, 1H), 1.83–1.69 (m, 4H), 1.67–1.51
(m, 5H), 1.48–1.43 (m, 2H), 1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s,
6H); 13
C NMR (100 MHz, CDCl3) δ 139.1, 138.8, 134.9, 128.9, 128.8, 128.5, 128.4, 126.3,
118.3, 100.9, 100.5, 74.4, 73.5, 73.42, 73.38, 68.1, 67.3, 43.6, 42.5, 42.3, 42.0, 38.5, 37.7, 36.9,
32.2, 30.2, 29.93, 29.90, 29.8, 29.6, 26.2, 24.7, 22.9, 18.4, 14.4, –4.0, –4.3; HRMS (ESI) calcd
for C49H81O6Si [M H]+: 793.5802 Found: 793.5804.
(S)-1-((2S,4S,6R)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-
phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-40):
To a stirred solution of I-39 (0.253 g, 0.319 mmol) in dichloromethane (1.0 mL) at room
temperature was added N,N'-dicyclohexylcarbodiimide (78.6 mg, 0.383 mmol), followed by
acrylic acid (28 µL, 0.383 mmol) and 4-dimethylaminopyridine (2.0 mg, 16.4 µmol). The
resulting mixture was stirred at the same temperature for 20 h, diluted with Et2O (10 mL) and
71
filtered through filter paper. The filtrate was concentrated under reduced pressure. The crude
residue was purified by flash chromatography (2 to 20% EtOAc in hexanes) on silica gel (20
mL) to afford I-40 (0.172 g, 64%) as a colorless oil.
Data for I-40: Rf = 0.32 (5% EtOAc in hexanes); [α]D21
= +10.6 (CH2Cl2, c = 0.65); IR (neat):
2926, 2854, 1725, 1461, 1405, 1341, 1295, 1255, 1192, 1027 cm-1
; 1H NMR (400 MHz, CDCl3)
δ 7.51–7.49 (m, 4H), 7.39–7.32 (m, 6H), 6.40 (dd, J = 17.6, 1.6 Hz, 1H), 6.12 (dd, J = 17.6, 10.4
Hz, 1H), 5.82 (dd, J = 10.4, 1.6 Hz, 1H), 5.77 (dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H), 5.50 (s,
2H), 5.40–5.34 (m, 1H), 5.10–5.06 (m, 2H), 4.11–4.05 (m, 2H), 4.03–3.98 (m, 2H), 3.92–3.87
(m, 1H), 2.47–2.34 (m, 2H), 2.15 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.91 (ddd, J = 14.8, 9.6, 3.6
Hz, 1H), 1.81 (ddd, J = 14.8, 9.2, 3.6 Hz, 1H), 1.76–1.61 (m, 4H), 1.56–1.43 (m, 5H), 1.28–1.25
(m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13
C NMR (100 MHz, CDCl3) δ
165.9, 139.1, 138.8, 133.5, 130.9, 128.9, 128.7, 128.4, 126.3, 126.2, 118.3, 100.6, 100.4, 73.6,
73.4, 73.2, 70.3, 68.1, 43.6, 42.0, 40.3, 39.5, 38.4, 37.7, 37.3, 32.2, 30.2, 29.90, 29.94, 29.8, 29.6,
26.2, 24.7, 22.9, 18.4, 14.4, –4.0, –4.3; HRMS (ESI) calcd for C52H83O7Si [M H]+: 847.5908
Found: 847.5912.
(S)-6-(((2S,4S,6R)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-
phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-5,6-dihydro-2H-pyran-2-
one (I-41):
To a stirred solution of I-40 (13.0 mg, 15.3 µmol) in dichloromethane (2 mL) at room
temperature was added the Grubbs first-generation catalyst (1.2 mg, 1.5 µmol) under N2. The
72
resulting solution was degassed by two freeze−pump−thaw cycles, and then heated to reflux.
After 2 h, the mixture was cooled to room temperature, and dimethyl sulfoxide was added. The
stirring was then continued for another 2 h. The mixture was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 30% EtOAc in
hexanes) on silica gel (10 mL) to afford I-41 (11.0 mg, 87%) as a colorless oil.
Data for I-41: Rf = 0.20 (20% EtOAc in hexanes); [α]D21
= –15.8 (CH2Cl2, c = 0.24); IR (neat):
2925, 2854, 1726, 1461, 1453, 1380, 1343, 1250, 1140, 1058, 1027 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.51–7.46 (m, 4H), 7.39–7.31 (m, 6H), 6.88 (ddd, J = 9.6, 6.0, 3.2 Hz, 1H), 6.03 (dd, J
= 9.6, 2.4 Hz, 1H), 5.58 (s, 1H), 5.50 (s, 1H), 4.83–4.76 (m, 1H), 4.30–4.25 (m, 1H), 4.17–4.11
(m, 1H), 4.10–4.06 (m, 1H), 4.06–3.98 (m, 2H), 2.41–2.29 (m, 2H), 2.15 (ddd, J = 14.0, 6.8, 6.8
Hz, 1H), 1.98 (ddd, J = 14.4, 9.6, 2.0 Hz, 1H), 1.88 (ddd, J = 14.4, 10.0, 2.4 Hz, 1H), 1.78–1.70
(m, 3H), 1.64–1.61 (m, 1H), 1.57–1.43 (m, 5H), 1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J =
7.6 Hz, 3H), 0.05 (s, 6H); 13
C NMR (100 MHz, CDCl3) δ 164.5, 145.3, 139.0, 138.7, 128.9,
128.7, 128.4, 128.3, 126.24, 126.20, 121.6, 100.7, 100.5, 74.1, 73.35, 73.31, 72.2, 68.0, 43.5,
42.0, 41.8, 38.4, 37.7, 37.2, 32.1, 30.1, 30.0, 29.89, 29.85, 29.8, 29.6, 26.2, 24.7, 22.9, 18.3, 14.3,
–4.0, –4.3; HRMS (ESI) calcd for C50H79O7Si [M H]+: 819.5595 Found: 819.5602.
(S)-6-((2S,4S,6S,8S,10R)-2,4,6,8,10-pentahydroxypentacosyl)-5,6-dihydro-2H-pyran-2-one
(or ent-cryptocaryol A) (I-42):
To a flask with I-41 (10.5 mg, 12.8 µmol) was added a solution of acetic acid (2 mL, 80%) in
water. The resulting mixture was heated to 80 °C and stirred for 1 h. The solvent was removed
73
under reduced pressure. The crude residue was purified by flash chromatography (2 to 8%
MeOH in EtOAc) on silica gel (10 mL) to afford I-42 (5.2 mg, 77%) as a white amorphous solid.
Data for I-42: Rf = 0.44 (10% MeOH in CH2Cl2); [α]D21
= –13.4 (MeOH, c = 0.10); IR (neat):
3313, 2918, 2850, 1721, 1456, 1329, 1258, 1137, 1073, 1027 cm-1
; 1H NMR (500 MHz,
CD3OD) δ 7.04 (ddd, J = 9.5, 6.0, 2.5 Hz, 1H), 5.97 (dd, J = 9.5, 2.5 Hz, 1H), 4.74–4.68 (m,
1H), 4.09 (dddd, J = 9.0, 6.5, 6.5, 2.5 Hz, 1H), 4.04–3.96 (m, 3H), 3.82–3.77 (m, 1H), 2.45 (ddd,
J = 19.0, 5.0, 5.0 Hz, 1H), 2.36 (dddd, J = 19.0, 11.5, 2.5, 2.5 Hz, 1H), 1.94 (ddd, J = 14.5, 9.5,
2.5 Hz, 1H), 1.71–1.55 (m, 7H), 1.52–1.50 (m, 2H), 1.46–1.40 (m, 2H), 1.32–1.25 (m, 26H),
0.89 (t, J = 7.0 Hz, 3H); 13
C NMR (125 MHz, CD3OD) δ 167.0, 148.6, 121.4, 76.6, 70.2, 69.9,
69.1, 68.2, 66.6, 46.0, 45.9, 45.8, 45.3, 43.9, 39.3, 33.1, 31.0, 30.9, 30.84, 30.81, 30.5, 26.8, 23.8,
14.5.14
(S)-1-((2S,4S,6R)-6-(((2S,4S,6S)-6-((R)-2-hydroxyheptadecyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-43):
To a flask with I-40 (95.5 mg, 0.113 mmol) was added a solution of tetra-n-butylammonium
fluoride (1 M, 5 mL, 5 mmol) at room temperature. The resulting mixture was stirred at the same
temperature for 3 h. The reaction was quenched by adding saturated aqueous sodium
bicarbonate, and extracted with Et2O (3 × 30 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was purified by flash chromatography (5 to 20% EtOAc in hexanes) on silica gel
(20 mL) to afford I-43 (75.0 mg, 91%) as a colorless oil.
74
Data for I-43: Rf = 0.37 (20% EtOAc in hexanes); [α]D20
= +20.8 (CH2Cl2, c = 0.65); IR (neat):
2923, 2853, 1723, 1453, 1405, 1342, 1295, 1193, 1112, 1026 cm-1
; 1H NMR (400 MHz, CDCl3)
δ 7.51–7.47 (m, 4H), 7.38–7.32 (m, 6H), 6.40 (d, J = 18.0 Hz, 1H), 6.12 (d, J = 18.0, 10.4 Hz,
1H), 5.82 (d, J = 10.4 Hz, 1H), 5.77 (dddd, J = 17.6, 10.0, 7.2, 7.2 Hz, 1H), 5.55 (s, 1H), 5.49 (s,
1H), 5.37 (dddd, J = 9.2, 5.6, 5.6, 3.6, 1H), 5.10–5.06 (m, 2H), 4.22-4.05 (m, 3H), 3.98–3.86 (m,
2H), 2.47–2.34 (m, 2H), 2.16 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.90 (ddd, J = 14.0, 9.6, 3.2 Hz,
1H), 1.83–1.73 (m, 3H), 1.71–1.62 (m, 4H), 1.53–1.43 (m, 3H), 1.28–1.25 (m, 26H), 0.88 (t, J =
7.2 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 165.8, 138.71, 138.68, 133.4, 130.8, 128.90, 128.86,
128.7, 128.4, 128.3, 126.2, 126.1, 118.3, 100.9, 100.4, 74.6, 73.5, 73.4, 73.1, 70.2, 68.4, 42.6,
41.9, 40.3, 39.4, 38.0, 37.2, 36.7, 32.1, 29.87, 29.81, 29.79, 29.5, 25.9, 22.9, 14.3, 14.2; HRMS
(ESI) calcd for C46H69O7 [M H]+: 733.5043 Found: 733.5043.
(S)-1-((2S,4S,6R)-6-(((2R,4S,6R)-6-((R)-2-acetoxyheptadecyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-44):
To a stirred solution of I-43 (75.0 mg, 0.102 mmol) in dichloromethane (1 mL) at 0 °C was
added triethylamine (29 µL, 0.204 mmol), followed by 4-dimethylaminopyridine (2.0 mg, 16
µmol) and acetic anhydride (15 µL, 0.159 mmol). The resulting mixture was stirred at the same
temperature for 1.5 h. The reaction was quenched by adding methanol (0.1 mL), and diluted with
Et2O (20 mL). The mixture was washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography (5
to 15% EtOAc in hexanes) on silica gel (20 mL) to afford I-44 (74.0 mg, 96%) as a colorless oil.
75
Data for I-44: Rf = 0.42 (15% EtOAc in hexanes); [α]D20
= +11.2 (CH2Cl2, c = 0.72); IR (neat):
2924, 2854, 1726, 1453, 1406, 1374, 1268, 1242, 1193, 1147, 1113, 1026 cm-1
; 1H NMR (400
MHz, CDCl3) δ 7.52–7.50 (m, 4H), 7.38–7.32 (m, 6H), 6.40 (dd, J = 17.6, 1.2 Hz, 1H), 6.12 (dd,
J = 17.6, 10.4 Hz, 1H), 5.82 (dd, J = 10.4, 1.6 Hz, 1H), 5.77 (dddd, J = 16.8, 10.0, 7.2, 7.2 Hz,
1H), 5.50 (s, 2H), 5.37 (dddd, J = 8.8, 5.6, 5.6, 3.2 Hz, 1H), 5.21 (dddd, J = 9.2, 6.0, 6.0, 3.6 Hz,
1H), 5.10–5.06 (m, 2H), 4.12–4.05 (m, 2H), 3.92–3.83 (m, 2H), 2.47–2.33 (m, 2H), 2.16 (ddd, J
= 14.4, 7.2, 7.2 Hz, 1H), 2.04 (s, 3H), 1.94–1.71 (m, 6H), 1.66–1.62 (m, 2H), 1.60–1.47 (m, 3H),
1.26–1.23 (m, 26H), 0.88 (t, J = 7.6 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 170.9, 165.8,
138.75, 138.71, 133.4, 130.8, 128.9, 128.72, 128.69, 128.33, 128.31, 126.16, 126.14, 118.3,
100.4, 73.7, 73.5, 73.1, 71.2, 70.2, 41.9, 40.8, 40.3, 39.4, 37.2, 35.1, 32.1, 29.88, 29.86, 29.85,
29.77, 29.71, 29.6, 25.3, 22.9, 21.5, 14.3; HRMS (ESI) calcd for C48H71O8 [M H]+: 775.5149
Found: 775.5156.
(R)-1-((2R,4R,6S)-6-(((2S,4R,6S)-6-(((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-2-
phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-45):
To a stirred solution of I-44 (69.0 mg, 89.0 µmol) in dichloromethane (5 mL) at room
temperature was added the Grubbs first-generation catalyst (3.7 mg, 4.5 µmol) under N2. The
resulting solution was degassed by two freeze−pump−thaw cycles, and then heated to reflux.
After 2 h, the mixture was cooled to room temperature, and dimethyl sulfoxide was added. The
stirring was then continued for another 2 h. The mixture was concentrated under reduced
76
pressure. The crude residue was purified by flash chromatography (10 to 40% EtOAc in
hexanes) on silica gel (20 mL) to afford I-45 (52.0 mg, 78%) as a colorless oil.
Data for I-45: Rf = 0.38 (40% EtOAc in hexanes); [α]D20
= –13.6 (CH2Cl2, c = 0.51); IR (neat):
2923, 2853, 1735, 1453, 1377, 1343, 1244, 1140, 1119, 1058, 1025 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.52–7.47 (m, 4H), 7.39–7.32 (m, 6H), 6.88 (ddd, J = 9.6, 5.2, 2.8 Hz, 1H), 6.03 (ddd,
J = 9.6, 1.6, 1.6 Hz, 1H), 5.58 (s, 1H), 5.50 (s, 1H), 5.21 (dddd, J = 9.6, 6.8, 6.8, 3.6 Hz, 1H),
4.79 (m, J = 9.6, 9.6, 5.6, 2.8 Hz, 1H), 4.30–4.24 (m, 1H), 4.16–4.06 (m, 2H), 3.89–3.84 (m,
1H), 2.40–2.30 (m, 2H), 2.16 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 2.04 (s, 3H), 1.97 (ddd, J = 14.8,
9.6, 2.0 Hz, 1H), 1.91–1.82 (m, 2H), 1.80–1.69 (m, 3H), 1.65–1.49 (m, 5H), 1.26–1.23 (m, 26H),
0.88 (t, J = 7.6 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 170.9, 164.5, 145.3, 138.7, 129.0, 128.7,
128.4, 128.3, 126.3, 126.1, 121.6, 100.7, 100.4, 74.1, 73.7, 73.3, 73.1, 72.2, 71.2, 41.9, 41.7,
40.8, 37.2, 35.1, 32.1, 30.1, 29.89, 29.84, 29.77, 29.73, 29.6, 25.3, 22.9, 21.5, 14.3; HRMS (ESI)
calcd for C46H67O8 [M H]+: 747.4836 Found: 747.4833.
(2S,4S,6R,8R,10R)-2,4,6,8-tetrahydroxy-1-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)
pentacosan -10-yl acetate (I-46):
To a flask with I-45 (22.7 mg, 30.4 µmol) was added a solution of acetic acid (2.5 mL, 80%) in
water. The resulting mixture was heated to 80 °C and stirred for 1 h. The solvent was removed
under reduced pressure. The crude residue was purified by flash chromatography (1 to 5%
MeOH in EtOAc) on silica gel (10 mL) to afford I-46 (13.0 mg, 75%) as a white amorphous
solid.
77
Data for I-46: Rf = 0.36 (5% MeOH in EtOAc); [α]D22
= –23.9 (MeOH, c = 0.20); IR (neat):
3407, 2918, 2850, 1710, 1650, 1467, 1426, 1377, 1255, 1105, 1051 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.04 (ddd, J = 9.6, 5.6, 2.8 Hz, 1H), 5.97 (dd, J = 9.6, 1.6 Hz, 1H), 5.07 (dddd, J = 9.6,
6.4, 6.4, 2.8 Hz, 1H), 4.74–4.67 (m, 1H), 4.08 (dddd, J = 9.2, 6.8, 6.8, 2.4 Hz, 1H), 4.01–3.92
(m, 2H), 3.81–3.75 (m, 1H), 2.45 (ddd, J = 18.4, 5.2, 5.2 Hz, 1H), 2.36 (dddd, J = 18.4, 11.2, 2.8,
2.8 Hz, 1H), 2.03 (s, 3H), 1.94 (ddd, J = 14.4, 9.6, 2.8 Hz, 1H), 1.72 (ddd, J = 14.4, 9.2, 2.8 Hz,
1H), 1.67–1.54 (m, 10 H), 1.28–1.25 (m, 26H), 0.89 (t, J = 6.8 Hz, 3H); 13
C NMR (125 MHz,
CDCl3) δ 173.1, 167.0, 148.6, 121.4, 76.6, 72.8, 69.93, 69.85, 67.5, 66.6, 45.9, 45.8, 45.3, 43.9,
43.3, 36.0, 33.1, 31.0, 30.8, 30.73, 30.69, 30.62, 30.5, 26.3, 23.8, 21.2, 14.5.14
2-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-47):
To a stirred solution of I-13 (3.04 g, 5.15 mmol) in dichloromethane (20 mL) at –78 °C was
added a solution of diisobutylaluminum hydride (1 M, 5.2 mL, 5.2 mmol) in hexane slowly via
syringe under N2. After the starting material was consumed, the reaction mixture was quenched
by adding 1 N hydrochloric acid (20 mL), and stirred at room temperature for 1 h. The mixture
was extracted with Et2O (4 × 40 mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (10 to 30% EtOAc in hexanes) on silica gel (120
mL) to afford I-47 (2.53 g, 90%) as a colorless oil.
Data for I-47: Rf = 0.25 (30% EtOAc in hexanes); [α]D21
= –19.9 (CH2Cl2, c = 0.95); IR (neat):
2948, 2918, 2861, 1725, 1612, 1513, 1453, 1344, 1248, 1112, 1027 cm-1
; 1H NMR (400 MHz,
78
CDCl3) δ 9.86 (t, J = 1.6 Hz, 1H), 7.49–7.44 (m, 4H), 7.38–7.33 (m, 6H), 7.26 (d, J = 8.8 Hz,
2H), 6.86 (d, J = 8.8 Hz, 2H), 5.58 (s, 1H), 5.52 (s, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.47–4.39 (m,
1H), 4.43 (d, J = 12.0 Hz, 1H), 4.19–4.10 (m, 1H), 4.10–4.00 (m, 2H), 3.78 (s, 3H), 3.67 (ddd, J
= 9.2, 9.2, 5.2 Hz, 1H), 3.58 (ddd, J = 9.2, 5.2, 5.2 Hz, 1H), 2.83 (ddd, J = 16.8, 7.2, 2.0 Hz, 1H),
2.63 (ddd, J = 16.8, 5.2, 1.6 Hz, 1H), 2.15 (ddd, J = 14.0, 6.8, 6.8 Hz, 1H), 1.93 (dddd, J = 13.2,
8.0, 5.2, 5.2 Hz, 1H), 1.84 (dddd, J = 13.2, 8.0, 5.2, 5.2 Hz, 1H), 1.80–1.73 (m, 2H), 1.69–1.43
(m, 3H); 13
C NMR (100 MHz, CDCl3) δ 200.6, 159.4, 139.0, 138.4, 130.7, 129.6, 129.1, 128.9,
128.5, 128.4, 126.3, 114.0, 101.0, 100.7, 74.0, 73.29, 73.23, 72.9, 72.1, 65.9, 55.5, 49.6, 41.9,
37.1, 36.7, 36.3; HRMS (ESI) calcd for C33H39O7 [M H]+: 547.2696 Found: 547.2698.
1-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadec-3-yn-2-one (I-48):
To a stirred solution of 1-pentadecyne (0.976 g, 4.68 mmol) in tetrahydrofuran (12 mL) at –78
°C was added a solution of n-butyllithium (1.82 M, 1.9 mL, 3.51 mmol) in hexane slowly via
syringe under N2. The resulting mixture was stirred at the same temperature for 30 min, and then
transferred to a stirred solution of I-47 (1.28 g, 2.34 mmol) in tetrahydrofuran (12 mL) at –78 °C
via syringe under N2. After the addition, the flask was taken out of the dry ice-acetone bath, kept
in the ambient environment for 8 min with stirring, and immersed in the bath again. The reaction
was quenched by adding saturated aqueous ammonium chloride (20 mL), and extracted with
Et2O (3 × 60 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure.
79
The crude residue was dissolved in dichloromethane (12 mL). The resulting solution was cooled
to 0 °C, and Dess–Martin periodinane (1.49 g, 3.51 mmol) was added. After 2 h at the same
temperature, the reaction was quenched by adding saturated aqueous sodium bicarbonate (10
mL) and sodium sulfite (0.884 g, 7.02 mmol). The mixture was stirred at room temperature for
30 min, and extracted with Et2O (3 × 60 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (5 to 20% EtOAc in hexanes) on silica gel (35
mL) to afford I-48 (1.20 g, 68%) as a colorless oil.
Data for I-48: Rf = 0.37 (20% EtOAc in hexanes); [α]D20
= –13.9 (CH2Cl2, c = 0.60); IR (neat):
2925, 2854, 2211, 1673, 1612, 1513, 1454, 1344, 1248, 1112, 1028 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.49–7.45 (m, 4H), 7.38–7.32 (m, 6H), 7.26 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz,
2H), 5.58 (s, 1H), 5.53 (s, 1H), 4.50–4.40 (m, 1H), 4.48 (d, J = 11.2 Hz, 1H), 4.43 (d, J = 11.2
Hz, 1H), 4.16–4.01 (m, 3H), 3.78 (s, 3H), 3.67 (ddd, J = 9.2, 8.4, 5.2 Hz, 1H), 3.58 (ddd, J = 9.2,
5.2, 5.2 Hz, 1H), 3.01 (dd, J = 16.4, 7.2 Hz, 1H), 2.73 (dd, J = 16.4, 5.6 Hz, 1H), 2.36 (t, J = 7.2
Hz, 2H), 2.14 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.93 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H),
1.85(dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.82–1.72 (m, 2H), 1.70–1.66 (m, 1H), 1.60–1.48 (m,
3H), 1.40–1.35 (m, 1H), 1.28–1.25 (m, 20H), 0.88 (t, J = 7.2 Hz, 3H); 13
C NMR (100 MHz,
CDCl3) δ 185.0, 159.3, 138.9, 138.5, 130.7, 129.5, 128.9, 128.7, 128.3, 126.22, 126.20, 113.9,
100.7, 100.6, 95.6, 81.2, 73.9, 73.2, 73.1, 72.8, 72.7, 65.8, 55.4, 51.5, 41.9, 37.0, 36.5, 36.3, 32.1,
29.83, 29.81, 29.76, 29.6, 29.5, 29.2, 29.1, 27.8, 22.9, 19.2, 14.3; HRMS (ESI) calcd for
C48H65O7 [M H]+: 753.4730 Found: 753.4733.
80
(R)-1-((2R,4R,6R)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadec-3-yn-2-ol (I-49):
To a stirred solution of I-48 (1.80 g, 2.39 mmol) in triethylamine (14.8 mL, 106 mmol) at 0 °C
was added formic acid (4.0 mL, 106 mmol) under N2. After the white smoke subsided, (R)-
RuCl[(1R,2R)-p-TsNCH(C6H5)CH(C6H5)NH2](η6-mesitylene) (74.0 mg, 120 µmol) was added.
The resulting mixture was stirred at room temperature for 12 h. The reaction was quenched by
adding water (20 mL), and extracted with Et2O (3 × 50 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5 to 40% EtOAc in hexanes)
on silica gel (80 mL) to afford I-49 (1.76 g, 98%) as a colorless oil.
Data for I-49: Rf = 0.38 (30% EtOAc in hexanes); [α]D20
= +0.87 (CH2Cl2, c = 1.25); IR (neat):
3449, 2924, 2854, 1612, 1513, 1454, 1406, 1344, 1248, 1112, 1028 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.48–7.44 (m, 4H), 7.38–7.32 (m, 6H), 7.25 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz,
2H), 5.58 (s, 1H), 5.52 (s, 1H), 4.68–4.62 (m, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 11.6
Hz, 1H), 4.38–4.32 (m, 1H), 4.15-4.00 (m, 3H), 3.78 (s, 3H), 3.66 (ddd, J = 9.2, 8.4, 5.2 Hz, 1H),
3.57 (ddd, J = 9.2, 5.6, 5.6 Hz, 1H), 2.21 (td, J = 7.2, 2.0 Hz, 2H), 2.14 (ddd, J = 14.0, 7.2, 7.2
Hz, 1H), 2.07 (ddd, J = 14.0, 9.6, 3.2 Hz, 1H), 1.92 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.85
(dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.75 (ddd, J = 14.0, 6.0, 6.0 Hz, 1H), 1.70–1.64 (m, 2H),
1.62–1.49 (m, 4H), 1.39–1.36 (m, 1H), 1.28–1.25 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13
C NMR
(100 MHz, CDCl3) δ 159.2, 138.9, 138.5, 130.6, 129.4, 128.8, 128.6, 128.3, 128.2, 126.14,
126.11, 113.9, 100.6, 100.5, 85.7, 80.9, 74.2, 73.9, 73.3, 73.1, 72.7, 65.7, 59.9, 55.3, 43.2, 41.8,
81
37.0, 36.7, 36.2, 32.0, 29.78, 29.75, 29.6, 29.5, 29.2, 29.0, 28.8, 22.8, 18.8, 14.2; HRMS (ESI)
calcd for C48H67O7 [M H]+: 755.4887 Found: 755.4886.
(S)-1-((2R,4R,6R)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-ol (I-50):
To a stirred solution of I-49 (1.75 g, 2.32 mmol) in dichloromethane (10 mL) at room
temperature was added triethylamine (6.46 mL, 46.4 mmol), followed by o-
nitrobenzenesulfonylhydrazide (5.03 g, 23.2 mmol). The resulting mixture was stirred at the
same temperature for 20 h. The reaction was quenched by adding saturated aqueous sodium
bicarbonate (20 mL), and extracted with Et2O (3 × 50 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 40% EtOAc in
hexanes) on silica gel (80 mL) to afford I-50 (1.72 g, 98%) as a colorless oil.
Data for I-50: Rf = 0.38 (30% EtOAc in hexanes); [α]D20
= –5.4 (CH2Cl2, c = 1.00); IR (neat):
3467, 2924, 2853, 1735, 1613, 1513, 1455, 1343, 1248, 1112, 1028 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.49–7.44 (m, 4H), 7.38–7.32 (m, 6H), 7.26 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz,
2H), 5.54 (s, 1H), 5.52 (s, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.21–4.15
(m, 1H), 4.15–4.00 (m, 3H), 3.99–3.94 (m, 1H), 3.78 (s, 3H), 3.67 (ddd, J = 9.2, 8.4, 5.2 Hz,
1H), 3.57 (ddd, J = 9.2, 5.6, 5.6 Hz, 1H), 2.26–2.19 (m, 1H), 2.14 (ddd, J = 14.0, 7.2, 7.2 Hz,
1H), 1.93 (dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.85 (dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.80–
1.75 (m, 1H), 1.72–1.62 (m, 4H), 1.54–1.45 (m, 3H), 1.28–1.25 (m, 26H), 0.88 (t, J = 6.8 Hz,
82
3H); 13
C NMR (100 MHz, CDCl3) δ 159.3, 138.9, 138.7, 130.7, 129.5, 128.9, 128.8, 128.4,
128.3, 126.22, 126.20, 114.0, 100.9, 100.6, 74.6, 74.0, 73.4, 73.3, 72.8, 68.4, 65.8, 55.4, 42.6,
41.9, 38.0, 37.1, 36.8, 36.3, 32.1, 30.5, 29.88, 29.85, 29.83, 29.81, 29.6, 25.9, 22.9, 14.3; HRMS
(ESI) calcd for C48H71O7 [M H]+: 759.5200 Found: 759.5199.
tert-butyl(((S)-1-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-
dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl)oxy)dimethylsilane (I-51):
To a stirred solution of I-50 (1.71 g, 2.25 mmol) in dimethylformamide (5.0 mL) at room
temperature was added tert-butyldimethylsilyl chloride (0.679 g, 4.51 mmol), followed by
imidazole (0.383 g, 5.63 mmol). The resulting mixture was stirred at the same temperature for 14
h. The reaction was quenched by adding water (20 mL) and extracted with Et2O (3 × 50 mL).
The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography (5
to 15% EtOAc in hexanes) on silica gel (80 mL) to afford I-51 (1.85 g, 94%) as a colorless oil.
Data for I-51: Rf = 0.28 (10% EtOAc in hexanes); [α]D21
= +0.96 (CH2Cl2, c = 1.36); IR (neat):
2925, 2854, 1613, 1513, 1463, 1388, 1342, 1249, 1112, 1059, 1028 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.51–7.45 (m, 4H), 7.37–7.33 (m, 6H), 7.26 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz,
2H), 5.53 (s, 1H), 5.50 (s, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.43 (d, J = 11.6 Hz, 1H), 4.12–3.98
(m, 5H), 3.78 (s, 3H), 3.68 (ddd, J = 9.2, 9.2, 5.2 Hz, 1H), 3.58 (ddd, J = 9.6, 5.6, 5.6 Hz, 1H),
2.14 (ddd, J = 14.0, 6.8, 6.8 Hz, 1H), 1.93 (dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.86 (dddd, J =
14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.77–1.62 (m, 4H), 1.56–1.43 (m, 5H), 1.28–1.25 (m, 26H), 0.90 (s,
83
9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13
C NMR (100 MHz, CDCl3) δ 159.3, 139.1, 139.0,
130.7, 129.5, 128.72, 128.67, 128.3, 126.2, 114.0, 100.6, 100.5, 73.9, 73.4, 72.8, 68.1, 65.9, 55.4,
43.5, 42.0, 38.4, 37.7, 37.1, 36.3, 32.1, 30.1, 29.89, 29.85, 29.79, 29.6, 26.2, 26.1, 24.7, 22.9,
18.3, 14.3, –4.0, –4.3; HRMS (ESI) calcd for C54H85O7Si [M H]+: 873.6065 Found: 873.6058.
2-((2S,4S,6S)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-phenyl-1,3-
dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)ethanol (I-52):
To a stirred solution of I-51 (1.84 g, 2.11 mmol) in dichloromethane (10 mL) at 0 °C was added
water (0.5 mL), followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.43 g, 6.32 mmol)
under N2. The resulting mixture was stirred at the same temperature for 2 h. The reaction was
quenched by adding saturated aqueous sodium bicarbonate (20 mL), and filtered through a pad
of Celite. The filtrate was extracted with Et2O (3 × 40 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 40% EtOAc in
hexanes) on silica gel (80 mL) to afford I-52 (1.46 g, 92%) as a colorless oil.
Data for I-52: Rf = 0.38 (30% EtOAc in hexanes); [α]D21
= +10.6 (CH2Cl2, c = 1.30); IR (neat):
3436, 2923, 2854, 1720, 1454, 1379, 1343, 1254, 1112, 1057, 1027 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.52–7.47 (m, 4H), 7.39–7.33 (m, 6H), 5.57 (s, 1H), 5.51 (s, 1H), 4.17–4.07 (m, 3H),
4.05–3.99 (m, 2H), 3.89–3.82 (m, 2H), 2.19–2.12 (m, 2H), 1.97–1.89 (m, 1H), 1.88–1.82 (m,
1H), 1.80–1.69 (m, 2H), 1.66–1.60 (m, 2H), 1.58–1.44 (m, 4H), 1.28–1.25 (m, 26H), 0.90 (s,
9H), 0.89 (t, J = 7.6 Hz, 3H), 0.06 (s, 6H); 13
C NMR (100 MHz, CDCl3) δ 139.0, 138.6, 128.9,
84
128.7, 128.4, 128.3, 126.2, 100.9, 100.5, 76.2, 73.41, 73.35, 73.29, 68.0, 60.4, 43.5, 41.9, 38.4,
38.2, 37.6, 36.8, 32.1, 30.1, 29.86, 29.83, 29.81, 29.77, 29.5, 26.14, 26.08, 24.7, 22.9, 18.3, 14.3,
–4.0, –4.4; HRMS (ESI) calcd for C46H77O6Si [M H]+: 753.5489 Found: 753.5489.
2-((2R,4R,6R)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-phenyl-
1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-53)
To a stirred solution of I-52 (0.820 g, 1.09 mmol) in dichloromethane (8.0 mL) at 0 °C was
added Dess–Martin periodinane (0.693 g, 1.63 mmol). After 2 h at the same temperature, the
reaction was quenched by adding saturated aqueous sodium bicarbonate (20 mL) and sodium
sulfite (0.412 g, 3.27 mmol). The mixture was stirred at room temperature for 30 min, and
extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (5 to 30% EtOAc in hexanes) on silica gel (60 mL) to afford I-
53 (0.510 g, 62%) as a colorless oil.
Data for I-53: Rf = 0.44 (20% EtOAc in hexanes); [α]D20
= +16.6 (CH2Cl2, c =1.17); IR (neat):
2926, 2854, 1727, 1461, 1388, 1343, 1255, 1112, 1060, 1027 cm-1
; 1H NMR (400 MHz, CDCl3)
δ 9.87 (s, 1H), 7.52–7.46 (m, 4H), 7.39–7.32 (m, 6H), 5.60 (s, 1H), 5.51 (s, 1H), 4.47–4.41 (m,
1H), 4.20–4.14 (m, 1H), 4.11–4.06 (m, 1H), 4.06–3.99 (m, 2H), 2.83 (ddd, J = 17.2, 7.2, 2.0 Hz,
1H), 2.64 (ddd, J = 17.2, 4.8, 1.6 Hz, 1H), 2.16 (ddd, J = 14.4, 7.2. 7.2 Hz, 1H), 1.84–1.79 (m,
1H), 1.77–1.69 (m, 2H), 1.66–1.60 (m, 2H), 1.57–1.50 (m, 2H), 1.49–1.44 (m, 2H), 1.28–1.25
(m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.06 (s, 6H); 13
C NMR (100 MHz, CDCl3) δ
85
200.5, 139.0, 138.4, 129.0, 128.7, 128.4, 128.3, 126.2, 100.9, 100.5, 73.3, 73.26, 73.21, 72.1,
68.0, 49.6, 43.5, 41.9, 38.4, 37.6, 36.6, 32.1, 30.1, 29.87, 29.83, 29.78, 29.5, 26.1, 24.7, 22.9,
18.3, 14.3, –4.0, –4.4; HRMS (ESI) calcd for C46H75O6Si [M H]+: 751.5333 Found: 751.5338.
(R)-1-((2S,4S,6S)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-phenyl-
1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-ol (I-54):
To a stirred solution of I-53 (0.440 g, 0.586 mmol) in dichloromethane (4 mL) at –10 °C was
added a solution of (S,S)-Leighton reagent (0.650 g, 1.17 mmol) in dichloromethane (4 mL)
slowly via syringe, followed by scandium triflate (14.4 mg, 29.3 µmol) under N2. Then the
resulting mixture was transferred to freezer at –10 °C. After 12 h, the reaction was quenched by
adding 1 N hydrochloric acid (10 mL). The formed solid was filtered through a fritted funnel,
and the filtrate was extracted with EtOAc (3 × 40 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5 to 20% EtOAc in hexanes)
on silica gel (30 mL) to afford I-54 (0.440 g, 95%) as a colorless oil.
Data for I-54: Rf = 0.41 (20% EtOAc in hexanes); [α]D20
= +5.5 (CH2Cl2, c = 1.00); IR (neat):
3474, 2925, 2854, 1460, 1388, 1342, 1255, 1111, 1058, 1027 cm-1
; 1H NMR (400 MHz, CDCl3)
δ 7.50–7.47 (m, 4H), 7.38–7.32 (m, 6H), 5.89–5.79 (m, 1H), 5.57 (s, 1H), 5.50 (s, 1H), 5.16–
5.12 (m, 2H), 4.22–4.16 (m, 1H), 4.15–4.10 (m, 1H), 4.09–3.98 (m, 4H), 2.33–2.19 (m, 2H),
2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.83–1.62 (m, 8H), 1.54–1.43 (m, 3H), 1.28–1.25 (m,
26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13
C NMR (100 MHz, CDCl3) δ 139.1,
86
138.7, 134.9, 128.9, 128.7, 128.4, 128.3, 126.3, 118.3, 100.9, 100.5, 74.4, 73.5, 73.36, 73.32,
68.0, 67.2, 43.5, 42.5, 42.3, 42.0, 38.4, 37.7, 36.9, 32.1, 30.1, 29.89, 29.85, 29.8, 29.6, 26.2, 24.7,
22.9, 18.4, 14.3, –4.0, –4.3; HRMS (ESI) calcd for C49H81O6Si [M H]+: 793.5802 Found:
793.5804.
(R)-1-((2R,4R,6S)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-
phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-55):
To a stirred solution of I-54 (0.430 g, 0.542 mmol) in dichloromethane (2.0 mL) at room
temperature was added N,N'-dicyclohexylcarbodiimide (0.223 g, 1.08 mmol), followed by
acrylic acid (78 µL, 1.08 mmol) and 4-dimethylaminopyridine (3.3 mg, 27 µmol). The resulting
mixture was stirred at the same temperature for 20 h, diluted with Et2O (10 mL) and filtered
through filter paper. The filtrate was concentrated under reduced pressure. The crude residue was
purified by flash chromatography (2 to 15% EtOAc in hexanes) on silica gel (30 mL) to afford I-
55 (0.365 g, 80%) as a colorless oil.
Data for I-55: Rf = 0.32 (5% EtOAc in hexanes); [α]D21
= –9.7 (CH2Cl2, c = 0.53); IR (neat):
2926, 2854, 1725, 1454, 1405, 1341, 1255, 1192, 1112, 1050, 1027 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.52–7.49 (m, 4H), 7.39–7.31 (m, 6H), 6.40 (dd, J = 17.6, 1.6 Hz, 1H), 6.12 (dd, J =
17.6, 10.4 Hz, 1H), 5.82 (dd, J = 10.4, 1.6 Hz, 1H), 5.77 (dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H),
5.50 (s, 2H), 5.40–5.34 (m, 1H), 5.10–5.06 (m, 2H), 4.11–4.05 (m, 2H), 4.03–3.98 (m, 2H),
3.92–3.87 (m, 1H), 2.47–2.34 (m, 2H), 2.15 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.91 (ddd, J = 14.8,
9.6, 3.6 Hz, 1H), 1.81 (ddd, J = 14.8, 9.2, 3.2 Hz, 1H), 1.78–1.61 (m, 4H), 1.56–1.43 (m, 5H),
87
1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13
C NMR (100 MHz,
CDCl3) δ 165.9, 139.1, 138.7, 133.5, 130.8, 128.9, 128.7, 128.3, 126.2, 126.1, 118.3, 100.5,
100.4, 73.5, 73.4, 73.2, 70.2, 68.0, 43.5, 42.0, 40.3, 39.4, 38.4, 37.6, 37.2, 32.1, 30.1, 29.89,
29.85, 29.8, 29.6, 26.2, 24.7, 22.9, 18.3, 14.3, –4.0, –4.3; HRMS (ESI) calcd for C52H83O7Si [M
H]+: 847.5908 Found: 847.5912.
(R)-6-(((2R,4R,6S)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-
phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-5,6-dihydro-2H-pyran-2-
one (I-56):
To a stirred solution of I-55 (0.205 g, 0.242 mmol) in dichloromethane (25 mL) at room
temperature was added the Grubbs first-generation catalyst (10.0 mg, 12.1 µmol) under N2. The
resulting solution was degassed by two freeze−pump−thaw cycles, and then heated to reflux.
After 2 h, the mixture was cooled to room temperature, and dimethyl sulfoxide was added. The
stirring was then continued for another 2 h. The mixture was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 40% EtOAc in
hexanes) on silica gel (30 mL) to afford I-56 (0.151 g, 76%) as a colorless oil.
Data for I-56: Rf = 0.20 (20% EtOAc in hexanes); [α]D20
= +14.1 (CH2Cl2, c = 0.96); IR (neat):
2926, 2854, 1725, 1517, 1461, 1382, 1343, 1249, 1112, 1059, 1027 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.52–7.47(m, 4H), 7.39–7.31 (m, 6H), 6.88 (ddd, J = 9.6, 5.6, 3.2 Hz, 1H), 6.03 (d, J =
9.6 Hz, 1H), 5.59 (s, 1H), 5.51 (s, 1H), 4.83–4.76 (m, 1H), 4.30–4.25 (m, 1H), 4.17–4.11 (m,
1H), 4.10–4.06 (m, 1H), 4.06–3.98 (m, 2H), 2.42–2.29 (m, 2H), 2.15 (ddd, J = 14.0, 6.8, 6.8 Hz,
88
1H), 1.98 (ddd, J = 14.4, 9.6, 2.0 Hz, 1H), 1.88 (ddd, J = 14.4, 10.4, 2.8 Hz, 1H), 1.79–1.71 (m,
3H), 1.65–1.62 (m, 1H), 1.57–1.45 (m, 5H), 1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6
Hz, 3H), 0.05 (s, 6H); 13
C NMR (100 MHz, CDCl3) δ 164.5, 145.3, 139.0, 138.7, 128.9, 128.7,
128.4, 128.3, 126.24, 126.20, 121.6, 100.7, 100.5, 74.1, 73.35, 73.31, 72.2, 68.0, 43.5, 42.0, 41.8,
38.4, 37.7, 37.2, 32.1, 30.1, 30.0, 29.89, 29.85, 29.8, 29.6, 26.2, 24.7, 22.9, 18.3, 14.3, –4.0, –
4.3; HRMS (ESI) calcd for C50H79O7Si [M H]+: 819.5595 Found: 819.5602.
(R)-1-((2R,4R,6S)-6-(((2R,4R,6R)-6-((S)-2-hydroxyheptadecyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-57):
To a flask with I-55 (0.150 g, 0.177 mmol) was added a solution of tetra-n-butylammonium
fluoride (1 M, 3.5 mL, 3.5 mmol) at room temperature. The resulting mixture was stirred at the
same temperature for 3 h. The reaction was quenched by adding saturated aqueous sodium
bicarbonate (10 mL), and extracted with Et2O (3 × 30 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5 to 30% EtOAc in hexanes)
on silica gel (30 mL) to afford I-57 (0.120 g, 92%) as a colorless oil.
Data for I-57: Rf = 0.37 (20% EtOAc in hexanes); [α]D21
= –17.2 (CH2Cl2, c = 0.30); IR (neat):
3497, 2924, 2853, 1724, 1553, 1454, 1405, 1342, 1269, 1193, 1113, 1027 cm-1
; 1H NMR (400
MHz, CDCl3) δ 7.51–7.47 (m, 4H), 7.38–7.32 (m, 6H), 6.40 (dd, J = 18.0, 1.6 Hz, 1H), 6.12 (d, J
= 18.0, 10.4 Hz, 1H), 5.82 (d, J = 10.4, 1.6 Hz, 1H), 5.77 (dddd, J = 17.6, 10.0, 7.2, 7.2 Hz, 1H),
5.55 (s, 1H), 5.49 (s, 1H), 5.37 (dddd, J = 9.2, 5.6, 5.6, 3.6, 1H), 5.10–5.06 (m, 2H), 4.22-4.05
89
(m, 3H), 3.98–3.86 (m 2H), 2.47–2.33 (m, 2H), 2.16 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.90 (ddd,
J = 14.0, 9.6, 3.2 Hz, 1H), 1.83–1.73 (m, 3H), 1.71–1.62 (m, 4H), 1.53–1.43 (m, 3H), 1.28–1.25
(m, 26H), 0.88 (t, J = 7.2 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 165.9, 138.72, 138.69, 133.5,
130.9, 128.93, 128.89, 128.7, 128.4, 128.3, 126.2, 126.1, 118.3, 100.9, 100.4, 74.6, 73.5, 73.4,
73.1, 70.2, 68.4, 42.6, 41.9, 40.3, 39.4, 38.0, 37.2, 36.7, 32.1, 29.89, 29.86, 29.83, 29.81, 29.6,
25.9, 22.9, 14.3, 14.2; HRMS (ESI) calcd for C46H69O7 [M H]+: 733.5043 Found: 733.5043.
(R)-1-((2R,4R,6S)-6-(((2S,4R,6S)-6-((S)-2-acetoxyheptadecyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-58):
To a stirred solution of I-57 (0.115 g, 0.157 mmol) in dichloromethane (0.6 mL) at 0 °C was
added triethylamine (66 µL, 0.471 mmol), followed by 4-dimethylaminopyridine (2.0 mg, 16
µmol) and acetic anhydride (30 µL, 0.314 mmol). The resulting mixture was stirred at the same
temperature for 1 h. The reaction was quenched by adding methanol (0.1 mL), and diluted with
Et2O (20 mL). The mixture was washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography (5
to 20% EtOAc in hexanes) on silica gel (25 mL) to afford I-58 (87.0 mg, 72%) as a colorless oil.
Data for I-58: Rf = 0.42 (15% EtOAc in hexanes); [α]D22
= –10.9 (CH2Cl2, c = 0.75); IR (neat):
2924, 2854, 1726, 1453, 1405, 1371, 1241, 1193, 1146, 1113, 1023 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.52–7.50 (m, 4H), 7.39–7.32 (m, 6H), 6.40 (dd, J = 17.2, 1.6 Hz, 1H), 6.12 (dd, J =
17.2, 10.4 Hz, 1H), 5.82 (dd, J = 10.4, 1.2 Hz, 1H), 5.77 (dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H),
5.50 (s, 2H), 5.37 (dddd, J = 9.2, 6.0, 6.0, 3.6 Hz, 1H), 5.21 (dddd, J = 9.2, 6.4, 6.4, 3.6 Hz, 1H),
90
5.10–5.06 (m, 2H), 4.12–4.05 (m, 2H), 3.92–3.83 (m, 2H), 2.47–2.33 (m, 2H), 2.16 (ddd, J =
14.4, 7.2, 7.2 Hz, 1H), 2.04 (s, 3H), 1.94–1.87 (m, 2H), 1.85–1.79 (m, 2H), 1.78–1.71 (m, 2H),
1.66–1.62 (m, 2H), 1.60–1.48 (m, 3H), 1.26–1.23 (m, 26H), 0.88 (t, J = 7.6 Hz, 3H); 13
C NMR
(100 MHz, CDCl3) δ 170.9, 165.8, 138.75, 138.71, 133.4, 130.8, 128.9, 128.72, 128.69, 128.33,
128.31, 126.16, 126.14, 118.3, 100.4, 73.7, 73.5, 73.1, 71.2, 70.2, 41.9, 40.8, 40.3, 39.4, 37.2,
35.1, 32.1, 29.88, 29.86, 29.76, 29.71, 29.6, 25.3, 22.9, 21.5, 14.3; HRMS (ESI) calcd for
C48H71O8 [M H]+: 775.5149 Found: 775.5156.
(S)-1-((2S,4S,6R)-6-(((2R,4S,6R)-6-(((R)-6-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-2-
phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-59):
To a stirred solution of I-58 (80 mg, 0.103 mmol) in dichloromethane (12 mL) at room
temperature was added the Grubbs first-generation catalyst (8.5 mg, 10 µmol) under N2. The
resulting solution was degassed by two freeze−pump−thaw cycles, and then heated to reflux.
After 2 h, the mixture was cooled to room temperature, and dimethyl sulfoxide was added. The
stirring was then continued for another 2 h. The mixture was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 40% EtOAc in
hexanes) on silica gel (25 mL) to afford I-59 (54 mg, 70%) as a colorless oil.
Data for I-59: Rf = 0.38 (40% EtOAc in hexanes); [α]D22
= +11.8 (CH2Cl2, c = 0.55); IR (neat):
2924, 2853, 1736, 1453, 1377, 1343, 1244, 1140, 1118, 1058, 1025 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 7.52–7.47 (m, 4H), 7.39–7.32 (m, 6H), 6.88 (ddd, J = 9.6, 5.6, 3.2 Hz, 1H), 6.03 (ddd,
J = 9.6, 1.6, 1.6 Hz, 1H), 5.58 (s, 1H), 5.50 (s, 1H), 5.21 (dddd, J = 9.6, 6.8, 6.8, 3.6 Hz, 1H),
4.83–4.76 (m, 1H), 4.30–4.25 (m, 1H), 4.16–4.06 (m, 2H), 3.90–3.84 (m, 1H), 2.40–2.30 (m,
91
2H), 2.16 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 2.04 (s, 3H), 1.97 (ddd, J = 14.8, 9.6, 2.0 Hz, 1H),
1.91–1.82 (m, 2H), 1.80–1.69 (m, 3H), 1.65–1.49 (m, 5H), 1.26–1.23 (m, 26H), 0.88 (t, J = 7.6
Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 170.8, 164.5, 145.3, 138.7, 128.9, 128.7, 128.4, 128.3,
126.3, 126.1, 121.6, 100.7, 100.4, 74.1, 73.7, 73.2, 73.0, 72.2, 71.2, 41.9, 41.7, 40.8, 37.2, 35.1,
32.1, 30.1, 29.87, 29.83, 29.76, 29.71, 29.5, 25.3, 22.9, 21.5, 14.3; HRMS (ESI) calcd for
C46H67O8 [M H]+: 747.4836 Found: 747.4833.
(3S,5S,7R,9R,11S)-hexacosane-1,3,5,7,9,11-hexaol (I-60):
To a flask with I-52 (22.3 mg, 29.6 µmol) was added a solution of acetic acid (1 mL, 80%) in
water. The resulting mixture was heated to 80 °C and stirred for 1 h. The solvent was removed
under reduced pressure. The crude residue was purified by flash chromatography (2.5 to 7.5%
MeOH in EtOAc) on silica gel (4 mL) to afford I-60 (9.0 mg, 65%) as a white amorphous solid.
Data for I-60: Rf = 0.27 (10% MeOH in EtOAc); [α]D21
= +2.8 (MeOH, c = 0.20); IR (neat):
3356, 2923, 2851, 1728, 1552, 1510, 1467, 1379, 1260, 1095, 1037 cm-1
; 1H NMR (500 MHz,
CD3OD) δ 4.04–3.95 (m, 3H), 3.93 (ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 3.82–3.77 (m, 1H), 3.69 (t, J
= 7.0 Hz, 2H), 1.75–1.70 (m, 1H), 1.69–1.53 (m, 7 H), 1.52–1.49 (m, 2H), 1.47–1.40 (m, 2H),
1.28–1.25 (m, 26H), 0.89 (t, J = 7.0 Hz, 3H); 13
C NMR (125 MHz, CD3OD) δ 70.22, 70.16,
69.1, 68.9, 68.2, 60.1, 46.0, 45.8, 45.5, 45.3, 41.0, 39.3, 33.1, 30.9, 30.84, 30.82, 30.5, 26.8, 23.8,
14.5; HRMS (ESI) calcd for C26H55O6 [M H]+: 463.3999 Found: 463.3997.
92
(S)-1-((2S,4S,6R)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-
yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-61):
To a stirred solution of I-50 (89.0 mg, 0.117 mmol) in dichloromethane (1 mL) at 0 °C was
added pyridine (47 µL, 0.585 mmol), followed by acetic anhydride (17 µL, 0.176 mmol) and 4-
dimethylaminopyridine (1.0 mg, 8.2 µmol). The mixture was stirred at the same temperature for
5 h. The reaction was quenched by adding water (10 mL), and extracted with EtOAc (3 × 20
mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude residue was purified by flash
chromatography (5 to 20% EtOAc in hexanes) on silica gel (25 mL) to afford I-61 (92.0 g, 98%)
as a colorless oil.
Data for I-61: Rf = 0.33 (20% EtOAc in hexanes); [α]D22
= –2.4 (CH2Cl2, c = 1.30); IR (neat):
2923, 2853, 1737, 1513, 1453, 1372, 1342, 1245, 1112, 1026 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 7.52–7.46 (m, 4H), 7.38–7.32 (m, 6H), 7.26 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 5.53
(s, 1H), 5.50 (s, 1H), 5.22 (dddd, J = 10.0, 7.0, 7.0, 3.5 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.43
(d, J = 12.0 Hz, 1H), 4.13–4.03 (m, 3H), 3.90–3.85 (m, 1H), 3.78 (s, 3H), 3.68 (ddd, J = 9.0, 8.5,
5.5 Hz, 1H), 3.58 (ddd, J = 9.5, 5.5, 5.5 Hz, 1H), 2.16 (ddd, J = 14.5, 7.0, 7.0 Hz, 1H), 2.05 (s,
3H), 1.96–1.90 (m, 1H), 1.88–1.83 (m, 2H), 1.78–1.72 (m, 2H), 1.71–1.68 (m, 1H), 1.65–1.62
(m, 1H), 1.59–1.48 (m, 4H), 1.28–1.25 (m, 26H), 0.89 (t, J = 7.5 Hz, 3H); 13
C NMR (125 MHz,
CDCl3) δ 170.8, 159.3, 139.0, 138.8, 130.7, 129.5, 128.7, 128.6, 128.32, 128.29, 126.2, 126.1,
114.0, 100.7, 100.4, 74.0, 73.7, 73.3, 73.1, 72.8, 71.2, 65.8, 55.4, 42.0, 40.8, 37.2, 37.1, 36.3,
93
35.1, 32.1, 29.88, 29.85, 29.84, 29.76, 29.71, 29.5, 25.3, 22.9, 21.5, 14.3; HRMS (ESI) calcd for
C50H73O8 [M H]+: 801.5305 Found: 801.5286.
(S)-1-((2S,4S,6R)-6-(((2S,4S,6S)-6-(2-hydroxyethyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-2-
phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-62):
To a stirred solution of I-61 (90.0 mg, 0.112 mmol) in dichloromethane (2.0 mL) at 0 °C was
added water (0.1 mL), followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (76.5 mg, 0.337
mmol) under N2. The resulting mixture was stirred at the same temperature for 2 h. The reaction
was quenched by adding saturated aqueous sodium bicarbonate (10 mL), and filtered through a
pad of Celite. The filtrate was extracted with EtOAc (3 × 15 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 40% EtOAc in
hexanes) on silica gel (20 mL) to afford I-62 (55 mg, 72%) as a colorless oil.
Data for I-62: Rf = 0.27 (40% EtOAc in hexanes); [α]D21
= +11.5 (CH2Cl2, c = 0.95); IR (neat):
3436, 2924, 2854, 1737, 1453, 1374, 1342, 1242, 1113, 1026 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 7.52–7.48 (m, 4H), 7.39–7.32 (m, 6H), 5.57 (s, 1H), 5.50 (s, 1H), 5.21 (dddd, J = 9.5, 6.5, 6.5,
3.5 Hz, 1H), 4.17–4.06 (m, 3H), 3.89–3.81 (m, 3H), 2.16 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 2.15–
2.10 (m, 1H ), 2.05 (s, 3H), 1.94–1.88 (m, 1H), 1.87–1.79 (m, 2H), 1.78–1.69 (m, 3H), 1.65–1.48
(m, 4H), 1.28–1.25 (m, 26H), 0.88 (t, J = 6.8 Hz, 3H); 13
C NMR (125 MHz, CDCl3) δ 170.9,
138.7, 138.6, 129.0, 128.7, 128.5, 128.3, 126.2, 126.1, 100.9, 100.4, 76.3, 73.7, 73.4, 73.1, 71.2,
94
60.5, 41.8, 40.8, 38.2, 37.2, 36.8, 35.1, 32.1, 29.88, 29.85, 29.76, 29.71, 29.5, 25.3, 22.9, 21.5,
14.3; HRMS (ESI) calcd for C42H65O7 [M H]+: 681.4730 Found: 681.4708.
(3S,5S,7S,9S,11S)-1,3,5,7,9-pentahydroxyhexacosan-11-yl acetate (I-63):
To a flask with I-62 (18.0 mg, 26.4 µmol) was added a solution of acetic acid (1 mL, 80%) in
water. The resulting mixture was heated to 80 °C and stirred for 1 h. The solvent was removed
under reduced pressure. The crude residue was purified by flash chromatography (0 to 5%
MeOH in EtOAc) on silica gel (4 mL) to afford I-63 (9.2 mg, 69%) as a white amorphous solid.
Data for I-63: Rf = 0.40 (10% MeOH in EtOAc); [α]D21
= +9.4 (MeOH, c = 0.34); IR (neat):
3356, 2918, 2850, 1737, 1468, 1376, 1245, 1088, 1054, 1024 cm-1
; 1H NMR (500 MHz,
CD3OD) δ 5.07 (dddd, J = 10.0, 7.0, 7.0, 3.0 Hz, 1H), 4.00–3.90 (m, 3H), 3.77 (dddd, J = 9.5,
8.0, 5.0, 3.0 Hz, 1H), 3.69 (t, J = 7.0 Hz, 1H), 2.03 (s, 3H), 1.75–1.69 (m, 2H), 1.67–1.53 (m,
10H), 1.28–1.25 (m, 26H), 0.89 (t, J = 7.0 Hz, 3H); 13
C NMR (125 MHz, CD3OD) δ 173.1, 72.9,
70.1, 69.9, 68.9, 67.5, 60.1, 45.8, 45.5, 45.3, 43.3, 41.0, 36.0, 33.1, 30.8, 30.73, 30.69, 30.6, 30.5,
26.4, 23.8, 21.2, 14.5; HRMS (ESI) calcd for C28H57O7 [M H]+: 505.4104 Found: 505.4114.
(2R,4R,6S,8S,10S)-2,4,6,8-tetrahydroxy-1-((R)-6-oxotetrahydro-2H-pyran-2-yl)pentacosan-
10-yl acetate (I-64):
To a stirred solution of I-10 (7.6 mg, 13 µmol) in EtOAc (0.5 mL) at room temperature was
added Pd/C (10% wt/wt, 2.8 mg, 2.6 µmol) under N2. The resulting mixture was stirred under H2
95
(1 atm). After 2 h, the mixture was filtered through filter paper and washed with EtOAc (3 × 5
mL). The filtrate was concentrated under vacuum. The crude residue was purified by flash
chromatography (1 to 5% MeOH in EtOAc) on silica gel (4 mL) to afford I-64 (5.0 mg, 66%) as
a colorless oil.
Data for I-64: Rf = 0.36 (5% MeOH in EtOAc); [α]D22
= –8.7 (MeOH, c = 0.37); IR (neat): 3387,
2919, 2851, 1732, 1467, 1442, 1375, 1246, 1109, 1082, 1048 m-1
; 1H NMR (500 MHz, CD3OD)
δ 5.07 (dddd , J = 9.5, 6.5, 6.5, 3.0 Hz, 1H), 4.60 (dddd, J = 10.5, 10.5, 3.0, 3.0 Hz, 1H), 4.06
(dddd, J = 9.5, 7.0, 7.0, 2.5 Hz, 1H), 4.00–3.93 (m, 2H), 3.78 (dddd, J = 9.5, 8.5, 5.5, 3.0 Hz,
1H), 2.59 (ddd, J = 17.5, 7.0, 7.0 Hz, 1H), 2.43 (ddd, J = 17.5, 7.5, 7.5 Hz, 1H), 2.03 (s, 3H),
1.95–1.87 (m, 3H), 1.80 (ddd, J = 14.5, 10.0, 2.5 Hz, 1H), 1.71 (ddd, J = 14.5, 9.5, 3.0 Hz, 1H),
1.66 (ddd, J = 14.0, 4.5, 4.5 Hz, 1H), 1.63–1.50 (m, 10H), 1.28–1.25 (m, 26H), 0.89 (t, J = 8.0
Hz, 3H); 13
C NMR (100 MHz, CD3OD) δ 175.0, 173.1, 78.9, 72.8, 69.89, 69.85, 67.5, 66.8, 45.9,
45.8, 45.2, 45.0, 43.2, 36.0, 33.1, 30.8, 30.74, 30.70, 30.6, 30.5, 30.2, 29.4, 26.3, 23.8, 21.2, 19.4,
14.5; HRMS (ESI) calcd for C32H61O8 [M H]+: 573.4366 Found: 573.4373.
96
Position cryptocaryol A (reported)* cryptocaryol A (synthesized) *δH
3 5.97 (dd, 9.8, 1.9) 5.97 (dd, 9.6, 2.5),
4 7.04 (ddd, 9.8, 6.0, 2.3) 7.04 (ddd, 9.6, 6.0, 2.8),
5a 2.45 (m) 2.45 (ddd, 19.2, 5.2, 5.2),
5b 2.36 (ddt, 18.5, 11.8, 2.6) 2.36 (dddd, 19.2, 11.6, 2.8, 2.8),
6 4.71 (m) 4.74–4.67 (m)
7a 1.94 (ddd, 14.5, 9.7, 2.3) 1.94 (ddd, 14.8, 9.6, 2.8)
7b 1.67 (m) 1.71–1.55 (m)
8 4.08 (m) 4.09 (dddd, 8.8, 6.4, 6.4, 2.4)
9 1.68 (m) 1.71–1.55 (m)
10 3.97 (m) 4.04–3.96 (m)
11 1.63 (m) 1.71–1.55 (m)
12 4.00 (m) 4.04–3.96 (m)
13 1.59 (m) 1.71–1.55 (m)
14 4.02 (m) 4.04–3.96 (m)
15 1.50 (m) 1.52–1.49 (m)
16 3.79 (m) 3.82–3.77 (m)
17 1.43 (m) 1.46–1.40 (m)
18 1.32 (m) 1.32–1.25 (m)
19–28 1.29–1.27 (br m) 1.32–1.25 (m)
29 1.29 (m) 1.32–1.25 (m)
30 1.27 (m) 1.32–1.25 (m)
31 0.89 (t, 6.9) 0.89 (t, 6.8)
Table S1. 1H NMR assignments of reported cryptcocaryol A and synthesized cryptocaryol A.
*δH (multiplicity, coupling constant (J) in Hz)
97
Position cryptocaryol A (reported) δC cryptocaryol A (synthesized) δC
2 167.0 167.0
3 121.4 121.4
4 148.6 148.6
5 31.0 31.0
6 76.6 76.6
7 43.9 43.9
8 66.6 66.6
9 46.0 46.0
10 69.9 69.9
11 45.3 45.3
12 70.2 70.2
13 45.9 45.9
14 68.3 68.2
15 45.8 45.8
16 69.1 69.1
17 39.3 39.3
18 26.8 26.8
19–28 30.5–31.0 30.5–31.0
29 33.2 33.1
30 23.8 23.8
31 14.5 14.5
Table S2. 13
C NMR assignments of reported cryptcocaryol A and synthesized cryptocaryol A.
98
Position cryptocaryol B
(reported) *δH cryptocaryol B
(synthesized)*δH 6-epi-ent-cryptocaryol B *δH
3 5.97 (dd, 9.7, 1.8) 5.97 (dd, 9.6, 1.6) 5.98 (ddd, 9.6, 2.4)
4 7.04 (ddd, 9.7, 6.0, 2.4) 7.04 (ddd, 9.6, 5.6, 2.8) 7.05 (ddd, 9.6, 6.0, 2.4)
5a 2.45 (dt, 18.7, 4.9) 2.45 (ddd, 18.4, 5.2, 5.2) 2.54 (dddd, 18.8, 5.6, 4.0, 0.8)
5b 2.36 (ddt, 18.7, 11.6, 2.4) 2.36 (dddd, 18.4, 11.2, 2.8, 2.8) 2.39 (dddd, 18.8, 11.6, 2.4, 2.4)
6 4.70 (m) 4.74–4.67 (m) 4.68 (dddd, 10.4, 6.8, 6.8, 3.6)
7a 1.94 (ddd, 14.3, 9.8, 2.3) 1.94 (ddd, 14.4, 9.6, 2.8) 1.97 (ddd, 14.4, 7.2, 7.2) (7a or 7b)
7b 1.65 (m) 1.67–1.54 (m) 1.86 (ddd, 14.0, 6.4, 5.2) (7a or 7b)
8 4.08 (m) 4.08 (dddd, 9.2, 6.4, 6.4, 2.4) 4.02–3.93 (m)
9 1.62 (m) 1.67–1.54 (m) 1.67–1.56 (m)
10 3.96 (m) 4.01–3.92 (m) 4.02–3.93 (m)
11a 1.65 (m) 1.67–1.54 (m) 1.67–1.56 (m)
11b 1.57 (m) 1.67–1.54 (m) 1.67–1.56 (m)
12 3.96 (m) 4.01–3.92 (m) 4.02–3.93 (m)
13 1.62 (m) 1.67–1.54 (m) 1.67–1.56 (m)
14 3.78 (m) 3.81–3.75 (m) 3.81–3.77 (m)
15a 1.72 (ddd, 14.6,12.9, 3.0) 1.72 (ddd, 14.4, 9.2, 2.8) 1.75–1.68 (m)
15b 1.57 (m) 1.67–1.54 (m) 1.67–1.56 (m)
16 5.07 (m) 5.07 (dddd, 9.2, 6.4, 6.4, 2.8) 5.08 (dddd, 9.6, 6.4, 6.4, 2.8)
17 1.59 (m) 1.67–1.54 (m) 1.67–1.56 (m)
18–30 1.34–1.28 (br m) 1.28–1.25 (br m) 1.29–1.27 (br m)
31 0.89 (t, 7.0) 0.89 (t, 6.8) 0.90 (t, 6.8)
2' 2.03 (s) 2.03 (s) 2.04 (s)
Table S3. 1H NMR assignments of reported cryptcocaryol B, synthesized cryptocaryol B and 6-
epi-ent-cryptocaryol B. *δH (multiplicity, coupling constant (J) in Hz)
99
Position cryptocaryol B δC
1
(reported)
cryptocaryol B δC2 (δC
2–
δC1)
(synthesized)
6-epi-ent-cryptocaryol B
δC3 (δC
3– δC
1)
2 167.0 167.0 (0.0) 167.0 (0.0)
3 121.4 121.4 (0.0) 121.4 (0.0)
4 148.6 148.6 (0.0) 148.4 (–0.2)
5 31.0 31.0 (0.0) 30.8 (–0.2)
6 76.6 76.6 (0.0) 77.4 (0.8)
7 43.9 43.9 (0.0) 43.3 (–0.6)
8 66.6 66.6 (0.0) 67.5 (0.9)
9 45.8 45.8 (0.0) 45.4 (–0.4)
10 69.87 69.84 (–0.03) 69.77 (–0.1)
11 45.3 45.3 (0.0) 45.0 (–0.3)
12 69.93 69.91 (–0.02) 69.84 (–0.09)
13 45.9 45.9 (0.0) 45.9 (0.0)
14 67.5 67.5 (0.0) 67.6 (0.1)
15 43.3 43.3 (0.0) 43.1 (–0.2)
16 72.9 72.9 (0.0) 72.9 (0.0)
17 36.0 36.0 (0.0) 36.0 (0.0)
18 26.4 26.3 (–0.1) 26.3 (–0.1)
19–28 31.0–30.5 31.0–30.5 (0.0) 30.8–30.2 (–0.3)
29 33.1 33.1 (0.0) 33.1 (0.0)
30 23.8 23.8 (0.0) 23.8 (0.0)
31 14.5 14.5 (0.0) 14.5 (0.0)
1' 173.2 173.1 (–0.1) 173.1 (–0.1)
2' 21.2 21.2 (0.0) 21.2 (0.0)
Table S4. 13
C NMR assignments of reported cryptocaryol B, synthesized cryptocaryol B and 6-
epi-ent-cryptocaryol B.
100
(S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (II-1)
To a stirred solution of II-25 (20.0 mg, 33.2 µmol) in acetic formic anhydride (1.5 mL) at room
temperature was added Pd/C (10% wt/wt, 3.5 mg, 3.3 µmol) under N2. The resulting mixture was
stirred under H2 (1 atm) for 1h. The mixture was filtered through a pad of Celite, and washed
with EtOAc. The filtrate was concentrated under reduced pressure. The crude residue was
purified by flash chromatography (30% EtOAc in hexanes) on silica gel (2 mL) to afford II-1
(14.7 mg, 80%) as a colorless oil.
Data for II-1: Rf = 0.27 (30% EtOAc in hexanes); [α]D23
= –33.7 (CHCl3, c = 0.48); IR (neat)
3380, 2926, 2854, 1823, 1738, 1666, 1553, 1467, 1378, 1253, 1187, 1123 cm-1
; 1H NMR (500
MHz, CDCl3) δ 8.22 (s, 1H), 5.91 (d, J = 8.0 Hz, 1H), 5.05–5.00 (m, 1H), 4.69 (ddd, J = 9.0, 9.0,
5.0 Hz, 1H), 4.29 (ddd, J = 7.5, 5.0, 5.0 Hz, 1H), 3.22 (ddd, J = 7.5, 7.5, 4.0 Hz, 1H), 2.17 (ddd,
J = 15.0, 7.5, 7.5 Hz, 1H), 2.00 (ddd, J = 15.0, 4.5, 4.5 Hz, 1H), 1.84–1.78 (m, 1H), 1.77–1.63
(m, 4H), 1.61–1.53 (m, 2H), 1.47–1.41 (m, 1H), 1.32–1.24 (m, 25H), 0.972 (d, J = 6.5 Hz, 3H),
0.967 (d, J = 6.5 Hz, 3H), 0.885 (t, J = 6.5 Hz, 3H), 0.878 (t, J = 7.0, 3H); 13
C NMR (100 MHz,
CDCl3) δ 171.92, 170.75, 160.60, 74.76, 72.76, 57.03, 49.60, 41.56, 38.70, 34.05, 31.89, 31.47,
29.60, 29.53, 29.42, 29.33, 29.29, 28.96, 27.61, 26.70, 25.09, 24.88, 22.87, 22.68, 22.51, 21.73,
14.12, 14.01 (CDCl3, δ 77.0 ppm, for comparison with existing papers); MALDI-TOF/CCA-
HRMS calcd for C29H53NO5Na [M Na]+: 518.3816, found 518.3814.
101
Position J. Antibiot.
1987, 1086 This Work
J. Org. Chem.
2012, 4885
Org. Lett. 2010,
1556
J. Org. Chem.
2009, 4508
Synthesis
2006, 3888
Org. Lett.
2006, 4497
CHO
(1H)
8.21 (s) 8.22 (s) 8.22 (s) 8.22 (s) 8.22 (s) 8.23 (s) 8.23 (s)
8.07 (d, 12) 8.06 (d, 11.5)
2''-NH
(1H) 6.43 (d, 9) 5.91 (d, 8.5) 5.90 (d, 8.5) 5.96 (d, 8.4) 5.91 (d, 8.1) 6.05 (d, 8.5) 5.92 (d, 8.7)
5
(1H) 5.03 (m) 5.03–5.00 (m)
5.03 (dddd, 7.0,
6.5, 5.5, 4.0)
5.06–4.99 (m,
1H) 5.05–5.00 (m) 5.02 (m, 1H) 5.10–4.98 (m)
2''
(1H)
4.68 (ddd, 9, 9,
5)
4.69 (ddd, 9.0, 9.0,
5.0)
4.69 (ddd, 13.0,
8.5, 4.0)
4.68 (td, 8.7,
4.1) 4.71–4.66 (m) 4.68 (m,1H)
4.70 (dt, 8.4,
4.8)
3
(1H)
4.32 (ddd, 9, 5,
4)
4.29 (ddd, 7.5, 5.0,
5.0)
4.29 (ddd, 8.0,
4.5, 4.5)
4.32–4.27 (m,
1H)
4.29(dt, 7.3,
4.7) 4.28 (m, 1H)
4.23 (ddd, 8.4,
4.2, 3.9)
2
(1H)
3.24 (ddd, 7.5,
7.5, 4)
3.22 (ddd, 7.5, 7.5,
4.0)
3.21 (ddd, 11.5,
4.5, 4.0 )
3.22 (ddd, 7.9,
7.2, 4.1)
3.22 (dt, 7.1,
3.2)
3.22 (dt, 7.6,
3.9)
3.28 (dt, 7.2,
3.9)
4, 4a
(2H)
1.9–2.25 (m,
2H)
2.17 (ddd, 15.0,
7.5, 7.5)
2.16 (dt, 15.0,
8.0, 7.0)
2.21–2.12 (m,
1H)
2.15–2.10 (m,
1H)
2.25–2.11 (m,
1H)
2.24–1.96 (m,
2H)
2.00 (ddd, 15.0,
4.5, 4.5)
2.01 (dt, 15.0,
4.5, 4.0)
1.99 (ddd, 14.9,
4.7, 4.1)
2.08–2.00 (m,
1H) 2.02 (m, 1H)
CH2
(33H) 1.15–1.85 (m) 1.84–1.78 (m, 1H)
1.85–1.50 (m,
6H)
1.86–1.49 (m,
7H)
1.85–1.51 (m,
7H)
1.80–1.15 (m,
33H)
1.85–1.53 (m,
5H)
1.77–1.63 (m, 4H)
1.61–1.53 (m, 2H)
1.47–1.41 (m, 1H) 1.50–1.15 (m,
27H)
1.49–1.03 (m,
26H)
1.41–1.15 (m,
26H)
1.27 (br s,
26H)
1.32–1.24 (m,
25H)
5'', 5'''
(6H)
0.97 (d, 6, 6H) 0.972 (d, 6.5, 3H) 1.05–0.82 (m,
12H)
0.97 (dd, 6.1,
2.5, 6H) 0.96 (t, 6.3, 6H)
0.95 (d, 5.2,
6H)
0.98 (dd, 6.3,
1.5, 6H)
0.967 (d, 6.5, 3H)
16, 6'
(6H) 0.89 (t, 7, 6H) 0.885 (t, 6.5, 3H) 0.89 (t, 6.9, 3H) 0.89 (t, 6.5, 6H)
0.87 (distorted
t, 6H)
0.89 (t, 6.6,
3H)
0.878 (t, 7.0, 3H) 0.88 (t, 6.9, 3H)
Table S5. 1H NMR assignments of THL. *δH (multiplicity, coupling constant (J) in Hz)
102
Position J. Antibiot.
1987, 1086
This
Work
J. Org. Chem.
2012, 4885
Org. Lett.
2010, 1556
J. Org. Chem.
2009, 4508
Synthesis
2006, 3888
Org. Lett.
2006, 4497
1, 1'' 171.93 171.92 171.9 171.9 171.9 171.9 172.2
170.73 170.75 170.7 170.7 170.7 170.8 171.0
1''' 160.83 160.60 160.6 160.6 160.5 160.7 160.8
3, 5 74.74 74.76 74.7 74.7 74.7 74.8 75.0
72.63 72.76 72.7 72.7 72.7 72.6 73.0
2, 2'' 57.07 57.03 57.0 57.0 57.0 56.9 57.3
49.76 49.60 49.6 49.6 49.6 49.7 49.9
4, 6, 9
12, 13,
14, 1', 2',
3' 4', 3'',
41.44 41.56 41.5 41.5 41.5 41.4 41.8
38.73 38.70 38.7 38.7 38.7 38.7 38.9
34.07 34.05 34.0 34.0 34.0 34.0 34.3
31.93 31.89 31.9 31.9 31.8 31.9 32.1
31.51 31.47 31.4 31.4 31.4 31.2 32.0
29.63 29.60 29.6 29.6 29.6 29.6 29.93
29.63 29.60 29.71
29.57 29.53 29.5 29.5 29.5 29.65
29.46 29.42 29.4 29.4 29.4 29.4 29.56
29.35 29.33 29.3 29.3 29.3 29.3 29.51
29.35 29.29 29.3 29.2 29.2 29.49
7, 8, 10,
11
28.99 28.96 28.9 28.9 28.9 28.8 29.40
27.67 27.61 27.6 27.6 27.6 27.7 27.8
26.73 26.70 26.7 26.7 26.6 26.8 27.0
25.12 25.09 25.1 25.0 25.0 25.2 25.3
4'' 24.93 24.88 24.9 24.8 24.8 24.9 25.1
5'' or 5''' 22.87 22.87 22.8 22.8 22.8 22.8 23.1
15, 5' 22.69 22.68 22.7 22.6 22.6 22.7 22.89
22.53 22.51 22.5 22.5 22.5 22.5 22.86
5'' or 5''' 21.78 21.73 21.7 21.7 21.7 21.7 22.0
16, 6' 14.10 14.12 14.1 14.1 14.1 14.1 14.3
14.00 14.01 14.0 14.0 14.0 14.0
unknown 21.9 25.8
Table S6. 13
C NMR assignments of THL.
Notes: 1) Residual solvent signal was used as reference: CDCl3 δc 77.0 ppm. (77.23 ppm for Org. Lett. 2006,
4497)
2) The paper (J. Org. Chem. 2012, 4885) reported one extra peak at 21.9 ppm. The paper (J. Org. Chem.
2009, 4508) reported one extra peak at 25.8 ppm.
103
(3S,4S)-3-Hexyl-4-((S)-2-hydroxytridecyl)oxetan-2-one (II-4b)
To a stirred solution of II-24 (56.6 mg, 0.142 mmol) in dichloromethane (1.5 mL) at 0 °C was
added 1,2-ethanedithiol (36 µL, 0.426 mmol), followed by boron trifluoride diethyl etherate (18
µL, 0.142 mmol) under N2. The resulting mixture was stirred at the same temperature for 30 min.
The reaction was quenched by adding saturated aqueous sodium bicarbonate (5 mL), and
extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (5 to 15% EtOAc in hexanes) on silica gel (35 mL) to afford
II-4b (42.0 mg, 83%) as a white solid.
Data for II-4b: mp 60.5–62.0 °C; Rf = 0.39 (20% EtOAc in hexanes); [α]D22
= –10.4 (CHCl3, c =
0.42); IR (neat) 3544, 2956, 2922, 2851, 1816, 1726, 1467, 1101 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 4.47 (ddd, J = 6.0, 6.0, 4.5 Hz, 1H), 3.81–3.75 (m, 1H), 3.31 (ddd, J = 8.5, 6.5, 4.0 Hz,
1H), 2.01 (ddd, J = 14.5, 8.5, 7.5 Hz, 1H), 1.90 (ddd, J = 15.5, 6.0, 3.5 Hz, 1H), 1.84 (dddd, J =
13.5, 10.0, 6.5, 6.5 Hz, 1H), 1.74 (dddd, J = 14.0, 9.0, 9.0, 6.0 Hz, 1H), 1.61 (brs, 1H), 1.53–1.49
(m, 2H), 1.47–1.37 (m, 3H), 1.34–1.24 (m, 23H), 0.883 (t, J = 7.0 Hz, 3H), 0.878 (t, J = 7.0 Hz,
3H); 13
C NMR (100 MHz, CDCl3) δ 171.5, 76.4, 69.5, 57.0, 41.4, 37.9, 32.1, 31.7, 29.83, 29.81,
29.75, 29.70, 29.5, 29.1, 28.0, 27.0, 25.6, 22.9, 22.7, 14.3, 14.2; MALDI-TOF/CCA-HRMS
calcd for C22H42O3Na [M Na]+: 377.3026, found 377.3021.
68
104
(S)-2-((S)-2-(Methoxymethoxy)tridecyl)oxirane (II-6a)
To a stirred solution of II-11 (0.36 g, 1.49 mmol) in dichloromethane (7 mL) at 0 °C was added
chloromethyl methyl ether (0.17 mL, 2.23 mmol) under N2, followed by N,N-
diisopropylethylamine (0.61 mL, 3.73 mmol). The resulting mixture was stirred at the same
temperature for 24 h. The reaction was quenched by adding water (10 mL), and extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash chromatography (2.5 to 20% EtOAc in hexanes) on silica gel (30 mL) to afford 6a (0.380 g,
88%) as a colorless oil.
Data for II-6a: Rf = 0.33 (10% EtOAc in hexanes); [α]D23
= +0.2 (CH2Cl2, c = 1.18); IR (neat)
2922, 2853, 1466, 1260, 1149, 1098, 1036 cm-1
; 1H NMR (500 MHz, CDCl3) δ 4.67 (s, 2H),
3.73 (dddd, J = 6.0, 6.0, 6.0, 6.0 Hz, 1H), 3.38 (s, 3H), 3.05–3.01 (m, 1H), 2.76 (dd, J = 4.5, 4.5
Hz, 1H), 2.47 (dd, J = 5.0, 2.5 Hz, 1H), 1.79–1.70 (m, 2H), 1.64–1.53 (m, 2H), 1.39–1.22 (m,
18H), 0.87 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 95.5, 75.6, 55.8, 49.8, 46.9, 37.6,
34.7, 32.1, 29.89, 29.84, 29.81, 29.80, 29.5, 25.6, 22.9, 14.3; MALDI-TOF/CCA-HRMS calcd
for C17H34O3Na [M Na]+: 309.2400, found 309.2410.
(2R,3S)-2-Hexyl-3-((S)-2-(methoxymethoxy)tridecyl)oxirane (II-6b)
To a stirred solution of II-23 (0.211 g, 0.646 mmol) in dichloromethane (4 mL) at room
temperature was added chloromethyl methyl ether (98 µL, 1.29 mmol) under N2, followed by
105
N,N-diisopropylethylamine (0.267 mL, 1.62 mmol) and 4-dimethylaminopyridine (2 mg). The
resulting mixture was stirred at the same temperature for 24 h. The reaction was quenched by
adding water (10 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (3 to 15% EtOAc in hexanes)
on silica gel (30 mL) to afford II-6b (0.202 g, 85%) as a colorless oil.
Data for II-6b: Rf = 0.42 (10% EtOAc in hexanes); [α]D20
= +1.3 (CH2Cl2, c = 0.51); IR (neat)
2925, 2855, 1467, 1378, 1150, 1100, 1041 cm-1
; 1H NMR (400 MHz, CDCl3) δ 4.67 (s, 2H),
3.73 (dddd, J = 6.0, 6.0. 6.0, 6.0 Hz, 1H), 3.39 (s, 3H), 3.05 (ddd, J = 7.0, 4.5, 4.5 Hz, 1H), 2.92–
2.88 (m, 1H), 1.78 (ddd, J = 15.0, 5.0, 5.0 Hz, 1H), 1.70 (ddd, J = 15.0, 6.0, 6.0 Hz, 1H), 1.63–
1.55 (m, 2H), 1.52–1.47 (m, 3H), 1.38–1.24 (m, 25H), 0.88 (t, J = 6.5 Hz, 3H), 0.87 (t, J = 7.0
Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 95.5, 75.9, 56.7, 55.7, 54.3, 34.7, 33.0, 32.1, 32.0,
29.89, 29.84, 29.80, 29.5, 29.4, 28.2, 26.8, 25.6, 22.9, 22.8, 14.29, 14.24; MALDI-TOF/CCA-
HRMS calcd for C23H46O3Na [M Na]+: 393.3339, found 393.3350.
106
Chapter 2. Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio-
and Diastereoselective Carbonylation of Epoxyhomoallylic Alcohols
General Procedure for Carbonylation of Epoxides
In a nitrogen glove box, a 4 mL glass vial equipped with a Teflon-coated magnetic stir bar
was charged with the appropriate amount of [ClTPPAl]+[Co(CO)4]
− and tetrahydrofuran. The
vial was placed in the glove box freezer at –30 °C along with a custom-made, six-well high-
pressure reactor (see Section A: General Information) to cool for 30 minutes. (In the absence of
CO, isomerization of the epoxide to ketone products69
can be minimized by keeping the
temperature of the reactor below 0 °C.) The appropriate amount of epoxide (also cooled at –30
°C for 30 minutes) was then added to the vial. After adding a cap with a Teflon-coated septum
pierced by a 20 G needle (to prevent the reaction solvent from refluxing into the reactor
chamber), the vial was placed quickly into the reactor. Subsequently, the reactor was sealed,
taken out of the glove box, placed in a well-ventilated hood, and pressurized with carbon
monoxide (900 psi). The reactor was then heated to 50 °C and the reaction mixture stirred for the
specified time. The reactor was cooled on dry ice for 10 minutes and carefully vented in a fume
hood. The crude reaction mixture was concentrated under reduced pressure and then purified via
flash column chromatography or preparative HPLC.
(S)-Pentadec-1-en-4-ol (II-7a)
To a stirred solution of dodecanal II-8a (1.91 g, 10.4 mmol) in dichloromethane (30 mL) at 0 °C
was added a solution of (S,S)-Leighton reagent (7.91 g, 14.3 mmol) in dichloromethane (10 mL)
107
via syringe, followed by scandium triflate (128 mg, 0.260 mmol) under N2. The resulting mixture
was stirred at the same temperature for 8 h. The reaction was quenched by adding 1 N
hydrochloric acid (20 mL). The formed solid was filtered through a fritted funnel, and the filtrate
was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (2 to 10% EtOAc in hexanes) on silica gel (140
mL) to afford II-7a (1.87 g, 80%, ee = 96%) as a colorless oil.
Data for II-7a: Rf = 0.34 (10% EtOAc in hexanes); [α]D20
= –4.1 (CH2Cl2, c = 1.05); IR (neat)
3347, 2922, 2853, 1641, 1466, 1275 cm-1
; 1H NMR (400 MHz, CDCl3) δ 5.88–5.78 (m, 1H),
5.16–5.12 (m, 2H), 3.67–3.61 (m, 1H), 2.34–2.27 (m, 1H), 2.13 (ddd, J = 15.2, 7.6, 7.6 Hz, 1H),
1.56 (s, 1H), 1.49–1.42 (m, 3H), 1.34–1.24 (m, 17H), 0.88 (t, J = 6.8 Hz, 3H); 13
C NMR (100
MHz, CDCl3) δ 135.1, 118.3, 70.9, 42.1, 37.0, 32.1, 29.85, 29.82, 29.80, 29.5, 25.9, 22.9, 14.3.70
(S,Z)-Henicos-7-en-10-ol (II-7b)
To a stirred suspension of palladium/calcium carbonate (5% wt/wt, 30.4 mg, 14.3 µmol) in
methanol (5 mL) at room temperature was added quinoline (36.9 mg, 0.286 mmol). The mixture
was stirred at the same temperature for 0.5 h. A solution of II-21 (0.441 g, 1.43 mmol) in
methanol (2 mL) was added to the mixture. The resulting mixture was stirred under H2 (1 atm)
atmosphere. After 18 h, the mixture was concentrated. The crude residue was purified by flash
chromatography (2 to 8% EtOAc in hexanes) on silica gel (30 mL) to afford II-7b (0.425 g,
96%) as a colorless oil.
108
Data for II-7b: Rf = 0.31 (10% EtOAc in hexanes); [α]D21
= –2.0 (CH2Cl2, c = 1.82); IR (neat)
3341, 2955, 2921, 2853, 1465, 1378, 1275, 1127, 1080, 1030 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 5.60–5.54 (m, 1H), 5.43–5.37 (m, 1H), 3.61 (dddd, J = 6.0, 6.0, 6.0, 6.0 Hz, 1H), 2.23–2.20 (m,
2H), 2.07–2.02 (m, 2H), 1.52 (s, 1H), 1.49–1.42 (m, 3H), 1.37–1.22 (m, 25H), 0.88 (t, J = 7.0
Hz, 6H); 13
C NMR (100 MHz, CDCl3) δ 133.7, 125.3, 71.7, 37.0, 35.5, 32.1, 31.9, 29.88, 29.85,
29.82, 29.5, 29.2, 27.6, 26.0, 22.9, 22.8, 14.30, 14.27; HRMS (CI) calcd for C21H41O [M – 1]+:
309.3157, found 309.3153.
(R,Z)-Henicos-7-en-10-ol (ent-II-7b)
To a stirred suspension of palladium-calcium carbonate (5% wt/wt, 150 mg, 70.7 µmol) in
methanol (10 mL) at room temperature was added quinoline (182 mg, 1.47 mmol). The mixture
was stirred at the same temperature for 0.5 h. A solution of ent-II-21 (2.18 g, 7.07 mmol) in
methanol (2 mL) was added to the mixture. The resulting mixture was stirred under H2 (1 atm)
atmosphere. After 7 h, the mixture was concentrated. The crude residue was purified by flash
chromatography (2 to 8% EtOAc in hexanes) on silica gel (30 mL) to afford ent-II-7b (1.91 g,
87%) as a colorless oil.
Data for ent-II-7b: Rf = 0.31 (10% EtOAc in hexanes); [α]D21
= +1.8 (CH2Cl2, c = 1.92); IR
(neat) 3341, 2955, 2921, 2853, 1465, 1378, 1275, 1127, 1080, 1030 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 5.59–5.53 (m, 1H), 5.43–5.36 (m, 1H), 3.63 (dddd, J = 6.0, 6.0, 6.0, 6.0 Hz, 1H), 2.21
(t, J = 6.4 Hz, 2H), 2.07–2.02 (m, 2H), 1.62 (s, 1H), 1.49–1.42 (m, 3H), 1.36–1.22 (m, 25H),
0.87 (t, J = 6.8 Hz, 6H); 13
C NMR (100 MHz, CDCl3) δ 133.7, 125.3, 71.7, 37.0, 35.5, 32.1,
109
31.9, 29.88, 29.86, 29.82, 29.5, 29.2, 27.6, 26.0, 22.9, 22.8, 14.30, 14.28; HRMS (CI) calcd for
C21H41O [M – H]+: 309.3157, found 309.3153.
Pentadec-2-yn-4-one (II-8b)
To a stirred solution of II-8c (22.0 g, 90.2 mmol) in tetrahydrofuran (50 mL) at –15 °C was
added a solution of 1-propynylmagnesium bromide (0.5 M, 216 mL, 108 mmol) in
tetrahydrofuran via syringe slowly under N2. The resulting mixture was stirred at the same
temperature for 0.5 h. The reaction was quenched by adding saturated aqueous ammonium
chloride (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (2 to 5% EtOAc in hexanes)
on silica gel (350 mL) to afford II-8b (20.1 g, 99%) as a colorless oil.
Data for II-8b: Rf = 0.44 (10% EtOAc in hexanes); IR (neat) 2922, 2853, 2219, 1673, 1466,
1275, 1164 cm-1
; 1H NMR (400 MHz, CDCl3) δ 2.50 (t, J = 7.6 Hz, 2H), 2.00 (s, 3H), 1.67–1.58
(m, 2H), 1.30–1.20 (m, 16H), 0.86 (t, J = 6.8 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 188.6,
89.9, 80.4, 45.6, 32.1, 29.76, 29.75, 29.6, 29.5, 29.1, 24.2, 22.8, 14.3, 4.2; MALDI-TOF/CCA-
HRMS calcd for C15H26ONa+ [M Na]
+: 245.1876, found 245.1864.
110
N-Methoxy-N-methyldodecanamide (II-8c)
To a stirred solution of ethyl laurate (10.7 g, 46.9 mmol) in tetrahydrofuran (80 mL) at –15 °C
was added N,O-dimethylhydroxylamine hydrochloride (6.85 g, 70.3 mmol), followed by a
solution of isopropylmagnesium chloride in tetrahyrofuran (2 M, 47 mL, 94 mmol) via syringe
slowly under N2. The resulting mixture was stirred at the same temperature for 30 min. The
reaction was quenched by adding saturated aqueous ammonium chloride (100 mL) and extracted
with EtOAc (3 × 120 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (5 to 20% EtOAc in hexanes) on silica gel (200 mL) to afford
II-8c (10.2 g, 89%) as a colorless oil.
Data for II-8c: Rf = 0.29 (20% EtOAc in hexanes); IR (neat) 2925, 2854, 1672, 1466, 1414,
1383, 1177, 1119 cm-1
; 1H NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 3.18 (s, 3H), 2.41 (t, J = 7.2
Hz, 2H), 1.66–1.58 (m, 3H), 1.34–1.24 (m, 15H), 0.87 (t, J = 6.4 Hz, 3H); 13
C NMR (100 MHz,
CDCl3) δ 61.3, 32.0, 29.75, 29.64, 29.59, 29.57, 29.47, 24.8, 22.8, 14.2; MALDI-TOF/CCA-
HRMS calcd for C14H30NO2+ [M H]
+: 244.2271, found 244.2285.
71
(S)-tert-Butyl pentadec-1-en-4-yl carbonate (II-9)
To a stirred solution of II-7a (2.24 g, 9.89 mmol) in tetrahydrofuran (33 mL) at 0 °C was added
a solution of n-butyllithium (1.8 M, 5.9 mL, 10.6 mmol) in hexane via syringe slowly under N2.
After 15 min, a solution of di-tert-butyl dicarbonate (4.32 g, 19.8 mmol) in tetrahydrofuran (10
111
mL) was added via syringe slowly. The resulting mixture was stirred at 0 °C for 1.5 h, and
warmed to room temperature. The stirring was continued for 1.5 h. The reaction was quenched
by adding saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3 × 80
mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude residue was purified by flash
chromatography (1 to 4% EtOAc in hexanes) on silica gel (60 mL) to afford II-9 (3.02 g, 93%)
as a colorless oil.
Data for II-9: Rf = 0.22 (hexanes); [α]D22
= –13.7 (CH2Cl2, c = 1.44); IR (neat) 2923, 2854,
1737, 1466, 1368, 1253, 1164 cm-1
; 1H NMR (500 MHz, CDCl3) δ 5.78 (dddd, J = 17.0, 10.0,
7.0, 7.0 Hz, 1H), 5.11–5.05 (m, 2H), 4.68 (dddd, J = 7.0, 6.0, 6.0, 6.0 Hz, 1H), 2.35–2.32 (m,
2H), 1.60–1.53 (m, 2H), 1.47 (s, 9H), 1.31–1.24 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H); 13
C NMR
(100 MHz, CDCl3) δ 153.6, 133.9, 117.9, 81.8, 76.8, 38.9, 33.9, 32.1, 29.81, 29.73, 29.70, 29.6,
29.5, 28.0, 25.5, 22.9, 14.3; HRMS (ESI) calcd for C20H39O3 [M H]+: 327.2899, found
327.2907.
(4S,6S)-4-(Iodomethyl)-6-undecyl-1,3-dioxan-2-one (II-10)
To a stirred solution of II-9 (2.59 g, 7.93 mmol) in acetonitrile (25 mL) at –20 °C was added
iodine (6.03 g, 23.8 mmol) in one portion under N2. The resulting mixture was stirred at the same
temperature for 2.5 h. The reaction was quenched by adding water (40 mL), and extracted with
EtOAc (3 × 60 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
112
flash chromatography (5 to 25% EtOAc in hexanes) on silica gel (60 mL) to afford II-10 (2.12 g,
67%) as a white solid.
Data for II-10: mp 65–66 °C; Rf = 0.34 (20% EtOAc in hexanes); [α]D22
= –11.4 (CH2Cl2, c =
1.07); IR (neat) 3055, 2927, 2855, 1752, 1398, 1265, 1189, 1105 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 4.48–4.40 (m, 2H), 3.40 (dd, J = 10.4, 4.4 Hz, 1H), 3.25 (dd, J = 10.4, 7.2 Hz, 1H),
2.38 (ddd, J = 14.4, 3.2, 3.2 Hz, 1H), 1.80–1.71 (m, 1H), 1.69–1.59 (m, 2H), 1.55–1.44 (m, 1H),
1.42–1.36 (m, 1H), 1.35–1.25 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ
148.7, 78.7, 77.3, 35.3, 33.4, 32.1, 29.77, 29.67, 29.57, 29.50, 29.4, 24.6, 22.9, 14.3, 5.5;
MALDI-TOF/CCA-HRMS calcd for C16H29IO3Na [M Na]+: 419.1054, found 416.1059.
(S)-1-((S)-Oxiran-2-yl)tridecan-2-ol (II-11)
To a stirred solution of II-10 (0.58 g, 1.46 mmol) in methanol (20 mL) at room temperature was
added potassium carbonate (0.81 g, 5.85 mmol) in one portion. The resulting mixture was stirred
at the same temperature for 10 h. The reaction was quenched by adding water, and extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash chromatography (5 to 20% EtOAc in hexanes) on silica gel (30 mL) to afford 11 (0.350 g,
99%) as a colorless oil.
Data for II-11: Rf = 0.32 (20% EtOAc in hexanes); [α]D23
= –8.4 (CH2Cl2, c = 1.23); IR (neat)
3418, 2921, 2852, 1466, 1260, 1025 cm-1
; 1H NMR (500 MHz, CDCl3) δ 3.90–3.85 (m, 1H),
3.08 (dddd, J = 7.0, 4.0, 4.0, 3.0 Hz, 1H), 2.78 (dd, J = 4.5, 4.5 Hz, 1H), 2.49 (dd, J = 5.0, 2.5
Hz, 1H), 1.98 (br s, 1H), 1.84 (ddd, J = 14.5, 4.0, 4.0 Hz, 1H), 1.54–1.47 (m, 3H), 1.44–1.40 (m,
113
1H), 1.35–1.24 (m, 17H), 0.87 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 70.7, 50.9,
46.8, 39.9, 37.7, 32.1, 29.83, 29.78, 29.5, 25.7, 22.9, 14.3; MALDI-TOF/CCA-HRMS calcd for
C15H30O2Na [M Na]+: 265.2138, found 265.2124.
Methyl (3S,5S)-3-hydroxy-5-(methoxymethoxy)hexadecanoate (II-12)
According to a modified literature procedure:72
In a nitrogen glove box, an 8 mL glass vial
equipped with a Teflon-coated magnetic stir bar was charged with dicobalt octacarbonyl
(Co2(CO)8) (35.8 mg, 0.105 mmol, 10 mol %) and 3-hydroxypyridine (20.0 mg, 0.210 mmol, 20
mol %). Tetrahydrofuran (1.0 mL) was added to the vial, followed by (II-6a) (0.301 g, 1.05
mmol). After taking the vial out of the glove box, methanol (1.0 mL) was added to the vial and
the vial was placed quickly into a custom-made six-well high-pressure reactor. Subsequently, the
reactor was sealed, placed in a well-ventilated hood, purged three times with carbon monoxide,
and then pressurized to 900 psi. The reactor was then heated to 60 °C and the reaction mixture
was stirred for 16 hours. The reactor was cooled on dry ice for 10 minutes and carefully vented
in a fume hood. The crude reaction mixture was concentrated under reduced pressure and then
purified via flash column chromatography (10 to 20% EtOAc in hexanes) on silica gel (60 mL)
to afford II-12 (0.322 g, 89%) as a colorless oil.
Data for II-12: Rf = 0.30 (30% EtOAc in hexanes); [α]D23
= +28.9 (CH2Cl2, c = 0.51); IR (neat)
3467, 2925, 2854, 1738, 1467, 1439, 1204, 1151, 1099, 1038 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 4.70 (d, J = 7.0 Hz, 1H), 4.63 (d, J = 7.0 Hz, 1H), 4.23–4.18 (m, 1H), 3.79 (dddd, J = 8.5, 5.5,
5.5, 5.5 Hz, 1H), 3.71 (s, 3H), 3.38 (s, 3H), 2.54–2.46 (m, 2H), 1.76 (ddd, J = 14.0, 8.5, 8.5 Hz,
1H), 1.64 (ddd, J = 14.0, 4.0, 4.0 Hz, 1H), 1.57–1.52 (m, 2H), 1.32–1.24 (m, 18H), 0.88 (t, J =
114
7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 173.0, 95.4, 76.8, 67.2, 56.0, 51.9, 41.8, 40.9, 34.4,
32.1, 29.96, 29.82, 29.80, 29.78, 29.5, 25.1, 22.9, 14.3; MALDI-TOF/CCA-HRMS calcd for
C19H38O5Na [M Na]+: 369.2611, found 369.2609.
(R)-1-((S)-Oxiran-2-yl)tridecan-2-yl 4-nitrobenzoate (II-13)
To a stirred solution of II-11 (0.78 g, 3.22 mmol) in tetrahydrofuran (12 mL) at 0 °C was added
triphenylphosphine (1.73 g, 6.60 mmol) and 4-nitrobenzoic acid (1.08 g, 6.44 mmol) under N2. A
solution of diisopropyl azodicarboxylate (1.30 g, 6.44 mmol) in tetrahydrofuran (3 mL) was
added slowly via syringe. The resulting mixture was stirred at the same temperature for 1.5 h.
The reaction was quenched by adding saturated aqueous sodium bicarbonate (5 mL), and
extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (5 to 15% EtOAc in hexanes) on silica gel (40 mL) to afford
II-13 (1.25 g, 99%) as a colorless oil.
Data for II-13: Rf = 0.19 (15% Et2O in hexanes); [α]D21
= –9.2 (CHCl3, c = 0.23); IR (neat)
2925, 2854, 1724, 1608, 1529, 1350, 1275, 1103, 1015 cm-1
; 1H NMR (500 MHz, CDCl3) δ 8.30
(ddd, J = 9.0, 2.0, 2.0 Hz, 2H), 8.21 (ddd, J = 9.0, 2.0, 2.0 Hz, 2H), 5.36 (dddd, J = 7.5, 7.5, 5.0,
5.0 Hz, 1H), 3.02 (dddd, J = 7.0, 4.5, 4.5, 2.5 Hz, 1H), 2.75 (dd, J = 4.5, 4.5 Hz, 1H), 2.47 (dd, J
= 5.0, 2.5 Hz, 1H), 1.99 (ddd, J = 14.5, 8.0, 5.0 Hz, 1H), 1.86 (ddd, J = 14.5, 7.0, 4.5 Hz, 1H),
1.83–1.72 (m, 2H), 1.43–1.31 (m, 4H), 1.30–1.22 (m, 14H), 0.87 (t, J = 7.0 Hz, 3H); 13
C NMR
115
(100 MHz, CDCl3) δ 164.4, 150.7, 136.0, 130.9, 123.8, 74.2, 49.2, 47.0, 37.6, 34.4, 32.1, 29.78,
29.70, 29.63, 29.55, 29.51, 25.5, 22.9, 14.3; HRMS (ESI) calcd for C22H34NO5 [M H]+:
392.2437, found 392.2431.
(R)-1-((S)-Oxiran-2-yl)tridecan-2-ol (II-14)
To a stirred solution of II-13 (3.32 g, 8.49 mmol) in methanol (17 mL) at 0 °C was added
potassium carbonate (2.35 g, 17.0 mmol). The resulting mixture was stirred at the same
temperature for 2 h. The reaction was quenched by adding water (10 mL), and extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash chromatography (10 to 40% EtOAc in hexanes) on silica gel (50 mL) to afford II-14 (1.84
g, 90%) as a white solid.
Data for II-14: mp 47–48 °C; Rf = 0.27 (30% EtOAc in hexanes); [α]D21
= –13.3 (CHCl3, c =
0.36); IR (neat) 3396, 2916, 2848, 1464, 1265, 1057 cm-1
; 1H NMR (500 MHz, CDCl3) δ 3.84–
3.79 (m, 1H), 3.15 (dddd, J = 7.0, 4.0, 4.0, 3.0 Hz, 1H), 2.82 (dd, J = 4.5, 4.5 Hz, 1H), 2.61 (dd,
J = 5.0, 3.0 Hz, 1H), 1.95 (br s, 1H), 1.83 (ddd, J = 14.5, 8.5, 4.0 Hz, 1H), 1.62 (ddd, J = 14.5,
6.0, 3.5 Hz, 1H), 1.53–1.39 (m, 3H), 1.34–1.24 (m, 17H), 0.88 (t, J = 7.0 Hz, 3H); 13
C NMR
(100 MHz, CDCl3) δ 69.5, 50.5, 47.0, 39.1, 37.8, 32.1, 29.84, 29.82, 29.78, 29.54, 25.7, 22.9,
14.3; HRMS (ESI) calcd for C15H30O2Na [M Na]+: 265.2144, found 265.2143.
116
(S)-2-((R)-2-(Methoxymethoxy)tridecyl)oxirane (II-15)
To a stirred solution of II-14 (1.73 g, 7.14 mmol) in dichloromethane (15 mL) at 0 °C was added
chloromethyl methyl ether (0.81 mL, 10.7 mmol) under N2, followed by N,N-
diisopropylethylamine (2.95 mL, 17.9 mmol). The resulting mixture was stirred at the same
temperature for 20 h. The reaction was quenched by adding water (20 mL), and extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash chromatography (0 to 10% EtOAc in hexanes) on silica gel (50 mL) to afford II-15 (1.94 g,
95%) as a colorless oil.
Data for II-15: Rf = 0.22 (15% Et2O in hexanes); [α]D21
= –18.2 (CHCl3, c = 0.48); IR (neat)
2925, 2854, 1467, 1150, 1100, 1041 cm-1
; 1H NMR (500 MHz, CDCl3) δ 4.69 (s, 2H), 3.77
(dddd, J = 7.0, 6.0, 6.0, 4.5 Hz, 1H), 3.39 (s, 3H), 3.04 (dddd, J = 7.0, 4.5, 4.0, 2.5 Hz, 1H), 2.80
(dd, J = 4.5, 4.5 Hz, 1H), 2.50 (dd, J = 5.0, 3.0 Hz, 1H), 1.76 (ddd, J = 14.5, 8.0, 5.0 Hz, 1H),
1.62 (ddd, J = 14.5, 7.0, 4.5 Hz, 1H), 1.59–1.50 (m, 2H), 1.38–1.24 (m, 18H), 0.88 (t, J = 7.0 Hz,
3H); 13
C NMR (100 MHz, CDCl3) δ 95.8, 75.6, 55.8, 49.9, 47.7, 38.1, 35.1, 32.1, 29.92, 29.84,
29.82, 29.79, 29.54, 25.4, 22.9, 14.3; HRMS (ESI) calcd for C17H34O3Na [M Na]+: 309.2406,
found 309.2400.
Methyl (3S,5R)-3-hydroxy-5-(methoxymethoxy)hexadecanoate (II-16)
According to a modified literature procedure:72
In a nitrogen glove box, an 8 mL glass vial
equipped with a Teflon-coated magnetic stir bar was charged with dicobalt octacarbonyl
117
(Co2(CO)8) (35.9 mg, 0.105 mmol, 10.1 mol %) and 3-hydroxypyridine (19.5 mg, 0.205 mmol,
19.7 mol %). Tetrahydrofuran (1.2 mL) was added to the vial, followed by (13) (0.299 g, 1.04
mmol). After taking the vial out of the glove box, methanol (1.2 mL) was added to the vial and
the vial was placed quickly into a custom-made six-well high-pressure reactor. Subsequently, the
reactor was sealed, placed in a well-ventilated hood, purged three times with carbon monoxide,
and then pressurized to 900 psi. The reactor was then heated to 60 °C and the reaction mixture
stirred for 16 hours. The reactor was cooled on dry ice for 10 minutes and carefully vented in a
fume hood. The crude reaction mixture was concentrated under reduced pressure and then
purified via flash column chromatography (10 to 20% EtOAc in hexanes) on silica gel (60 mL)
to afford II-16 (0.315 g, 87%) as a colorless oil.
Data for II-16: Rf = 0.31 (30% EtOAc in hexanes); [α]D24
= –29.2 (CH2Cl2, c = 0.94); IR (neat)
3481, 2925, 2854, 1740, 1466, 1438, 1376, 1205, 1150, 1101, 1039 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 4.68 (d, J = 7.0 Hz, 1H), 4.66 (d, J = 7.0 Hz, 1H), 4.29 (dddd, J = 10.5, 8.0, 5.0, 3.0
Hz, 1H), 3.81 (dddd, J = 9.0, 6.0, 6.0, 3.0 Hz, 1H), 3.70 (s, 3H), 3.04 (s, 3H), 2.52–2.44 (m, 2H),
1.65 (ddd, J = 14.5, 9.5, 3.0 Hz, 1H), 1.60–1.55 (m, 1H), 1.56 (ddd, J = 14.5, 8.5, 2.5 Hz, 1H),
1.52–1.45 (m, 1H), 1.32–1.22 (m, 18H), 0.87 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ
173.0, 96.5, 75.7, 64.9, 56.0, 51.9, 41.8, 41.2, 35.1, 32.1, 29.94, 29.82, 29.80, 29.77, 29.5, 25.4,
22.9, 14.3; MALDI-TOF/CCA-HRMS calcd for C19H38O5Na [M Na]+: 369.2611, found
369.2600.
118
(S)-Pentadec-2-yn-4-ol (II-17)
To a stirred solution of II-8b (7.90 g, 35.5 mmol) in triethylamine (49.5 mL, 355 mmol) at 0 °C
was added formic acid (13.4 mL, 355 mmol) slowly under N2. After the white smoke subsided,
(S)-RuCl[(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2](η6-mesitylene) (110 mg, 178 µmol) was
added. The resulting mixture was stirred at room temperature for 12 h. The reaction was
quenched by adding water (20 mL), and extracted with EtOAc (3 × 100 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude residue was purified by flash chromatography (1 to 15%
EtOAc in hexanes) on silica gel (180 mL) to afford II-17 (6.60 g, 83%, brsm 93%, ee = 95.5%)
as a white solid.
Data for II-17: mp 36.5–37.5 °C; Rf = 0.27 (10% EtOAc in hexanes); [α]D23
= +2.1 (CH2Cl2, c =
1.37); IR (neat) 3355, 2921, 2853, 1466, 1340, 1266, 1147, 1113, 1031 cm-1
; 1H NMR (500
MHz, CDCl3) δ 4.32–4.27 (m, 1H), 2.00 (brs, 1H), 1.82 (d, J = 2.5 Hz, 3H), 1.69–1.58 (m, 2H),
1.43–1.37 (m, 2H), 1.30–1.20 (m, 16H), 0.86 (t, J = 6.5 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ
80.9, 80.7, 62.8, 38.3, 32.1, 29.81, 29.79, 29.74, 29.72, 29.50, 29.47, 25.4, 22.8, 14.3, 3.7;
HRMS (EI) calcd for C15H27O [M – 1]+: 223.2062, found 223.2058.
(R)-Pentadec-2-yn-4-ol (ent-II-17)
To a stirred solution of II-8b (3.24 g, 14.6 mmol) in triethylamine (20.3 mL, 146 mmol) at 0 °C
was added formic acid (5.5 mL, 146 mmol) slowly under N2. After the white smoke subsided,
119
(R)-RuCl[(1R,2R)-p-TsNCH(C6H5)CH(C6H5)NH2](6-mesitylene) (46.0 mg, 74.0 µmol) was
added. The resulting mixture was stirred at room temperature for 40 h. The reaction was
quenched by adding water (20 mL), and extracted with EtOAc (3 × 60 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude residue was purified by flash chromatography (5 to 20%
EtOAc in hexanes) on silica gel (100 mL) to afford ent-II-17 (2.75 g, 85%, ee = 96%) as a white
solid.
Data for ent-II-17: mp 36–37 °C; Rf = 0.27 (10% EtOAc in hexanes); [α]D21
= –5.5 (CH2Cl2, c =
1.13); IR (neat) 3322, 2918, 2850, 1467, 1316, 1266, 1148, 1064 cm-1
; 1H NMR (400 MHz,
CDCl3) δ 4.34–4.29 (m, 1H), 1.84 (d, J = 2.0 Hz, 3H), 1.74 (d, J = 5.2 Hz, 1H), 1.70–1.60 (m,
2H), 1.45–1.38 (m, 2H), 1.31–1.21 (m, 16H), 0.87 (t, J = 6.8 Hz, 3H); 13
C NMR (100 MHz,
CDCl3) δ 81.0, 80.7, 63.0, 38.4, 32.1, 29.84, 29.82, 29.77, 29.75, 29.54, 29.50, 25.4, 22.9, 14.3,
3.7; HRMS (EI) calcd for C15H27O [M – H]+: 223.2062, found 223.2058.
(S)-Pentadec-1-yn-4-ol (II-18)
To a flask with oil-free potassium hydride (4.61 g, 115 mmol) at 15 °C was added 1,3-
diaminopropane (45 mL) via syringe slowly under N2. The mixture was stirred at the same
temperature for 1.5 h. A solution of II-17 (6.45 g, 28.7 mmol) in 1,3-diaminopropane (30 mL)
was added to the mixture. The resulting mixture was warmed to room temperature, and stirred
for 18 h. The reaction was quenched by pouring onto ice, and extracted with EtOAc (3 × 80 mL).
The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
120
concentrated under reduced pressure. The crude residue was purified by flash chromatography (5
to 15% EtOAc in hexanes) on silica gel (200 mL) to afford II-18 (5.16 g, 80%) as a colorless oil.
Data for II-18: Rf = 0.27 (10% EtOAc in hexanes); [α]D21
= –0.5 (CH2Cl2, c = 2.26); IR (neat)
3313, 2921, 2852, 1465, 1377, 1275, 1260, 1128, 1066, 1033 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 3.76–3.70 (m, 1H), 2.40 (ddd, J = 16.5, 5.0, 2.5 Hz, 1H), 2.29 (ddd, J = 16.5, 6.5, 2.5 Hz, 1H),
2.12 (d, J = 4.5 Hz, 1H), 2.03 (t, J = 2.5 Hz, 1H), 1.54–1.49 (m, 2H), 1.44–1.37 (m, 1H), 1.33–
1.20 (m, 17H), 0.86 (t, J = 6.5 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 81.1, 70.9, 70.0, 36.3,
32.1, 29.77, 29.72, 29.69, 29.5, 27.5, 25.7, 22.8, 14.2.73
(R)-Pentadec-1-yn-4-ol (ent-II-18)
To a flask with oil-free potassium hydride (1.85 g, 46.2 mmol) at 15 °C was added 1,3-
diaminopropane (20 mL) via syringe slowly under N2. The mixture was stirred at the same
temperature for 1 h. A solution of ent-II-17 (2.59 g, 11.5 mmol) in 1,3-diaminopropane (10 mL)
was added to the mixture. The resulting mixture was warmed to room temperature, and stirred
for 18 h. The reaction was quenched by pouring onto ice, and extracted with EtOAc (3 × 80 mL).
The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography (5
to 20% EtOAc in hexanes) on silica gel (80 mL) to afford ent-II-18 (2.01 g, 78%) as a colorless
oil.
Data for ent-II-18: Rf = 0.27 (10% EtOAc in hexanes); [α]D23
= +0.6 (CH2Cl2, c = 2.50); IR
(neat) 3400, 2916, 2849, 1465, 1377, 1275, 1260, 1128, 1092, 1066, 1033 cm-1
; 1H NMR (400
MHz, CDCl3) δ 3.79–3.71 (m, 1H), 2.43 (ddd, J = 16.8, 4.8, 2.8 Hz, 1H), 2.31 (ddd, J = 16.8,
121
6.8, 2.8 Hz, 1H), 2.05 (t, J = 2.8 Hz, 1H), 1.97 (d, J = 4.8 Hz, 1H), 1.53–1.49 (m, 2H), 1.44–1.37
(m, 1H), 1.32–1.20 (m, 17H), 0.86 (t, J = 6.4 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 81.1, 70.9,
70.1, 36.4, 32.1, 29.83, 29.81, 29.76, 29.74, 29.71, 29.5, 27.5, 25.8, 22.9, 14.3.
(S)-tert-Butyldimethyl(pentadec-1-yn-4-yloxy)silane (II-19)
To a stirred solution of II-18 (3.32 g, 14.8 mmol) in dimethylformamide (15 mL) at room
temperature was added imidazole (2.52 g, 37.0 mmol), followed by tert-butyldimethylsilyl
chloride (4.46 g, 29.6 mmol) under N2. The resulting mixture was stirred at the same temperature
for 16 h. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (3 × 50
mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude residue was purified by flash
chromatography (0 to 1% EtOAc in hexanes) on silica gel (100 mL) to afford II-19 (4.83 g,
97%) as a colorless oil.
Data for II-19: Rf = 0.25 (hexanes); [α]D20
= –17.5 (CH2Cl2, c = 1.13); IR (neat) 2955, 2925,
2854, 1463, 1361, 1256, 1099, 1045 cm-1
; 1H NMR (500 MHz, CDCl3) δ 3.81–3.76 (m, 1H),
2.32–2.30 (m, 2H), 1.96 (t, J = 3.0 Hz, 1H), 1.64–1.57 (m, 1H), 1.54–1.46 (m, 1H), 1.40–1.34
(m, 1H), 1.30–1.20 (m, 17H), 0.89 (s, 9H), 0.88 (t, J = 6.5 Hz, 3H), 0.08 (s, 3H), 0.06 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 82.1, 71.1, 69.9, 36.8, 32.1, 29.84, 29.79, 29.5, 27.6, 26.0, 25.3,
22.9, 18.3, 14.3, –4.3, –4.5; HRMS (EI) calcd for C21H41OSi [M – 1]+: 337.2927, found
337.2930.
122
(R)-tert-Butyldimethyl(pentadec-1-yn-4-yloxy)silane (ent-II-19)
To a stirred solution of ent-II-18 (1.53 g, 6.82 mmol) in dimethylformamide (7 mL) at room
temperature was added imidazole (1.16 g, 17.1 mmol), followed by tert-butyldimethylsilyl
chloride (2.05 g, 13.6 mmol) under N2. The resulting mixture was stirred at the same temperature
for 13 h. The reaction was quenched by adding water (20 mL) and extracted with Et2O (3 × 25
mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude residue was purified by flash
chromatography (0 to 1% EtOAc in hexanes) on silica gel (50 mL) to afford ent-II-19 (4.31 g,
99%) as a colorless oil.
Data for ent-II-19: Rf = 0.25 (hexanes); [α]D24
= +16.8 (CH2Cl2, c = 1.64); IR (neat) 2955, 2925,
2854, 1463, 1257, 1099, 1045 cm-1
; 1H NMR (400 MHz, CDCl3) δ 3.82–3.76 (m, 1H), 2.37–2.26
(m, 2H), 1.97 (t, J = 2.8 Hz, 1H), 1.64–1.57 (m, 1H), 1.54–1.46 (m, 1H), 1.41–1.34 (m, 1H),
1.32–1.21 (m, 17H), 0.89 (s, 9H), 0.86 (t, J = 6.4 Hz, 3H), 0.08 (s, 3H), 0.06 (s, 3H); 13
C NMR
(100 MHz, CDCl3) δ 82.1, 71.2, 69.9, 36.9, 32.1, 29.86, 29.85, 29.6, 27.6, 26.1, 25.3, 23.0, 18.3,
14.3, –4.3, –4.4; HRMS (EI) calcd for C21H41OSi [M – H]+: 337.2927, found 337.2930.
(S)-tert-Butyl(henicos-7-yn-10-yloxy)dimethylsilane (II-20)
To a stirred solution of II-19 (2.75 g, 8.12 mmol) in tetrahydrofuran (9 mL) and
hexamethylphosphoramide (6 mL) at –20 °C was added n-butyllithium (1.8 M, 5.4 mL, 9.75
mmol) via syringe slowly under N2. After 1 h at the same temperature, 1-iodohexane was added
in one portion. The resulting mixture was stirred at –20 °C for 1 h, warmed slowly to room
123
temperature, and stirred at the temperature for 11 h. The reaction was quenched by adding water
(20 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (0 to 1% EtOAc in hexanes) on silica gel (100
mL) to afford II-20 (3.67 g, 88%) as a colorless oil.
Data for II-20: Rf = 0.25 (hexanes); [α]D22
= –12.0 (CH2Cl2, c = 1.23); IR (neat) 2955, 2925,
2854, 1741, 1463, 1361, 1257, 1097, 1046 cm-1
; 1H NMR (500 MHz, CDCl3) δ 3.75–3.70 (m,
1H), 2.28–2.24 (m, 2H), 2.15–2.11 (m, 2H), 1.63–1.56 (m, 1H), 1.50–1.44 (m, 2H), 1.40–1.34
(m, 2H), 1.32–1.24 (m, 23H), 0.88 (s, 9H), 0.90–0.87 (m, 6H), 0.07 (s, 3H), 0.05 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 82.0, 77.6, 71.8, 36.9, 32.1, 31.6, 29.90, 29.88, 29.85, 29.82, 29.6,
29.2, 28.8, 28.0, 26.1, 25.3, 22.9, 22.8, 19.0, 18.3, 14.31, 14.26, –4.3, –4.5; HRMS (CI) calcd for
C27H53OSi [M – 1]+: 421.3866, found 421.3861.
(R)-tert-Butyl(henicos-7-yn-10-yloxy)dimethylsilane (ent-II-20)
To a stirred solution of ent-II-19 (7.60 g, 22.4 mmol) in tetrahydrofuran (8 mL) and
hexamethylphosphoramide (8 mL) at –20 °C was added n-butyllithium (2.5 M, 9.4 mL, 23.6
mmol) via syringe slowly under N2. After 1 h at the same temperature, 1-iodohexane (4.3 mL,
29.1 mmol) was added in one portion. The resulting mixture was stirred at –20 °C for 1 h,
warmed slowly to room temperature, and stirred at the temperature for 20 h. The reaction was
quenched by adding water (50 mL), and extracted with EtOAc (3 × 100 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated
124
under reduced pressure. The crude residue was purified by flash chromatography (0 to 1%
EtOAc in hexanes) on silica gel (200 mL) to afford ent-II-20 (8.80 g, 93%) as a colorless oil.
Data for ent-II-20: Rf = 0.25 (hexanes); [α]D23
= +11.6 (CH2Cl2, c = 1.05); IR (neat) 2956, 2927,
2856, 1464, 1361, 1254, 1099, 1048 cm-1
; 1H NMR (500 MHz, CDCl3) δ 3.75–3.71 (m, 1H),
2.31–2.21 (m, 2H), 2.14 (dddd, J = 7.0, 7.0, 2.5, 2.5 Hz, 2H), 1.63–1.55 (m, 1H), 1.50–1.44 (m,
2H), 1.40–1.34 (m, 2H), 1.33–1.24 (m, 23H), 0.89 (s, 9H), 0.90–0.86 (m, 6H), 0.07 (s, 3H), 0.06
(s, 3H); 13
C NMR (100 MHz, CDCl3) δ 82.0, 77.6, 71.8, 36.9, 32.1, 31.6, 29.91, 29.89, 29.86,
29.83, 29.6, 29.2, 28.8, 28.0, 26.1, 25.4, 22.9, 22.8, 19.0, 18.3, 14.34, 14.28, –4.2, –4.5; HRMS
(CI) calcd for C27H53OSi [M – H]+: 421.3866, found 421.3861.
(S)-Henicos-7-yn-10-ol (II-21)
To a flask with II-20 (0.968 g, 2.29 mmol) was added a solution of tetra-n-butylammonium
fluoride (1 M, 12 mL, 12 mmol) in tetrahydrofuran at room temperature. The resulting mixture
was stirred at the same temperature for 14 h. The reaction was quenched by adding saturated
aqueous sodium bicarbonate, and extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude residue was purified by flash chromatography (0 to 4% EtOAc in
hexanes) on silica gel (30 mL) to afford II-21 (0.678 g, 96%) as a colorless oil.
Data for II-21: Rf = 0.31 (10% EtOAc in hexanes); [α]D24
= +1.5 (CH2Cl2, c = 3.63); IR (neat)
3373, 2955, 2922, 2853, 1465, 1378, 1275, 1261, 1126, 1085, 1032 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 3.70–3.66 (m, 1H), 2.40 (dddd, J = 16.5, 5.0, 2.5, 2.5 Hz, 1H), 2.26 (dddd, J = 16.5,
6.5, 2.5, 2.5 Hz, 1H), 2.17 (m, 2H), 1.92 (s, 1H), 1.53–1.48 (m, 4H), 1.44–1.34 (m, 3H), 1.32–
125
1.25 (m, 21H), 0.89 (t, J = 7.0 Hz, 3H), 0.88 (t, J = 7.0, 3H); 13
C NMR (100 MHz, CDCl3) δ
83.4, 76.3, 70.4, 36.4, 32.1, 31.5, 29.84, 29.81, 29.78, 29.5, 29.1, 28.7, 27.9, 25.8, 22.9, 22.7,
18.9, 14.3, 14.2; HRMS (EI) calcd for C21H40O [M]+: 308.3079, found 308.3074.
(R)-Henicos-7-yn-10-ol (ent-II-21)
To a flask with ent-II-20 (4.68 g, 11.1 mmol) was added a solution of tetra-n-butylammonium
fluoride (1 M, 50 mL, 50 mmol) in tetrahydrofuran at room temperature. The resulting mixture
was stirred at the same temperature for 24 h. The reaction was quenched by adding saturated
aqueous sodium bicarbonate, and extracted with EtOAc (3 × 80 mL). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude residue was purified by flash chromatography (2 to 8% EtOAc in
hexanes) on silica gel (80 mL) to afford ent-II-21 (3.20 g, 94%) as a colorless oil.
Data for ent-II-21: Rf = 0.31 (10% EtOAc in hexanes); [α]D19
= –1.7 (CH2Cl2, c = 3.20); IR
(neat) 3367, 2955, 2922, 2853, 1466, 1378, 1275, 1261, 1126, 1085, 1032 cm-1
; 1H NMR (400
MHz, CDCl3) δ 3.71–3.65 (m, 1H), 2.40 (dddd, J = 16.8, 4.8, 2.4, 2.4 Hz, 1H), 2.26 (dddd, J =
16.8, 6.8, 2.4, 2.4 Hz, 1H), 2.16 (dddd, J = 7.2, 7.2, 2.4, 2.4 Hz, 2H), 1.88 (s, 1H), 1.53–1.45 (m,
4H), 1.44–1.36 (m, 3H), 1.35–1.25 (m, 21H), 0.89 (t, J = 6.8 Hz, 3H), 0.88 (t, J = 6.8, 3H); 13
C
NMR (100 MHz, CDCl3) δ 83.5, 76.3, 70.4, 36.4, 32.1, 31.5, 29.85, 29.82, 29.79, 29.5, 29.1,
28.8, 27.9, 25.8, 22.9, 22.8, 18.9, 14.3, 14.2; HRMS (EI) calcd for C21H40O [M]+: 308.3079,
found 308.3074.
126
(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-ol (II-23)
To a stirred solution of II-7b (0.408 g, 1.31 mmol) in dichloromethane (4 mL) at 0 °C was added
vanadyl acetylacetonate (6.7 mg, 26 µmol), followed by a solution of tert-butyl hydroperoxide
(5.5 M, 0.36 mL, 1.97 mmol) in decane slowly via syringe. The resulting mixture was stirred at
the same temperature for 2 h, and warmed to room temperature slowly. After 21 h, the reaction
was quenched by adding water (10 mL) and sodium sulfite (0.497 g, 3.94 mmol). After 30 min,
the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was purified by flash chromatography (5 to 10% EtOAc in hexanes) on silica gel
(30 mL) to afford II-23 (0.403 g, 94%) as a colorless oil.
Data for II-23: Rf = 0.24 (10% EtOAc in hexanes); [α]D23
= –3.2 (CH2Cl2, c = 1.31); IR (neat)
3427, 2955, 2922, 2853, 1465, 1378, 1275, 1261, 1128, 1110, 1070, 1038 cm-1
; 1H NMR (500
MHz, CDCl3) δ 3.93–3.88 (m, 1H), 3.12 (ddd, J = 8.0, 4.0, 4.0 Hz, 1H), 2.91 (ddd, J = 6.0, 5.0,
5.0 Hz, 1H), 2.28 (s, 1H), 1.80 (ddd, J = 14.5, 4.0, 4.0 Hz, 1H), 1.56–1.45 (m, 5H), 1.44–1.39
(m, 1H), 1.37–1.24 (m, 25H), 0.88 (t, J = 6.5 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H); 13
C NMR (100
MHz, CDCl3) δ 71.0, 56.5, 55.6, 37.6, 34.8, 32.1, 31.9, 29.81, 29.79, 29.76, 29.5, 29.3, 28.1,
26.6, 25.7, 22.8, 22.7, 14.26, 14.20; MALDI-TOF/CCA-HRMS calcd for C21H42O2Na [M
Na]+: 349.3077, found 349.3070.
127
(R)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-ol (ent-II-23)
To a stirred solution of ent-II-7b (1.85 g, 5.96 mmol) in dichloromethane (8 mL) at 0 °C was
added vanadyl acetylacetonate (31.6 mg, 0.119 µmol), followed by a solution of tert-butyl
hydroperoxide (5.5 M, 1.6 mL, 8.94 mmol) in decane slowly via syringe. The resulting mixture
was stirred at the same temperature for 2 h, and warmed to room temperature slowly. After 6 h,
the reaction was quenched by adding water (30 mL) and sodium sulfite (2.25 g, 17.9 mmol).
After 30 min, the mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5 to 20% EtOAc in hexanes)
on silica gel (60 mL) to afford ent-II-23 (1.74 g, 90%) as a colorless oil.
Data for ent-II-23: Rf = 0.24 (10% EtOAc in hexanes); [α]D17
= +3.9 (CH2Cl2, c = 1.42); IR
(neat) 3459, 2955, 2922, 2853, 1465, 1378, 1275, 1261, 1128, 1110, 1070, 1038 cm-1
; 1H NMR
(400 MHz, CDCl3) δ 3.93–3.88 (m, 1H), 3.12 (ddd, J = 8.0, 4.0, 4.0 Hz, 1H), 2.91 (ddd, J = 6.4,
6.4, 4.4 Hz, 1H), 2.32 (s, 1H), 1.80 (ddd, J = 14.4, 4.0, 4.0 Hz, 1H), 1.56–1.45 (m, 6H), 1.44–
1.39 (m, 1H), 1.37–1.24 (m, 24H), 0.88 (t, J = 6.5 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H); 13
C NMR
(100 MHz, CDCl3) δ 71.1, 56.5, 55.7, 37.6, 34.9, 32.1, 31.9, 29.81, 29.79, 29.79, 29.5, 29.3,
28.1, 26.6, 25.7, 22.9, 22.7, 14.30, 14.24; MALDI-TOF/CCA-HRMS calcd for C21H42O2Na [M
Na]+: 349.3077, found 349.3070.
128
(3S,4S)-3-Hexyl-4-((S)-2-(methoxymethoxy)tridecyl)oxetan-2-one (II-24)
The general procedure for carbonylation of epoxides was followed using II-6b (99.1 mg 0.267
mmol), [ClTPPAl]+[Co(CO)4]
− (2.8 mg, 0.0026 mmol, 0.97 mol %) and tetrahydrofuran (0.53
mL) for 12 hours. The crude residue was purified by flash column chromatography (5 to 15%
EtOAc in hexanes) on silica gel (30 mL) to afford II-24 (86.0 mg, 81%) as a colorless oil.
Data for II-24: Rf = 0.32 (10% EtOAc in hexanes); [α]D21
= –10.5 (CH2Cl2, c = 0.44); IR (neat)
2926, 2855, 1825, 1467, 1378, 1151, 1123, 1099, 1039 cm-1
; 1H NMR (500 MHz, CDCl3) δ 4.65
(d, J = 7.0 Hz, 1H), 4.62 (d, J = 7.0 Hz, 1H), 4.42 (ddd, J = 6.5, 6.5, 4.0 Hz, 1H), 3.66 (dddd, J =
5.5, 5.5, 5.5, 5.5 Hz, 1H), 3.37 (s, 3H), 3.25 (ddd, J = 7.5, 7.5, 4.5 Hz, 1H), 2.12 (ddd, J = 14.5,
7.0, 6.0 Hz, 1H), 1.94 (ddd, J = 14.5, 6.0, 5.5 Hz, 1H), 1.86–1.80 (m, 1H), 1.79–1.71 (m, 1H),
1.62–1.50 (m, 1H), 1.49–1.44 (m, 1H), 1.42–1.36 (m, 1H), 1.35–1.24 (m, 25H), 0.884 (t, J = 7.0
Hz, 3H), 0.879 (t, J = 7.5 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 171.7, 95.9, 75.3, 75.0, 57.1,
55.9, 39.1, 34.4, 32.1, 31.7, 29.83, 29.77, 29.5, 29.2, 28.0, 26.9, 25.5, 22.9, 22.7, 14.3, 14.2;
MALDI-TOF/CCA-HRMS calcd for C24H46O4Na [M Na]+: 421.3288, found 421.3268.
(S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate
(II-25)
To a stirred solution of II-4b (19.6 mg, 55.3 µmol) in dichloromethane (1 mL) at room
temperature was added N-Cbz-L-Leu-OH (44.0 mg, 166 µmol), followed by N,N-
129
dicyclohexylcarbodiimide (45.4 mg, 221 µmol) and 4-dimethylaminopyridine (1 mg). The
resulting mixture was stirred at the same temperature for 22 h. The mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5% EtOAc in hexanes) on
silica gel (2 mL) to afford II-25 (31.0 mg, 93%) as a colorless oil.
Data for II-25: Rf = 0.24 (10% EtOAc in hexanes); [α]D23
= –24.1 (CHCl3, c = 0.56); IR (neat)
3357, 2926, 2855, 1824, 1727, 1524, 1467, 1333, 1262, 1218, 1171, 1121, 1048 cm-1
; 1H NMR
(500 MHz, CDCl3) δ 7.37–7.30 (m, 5H), 5.11 (s, 2H), 5.08 (d, J = 8.5 Hz, 1H), 5.02–4.98 (m,
1H), 4.34 (ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 4.30–4.26 (m, 1H), 3.20 (ddd, J = 7.0, 7.0, 4.0 Hz, 1H),
2.15 (ddd, J = 15.0, 7.5, 7.5 Hz, 1H), 1.96 (ddd, J = 15.0, 4.5, 4.5 Hz, 1H), 1.82–1.67 (m, 3H),
1.65–1.57 (m, 3H), 1.51 (ddd, J = 14.0, 9.5, 5.5 Hz, 1H), 1.46–1.41 (m, 1H), 1.32–1.24 (m,
25H), 0.947 (d, J = 6.0 Hz, 3H), 0.939 (d, J = 6.0 Hz, 3H), 0.882 (t, J = 6.5 Hz, 3H), 0.878 (t, J =
7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.7, 171.1, 156.1, 136.4, 128.7, 128.4, 128.3,
74.8, 72.5, 67.2, 57.2, 52.9, 41.8, 38.8, 34.2, 32.1, 31.7, 29.82, 29.73, 29.63, 29.54, 29.49, 29.2,
27.8, 26.9, 25.3, 25.0, 23.1, 22.9, 22.7, 21.9, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for
C36H59NO6Na [M Na]+: 624.4235, found 624.4238.
74
(R)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate
(ent-II-25)
The general procedure for carbonylation of epoxides was followed using ent-II-28 (76.8 mg,
0.164 mmol), [ClTPPAl]+[Co(CO)4]
− (3.0 mg, 0.0027 mmol, 1.6 mol %) and tetrahydrofuran
130
(0.28) mL for 24 hours. The crude residue was purified by preparative HPLC to afford ent-II-25
(60.3 mg, 75%) as a colorless oil.
Data for ent-II-25: Rf = 0.24 (10% EtOAc in hexanes); [α]D21
= +20.3 (CHCl3, c = 1.06); IR
(neat) 3355, 2923, 2855, 1823, 1731, 1522, 1456, 1369, 1333, 1264, 1219, 1121, 1029 cm-1
; 1H
NMR (400 MHz, CDCl3) δ 7.37–7.30 (m, 5H), 5.11 (s, 2H), 5.08 (d, J = 8.5 Hz, 1H), 5.02–4.98
(m, 1H), 4.34 (ddd, J = 8.8, 8.8, 5.2 Hz, 1H), 4.30–4.26 (m, 1H), 3.20 (ddd, J = 7.2, 7.2, 4.4 Hz,
1H), 2.16 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.96 (ddd, J = 14.4, 4.4, 4.4 Hz, 1H), 1.82–1.68 (m,
3H), 1.65–1.57 (m, 3H), 1.55–1.47 (m, 1H), 1.46–1.41 (m, 1H), 1.32–1.24 (m, 25H), 0.97–0.94
(m, 6H), 0.89–0.86 (m, 6H); 13
C NMR (100 MHz, CDCl3) δ 172.7, 171.0, 156.1, 136.4, 128.7,
128.4, 128.3, 74.7, 72.5, 67.2, 57.2, 53.0, 41.8, 38.9, 34.2, 32.1, 31.7, 29.80, 29.73, 29.62, 29.52,
29.48, 29.2, 27.8, 26.9, 25.3, 25.0, 23.1, 22.9, 22.7, 21.9, 14.3, 14.2; MALDI-TOF/CCA-HRMS
calcd for C36H59NO6Na [M Na]+: 624.4235, found 624.4242.
(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-L-leucinate (II-26)
To a stirred solution of II-28 (175 mg, 0.305 mmol) in tetrahydrofuran (2 mL) at room
temperature was added Pd/C (10% wt/wt, 32 mg, 30.6 µmol) under N2. The resulting mixture
was then stirred at the same temperature under H2 (1 atm) for 2 h. The mixture was filtered
through a pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced
pressure. The residue was dissolved in dichloromethane (1 mL). Then a premixed mixture of
N,N-dicyclohexylcarbodiimide (314 mg, 1.53 mmol) and formic acid (35 µL, 0.918 mmol) in
dichloromethane (4 mL) was added to the solution. After 5 min, the mixture was diluted with
131
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (0 to 20% EtOAc in hexanes)
on silica gel (2 mL) to afford II-26 (113 mg, 79%) as a colorless oil.
Data for II-26: Rf = 0.32 (30% EtOAc in hexanes); [α]D23
= –21.3 (CH2Cl2, c = 0.77); IR (neat)
3301, 2957, 2926, 2855, 1740, 1668, 1528, 1467, 1382, 1274, 1253, 1195 cm-1
; 1H NMR (500
MHz, CDCl3) δ 8.21 (s, 1H), 6.07 (d, J = 9.0 Hz, 1H), 5.09 (dddd, J = 8.0, 8.0, 5.0, 4.5 Hz, 1H),
4.72 (ddd, J = 8.5, 8.5, 5.0 Hz, 1H), 2.93 (ddd, J = 7.5, 4.0, 4.0 Hz, 1H), 2.87 (ddd, J = 6.0, 6.0,
4.5 Hz, 1H), 1.87 (ddd, J = 14.5, 4.5, 4.5 Hz, 1H), 1.74–1.58 (m, 5H), 1.52–1.39 (m, 4H), 1.36–
1.24 (m, 25H), 0.96 (d, J = 6.0 Hz, 3H), 0.95 (d, J = 6.0 Hz, 3H), 0.885 (t, J = 6.5 Hz, 3H), 0.871
(t, J = 6.5 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.2, 160.8, 74.3, 56.4, 53.8, 49.9, 41.9,
34.3, 32.7, 32.1, 31.9, 29.79, 29.74, 29.64, 29.55, 29.52, 29.3, 28.1, 26.7, 25.4, 25.1, 23.0, 22.9,
22.7, 22.1, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C28H53NO4Na [M Na]+: 490.3867,
found 490.3861.
(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-D-leucinate (II-27)
To a stirred solution of II-32 (45.5 mg, 79.3 µmol) in tetrahydrofuran (2 mL) at room
temperature was added Pd/C (10% wt/wt, 8.4 mg, 7.93 µmol) under N2. The resulting mixture
was then stirred at the same temperature under H2 (1 atm) for 2 h. The mixture was filtered
through a pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced
pressure. The residue was dissolved in dichloromethane (1 mL). Then a premixed mixture of
N,N-dicyclohexylcarbodiimide (65.1 mg, 317 µmol) and formic acid (9.0 µL, 238 µmol) in
132
dichloromethane (2 mL) was added to the solution. After 5 min, the mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (0 to 20% EtOAc in hexanes)
on silica gel (2 mL) to afford II-27 (30.5 mg, 82%) as a colorless oil.
Data for II-27: Rf = 0.32 (30% EtOAc in hexanes); [α]D21
= +2.9 (CH2Cl2, c = 1.42); IR (neat)
3296, 2957, 2925, 2855, 1740, 1668, 1529, 1467, 1381, 1273, 1253, 1193, 1144 cm-1
; 1H NMR
(500 MHz, CDCl3) δ 8.20 (s, 1H), 6.11 (d, J = 9.0 Hz, 1H), 5.09 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz,
1H), 4.72 (ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 2.97 (ddd, J = 8.0, 4.0, 4.0 Hz, 1H), 2.89–2.86 (m, 1H),
1.88 (ddd, J = 14.5, 5.0, 5.0 Hz, 1H), 1.75–1.58 (m, 5H), 1.49–1.38 (m, 4H), 1.36–1.24 (m,
25H), 0.96 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.877 (t, J = 7.0 Hz, 3H), 0.866 (t, J =
7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.4, 160.8, 74.3, 56.4, 53.6, 49.7, 41.9, 34.0, 32.6,
32.1, 31.9, 29.79, 29.70, 29.65, 29.51, 29.47, 29.3, 28.1, 26.7, 25.5, 25.0, 23.0, 22.9, 22.7, 22.0,
14.29, 14.24; HRMS (ESI) calcd for C28H53NO4Na [M Na]+: 490.3867, found 490.3853.
Acetic formic anhydride
To a flask with acetic anhydride (2.0 mL, 21.2 mmol) at room temperature was added formic
acid (0.88 mL, 23.3 mmol). The resulting mixture was stirred at reflux for 1.5 h. The mixture
was used directly for next step.
133
(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate (II-28)
To a stirred solution of II-23 (100 mg, 0.306 mmol) in dichloromethane (1.5 mL) at room
temperature was added N-Cbz-L-Leu-OH (122 mg, 0.459 mmol), followed by N,N-
dicyclohexylcarbodiimide (126 mg, 0.612 mmol) and 4-dimethylaminopyridine (4 mg). The
resulting mixture was stirred at the same temperature for 20 h. The mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10% EtOAc in hexanes) on
silica gel (2 mL) to afford II-28 (175 mg, 99%) as a colorless oil.
Data for II-28: Rf = 0.21 (10% EtOAc in hexanes); [α]D23
= –14.1 (CH2Cl2, c = 1.06); IR (neat)
3336, 2957, 2926, 2855, 1726, 1527, 1467, 1333, 1262, 1218, 1171, 1048 cm-1
; 1H NMR (500
MHz, CDCl3) δ 7.36–7.30 (m, 5H), 5.17 (d, J = 8.5 Hz, 1H), 5.13–5.06 (m, 1H), 5.10 (s, 2H),
4.38 (ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 2.95–2.91 (m, 1H), 2.87–2.84 (m, 1H), 1.83 (ddd, J = 15.0,
4.5, 4.5 Hz, 1H), 1.73 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 1.69–1.60 (m, 3H), 1.55–1.39 (m, 5H),
1.35–1.24 (m, 25H), 0.96 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H), 0.889 (t, J = 7.0 Hz, 3H),
0.877 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.9, 156.1, 136.4, 128.8, 128.7,
128.32, 128.25, 74.0, 67.1, 56.4, 53.7, 52.9, 41.9, 34.2, 32.6, 32.1, 31.9, 29.82, 29.80, 29.75,
29.66, 29.53, 29.4, 28.1, 26.7, 25.4, 25.0, 23.1, 22.9, 22.7, 22.0, 14.31, 14.25; MALDI-
TOF/CCA-HRMS calcd for C35H59NO5Na [M Na]+: 596.4285, found 596.4294.
134
(R)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate (ent-II-
28)
To a stirred solution of ent-II-23 (47.0 mg, 0.144 mmol) in dichloromethane (1.0 mL) at room
temperature was added N-Cbz-D-Leu-OH (76.4 mg, 0.288 mmol), followed by N,N-
dicyclohexylcarbodiimide (73.9 mg, 0.360 mmol) and 4-dimethylaminopyridine (2 mg). The
resulting mixture was stirred at the same temperature for 22 h. The mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5 to 15% EtOAc in hexanes)
on silica gel (10 mL) to afford ent-II-28 (82.0 mg, 99%) as a colorless oil.
Data for ent-II-28: Rf = 0.21 (10% EtOAc in hexanes); [α]D21
= +11.9 (CHCl3, c = 0.82); IR
(neat) 3341, 2926, 2855, 1728, 1526, 1456, 1334, 1264, 1218, 1048 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 7.36–7.30 (m, 5H), 5.17 (d, J = 8.5 Hz, 1H), 5.13–5.06 (m, 1H), 5.10 (s, 2H), 4.38
(ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 2.95–2.91 (m, 1H), 2.87–2.84 (m, 1H), 1.83 (ddd, J = 15.0, 4.5,
4.5 Hz, 1H), 1.73 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 1.69–1.60 (m, 3H), 1.55–1.39 (m, 5H), 1.35–
1.24 (m, 25H), 0.96 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H), 0.890 (t, J = 7.0 Hz, 3H), 0.877
(t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.8, 156.1, 136.5, 128.7, 128.7, 128.33,
128.25, 74.0, 67.1, 56.4, 53.7, 53.0, 41.9, 34.3, 32.7, 32.1, 31.9, 29.82, 29.81, 29.75, 29.66,
29.56, 29.4, 28.1, 26.7, 25.4, 25.0, 23.1, 22.9, 22.7, 22.0, 14.31, 14.25; MALDI-TOF/CCA-
HRMS calcd for C35H59NO5Na [M Na]+: 596.4285, found 596.4283.
135
(S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (II-1)
The general procedure for carbonylation of epoxides was followed using II-26 (69.8 mg, 0.149
mmol), [ClTPPAl]+[Co(CO)4]
− (3.4 mg, 0.0031 mmol, 2.1 mol %), and tetrahydrofuran (0.30
mL) for 24 hours. The crude residue was purified by preparative HPLC to afford II-1 (59.4 mg,
80%) as a colorless oil.
(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl 4-nitrobenzoate (II-29)
To a stirred solution of ent-II-23 (1.08 g, 3.31 mmol) in tetrahydrofuran (6 mL) at 0 °C was
added triphenylphosphine (1.78 g, 6.78 mmol), followed by p-nitrobenzoic acid (1.10 g, 6.62
mmol) under N2. A solution of diisopropyl azodicarboxylate (94%, 1.42 g, 6.62 mmol) in
tetrahydrofuran (4 mL) was added to the solution slowly via syringe. The resulting mixture was
stirred at the same temperature for 40 min. The reaction was quenched by adding saturated
aqueous sodium bicarbonate (10 mL), and extracted with EtOAc (3 × 30 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude residue was purified by flash chromatography (2 to 10% Et2O
in hexanes) on silica gel (40 mL) to afford II-29 (1.50 g, 96%) as a colorless oil.
136
Data for II-29: Rf = 0.30 (5% EtOAc in hexanes); [α]D24
= –2.3 (CH2Cl2, c = 0.69); IR (neat)
2926, 2855, 1725, 1608, 1530, 1467, 1349, 1275, 1102, 1015 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 8.29 (d, J = 8.5 Hz, 2H), 8.21 (d, J = 8.5 Hz, 2H), 5.35 (ddd, J = 7.5, 7.5, 5.5, 5.5 Hz, 1H), 3.03
(ddd, J = 7.0, 4.5, 4.5 Hz, 1H), 2.91 (ddd, J = 6.0, 6.0, 4.5 Hz, 1H), 2.01 (ddd, J = 14.5, 7.5, 5.0
Hz, 1H), 1.86–1.76 (m, 3H), 1.51–1.45 (m, 3H), 1.40–1.24 (m, 25H), 0.88–0.86 (m, 6H); 13
C
NMR (100 MHz, CDCl3) δ 164.4, 150.7, 136.0, 130.9, 123.7, 74.6, 57.0, 53.8, 34.5, 32.9, 32.1,
31.9, 29.79, 29.71, 29.65, 29.57, 29.51, 29.3, 28.1, 26.7, 25.5, 22.9, 22.7, 14.3, 14.2; MALDI-
TOF/CCA-HRMS calcd for C28H45NO5Na [M Na]+: 498.3190, found 498.3193.
(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-ol (II-30)
To a stirred solution of II-29 (1.56 g, 3.28 mmol) in methanol (7 mL) at 0 °C was added
potassium carbonate (0.91 g, 6.58 mmol). The resulting mixture was stirred at the same
temperature for 6 h. The reaction was quenched by adding water (20 mL), and extracted with
EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash chromatography (10 to 20% EtOAc in hexanes) on silica gel (40 mL) to afford II-30 (0.861
g, 80%) as a colorless oil.
Data for II-30: mp 41–42 °C; Rf = 0.38 (10% EtOAc in hexanes); [α]D22
= +14.4 (CH2Cl2, c =
1.63); IR (neat) 3459, 2955, 2922, 2853, 1465, 1378, 1275, 1261, 1128, 1110, 1070, 1038 cm-1
;
1H NMR (400 MHz, CDCl3) δ 3.87–3.81 (m, 1H), 3.15 (ddd, J = 8.8, 4.4, 4.4 Hz, 1H), 2.96
(ddd, J = 6.0, 6.0, 4.4 Hz, 1H), 1.81 (brs, 1H), 1.74 (ddd, J = 14.4, 8.0, 4.4 Hz, 1H), 1.56 (ddd, J
= 14.4, 8.0, 4.4 Hz, 1H), 1.55–1.40 (m, 6H), 1.35–1.22 (m, 24H), 0.88 (t, J = 6.4 Hz, 3H), 0.87
137
(t, J = 6.8 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 70.4, 57.4, 54.6, 37.9, 35.2, 32.10, 31.95,
29.84, 29.81, 29.78, 29.5, 29.4, 28.2, 26.7, 25.8, 22.9, 22.8, 14.30, 14.25; MALDI-TOF/CCA-
HRMS calcd for C21H42O2Na [M Na]+: 349.3077, found 349.3059.
(2S,3R)-2-Hexyl-3-((S)-2-(methoxymethoxy)tridecyl)oxirane (II-31)
To a stirred solution of II-30 (0.325 g, 1.00 mmol) in dichloromethane (3 mL) at room
temperature was added chloromethyl methyl ether (0.151 mL, 2.00 mmol) under N2, followed by
N,N-diisopropyl-ethylamine (0.413 mL, 2.50 mmol) and 4-dimethylaminopyridine (3 mg). The
resulting mixture was stirred at the same temperature for 11 h. The reaction was quenched by
adding water (10 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (2 to 8% EtOAc in hexanes)
on silica gel (30 mL) to afford II-31 (0.309 g, 84%) as a colorless oil.
Data for II-31: Rf = 0.42 (10% EtOAc in hexanes); [α]D22
= +8.9 (CH2Cl2, c = 1.77); IR (neat)
2922, 2854, 1466, 1275, 1099, 1037 cm-1
; 1H NMR (400 MHz, CDCl3) δ 4.68 (s, 2H), 3.75
(dddd, J = 7.6, 5.6, 5.6, 5.6 Hz, 1H), 3.38 (s, 3H), 3.05 (ddd, J = 7.2, 4.4, 4.4 Hz, 1H), 2.95–2.91
(m, 1H), 1.78 (ddd, J = 14.4, 7.2, 4.4 Hz, 1H), 1.60 (ddd, J = 14.4, 7.2, 4.8 Hz, 1H), 1.58–1.55
(m, 2H), 1.52–1.47 (m, 3H), 1.38–1.24 (m, 25H), 0.88 (t, J = 6.4 Hz, 3H), 0.87 (t, J = 6.8 Hz,
3H); 13
C NMR (100 MHz, CDCl3) 95.8, 75.9, 57.4, 55.8, 54.6, 35.1, 33.2, 32.1, 32.0, 29.92,
29.84, 29.81, 29.78, 29.5, 29.4, 28.3, 26.7, 25.4, 22.9, 22.7, 14.30, 14.24; MALDI-TOF/CCA-
HRMS calcd for C23H46O3Na [M Na]+: 393.3339, found 393.3329.
138
(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate (II-32)
To a stirred solution of II-23 (32.0 mg, 98.0 µmol) in dichloromethane (0.8 mL) at room
temperature was added N-Cbz-D-Leu-OH (39.0 mg, 147 µmol), followed by N,N-
dicyclohexylcarbodiimide (40.2 mg, 196 µmol) and 4-dimethylaminopyridine (1 mg). The
resulting mixture was stirred at the same temperature for 20 h. The mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5 to 10% EtOAc in hexanes)
on silica gel (2 mL) to afford II-32 (54.0 mg, 96%) as a colorless oil.
Data for II-32: Rf = 0.21 (10% EtOAc in hexanes); [α]D21
= +2.5 (CH2Cl2, c = 0.90); IR (neat)
3346, 2956, 2926, 2855, 1727, 1529, 1468, 1334, 1262, 1220, 1200, 1119, 1049 cm-1
; 1H NMR
(500 MHz, CDCl3) δ 7.37–7.29 (m, 5H), 5.20 (d, J = 8.5 Hz, 1H), 5.10 (s, 2H), 5.10–5.05 (m,
1H), 4.38 (ddd, J = 9.0, 9.0, 5.5 Hz, 1H), 3.00–2.97 (m, 1H), 2.88–2.85 (m, 1H), 1.86 (ddd, J =
14.5, 4.5, 4.5 Hz, 1H), 1.74 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 1.69–1.59 (m, 3H), 1.55–1.39 (m,
5H), 1.37–1.24 (m, 25H), 0.96 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.887 (t, J = 6.5 Hz,
3H), 0.875 (t, J = 6.5 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.9, 156.1, 136.5, 128.7, 128.3,
128.2, 73.9, 67.1, 56.4, 53.5, 52.9, 42.0, 34.0, 32.5, 32.1, 31.9, 29.81, 29.71, 29.66, 29.51, 29.50,
29.35, 28.1, 26.7, 25.5, 25.0, 23.1, 22.9, 22.7, 22.0, 14.30, 14.26; MALDI-TOF/CCA-HRMS
calcd for C35H59NO5Na [M Na]+: 596.4285, found 596.4265.
139
(R)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate (II-34)
To a stirred solution of II-23 (32.4 mg, 99.2 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was
added triphenylphosphine (53.4 mg, 203 µmol) and N-Cbz-D-Leu-OH (52.5 mg, 198 µmol)
under N2. A solution of diisopropyl azodicarboxylate (42.6 mg, 198 µmol) in tetrahydrofuran
(0.5 mL) was added slowly via syringe. The resulting mixture was stirred at the same
temperature for 0.5 h. The reaction was quenched by adding water (5 mL), and extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash chromatography (5 to 15% EtOAc in hexanes) on silica gel (10 mL) to afford II-34 (53.0
mg, 93%) as a colorless oil.
Data for II-34: Rf = 0.21 (10% EtOAc in hexanes); [α]D21
= +11.9 (CHCl3, c = 0.93); IR (neat)
3338, 2926, 2857, 1729, 1523, 1461, 1335, 1261, 1215, 1119, 1049 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 7.36–7.30 (m, 5H), 5.15 (d, J = 9.0 Hz, 1H), 5.09–5.04 (m, 1H), 5.11 (s, 2H), 4.38
(ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 2.94–2.88 (m, 2H), 1.86 (ddd, J = 15.0, 7.5, 4.5 Hz, 1H), 1.76–
1.60 (m, 5H), 1.54–1.42 (m, 4H), 1.36–1.24 (m, 25H), 0.96 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 7.0
Hz, 3H), 0.888 (t, J = 7.0 Hz, 3H), 0.876 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ
172.8, 156.1, 136.4, 128.7, 128.3, 128.2, 74.1, 67.1, 57.0, 53.7, 52.9, 42.0, 34.3, 32.6, 32.1, 31.9,
29.81, 29.76, 29.67, 29.58, 29.54, 29.4, 28.2, 26.7, 25.3, 24.9, 23.1, 22.9, 22.8, 22.0, 14.32,
14.26; MALDI-TOF/CCA-HRMS calcd for C35H59NO5Na [M Na]+: 596.4285, found
596.4304.
140
(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate (ent-II-
34)
To a stirred solution of ent-II-23 (43.0 mg, 0.132 mmol) in dichloromethane (1.0 mL) at room
temperature was added N-Cbz-D-Leu-OH (70.0 mg, 0.264 mmol), followed by N,N-
dicyclohexylcarbodiimide (67.5 mg, 0.329 mmol) and 4-dimethylaminopyridine (2 mg). The
resulting mixture was stirred at the same temperature for 22 h. The mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5 to 15% EtOAc in hexanes)
on silica gel (10 mL) to afford ent-II-34 (70.0 mg, 93%) as a colorless oil.
Data for ent-II-34: Rf = 0.21 (10% EtOAc in hexanes); [α]D22
= –15.9 (CHCl3, c = 1.58); IR
(neat) 3339, 2926, 2857, 1729, 1523, 1461, 1335, 1262, 1216, 1049 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 7.37–7.30 (m, 5H), 5.15 (d, J = 9.0 Hz, 1H), 5.09–5.04 (m, 1H), 5.11 (s, 2H), 4.38
(ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 2.94–2.88 (m, 2H), 1.86 (ddd, J = 14.5, 7.5, 4.5 Hz, 1H), 1.75–
1.59 (m, 5H), 1.54–1.42 (m, 4H), 1.36–1.24 (m, 25H), 0.96 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 7.0
Hz, 3H), 0.888 (t, J = 7.0 Hz, 3H), 0.876 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ
172.8, 156.1, 136.4, 128.7, 128.3, 128.2, 74.1, 67.1, 57.0, 53.7, 52.8, 42.1, 34.3, 32.6, 32.1, 31.9,
29.80, 29.76, 29.67, 29.58, 29.54, 29.3, 28.2, 26.7, 25.3, 24.9, 23.1, 22.9, 22.7, 22.0, 14.32,
14.26; MALDI-TOF/CCA-HRMS calcd for C35H59NO5Na [M Na]+: 596.4285, found
596.4283.
141
(R)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-D-leucinate (II-35)
To a stirred solution of II-34 (47.7 mg, 83.1 µmol) in tetrahydrofuran (1 mL) at room
temperature was added Pd/C (10% wt/wt, 17.7 mg, 16.6 µmol) under N2. The resulting mixture
was then stirred at the same temperature under H2 (1 atm) for 0.5 h. The mixture was filtered
through a pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced
pressure. The residue was dissolved in dichloromethane (1 mL). Then a premixed mixture of
N,N-dicyclohexylcarbodiimide (85.3 mg, 416 µmol) and formic acid (9.4 µL, 249 µmol) in
dichloromethane (1 mL) was added to the solution. After 5 min, the mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 30% EtOAc in
hexanes) on silica gel (10 mL) to afford II-35 (26.0 mg, 67%) as a colorless oil.
Data for II-35: Rf = 0.32 (30% EtOAc in hexanes); [α]D22
= +12.1 (CHCl3, c = 0.62); IR (neat)
3289, 2926, 2856, 1739, 1669, 1523, 1462, 1380, 1267, 1193 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 8.21 (s, 1H), 6.01 (d, J = 9.0 Hz, 1H), 5.09 (dddd, J = 7.0, 7.0, 5.5, 5.5 Hz, 1H), 4.73 (ddd, J =
9.0, 9.0, 4.5 Hz, 1H), 2.95–2.90 (m, 2H), 1.88 (ddd, J = 14.5, 7.5, 4.0 Hz, 1H), 1.72–1.60 (m,
5H), 1.59–1.39 (m, 4H), 1.38–1.24 (m, 25H), 0.97 (d, J = 6.0 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H),
0.887 (t, J = 7.0 Hz, 3H), 0.873 (t, J = 6.5 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.3, 160.7,
74.4, 57.0, 53.6, 49.7, 42.0, 34.2, 32.5, 32.1, 31.9, 29.80, 29.75, 29.65, 29.53, 29.3, 28.1, 26.7,
25.4, 25.0, 23.1, 23.0, 22.9, 22.7, 22.0, 14.30, 14.25; HRMS (ESI) calcd for C28H53NO4Na [M
Na]+: 490.3867, found 490.3845.
142
(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl 4-methylpentanoate (II-36)
To a stirred solution of ent-II-23 (21.2 mg, 64.9 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was
added triphenylphosphine (34.9 mg, 133 µmol) and 2-methylvaleric acid (15.1 mg, 130 µmol)
under N2. A solution of diisopropyl azodicarboxylate (28.0 µL, 130 µmol) in tetrahydrofuran
(0.5 mL) was added slowly via syringe. The resulting mixture was stirred at the same
temperature for 2 h. The reaction was quenched by adding water (5 mL), and extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash chromatography (2.5 to 5% EtOAc in hexanes) on silica gel (20 mL) to afford II-36 (20.0
mg, 62%) as a colorless oil.
Data for II-36: Rf = 0.37 (10% Et2O in hexanes); [α]D21
= –6.2 (CHCl3, c = 0.50); IR (neat)
2926, 2857, 1735, 1462, 1378, 1266, 1177, 1107 cm-1
; 1H NMR (500 MHz, CDCl3) 5.05 (ddd, J
= 13.0, 7.0, 5.5 Hz, 1H), 2.95 (ddd, J = 6.5, 4.5, 4.5 Hz, 1H), 2.92–2.88 (m, 1H), 2.31 (d, J = 7.0
Hz, 1H), 2.29 (d, J = 7.0 Hz, 1H), 1.81 (ddd, J = 14.5, 7.5, 5.0 Hz, 1H), 1.71 (ddd, J = 14.5, 6.5,
5.0 Hz, 1H), 1.63–1.59 (m, 2H), 1.57–1.40 (m, 5H), 1.38–1.24 (m, 26H), 0.91–0.86 (m, 12H);
13C NMR (100 MHz, CDCl3) δ 173.8, 72.4, 57.1, 54.2, 34.6, 34.0, 33.0, 32.9, 32.1, 32.0, 29.83,
29.74, 29.71, 29.61, 29.54, 29.4, 28.2, 27.9, 26.7, 25.4, 22.9, 22.8, 22.4, 14.32, 14.26; HRMS
(ESI) calcd for C27H53O3 [M H]+: 425.3995, found 425.3996.
143
(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate (II-37)
To a stirred solution of ent-II-23 (43.0 mg, 0.132 mmol) in dichloromethane (1.0 mL) at room
temperature was added N-Cbz-D-Leu-OH (70.0 mg, 0.264 mmol), followed by N,N-
dicyclohexylcarbodiimide (67.5 mg, 0.329 mmol) and 4-dimethylaminopyridine (2 mg). The
resulting mixture was stirred at the same temperature for 22 h. The mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5 to 15% EtOAc in hexanes)
on silica gel (10 mL) to afford II-37 (74.0 mg, 98%) as a colorless oil.
Data for II-37: Rf = 0.21 (10% EtOAc in hexanes); [α]D22
= –2.4 (CHCl3, c = 1.50); IR (neat)
3339, 2926, 2857, 1728, 1525, 1461, 1379, 1335, 1262, 1216, 1119, 1049 cm-1
; 1H NMR (500
MHz, CDCl3) δ 7.37–7.29 (m, 5H), 5.16 (d, J = 8.5 Hz, 1H), 5.12–5.06 (m, 1H), 5.10 (s, 2H),
4.36 (ddd, J = 8.5, 8.5, 5.0 Hz, 1H), 2.96–2.89 (m, 2H), 1.88 (ddd, J = 14.0, 7.5, 5.0 Hz, 1H),
1.76–1.68 (m, 2H), 1.67–1.59 (m, 3H), 1.54–1.41 (m, 4H), 1.37–1.24 (m, 25H), 0.96 (d, J = 7.0
Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.888 (t, J = 7.0 Hz, 3H), 0.875 (t, J = 7.0 Hz, 3H); 13
C NMR
(100 MHz, CDCl3) δ 173.0, 156.1, 136.4, 128.7, 128.3, 128.2, 73.9, 67.1, 57.1, 53.9, 52.8, 42.1,
34.4, 32.9, 32.1, 31.9, 29.80, 29.70, 29.66, 29.51, 29.4, 28.2, 26.7, 25.3, 24.9, 23.1, 22.9, 22.7,
22.0, 14.30, 14.26; MALDI-TOF/CCA-HRMS calcd for C35H59NO5Na [M Na]+: 596.4285,
found 596.4316.
144
(3R,4R)-3-Hexyl-4-((S)-2-(methoxymethoxy)tridecyl)oxetan-2-one (II-38)
The general procedure for carbonylation of epoxides was followed using II-31 (53.7 mg, 0.145
mmol), [ClTPPAl]+[Co(CO)4]
− (1.6 mg, 0.0015 mmol, 1.0 mol %) and tetrahydrofuran (0.30
mL) for 12 hours. The crude residue was purified by preparative HPLC to afford II-38(50.5 mg,
88%) as a colorless oil.
Data for II-38: Rf = 0.31 (10% EtOAc in hexanes); [α]D23
= +45.2 (CH2Cl2, c = 0.82); IR (neat)
2926, 2855, 1825, 1467, 1390, 1152, 1118, 1101, 1040 cm-1
; 1H NMR (500 MHz, CDCl3) δ 4.68
(d, J = 7.0 Hz, 1H), 4.64 (d, J = 7.0 Hz, 1H), 4.44 (ddd, J = 6.5, 6.5, 4.5 Hz, 1H), 3.70 (ddd, J =
12.0, 6.0, 6.0 Hz, 1H), 3.38 (s, 3H), 3.21 (ddd, J = 8.0, 8.0, 4.5 Hz, 1H), 1.95–1.89 (m, 2H), 1.82
(dddd, J = 13.5, 10.5, 6.0, 6.0 Hz, 1H), 1.74 (dddd, J = 13.5, 9.0, 9.0, 6.0 Hz, 1H), 1.62–1.56 (m,
1H), 1.52–1.48 (m, 1H), 1.46–1.42 (m, 1H), 1.40–1.35 (m, 1H), 1.34–1.24 (m, 24H), 0.880 (t, J
= 7.0 Hz, 3H), 0.875 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 171.7, 96.0, 75.3, 74.6,
56.7, 55.9, 40.1, 34.9, 32.1, 31.7, 29.9, 29.82, 29.80, 29.76, 29.5, 29.1, 27.9, 27.0, 25.0, 22.9,
22.7, 14.3, 14.2.75
(S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (II-39)
The general procedure for carbonylation of epoxides was followed using II-27 (20.0 mg, 0.0428
mmol), [ClTPPAl]+[Co(CO)4]
− (2.6 mg, 0.0024 mmol, 5.6 mol %) and tetrahydrofuran (0.25)
145
mL for 3 days. The crude residue was purified by flash column chromatography (50% Et2O in
hexanes) on silica gel (30 mL) to afford II-39 (16.3 mg, 77%) as a colorless oil.
Data for II-39: Rf = 0.27 (30% EtOAc in hexanes); [α]D22
= –5.3 (CHCl3, c = 0.17); IR (neat)
3325, 2957, 2927, 2855, 1824, 1740, 1685, 1511, 1467, 1379, 1252, 1188, 1125 cm-1
; 1H NMR
(500 MHz, CDCl3) δ 8.21 (s, 1H), 5.87 (d, J = 8.0 Hz, 1H), 5.03 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz,
1H), 4.66 (ddd, J = 8.5, 8.5, 5.5 Hz, 1H), 4.35 (ddd, J = 8.0, 5.0, 4.0 Hz, 1H), 3.22 (ddd, J = 7.5,
7.5, 4.5 Hz, 1H), 2.18 (ddd, J = 15.0, 7.5, 7.5 Hz, 1H), 2.02 (ddd, J = 15.0, 5.0, 4.5 Hz, 1H),
1.84–1.77 (m, 1H), 1.76–1.71 (m, 1H), 1.70–1.64 (m, 3H), 1.60–1.53 (m, 2H), 1.47–1.41 (m,
1H), 1.38–1.24 (m, 25H); 0.970 (d, J = 6.5 Hz, 3H), 0.967 (d, J = 6.5 Hz, 3H), 0.882 (t, J = 7.0
Hz, 3H), 0.879 (t, J = 7.0, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.4, 171.2, 160.8, 74.8, 72.8,
57.2, 49.8, 41.6, 38.7, 34.0, 32.1, 31.6, 29.8, 29.7, 29.6, 29.5, 29.4, 29.2, 27.8, 26.9, 25.4, 25.0,
23.0, 22.9, 22.7, 22.0, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+:
518.3816, found 518.3813.
(R)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (ent-II-1)
(R)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (ent-II-39)
The general procedure for carbonylation of epoxides was followed using 102.7 mg (0.2196
mmol) (R)-1-((2R,3S)-3-hexyloxiran-2-yl)tridecan-2-yl formyl-D,L-leucinate, 12.8 mg (0.0117
mmol, 5.33 mol %) [ClTPPAl][Co(CO)4], and 0.50 mL tetrahydrofuran for 3 days. The crude
residue was purified by flash column chromatography (50% Et2O in hexanes) on silica gel (30
146
mL) to afford a mixture of ent-II-1 and ent-II-39 (90.0 mg, 82%) as a colorless oil. The mixture
of ent-II-1 and ent-II-39 was separated with HPLC.
Data for ent-II-1: Rf = 0.27 (30% EtOAc in hexanes); [α]D21
= +22.3 (CHCl3, c = 0.45); IR (neat)
3304, 2956, 2926, 2855, 1823, 1739, 1671, 1523, 1467, 1381, 1252, 1193, 1124 cm-1
; 1H NMR
(500 MHz, CDCl3) δ 8.22 (s, 1H), 5.91 (d, J = 8.5 Hz, 1H), 5.05–5.00 (m, 1H), 4.69 (ddd, J =
9.0, 9.0, 5.0 Hz, 1H), 4.29 (ddd, J = 7.5, 5.0, 5.0 Hz, 1H), 3.22 (ddd, J = 7.5, 7.5, 4.0 Hz, 1H),
2.17 (ddd, J = 15.0, 7.5, 7.5 Hz, 1H), 2.00 (ddd, J = 15.0, 4.5, 4.5 Hz, 1H), 1.84–1.78 (m, 1H),
1.77–1.63 (m, 4H), 1.61–1.53 (m, 2H), 1.47–1.41 (m, 1H), 1.32–1.24 (m, 25H), 0.973 (d, J = 6.5
Hz, 3H), 0.965 (d, J = 6.5 Hz, 3H), 0.884 (t, J = 6.5 Hz, 3H), 0.877 (t, J = 7.0, 3H); 13
C NMR
(100 MHz, CDCl3) δ 171.9, 170.8, 160.6, 74.8, 72.8, 57.0, 49.6, 41.6, 38.7, 34.1, 31.89, 31.5,
29.6, 29.5, 29.4, 29.3, 29.3, 29.0, 27.6, 26.7, 25.1, 24.9, 22.9, 22.7, 22.5, 21.7, 14.1, 14.0
(CDCl3, δ 77.0 ppm); MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+: 518.3816,
found 518.3780.
Data for ent-II-39: Rf = 0.27 (30% EtOAc in hexanes); [α]D22
= +4.4 (CHCl3, c = 0.81); IR (neat)
3307, 2926, 2855, 1824, 1740, 1687, 1523, 1467, 1380, 1251, 1190, 1125 cm-1
; 1H NMR (500
MHz, CDCl3) δ 8.20 (s, 1H), 5.92 (d, J = 8.5 Hz, 1H), 5.02 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz, 1H),
4.66 (ddd, J = 8.5, 8.5, 5.5 Hz, 1H), 4.35 (ddd, J = 8.0, 5.0, 4.0 Hz, 1H), 3.22 (ddd, J = 7.5, 7.5,
4.5 Hz, 1H), 2.17 (ddd, J = 15.0, 7.5, 7.5 Hz, 1H), 2.01 (ddd, J = 15.0, 5.0, 4.5 Hz, 1H), 1.84–
1.77 (m, 1H), 1.76–1.71 (m, 1H), 1.70–1.64 (m, 3H), 1.60–1.53 (m, 2H), 1.47–1.41 (m, 1H),
1.38–1.24 (m, 25H), 0.970 (d, J = 6.5 Hz, 3H), 0.967 (d, J = 6.5 Hz, 3H), 0.882 (t, J = 7.0 Hz,
3H), 0.879 (t, J = 7.0, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.4, 171.2, 160.8, 74.8, 72.7, 57.1,
49.8, 41.6, 38.7, 34.0, 32.1, 31.6, 29.8, 29.7, 29.6, 29.5, 29.4, 29.1, 27.8, 26.8, 25.4, 25.0, 23.0,
147
22.9, 22.7, 22.0, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+:
518.3816, found 518.3813.
(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (ent-II-41)
To a stirred solution of ent-II-43 (10.0 mg, 16.6 µmol) in tetrahydrofuran (1 mL) at room
temperature was added Pd/C (10% wt/wt, 3.5 mg, 3.3 µmol) under N2. The resulting mixture was
then stirred at the same temperature under H2 (1 atm) for 2 h. The mixture was filtered through a
pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure.
The residue was dissolved in dichloromethane (0.5 mL). Then a premixed mixture of N,N-
dicyclohexylcarbodiimide (17.0 mg, 83.0 µmol) and formic acid (2.0 µL, 50.4 µmol) in
dichloromethane (0.5 mL) was added to the solution. After 5 min, the mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (0 to 20% EtOAc in hexanes)
on silica gel (2 mL) to afford ent-II-41 (5.8 mg, 70%) as a colorless oil.
Data for ent-II-41: Rf = 0.27 (30% EtOAc in hexanes); [α]D21
= +12.6 (CHCl3, c = 0.55); IR
(neat) 3311, 2926, 2857, 1823, 1739, 1673, 1521, 1462, 1380, 1251, 1193, 1122 cm-1
; 1H NMR
(500 MHz, CDCl3) δ 8.21 (s, 1H), 5.94 (d, J = 8.5 Hz, 1H), 5.01(ddd, J = 7.0, 7.0, 5.5, 5.5 , 1H),
4.71 (ddd, J = 9.0, 9.0, 4.5 Hz, 1H), 4.26 (ddd, J = 8.5, 4.5, 4.5 Hz, 1H), 3.24 (ddd, J = 7.0, 7.0,
4.0 Hz, 1H), 2.09–2.00 (m, 2H), 1.86–1.79 (m, 1H), 1.76–1.63 (m, 4H), 1.61–1.54 (m, 2H),
1.47–1.41 (m, 1H), 1.38–1.24 (m, 25H), 0.972 (d, J = 6.0 Hz, 3H), 0.960 (d, J = 6.0 Hz, 3H),
0.883 (t, J = 7.0 Hz, 3H), 0.875 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.2, 170.9,
148
160.8, 74.4, 72.7, 56.8, 49.8, 41.9, 39.1, 34.3, 32.1, 31.7, 29.8, 29.7, 29.6, 29.52, 29.50, 29.1,
27.9, 27.0, 25.2, 25.1, 23.0, 22.9, 22.7, 22.1, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for
C29H53NO5Na [M Na]+: 518.3816, found 518.3801.
(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (ent-II-40)
To a stirred solution of ent-II-44 (10.0 mg, 16.6 µmol) in tetrahydrofuran (1 mL) at room
temperature was added Pd/C (10% wt/wt, 3.5 mg, 3.3 µmol) under N2. The resulting mixture was
then stirred at the same temperature under H2 (1 atm) for 2 h. The mixture was filtered through a
pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure.
The residue was dissolved in dichloromethane (0.5 mL). Then a premixed mixture of N,N-
dicyclohexylcarbodiimide (17.0 mg, 83.0 µmol) and formic acid (2.0 µL, 50.4 µmol) in
dichloromethane (0.5 mL) was added to the solution. After 5 min, the mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (0 to 20% EtOAc in hexanes)
on silica gel (2 mL) to afford ent-II-40 (6.0 mg, 70%) as a colorless oil.
Data for ent-II-40: Rf = 0.27 (30% EtOAc in hexanes); [α]D21
= +23.5 (CHCl3, c = 0.61); IR
(neat) 3353, 2926, 2857, 1822, 1739, 1684, 1462, 1380, 1251, 1189, 1124 cm-1
; 1H NMR (500
MHz, CDCl3) δ 8.21 (s, 1H), 5.92 (d, J = 8.5 Hz, 1H), 5.04 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz, 1H),
4.68 (ddd, J = 8.5, 8.5, 5.0 Hz, 1H), 4.29 (ddd, J = 9.0, 4.5, 4.5 Hz, 1H), 3.22 (ddd, J = 7.5, 7.5,
4.5 Hz, 1H), 2.10–2.00 (m, 2H), 1.85–1.78 (m, 1H), 1.77–1.53 (m, 6H), 1.49–1.42 (m, 1H),
1.38–1.24 (m, 25H), 0.975 (d, J = 6.0 Hz, 3H), 0.965 (d, J = 6.5 Hz, 3H), 0.89–0.87 (m, 6H); 13
C
149
NMR (100 MHz, CDCl3) δ 172.5, 171.1, 160.8, 74.5, 72.7, 56.9, 49.7, 41.9, 39.3, 34.4, 32.1,
31.7, 29.8, 29.7, 29.6, 29.5, 29.4, 29.1, 27.8, 27.0, 25.2, 25.1, 23.0, 22.9, 22.7, 22.1, 14.3, 14.2;
MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+: 518.3816, found 518.3792.
150
Table S7. 1H NMR assignments of II-39. *δH (multiplicity, coupling constant (J) in Hz)
Position
Helv. Chim. Acta 1987,
70, 196.
(enatiomer) This Work
J. Med. Chem. 2008, 51,
6970.
CHO
(1H) 8.21 (s) 8.21 (s) 8.20 (s)
2''-NH
(1H) 5.88 (d, 8) 5.87 (d, 8.0) 6.19 (d, 8.0)
5
(1H) 5.09–4.96 (m) 5.03 (dddd, 7.5, 7.5, 5.0, 5.0) 5.03 (m)
2''
(1H) 4.67 (dt, 7.5, 7.5, 4.0) 4.66 (ddd, 8.5, 8.5, 5.5) 4.65 (m)
3
(1H) 4.36–4.25 (m, 1H) 4.35 (ddd, 8.0, 5.0, 4.0) 4.37 (m)
2
(1H) 3.22 (dt, 7.5, 7.5, 4.0) 3.22 (ddd, 7.5, 7.5, 4.5) 3.23 (m)
4, 4a
(2H) 2.26–1.97 (m) 2.18 (ddd, 15.0, 7.5, 7.5, 1H) 2.18 (m)
2.02 (ddd, 15.0, 5.0, 4.5, 1H) 2.00 (m)
CH2
(33H) 1.50–1.03 (m) 1.84–1.77 (m, 1H) 1.78–1.54 (m)
1.76–1.71 (m, 1H)
1.70–1.53 (m, 5H)
1.47–1.24 (m, 1H)
1.38–1.24 (m, 25H)
5'', 5'''
(6H)
1.03–0.94 (m) 0.970 (d, 6.5, 3H) 0.96 (m)
0.967 (d, 6.5, 3H)
16, 6'
(6H) 0.94–0.75 (m) 0.882 (t, 7.0, 3H) 0.89 (m)
0.879 (t, 7.0, 3H)
151
Position J. Med. Chem. 2008, 51,
6970. This Work
1, 1'' 172.27 172.40
171.07 171.21
1''' 160.77 160.78
3, 5 74.60 74.78
72.50 72.75
2, 2'' 56.99 57.16
49.69 49.77
4, 6, 9
12, 13, 14, 1', 2', 3'
4', 3'',
41.36 41.63
38.53 38.71
33.83 34.00
31.91 32.09
31.48 31.65
29.63 29.80
29.52 29.70
29.46 29.63
29.34 29.53
29.26 29.42
28.98 29.16
7, 8, 10, 11
27.64 27.79
26.68 26.86
25.21 25.38
24.87 25.03
4'' 22.82 23.01
5'' 5'''
15, 5'
22.69 22.88
22.53 22.72
21.86 22.03
16, 6' 14.12 14.32
14.03 14.24
Table S8. 13
C NMR assignments of II-39.
152
(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (II-40)
The general procedure for carbonylation of epoxides was followed using II-33 (61.6 mg, 0.132
mmol), [ClTPPAl]+[Co(CO)4]
− (5.8 mg, 0.0053 mmol, 4.0 mol %) and tetrahydrofuran (0.30)
mL for 24 hours. The crude residue was purified by preparative HPLC to afford 38 (46.5 mg,
72%, regioselectivity II-40: II-40a = 6:1; the ratio determined by 1H NMR) as a colorless oil.
Data for II-40: Rf = 0.27 (30% EtOAc in hexanes); [α]D21
= –21.5 (CHCl3, c = 0.36); IR (neat)
3353, 2925, 2855, 1822, 1736, 1685, 1461, 1380, 1272, 1187, 1125 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 8.21 (s, 1H), 5.92 (d, J = 8.0 Hz, 1H), 5.04 (dddd, J = 7.0, 7.0, 5.5, 5.5 Hz, 1H), 4.68
(ddd, J = 8.5, 8.5, 5.0 Hz, 1H), 4.29 (ddd, J = 9.0, 4.5, 4.5 Hz, 1H), 3.22 (ddd, J = 7.5, 7.5, 4.5
Hz, 1H), 2.10–2.00 (m, 2H), 1.85–1.78 (m, 1H), 1.77–1.53 (m, 6H), 1.49–1.42 (m, 1H), 1.38–
1.24 (m, 25H), 0.976 (d, J = 6.5 Hz, 3H), 0.963 (d, J = 6.5 Hz, 3H), 0.89–0.87 (m, 6H); 13
C
NMR (100 MHz, CDCl3) δ 172.5, 171.1, 160.8, 74.5, 72.7, 56.9, 49.7, 41.9, 39.3, 34.4, 32.1,
31.7, 29.8, 29.7, 29.6, 29.5, 29.4, 29.1, 27.8, 27.0, 25.2, 25.0, 23.0, 22.9, 22.7, 22.1, 14.3, 14.2;
MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+: 518.3816, found 518.3798.
(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (II-40)
To a stirred solution of II-44 (10.0 mg, 16.6 µmol) in tetrahydrofuran (1 mL) at room
temperature was added Pd/C (10% wt/wt, 3.5 mg, 3.3 µmol) under N2. The resulting mixture was
153
then stirred at the same temperature under H2 (1 atm) for 2 h. The mixture was filtered through a
pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure.
The residue was dissolved in dichloromethane (0.5 mL). Then a premixed mixture of N,N-
dicyclohexylcarbodiimide (17.0 mg, 83.0 µmol) and formic acid (2.0 µL, 50.4 µmol) in
dichloromethane (0.5 mL) was added to the solution. After 5 min, the mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (0 to 20% EtOAc in hexanes)
on silica gel (2 mL) to afford II-40 (5.2 mg, 63%) as a colorless oil.
154
Table S9. 1H NMR assignments of II-40. *δH (multiplicity, coupling constant (J) in Hz)
Note: No 13
C NMR available for comparison.
Position
Helv. Chim. Acta 1987,
70, 196.
(enantiomer) This Work
CHO
(1H) 8.21 (s) 8.21 (s)
2''-NH
(1H) 5.93 (d, 8.5) 5.92 (d, 8.0)
5
(1H) 5.12–5.00 (m) 5.04 (dddd, 7.0, 7.0, 5.5, 5.5)
2''
(1H) 4.68 (dt, 8.5, 8.5, 5.0) 4.68 (ddd, 8.5, 8.5, 5.0)
3
(1H) 4.36–4.25 (m) 4.29 (ddd, 9.0, 4.5, 4.5)
2
(1H) 3.32 (dt, 8.0, 8.0, 5.0) 3.22 (ddd, 7.5, 7.5, 4.5)
4, 4a
(2H) 2.12–2.01 (m) 2.10–2.00 (m)
CH2
(33H) 1.90–1.06 (m) 1.85–1.78 (m, 1H)
1.77–1.53 (m, 6H)
1.49–1.42 (m, 1H)
1.38–1.24 (m, 25H)
5'', 5'''
(6H) 1.06–0.93 (m) 0.976 (d, 6.5, 3H),
0.963 (d, 6.5, 3H),
16, 6'
(6H)
0.93–0.77 (m) 0.89–0.87 (m)
155
(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (II-41)
The general procedure for carbonylation of epoxides was followed using II-35 (71.1 mg, 0.152
mmol), [ClTPPAl]+[Co(CO)4]
− (6.7 mg, 0.0061 mmol, 4.0 mol %) and tetrahydrofuran (0.30)
mL for 24 hours. The crude residue was purified by preparative HPLC to afford 39 (58.2 mg,
77%, regioselectivity II-41: II-41a = 5:1; the ratio determined by 1H NMR) as a colorless oil.
Data for II-41: Rf = 0.32 (30% EtOAc in hexanes); [α]D21
= –12.3 (CHCl3, c = 0.32); IR (neat)
3324, 2926, 2856, 1823, 1736, 1684, 1461, 1256, 1189, 1123 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 8.22 (s, 1H), 5.90 (d, J = 9.0 Hz, 1H), 5.04–4.99 (m, 1H), 4.71 (ddd, J = 8.5, 8.5, 4.5 Hz, 1H),
4.26 (ddd, J = 8.5, 4.5, 4.5 Hz, 1H), 3.23 (ddd, J = 7.0, 7.0, 4.0 Hz, 1H), 2.09–2.00 (m, 2H),
1.86–1.79 (m, 1H), 1.76–1.63 (m, 4H), 1.61–1.54 (m, 2H), 1.47–1.41 (m, 1H), 1.38–1.24 (m,
25H), 0.976 (d, J = 6.0 Hz, 3H), 0.964 (d, J = 6.0 Hz, 3H), 0.887 (t, J = 7.0 Hz, 3H), 0.879 (t, J =
7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.2, 170.9, 160.7, 74.4, 72.8, 56.8, 49.8, 41.9,
39.1, 34.2, 32.1, 31.7, 29.8, 29.7, 29.6, 29.5, 29.4, 29.1, 27.9, 27.0, 25.2, 25.1, 23.0, 22.9, 22.7,
22.1, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+: 518.3816, found
518.3843.
156
(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (II-41)
To a stirred solution of II-43 (16.0 mg, 26.6 µmol) in tetrahydrofuran (0.5 mL) at room
temperature was added Pd/C (10% wt/wt, 5.6 mg, 2.66 µmol) under N2. The resulting mixture
was then stirred at the same temperature under H2 (1 atm) for 1 h. The mixture was filtered
through a pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced
pressure. The residue was dissolved in dichloromethane (0.5 mL). Then a premixed mixture of
N,N-dicyclohexylcarbodiimide (27.3 mg, 133 µmol) and formic acid (3.0 µL, 79.8 µmol) in
dichloromethane (1 mL) was added to the solution. After 5 min, the mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 30% EtOAc in
hexanes) on silica gel (2 mL) to afford II-41 (7.9 mg, 60%) as a colorless oil.
157
Table S10. 1H NMR assignments of II-41. *δH (multiplicity, coupling constant (J) in Hz)
Position
Helv. Chim. Acta 1987,
70, 196.
(enantiomer) This Work
Synthesis 1994, 1294
(enantiomer)
CHO
(1H) 8.25 (s) 8.22 (s) 8.12 (s)
2''-NH
(1H) 5.97 (d, 8) 5.90 (d, 9.0) 5.94 (d, 7.7)
5
(1H) 5.06–4.94 (m) 5.04–4.99 (m) 5.02 (m)
2''
(1H) 4.71 (dt, 9.0, 9.0, 5.0) 4.71 (ddd, 8.5, 8.5, 4.5) 4.72 (ddd, 8.9. 8.6. 4.3)
3
(1H) 4.33–4.20 (m, 1H) 4.26 (ddd, 8.5, 4.5, 4.5) 4.27 (m)
2
(1H) 3.29–3.20 (m) 3.23 (ddd, J = 7.0, 7.0, 4.0) 3.25 (ddd, 5.3, 4.2, 1.4)
4, 4a
(2H) 2.09–2.00 (m) 2.09–2.00 (m) 2.05 (m)
CH2
(33H) 1.87–1.04 (m) 1.86–1.79 (m, 1H) 1.70 (m, 7H)
1.76–1.63 (m, 4H) 1.30 (m, 26H)
1.61–1.54 (m, 2H)
1.47–1.41 (m, 1H)
1.38–1.24 (m, 25H)
5'', 5'''
(6H) 1.03–0.93 (m) 0.976 (d, 6.0, 3H) 0.982 (d, 6.2, 3H)
16, 6'
(6H)
0.964 (d, 6.0, 3H) 0.968 (d, 6.2, 3H)
0.93–0.78 (m) 0.887 (t, 7.0, 3H), 0.88 (m)
0.879 (t, 7.0, 3H);
158
Position Synthesis 1994, 1294 This Work
1, 1'' 172.2 172.2
170.8 170.9
1''' 160.7 160.7
3, 5 74.3 74.4
72.8 72.8
2, 2'' 56.8 56.8
49.8 49.8
4, 6, 9
12, 13, 14, 1', 2', 3'
4', 3'',
41.9 41.9
39.1 39.1
34.2 34.2
32.1 32.1
31.6 31.7
29.9 29.8
29.8 29.7
29.7 29.6
29.6 29.5
29.5 29.4
29.1 29.1
7, 8, 10, 11
27.8 27.9
26.9 27.0
25.1 25.2, 25.1
23.0 23.0
4'' 22.8 22.9
5'' 5'''
15, 5'
22.7 22.7
22.1 22.1
16, 6' 14.3 14.3
14.1 14.2
Table S11. 13
C NMR assignments of II-41.
159
(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (II-41)
To a stirred solution of II-43 (16.0 mg, 26.6 µmol) in tetrahydrofuran (0.5 mL) at room
temperature was added Pd/C (10% wt/wt, 5.6 mg, 2.66 µmol) under N2. The resulting mixture
was then stirred at the same temperature under H2 (1 atm) for 1 h. The mixture was filtered
through a pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced
pressure. The residue was dissolved in dichloromethane (0.5 mL). Then a premixed mixture of
N,N-dicyclohexylcarbodiimide (27.3 mg, 133 µmol) and formic acid (3.0 µL, 79.8 µmol) in
dichloromethane (1 mL) was added to the solution. After 5 min, the mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 30% EtOAc in
hexanes) on silica gel (2 mL) to afford II-41 (7.9 mg, 60%) as a colorless oil.
(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl 4-methylpentanoate (II-42)
The general procedure for carbonylation of epoxides was followed using II-36 (12.8 mg, 0.0301
mmol), [ClTPPAl]+[Co(CO)4]
− (0.8 mg, 0.0007 mmol, 2 mol %) and tetrahydrofuran (0.10) mL
for 24 hours. The crude residue was purified by preparative HPLC to afford II-42 (7.2 mg, 53%)
as a colorless oil.
160
Data for II-42: Rf = 0.29 (10% Et2O in hexanes); [α]D21
= +16.4 (CHCl3, c = 0.52); IR (neat)
2925, 2855, 1826, 1736, 1466, 1378, 1269, 1178, 1121 cm-1
; 1H NMR (400 MHz, CDCl3) δ 4.96
(dddd, J = 7.2, 7.2, 5.2, 5.2 Hz, 1H), 4.26 (ddd, J = 8.8, 4.4, 4.4 Hz, 1H), 3.24 (ddd, J = 7.6, 7.6,
4.0 Hz, 1H), 2.32–2.28 (m, 2H), 2.10–1.97 (m, 2H), 1.85–1.75 (m, 1H), 1.74–1.67 (m, 1H),
1.61–1.44 (m, 5H), 1.34–1.24 (m, 26H), 0.92–0.86 (m, 12H); 13
C NMR (100 MHz, CDCl3) δ
173.7, 171.2, 74.9, 71.1, 56.9, 39.3, 34.6, 34.0, 32.8, 32.1, 31.7, 29.8, 29.71, 29.66, 29.54, 29.2,
27.92, 27.87, 27.0, 25.2, 22.9, 22.7, 22.4, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for
C28H52O4Na [M Na]+: 475.3758, found 475.3733.
(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate
(ent-II-43)
The general procedure for carbonylation of epoxides was followed using ent-II-34 (83.0 mg,
0.145 mmol), [ClTPPAl]+[Co(CO)4]
− (3.2 mg, 0.0029 mmol, 2.0 mol %) and tetrahydrofuran
(0.30) mL for 24 hours. The crude residue was purified by preparative HPLC to afford ent-II-43
(70.2mg, 80%) as a colorless oil.
Data for ent-II-43: Rf = 0.24 (10% EtOAc in hexanes); [α]D21
= +8.2 (CHCl3, c = 0.76); IR
(neat) 3348, 2926, 2855, 1823, 1729, 1525, 1467, 1336, 1263, 1219, 1171, 1120, 1050 cm-1
; 1H
NMR (400 MHz, CDCl3) δ 7.38–7.31 (m, 5H), 5.11 (s, 2H), 5.09 (d, J = 8.4 Hz, 1H), 5.01–4.96
(m, 1H), 4.36 (ddd, J = 8.8, 8.8, 4.8 Hz, 1H), 4.27–4.23 (m, 1H), 3.21 (ddd, J = 7.2, 7.2, 4.0 Hz,
1H), 2.02–1.99 (m, 2H), 1.83–1.76 (m, 1H), 1.74–1.67 (m, 2H), 1.66–1.57 (m, 3H), 1.55–1.49
(m, 1H), 1.46–1.40 (m, 1H), 1.36–1.24 (m, 25H), 0.97 (m, 6H), 0.89 (m, 6H); 13
C NMR (100
161
MHz, CDCl3) δ 172.7, 171.0, 156.1, 136.4, 128.7, 128.4,128.2, 74.4, 72.5, 67.2, 56.9, 52.9, 41.9,
39.2, 34.3, 32.1, 31.7, 29.80, 29.73, 29.64, 29.52, 29.51, 29.1, 27.8, 26.9, 25.2, 25.0, 23.1, 22.9,
22.7, 22.0, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C36H59NO6Na [M Na]+: 624.4235,
found 624.4243.
(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate
(II-43)
To a stirred solution of II-4b (20.0 mg, 56.4 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was
added triphenylphosphine (44.4 mg, 169 µmol) and N-Cbz-D-Leu-OH (44.8 mg, 169 µmol)
under N2. A solution of diisopropyl azodicarboxylate (36.3 mg, 169 µmol) in tetrahydrofuran
(0.5 mL) was added slowly via syringe. The resulting mixture was stirred at the same
temperature for 0.5 h. The reaction was quenched by adding water (5 mL), and extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash chromatography (2.5 to 15% EtOAc in hexanes) on silica gel (10 mL) to afford II-43 (28.0
mg, 82%) as a colorless oil.
Data for II-43: Rf = 0.24 (10% EtOAc in hexanes); [α]D21
= –10.0 (CHCl3, c = 0.79); IR (neat)
3349, 2927, 2857, 1823, 1728, 1524, 1461, 1260, 1217, 1121, 1051 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 7.38–7.31 (m, 5H), 5.11 (s, 2H), 5.09 (d, J = 8.5 Hz, 1H), 5.01–4.96 (m, 1H), 4.35
(ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 4.27–4.23 (m, 1H), 3.20 (ddd, J = 7.5, 7.5, 4.5 Hz, 1H), 2.01–
1.99 (m, 2H), 1.83–1.76 (m, 1H), 1.74–1.67 (m, 2H), 1.66–1.57 (m, 3H), 1.55–1.49 (m, 1H),
162
1.46–1.40 (m, 1H), 1.36–1.24 (m, 25H), 0.963 (d, J = 6.0 Hz, 3H), 0.951 (d, J = 6.0 Hz, 3H),
0.880 (t, J = 7.0 Hz, 3H), 0.877 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.7, 171.0,
156.1, 136.4, 128.7, 128.4, 128.2, 74.4, 72.5, 67.1, 56.8, 52.9, 41.9, 39.2, 34.3, 32.1, 31.7, 29.80,
29.73, 29.64, 29.52, 29.50, 29.1, 27.8, 26.9, 25.2, 25.0, 23.1, 22.9, 22.7, 22.0, 14.3, 14.2;
MALDI-TOF/CCA-HRMS calcd for C36H59NO6Na [M Na]+: 624.4235, found 624.4250.
(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate
(ent-II-44)
The general procedure for carbonylation of epoxides was followed using II-37 (87.3 mg, 0.152
mmol), [ClTPPAl]+[Co(CO)4]
− (3.3 mg, 0.0030 mmol, 2.0 mol %) and tetrahydrofuran (0.30)
mL for 24 hours. The crude residue was purified by preparative HPLC to afford ent-II-44 (68.2
mg, 74%) as a colorless oil.
Data for ent-II-44: Rf = 0.24 (10% EtOAc in hexanes); [α]D22
= +17.3 (CHCl3, c = 1.10); IR
(neat) 3349, 2926, 2855, 1823, 1725, 1521, 1467, 1336, 1265, 1221, 1199, 1122, 1049 cm-1
; 1H
NMR (400 MHz, CDCl3) δ 7.38–7.30 (m, 5H), 5.12 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 5.05–5.00
(m, 1H), 4.36–4.29 (m, 2H), 3.21 (ddd, J = 7.2, 7.2, 4.0 Hz, 1H), 2.08–1.99 (m, 2H), 1.83–1.68
(m, 3H), 1.64–1.49 (m, 4H), 1.48–1.42 (m, 1H), 1.39–1.24 (m, 25H), 0.97–0.95 (m, 6H), 0.89–
0.86 (m, 6H); 13
C NMR (100 MHz, CDCl3) δ 173.1, 171.2, 156.2, 136.4, 128.7, 128.4, 128.2,
74.5, 72.4, 67.2, 56.9, 52.9, 41.9, 39.5, 34.4, 32.1, 31.7, 29.80, 29.68, 29.64, 29.52, 29.46, 29.1,
27.8, 26.9, 25.2, 25.0, 23.1, 22.9, 22.7, 22.0, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for
C36H59NO6Na [M Na]+: 624.4235, found 624.4250.
163
(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate
(II-44)
To a stirred solution of II-4b (18.0 mg, 50.8 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was
added triphenylphosphine (40.0 mg, 152 µmol) and N-Cbz-D-Leu-OH (40.3 mg, 152 µmol)
under N2. A solution of diisopropyl azodicarboxylate (33 µL, 152 µmol) in tetrahydrofuran (0.5
mL) was added slowly via syringe. The resulting mixture was stirred at the same temperature for
0.5 h. The reaction was quenched by adding water (5 mL), and extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude residue was purified by flash
chromatography (5 to 15% EtOAc in hexanes) on silica gel (10 mL) to afford II-44 (22.0 mg,
72%) as a colorless oil.
Data for II-44: Rf = 0.24 (10% EtOAc in hexanes); [α]D21
= –26.2 (CHCl3, c = 0.51); IR (neat)
3356, 2926, 2855, 1823, 1720, 1523, 1467, 1335, 1263, 1221, 1198, 1171, 1121, 1050 cm-1
; 1H
NMR (500 MHz, CDCl3) δ 7.38–7.30 (m, 5H), 5.12 (d, J = 8.5 Hz, 1H), 5.10 (s, 2H), 5.05–5.00
(m, 1H), 4.36–4.29 (m, 2H), 3.21 (ddd, J = 8.0, 8.0, 4.0 Hz, 1H), 2.08–1.99 (m, 2H), 1.83–1.68
(m, 3H), 1.63–1.49 (m, 4H), 1.48–1.42 (m, 1H), 1.39–1.24 (m, 25H), 0.97–0.95 (m, 6H), 0.89–
0.86 (m, 6H); 13
C NMR (100 MHz, CDCl3) δ 173.1, 171.2, 156.2, 136.4, 128.7, 128.4, 128.2,
74.5, 72.4, 67.2, 56.9,, 52.9, 41.9, 39.5, 34.4, 32.1, 31.7, 29.81, 29.69, 29.64, 29.52, 29.47, 29.2,
27.8, 26.9, 25.2, 25.0, 23.1, 22.9, 22.7, 22.0, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for
C36H59NO6Na [M Na]+: 624.4235, found 624.4216.
164
Thermolysis of II-40 and II-40a
To a resealed tube was added β-lactone II-40 and II-40a (as a 2:1 mixture, 5.6 mg, 11.3 µmol).
The tube was sealed under Ar, and heated to 230 °C for 1 h. The crude residue was purified by
flash chromatography (30% EtOAc in hexanes) on silica gel (3 mL) to afford II-45 (2.6 mg,
51%) as a colorless oil.
Data for II-45: 1H NMR (500 MHz, CDCl3) 8.21 (s, 1H), 5.94 (d, J = 8.5 Hz, 1H), 5.47 (ddd, J =
15.0, 7.0, 7.0 Hz, 1H), 5.31 (ddd, J = 15.0, 7.0, 7.0 Hz, 1H); 4.88 (ddd, J = 13.0, 6.5, 6.5 Hz,
1H), 4.70 (ddd, J = 8.5, 8.5, 5.0 Hz), 2.30–2.21 (m, 2H), 1.99–1.95 (m, 2H), 1.72–1.63 (m, 2H),
1.57–1.51 (m, 3H), 1.33–1.24 (m, 26H), 0.97 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.89–
0.86 (m, 6H); 13
C NMR (100 MHz, CDCl3) δ 172.4, 160.5, 134.6, 124.5, 75.8, 49.8, 42.3, 37.4,
33.4, 32.8, 32.1, 31.9, 29.83, 29.73, 29.69, 29.54, 29.0, 25.4, 25.1, 23.0, 22.88, 22.84, 22.2,
14.30, 14.28. (For complete characterization see below)
(R,E)-Henicos-7-en-10-yl formyl-L-leucinate (II-45)
To a stirred solution of II-46 (49.0 mg, 158 µmol) in tetrahydrofuran (1 mL) at 0 °C was added
triphenylphosphine (82.9 mg, 316 µmol) and N-formyl-L-Leu-OH (50.3 mg, 316 µmol) under
N2. A solution of diisopropyl azodicarboxylate (71 µL, 316 µmol) in tetrahydrofuran (1 mL) was
added slowly via syringe. The resulting mixture was stirred at the same temperature for 2 h. The
165
reaction was quenched by adding water (5 mL), and extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography (5
to 15% EtOAc in hexanes) on silica gel (15 mL) to afford II-45 (49.0 mg, 69%) as a colorless
oil.
Data for II-45: Rf = 0.28 (20% EtOAc in hexanes); [α]D21
= +4.0 (CHCl3, c = 1.35); IR (neat)
3293, 2925, 2855, 1739, 1666, 1530, 1467, 1380, 1273, 1252, 1195, 1144 cm-1
; 1H NMR (400
MHz, CDCl3) 8.20 (s, 1H), 6.05 (d, J = 8.8 Hz, 1H), 5.46 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 5.30
(ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 4.87 (ddd, J = 12.4, 6.4, 6.4 Hz, 1H), 4.69 (ddd, J = 8.4, 8.4, 6.0
Hz, 1H); 2.62–2.63 (m, 2H), 2.02–1.94 (m, 2H), 1.71–1.61 (m, 2H), 1.59–1.49 (m, 3H), 1.35–
1.24 (m, 26H), 0.97–0.93 (m, 6H), 0.89–0.85(m, 6H); 13
C NMR (100 MHz, CDCl3) δ 172.4,
160.6, 134.6, 124.4, 75.8, 49.8, 42.3, 37.4, 33.3, 32.7, 32.1, 31.9, 29.80, 29.70, 29.66, 29.55,
29.51, 29.0, 25.4, 25.0, 23.0, 22.9, 22.8, 22.2, 14.3; MALDI-TOF/CCA-HRMS C28H53NO3Na
[M Na]+: 474.3918, found 474.3916.
(S,E)-Henicos-7-en-10-ol (II-46)
To a stirred solution of II-7a (1.37 g, 6.05 mmol) in dichloromethane at room temperature was
added 1-octene (2.18 g, 19.5 mmol), followed by the Grubbs second-generation catalyst26
(275
mg, 0.32 mmol) under N2. The resulting mixture was degassed by two freeze−pump−thaw
cycles, and then heated to reflux. After 7.5 h, the mixture was concentrated, and the crude
residue was purified by flash chromatography (5 to 15% EtOAc in hexanes) on silica gel (40
mL) to afford II-46 (1.10 g, 59%, E:Z = 6:1) as a colorless oil.
166
Data for II-46: Rf = 0.22 (8% Et2O in hexanes); [α]D21
= –3.0 (CH2Cl2, c = 0.93); IR (neat) 3396,
2924, 2854, 1719, 1466, 1378, 1263, 1072 cm-1
; 1H NMR (400 MHz, CDCl3) δ 5.54 (ddd, J =
13.6, 6.8, 6.8 Hz, 1H), 5.40 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 3.62–3.54 (m, 1H), 2.26–2.19 (m,
1H), 2.08–1.99 (m, 3H), 1.47–1.40 (m, 3H), 1.36–1.24 (m, 25H), 0.89–0.86 (m, 6H); 13
C NMR
(100 MHz, CDCl3) δ 135.0, 126.0, 71.1, 40.9, 36.9, 32.9, 32.1, 31.9, 29.88, 29.86, 29.81, 29.6,
29.5, 29.0, 25.9, 22.9, 22.8, 14.32, 14.30; HRMS (EI) calcd for C21H42O [M]+: 310.3236, found
310.3245.
(R,Z)-Henicos-7-en-10-yl formyl-L-leucinate (II-47)
To a stirred solution of II-7b (32.4 mg, 104 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was added
triphenylphosphine (54.8 mg, 209 µmol) and N-formyl-L-Leu-OH (33.2 mg, 209 µmol) under
N2. A solution of diisopropyl azodicarboxylate (44 µL, 209 µmol) in tetrahydrofuran (0.5 mL)
was added slowly via syringe. The resulting mixture was stirred at the same temperature for 2 h.
The reaction was quenched by adding water (5 mL), and extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography (5
to 20% EtOAc in hexanes) on silica gel (15 mL) to afford II-47 (41.2 mg, 87%) as a colorless
oil.
Data for II-47: Rf = 0.28 (20% EtOAc in hexanes); [α]D22
= +12.8 (CHCl3, c = 1.26); IR (neat)
3293, 2925, 2855, 1739, 1667, 1530, 1467, 1380, 1332, 1273, 1252, 1195, 1144 cm-1
; 1H NMR
(400 MHz, CDCl3) 8.20 (s, 1H), 6.02 (d, J = 8.0 Hz, 1H), 5.52–5.45 (m, 1H), 5.33–5.26 (m, 1H),
167
4.89 (ddd, J = 12.0, 6.0, 6.0 Hz, 1H), 4.70 (ddd, J = 8.8, 8.8, 4.8 Hz, 1H), 2.38–2.25 (m, 2H),
2.04–1.99 (m, 2H), 1.74–1.62 (m, 2H), 1.58–1.51 (m, 3H), 1.34–1.24 (m, 26H), 0.97–0.93 (m,
6H), 0.89–0.86 (m, 6H); 13
C NMR (100 MHz, CDCl3) δ 172.5, 160.6, 133.3, 123.7, 75.9, 49.8,
42.3, 33.5, 32.1, 31.9, 29.8, 29.71, 29.68, 29.57, 29.52, 29.2, 27.6, 25.5, 25.0, 23.0, 22.9, 22.86,
22.81, 22.2, 14.3; MALDI-TOF/CCA-HRMS C28H53NO3Na [M Na]+: 474.3918, found
474.3903.
168
172.4 172.4 172.5
160.6 160.5 160.6
134.6 134.6 133.3
124.4 124.5 123.7
75.8 75.8 75.9
49.8 49.8 49.8
42.3 42.3 42.3
37.4 37.4 33.5
33.3 33.4 32.1
32.7 32.8 31.9
32.1 32.1
31.9 31.9
29.80–29.51 29.83–29.54 29.80–29.52
29.0 29.0 29.2
27.6
25.4 25.4 25.5
25.0 25.1 25.0
23.0 23.0 23.0
22.9
22.9 22.88 22.86
22.8 22.84 22.81
22.2 22.2 22.2
14.30 14.30 14.30
14.28 14.28 14.28
Table S12. 13
C NMR comparison of II-45 and II-47.
169
(R)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-D-leucinate (ent-II-26)
(R)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-L-leucinate (ent-II-27)
To a stirred solution of ent-II-23 (0.351 g, 1.08 mmol) in dichloromethane (2 mL) at room
temperature was added N-formyl-L-Leu-OH (0.189 g, 1.19 mmol), followed by N,N-
dicyclohexyl carbodiimide (0.443 g, 2.16 mmol) and 4-dimethylaminopyridine (5 mg). The
resulting mixture was stirred at the same temperature for 24 h. The mixture was diluted with
hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography (10 to 30% EtOAc in
hexanes) on silica gel (40 mL) to afford a mixture of ent-II-26 and ent-II-27 (0.42 g, 86%) as a
colorless oil. The product contained two isomers ent-II-26 and ent-II-27, which were separated
by HPLC for characterization.
Data for ent-II-26: Rf = 0.32 (30% EtOAc in hexanes); [α]D21
= +15.6 (CHCl3, c = 0.42); IR
(neat) 3296, 2926, 2857, 1739, 1670, 1523, 1462, 1380, 1251, 1195 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 8.21 (s, 1H), 6.07 (d, J = 9.0 Hz, 1H), 5.10 (dddd, J = 8.0, 8.0, 5.0, 4.5 Hz, 1H), 4.72
(ddd, J = 8.5, 8.5, 5.0 Hz, 1H), 2.93 (ddd, J = 7.5, 4.0, 4.0 Hz, 1H), 2.87 (ddd, J = 6.0, 6.0, 4.5
Hz, 1H), 1.87 (ddd, J = 14.5, 4.5, 4.5 Hz, 1H), 1.75–1.55 (m, 5H), 1.53–1.39 (m, 4H), 1.36–1.24
(m, 25H), 0.96 (d, J = 6.0 Hz, 3H), 0.95 (d, J = 6.0 Hz, 3H), 0.890 (t, J = 6.5 Hz, 3H), 0.876 (t, J
= 6.5 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 172.2, 160.8, 74.4, 56.4, 53.8, 49.9, 41.9, 34.3,
32.8, 32.1, 31.9, 29.81, 29.76, 29.66, 29.55, 29.54, 29.4, 28.1, 26.7, 25.4, 25.1, 23.0, 22.9, 22.8,
22.1, 14.3, 14.2; HRMS (ESI) calcd for C28H53NO4Na [M Na]+: 490.3867, found 490.3849.
170
Data for ent-II-27: Rf = 0.32 (30% EtOAc in hexanes); [α]D21
= –2.2 (CHCl3, c = 0.54); IR (neat)
3290, 2926, 2857, 1739, 1670, 1523, 1462, 1380, 1269, 1193 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 8.21 (s, 1H), 6.04 (d, J = 8.5 Hz, 1H), 5.09 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz, 1H), 4.73 (ddd, J =
8.5, 8.5, 5.0 Hz, 1H), 2.98 (ddd, J = 8.0, 4.0, 4.0 Hz, 1H), 2.90–2.87 (m, 1H), 1.88 (ddd, J =
14.5, 4.5, 4.5 Hz, 1H), 1.74–1.54 (m, 5H), 1.50–1.40 (m, 4H), 1.38–1.24 (m, 25H), 0.96 (d, J =
6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.887 (t, J = 7.0 Hz, 3H), 0.875 (t, J = 7.0 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 172.4, 160.7, 74.3, 56.4, 53.6, 49.7, 42.0, 34.0, 32.6, 32.1, 31.9,
29.81, 29.72, 29.66, 29.53, 29.47, 29.4, 28.1, 26.7, 25.5, 25.0, 23.1, 22.9, 22.8, 22.1, 14.30,
14.25; HRMS (ESI) calcd for C28H53NO4Na [M Na]+: 490.3867, found 490.3867.
171
Chapter 3. Total Synthesis of EBC-23
Tetradecanal (III-13)
To a stirred suspension of sulfur trioxide pyridine complex (107 g, 0.670 mol) in
dichloromethane/dimethyl sulfoxide (4:1, 500 mL) at 0 °C was added triethylamine (93.4 ml,
0.670 mol). After 15 min, a solution of 1-tetradecanol (50.0 g, 0.233 mol) in dichloromethane
(100 mL) was added to the mixture slowly via syringe. After 1 h at the same temperature, the
reaction was quenched by adding water, and extracted with dichloromethane (3 × 150 mL). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography (1
to 5% EtOAc in hexanes) on silica gel (500 mL) t-o afford III-13 (43.9 g, 89%) as a colorless
oil.
Data for III-13: Rf = 0.39 (10% Et2O in Hexanes); IR (neat) 2953, 2915, 2850, 2715, 1728,
1471, 1411 cm-1
; 1H NMR (500 MHz, CDCl3) δ 9.75 (t, J = 1.5 Hz, 1H), 2.41 (td, J = 7.5, 2.0
Hz, 2H), 1.65–1.59 (m, 2H), 1.32–1.24 (m, 20H), 0.87 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz,
CDCl3) δ 203.2, 44.1, 32.1, 29.84, 29.82, 29.76, 29.60, 29.54, 29.3, 22.9, 22.2, 14.3.76
1-((2S,4S,6S)-2-Phenyl-6-tridecyl-1,3-dioxan-4-yl)propan-2-one (III-16)
To a stirred solution of III-23 (0.776 g, 1.73 mmol) in tetrahydrofuran (5 mL) at –10 °C was
added a solution of methylmagnesium bromide (3 M, 0.87 mL, 2.60 mmol) in tetrahydrofuran
via syringe slowly under N2. The resulting mixture was stirred at the same temperature for 0.5 h.
172
The reaction was quenched by adding saturated aqueous ammonium chloride (20 mL) and
extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (5 to 10% EtOAc in hexanes) on silica gel (40 mL) to afford
III-16 (0.558 g, 80%) as a white solid.
Data for III-16: Rf = 0.26 (10% EtOAc in Hexanes); mp: 47–48 °C; [α]D22
= –3.3 (CHCl3, c =
3.4); IR (neat) 2914, 2849, 1724, 1692, 1470, 1452, 1404, 1344, 1137, 1123, 1098, 1056, 1019
cm-1
; 1H NMR (500 MHz, CDCl3) δ 7.49–7.47 (m, 2H), 7.37–7.29 (m, 3H), 5.55 (s, 1H), 4.32
(dddd, J = 9.5, 8.0, 6.0, 2.5 Hz, 1H), 3.84 (dddd, J = 10.0, 7.5, 5.0, 2.5 Hz, 1H), 2.87 (dd, J =
16.0, 7.0 Hz, 1H), 2.56 (dd, J = 16.0, 6.0 Hz, 1H), 2.21 (s, 3H), 1.69 (ddd, J = 13.5, 2.5, 2.5 Hz,
1H), 1.70–1.63 (m, 1H), 1.55–1.44 (m, 2H), 1.42–1.35 (m, 2H), 1.32–1.25 (m, 20H), 0.89 (t, J =
7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 206.9, 138.7, 128.7, 128.3, 126.1, 100.7, 76.9, 73.2,
49.7, 36.9, 36.0, 32.1, 31.4, 29.81, 29.76, 29.73, 29.5, 25.2, 22.8, 14.3; MALDI-TOF/CCA-
HRMS calcd for C26H42O3Na [M Na]+: 425.3026, found 425.3055.
(S)-Heptadec-1-en-4-ol (III-18)
To a stirred solution of III-13 (18.5 g, 87.1 mmol) in dichloromethane (150 mL) at 0 °C was
added a solution of (S,S)-Leighton reagent (58.3 g, 105 mmol) in dichloromethane (50 mL) via
syringe, followed by followed by scandium triflate (1.07 mg, 2.18 mmol) under N2. The resulting
mixture was stirred at the same temperature for 20 h. The reaction was quenched by adding 1 N
hydrochloric acid (100 mL). The formed solid was filtered through a fritted funnel, and the
173
filtrate was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (2.5 to 10% EtOAc in hexanes) on silica gel (250
mL) to afford III-18 (16.1 g, 73%) as a white solid.
Data for III-18: Rf = 0.33 (10% EtOAc in Hexanes); mp: 29–30 °C; [α]D21
= –4.0 (CHCl3, c =
0.61); IR (neat) 3331, 2955, 2922, 2851, 1642, 1470, 1341, 1264, 1070 cm-1
; 1H NMR (500
MHz, CDCl3) δ 5.87–5.79 (m, 1H), 5.14–5.11 (m, 2H), 3.66–3.61 (m, 1H), 2.32–2.27 (m, 1H),
2.16–2.10 (m, 1H), 1.64–1.58 (m, 1H), 1.48–1.42 (m, 3H), 1.32–1.22 (m, 20H), 0.88 (t, J = 7.0
Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 135.1, 118.3, 70.8, 42.1, 37.0, 32.1, 29.85, 29.80, 29.6,
25.9, 22.9, 14.3.77
Methyl (S)-3-(furan-2-yl)-3-hydroxypropanoate (III-19)
To a stirred suspension of III-24 (111 mg, 0.660 mol) in water (400 mL) at room temperature
was added sodium formate (449 g, 6.60 mol), followed by cetyl trimethylammonium bromide
(24.1 g, 66.0 mmol) and (S)-RuCl[(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2](η6-mesitylene) (1.02
g, 1.65 mmol). The mixture was stirred at the same temperature for 3 d. The mixture was
extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (10 to 40% EtOAc in hexanes) on silica gel (400 mL) to afford
III-19 (112 g, 99%) as a pale yellow oil.
Data for III-19: Rf = 0.35 (40% EtOAc in Hexanes); [α]D22
= –30.5 (CHCl3, c = 2.72); IR (neat)
3447, 2955, 1734, 1505, 1439, 1363, 1286, 1213, 1266, 1066, 1032, 1012 cm-1
; 1H NMR (500
174
MHz, CDCl3) δ 7.36 (d, J = 1.5 Hz, 1H), 6.32 (dd, J = 3.5, 2.0 Hz, 1H), 6.26 (d, J = 3.5 Hz, 1H),
5.13 (dd, J = 8.5, 4.0 Hz, 1H), 3.71 (s, 3H), 3.08 (br s, 1H), 2.89 (dd, J = 16.0, 8.0 Hz, 1H), 2.82
(dd, J = 16.0, 4.0 Hz, 1H); 13
C NMR (100 MHz, CDCl3) δ 172.5, 154.8, 142.4, 110.4, 106.5,
64.2, 52.1, 39.7.78
Ethyl (S,E)-5-hydroxyoctadec-2-enoate (III-21)
To a stirred solution of III-18 (14.6 g, 57.3 mmol) in dichloromethane (20 mL) at room
temperature was added ethyl acrylate (123 mL, 1.15 mol), followed by the Grubbs second-
generation catalyst (486 mg, 0.573 mmol) under N2. The resulting mixture was degassed by two
freeze−pump−thaw cycles, then warmed to room temperature and stirred at the same
temperature. After 16 h, the mixture was diluted with hexanes (400 mL), and purified by flash
chromatography (2.5 to 20% EtOAc in hexanes) on silica gel (400 mL) to afford III-21 (11.7 g,
63%) as a white solid.
Data for III-21: Rf = 0.29 (20% EtOAc in Hexanes); mp: 31–33 °C; [α]D21
= +2.5 (CHCl3, c =
1.01); IR (neat) 3404, 2955, 2918, 2849, 1723, 1695, 1655, 1472, 1369, 1332, 1319, 1177, 1072
cm-1
; 1H NMR (500 MHz, CDCl3) δ 6.97 (ddd, J = 15.0, 7.5, 7.5 Hz, 1H), 5.90 (ddd, J = 15.0,
1.5, 1.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.75 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz, 1H), 2.40 (dddd,
J = 14.0, 7.0, 4.5, 1.5 Hz, 1H), 2.31 (dddd, J = 14.0, 8.0, 8.0, 1.5 Hz, 1H), 1.65 (s, 1H), 1.50–
1.39 (m, 4H), 1.33–1.22 (m, 20H), 1.28 (t, J = 7.0 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H); 13
C NMR
(100 MHz, CDCl3) δ 166.5, 145.4, 124.0, 70.8, 60.5, 40.4, 37.3, 32.1, 29.86, 29.83, 29.82, 29.76,
29.73, 29.53, 25.8, 22.9, 14.4, 14.3; MALDI-TOF/CCA-HRMS calcd for C20H38O3Na [M
Na]+: 349.2713, found 349.2703.
175
Ethyl 2-((2S,4S,6S)-2-phenyl-6-tridecyl-1,3-dioxan-4-yl)acetate (III-22)
To a stirred solution of III-21 (1.22 g, 3.74 mmol) in tetrahydrofuran (10 mL) at 0 °C was added
benzaldehyde (0.38 mL, 3.73 mmol), followed by potassium tert-butoxide (42.0 mg, 0.373
mmol) under N2. The resulting mixture was stirred for 15 min. Then the addition of
benzaldehyde/ potassium tert-butoxide was repeated two more times. The mixture was passed
through a pad of silica gel, and the silica gel was washed with EtOAc (30 mL). The filtrate was
concentrated, and the crude residue was purified by flash chromatography (5% EtOAc in
hexanes) on silica gel (80 mL) to afford III-22 (0.936 g, 58%) as a white solid.
Data for III-22: Rf = 0.33 (10% Et2O in Hexanes); mp: 38–40 °C; [α]D23
= –5.2 (CHCl3, c =
3.31); IR (neat) 2925, 2854, 1738, 1466, 1456, 1372, 1346, 1177, 1149, 1114, 1028 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.51–7.48 (m, 2H), 7.37–7.30 (m, 3H), 5.56 (s, 1H), 4.31 (dddd, J
= 11.0, 6.5, 6.5, 2.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.84 (dddd, J = 11.0, 7.0, 5.0, 2.0 Hz, 1H),
2.73 (dd, J = 15.5, 7.0 Hz, 1H), 2.51 (dd, J = 15.5, 6.0 Hz, 1H), 1.73 (ddd, J = 13.0, 2.5, 2.5 Hz,
1H), 1.72–1.64 (m, 1H), 1.56–1.38 (m, 4H), 1.33–1.26 (m, 23H), 0.90 (t, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 171.0, 138.8, 128.7, 128.3, 126.2, 100.7, 73.4, 60.7, 41.2, 36.7,
36.0, 32.1, 29.82, 29.78, 29.74, 29.5, 25.2, 22.9, 14.4, 14.3; MALDI-TOF/CCA-HRMS calcd for
C27H44O4Na [M Na]+: 455.3132, found 455.3162.
176
N-methoxy-N-methyl-2-((2S,4S,6S)-2-phenyl-6-tridecyl-1,3-dioxan-4-yl)acetamide (III-23)
To a stirred solution of III-22 (1.85 g, 4.42 mmol) in tetrahydrofuran (16 mL) at –10 °C was
added N,O-dimethylhydroxylamine hydrochloride (0.647 g, 6.63 mmo), followed by a solution
of isopropylmagnesium chloride in tetrahyrofuran (2 M, 6.65 mL, 13.3 mmol) via syringer
slowly under N2. The resulting mixture was stirred at the same temperature for 30 min. The
reaction was quenched by adding saturated aqueous ammonium chloride (20 mL) and extracted
with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (10 to 30% EtOAc in hexanes) on silica gel (80 mL) to afford
III-23 (1.60 g, 81%) as a colorless oil.
Data for III-23: Rf = 0.32 (30% EtOAc in Hexanes); [α]D24
= –16.3 (CHCl3, c = 1.36); IR (neat)
2924, 2853, 1667, 1458, 1388, 1342, 1117, 1027 cm-1
; 1H NMR (500 MHz, CDCl3) δ 7.50–7.48
(m, 2H), 7.37–7.28 (m, 3H), 5.57 (s, 1H), 4.38 (dddd, J = 11.0, 7.0, 7.0, 2.5 Hz, 1H), 3.85 (dddd,
J = 11.0, 7.0, 5.0, 2.0 Hz, 1H), 3.67 (s, 3H), 3.20 (s, 3H), 2.98 (dd, J = 15.5, 6.0 Hz, 1H), 2.55
(dd, J = 15.5, 6.0 Hz, 1H), 1.80 (ddd, J = 13.0, 2.5, 2.5 Hz, 1H), 1.71–1.65 (m, 1H), 1.55–1.36
(m, 4H), 1.34–1.24 (m, 20H), 0.88 (t, J = 7.0 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ 171.6,
138.9, 128.7, 128.3, 126.3, 100.8, 76.9, 73.7, 61.6, 38.4, 37.1, 36.1, 32.1, 29.85, 29.79, 29.76,
29.5, 25.2, 22.9, 14.3; MALDI-TOF/CCA-HRMS calcd for C27H45O4NNa [M Na]+: 470.3241,
found 470.3250.
177
Methyl 3-(furan-2-yl)-3-oxopropanoate (III-24)
To a flask with oil-free sodium hydride (83.5 g, 2.09 mol) was added tetrahydrofuran (600 mL)
followed by dimethyl carbonate (141 g, 1.67 mol) and potassium hydride (2.05 g, 50.0 mmol).
The mixture was heated to reflux. A solution of 2-acetylfuran II-20 (83.6 mL, 0.835 mol) in
tetrahydrofuran (200 mL) was added slowly via syringe. After addition, the reflux was continued
for 40 min. The reaction was quenched by pouring into a cooled mixture of acetic acid/water
(1:2, 500 mL) slowly. The mixture was extracted with EtOAc/hexanes (1:1, 3 × 200 mL). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash chromatography
(10 to 40% EtOAc in hexanes) on silica gel (600 mL) to afford III-24 (120.8 g, 84%) as a pale
yellow oil.
Data for III-24: Rf = 0.33 (30% EtOAc in Hexanes); IR (neat) 2956, 2922, 2851, 1740, 1677,
1568, 1465, 1438, 1283, 1167, 1016 cm-1
; 1H NMR (500 MHz, CDCl3) δ 7.61 (dd, J = 2.0, 1.0
Hz, 1H), 7.28 (dd, J = 4.0, 0.5 Hz, 1H), 6.58 (dd, J = 3.5, 1.5 Hz, 1H), 3.86 (s, 2H), 3.74 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 181.1, 167.6, 152.0, 147.3, 118.6, 112.9, 52.7, 45.3.
64,65
Methyl 2-((2S)-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)acetate (III-25)
To a stirred solution of III-19 (5.30 g, 31.1 mmol) in tetrahydrofuran/water at 0 °C (4:1, 60 mL)
was added sodium bicarbonate (5.23 g, 62.3 mmol) and sodium acetate trihydrate (4.24 g, 31.1
178
mmol). Then N-bromosuccinimide (5.54 g, 31.1 mmol) was added in portions to the mixture.
After 30 min, the reaction was quenched by adding saturated aqueous solution of sodium
bicarbonate and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was used directly for next step.
Data for III-25: Rf = 0.37 (60% EtOAc in Hexanes); [α]D22
= –8.0 (CHCl3, c = 0.80); IR (neat)
3429, 2956, 1740, 1698, 1440, 1371, 1293, 1231, 1175, 1092, 1033 cm-1
; 1H NMR (500 MHz,
CDCl3) δ 6.91 (dd, J = 10.0, 3.5 Hz, 1H), 6.14 (d, J = 10.0 Hz, 1H), 5.63 (d, J = 3.5 Hz, 1H),
5.02 (dd, J = 7.5, 4.0 Hz, 1H), 3.70 (s, 3H), 3.01 (dd, J = 16.5, 3.5 Hz, 1H), 2.74 (dd, J = 16.5,
7.5 Hz, 1H); 13
C NMR (100 MHz, CDCl3) δ 195.0, 171.6, 144.7, 127.3, 87.9, 70.9, 52.2, 35.2;
MALDI-TOF/CCA-HRMS calcd for C8H10O3Na [M Na]+: 209.0420, found 209.0408.
Methyl (S)-2-(3,6-dioxo-3,6-dihydro-2H-pyran-2-yl)acetate (III-26)
To a stirred solution of III-25 (5.80 g, 31.1 mmol) in acetone (70 mL) at 0 °C was added Jones
reagent (2.5 M, 18.7 mL, 46.7 mmol) slowly via syringe. The resulting mixture was stirred at the
same temperature for 15 min. The reaction was quenched by adding isopropanol slowly and
filtered through Celite. The filtrate was extracted with EtOAc (3 × 80 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude residue was used directly for next step.
Data for III-26: Rf = 0.30 (70% EtOAc in Hexanes); [α]D21
= –41.5 (CHCl3, c = 1.67); IR (neat)
3437, 3071, 2958, 1731, 1622, 1440, 1372, 1265, 1212, 1112 cm-1
; 1H NMR (500 MHz, CDCl3)
179
δ 6.93 (d, J = 12.0 Hz, 1H), 6.85 (d, J = 12.0 Hz, 1H), 5.14 (t, J = 4.0 Hz, 1H), 3.70 (s, 3H), 3.25
(dd, J = 17.5, 4.5 Hz, 1H), 3.08 (dd, J = 17.5, 4.5 Hz, 1H); 13
C NMR (100 MHz, CDCl3) δ 191.9,
169.8, 160.2, 138.4, 135.5, 79.5, 52.5, 37.5; MALDI-TOF/CCA-HRMS calcd for C8H8O5Na [M
Na]+: 207.0264, found 207.0249.
Methyl 2-((2S,3R)-3-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetate (III-27)
To a stirred solution of III-26 (5.73 g, 31.1 mmol) in a mixed solvent of
dichloromethane/methanol (1:1, 100 mL) at –78 °C was added sodium boronhydride (1.77 g,
46.7 mmol). The resulting mixture was stirred at the temperature for 30 s. The reaction was
quenched by adding water (50 mL) and 1 N hydrochloride acid (50 mL) and extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash chromatography (30 to 80% EtOAc in hexanes) on silica gel (80 mL) to afford III-25 (2.16
g, 51%) as a white solid.
Data for III-27: Rf = 0.29 (70% EtOAc in Hexanes); mp: 115–117 °C; [α]D20
= –52.2 (MeOH, c
= 0.67); IR (neat) 3435, 2956, 2926, 1735, 1440, 1378, 1334, 1228, 1155, 1082, 1039 cm-1
;
1H NMR (500 MHz, CDCl3) δ 6.86 (dd, J = 10.0, 2.0 Hz, 1H), 5.99 (dd, J = 10.0, 2.0 Hz, 1H),
4.65 (ddd, J = 10.0, 6.0, 6.0 Hz, 1H), 4.51 (ddd, J = 8.0, 2.0, 2.0 Hz, 1H), 3.75 (s, 3H), 2.98 (br s,
1H), 2.93 (dd, J = 16.0, 5.5 Hz, 1H), 2.86 (dd, J = 16.0, 6.5 Hz, 1H); 13
C NMR (100 MHz,
CDCl3) δ 171.1, 162.6, 149.5, 120.3, 78.4, 66.3, 52.6, 37.6; MALDI-TOF/CCA-HRMS calcd for
C8H10O5Na [M Na]+: 209.0420, found 206.0407.
180
(2S,3S)-2-(2-Methoxy-2-oxoethyl)-6-oxo-3,6-dihydro-2H-pyran-3-yl 4-nitrobenzoate (III-
28)
To a stirred solution of III-27 (1.96 g, 10.6 mmol) in tetrahydrofuran (40 mL) at 0 °C was added
triphenylphosphine (5.71 g, 21.7 mmol) and 4-nitrobenzoic acid (3.55 g, 21.3 mmol) under N2. A
solution of diisopropyl azodicarboxylate (4.58 g, 21.3 mmol) in tetrahydrofuran (10 mL) was
added slowly via syringe. The resulting mixture was stirred at the same temperature for 1.5 h.
The reaction was quenched by adding saturated aqueous sodium bicarbonate (40 mL), and
extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (20 to 50% EtOAc in hexanes) on silica gel (80 mL) to afford
III-28 (2.60 g, 74%) as a white solid.
Data for III-28: Rf = 0.24 (40% EtOAc in Hexanes); mp: 112–114 °C; [α]D22
= +281.5 (CHCl3, c
= 1.89); IR (neat) 3114, 3080, 2999, 2956, 2856, 1731, 1609, 1530, 1439, 1343, 1267, 1099,
1014 cm-1
; 1H NMR (500 MHz, CDCl3) δ 8.30 (ddd, J = 8.5, 2.0, 2.0 Hz, 2H), 8.19 (ddd, J = 8.5,
2.0, 2.0 Hz, 2H), 7.13 (ddd, J = 10.0, 6.0 Hz, 1H), 7.32 (d, J = 10.0 Hz, 1H), 5.61 (dd, J = 5.5,
2.5 Hz, 1H), 5.14 (ddd, J = 7.0, 7.0, 2.5 Hz, 1H), 3.71 (s, 3H), 2.98 (dd, J = 16.5, 7.5 Hz, 1H),
2.85 (dd, J = 16.5, 7.0 Hz, 1H); 13
C NMR (100 MHz, CDCl3) δ 169.5, 163.8, 161.9, 151.1,
139.6, 134.0, 131.2, 125.8, 124.0, 75.1, 64.1, 52.5, 35.3; MALDI-TOF/CCA-HRMS calcd for
C15H13O8NNa [M Na]+: 358.0533, found 358.0560.
181
Methyl 2-((2S,3S)-3-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetate (III-29)
To a stirred solution of III-28 (2.40 g, 7.16 mml) in methanol/dichloromethane (3:1, 24 mL) at 0
°C was added triethylamine (2.00 mL, 14.3 mmol) in one portion via syringe under N2. The
resulting mixture was warmed to room temperature and stirred for 3 h. The mixture was
concentrated, and the crude residue was purified by flash chromatography (40 to 70% EtOAc in
hexanes) on silica gel (80 mL) to afford III-29 (0.705 g, 53%) as a white solid.
Data for III-29: Rf = 0.29 (70% EtOAc in Hexanes); [α]D21
= +11.7 (CHCl3, c = 0.57); IR (neat)
3422, 2955, 1732, 1440, 1384, 1257, 1181, 1092, 1051, 1002 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 7.02 (dd, J = 10.0, 6.0 Hz, 1H), 6.12 (d, J = 10.0 Hz, 1H), 4.83 (ddd, J = 6.5, 6.5, 2.5 Hz, 1H),
4.26 (ddd, J = 9.0, 6.0, 2.5 Hz, 1H), 3.73 (s, 3H), 2.98 (dd, J = 17.0, 7.0 Hz, 1H), 2.92 (dd, J =
17.0, 7.0 Hz, 1H), 2.86 (d, J = 9.5 Hz, 1H); 13
C NMR (100 MHz, CDCl3) δ 170.8, 163.4, 144.4,
122.8, 77.2, 61.5, 52.4, 35.0; MALDI-TOF/CCA-HRMS calcd for C8H10O5Na [M Na]+:
209.0420, found 209.0409.
Methyl 2-((2S,3S)-3-((tert-butyldimethylsilyl)oxy)-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetate
(III-30)
To a stirred solution of III-29 (0.705 g, 3.79 mmol) in dichloromethane (10 mL) at –78 °C was
added 2,6-lutidine (0.50 mL, 5.05 mmol), followed by trimethylsilyl trifluoromethanesulfonate
(0.80 mL, 4.42 mmol). The resulting mixture was stirred at the same temperature for 30 min. The
182
reaction was quenched by adding 1 N hydrochloric acid (50 mL) and extracted with EtOAc (3 ×
30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude residue was purified by flash
chromatography (5 to 20% EtOAc in hexanes) on silica gel (70 mL) to afford III-30 (0.480 g,
42%) as a white solid.
Data for III-30: Rf = 0.29 (20% EtOAc in Hexanes); [α]D21
= +178.2 (CHCl3, c = 1.76); IR
(neat) 2955, 2858, 1731, 1440, 1386, 1327, 1254, 1178, 1061 cm-1
; 1H NMR (500 MHz, CDCl3)
δ 6.84 (dd, J = 9.5, 5.0 Hz, 1H), 6.08 (d, J = 9.5 Hz, 1H), 4.79 (ddd, J = 6.5, 6.5, 3.0 Hz, 1H),
4.33 (dd, J = 5.0, 2.5 Hz, 1H), 3.71 (s, 3H), 2.88 (dd, J = 17.0, 7.5 Hz, 1H), 2.84 (dd, J = 17.0,
6.5 Hz, 1H), 0.86 (s, 9H), 0.066 (s, 3H), 0.056 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 170.6,
162.9, 144.4, 122.5, 77.2, 61.9, 52.1, 34.8, 25.7, 18.1, –4.0, –4.9; MALDI-TOF/CCA-HRMS
calcd for C14H24O5NaSi [M Na]+: 323.1285, found 323.1270.
2-((2S,3S)-3-((tert-Butyldimethylsilyl)oxy)-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetic acid
(III-31)
To a stirred solution of III-30 (115 mg, 0.383 mmol) in tetrahydrofuran/water (4:1, 5 mL) at 0
°C was added lithium hydroxide monohydrate (32.0 mg, 0.766 mmol) in one portion. The
resulting mixture was stirred at the same temperature for 5 min. The reaction was quenched by
adding 1 N hydrochloric acid (1 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated
183
under reduced pressure. The crude residue was purified by flash chromatography (20 to 50%
EtOAc in hexanes) on silica gel (20 mL) to afford III-31 (82.0 mg, 75%) as a white solid.
Data for III-31: Rf = 0.29 (1% isopropanol in EtOAc); [α]D22
= +170.9 (CHCl3, c = 0.55);
IR (neat) 3034, 2936, 1742, 1709, 1432, 1255, 1194, 1069, 1098, 1033 cm-1
; 1H NMR (500
MHz, CDCl3) δ 6.50 (dd, J = 12.0, 7.0 Hz, 1H), 6.06 (dd, J = 12.0, 1.0 Hz, 1H), 5.84 (ddd, J =
6.5, 4.0, 1.5 Hz, 1H), 4.81 (dd, J = 4.5, 4.5 Hz, 1H), 2.80 (dd, J = 17.0, 5.0 Hz, 1H), 2.49 (d, J =
17.0 Hz, 1H), 0.85 (s, 9H), 0.033 (s, 3H), –0.012 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 175.5,
170.4, 147.7, 121.3, 82.2, 71.1, 39.8, 25.7, 18.1, –4.7, –5.0; MALDI-TOF/CCA-HRMS calcd for
C13H22O5NaSi [M Na]+: 309.1129, found 309.1143.
2-((2S,3R)-3-((tert-Butyldimethylsilyl)oxy)-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetyl chloride
(III-17)
To a stirre solution of III-31 (29.5 mg, 0.103 mmol) in dichloromethane (0.5 mL) at 0 °C was
added 1-chloro-N,N,2-trimethyl-1-propenylamine III-32 (27.4 µL, 0.206 mmol) under N2. The
resulting mixture was warmed to room temperature and stirred for 0.5 h. The mixture was diluted
with dichloromethane, washed with brine, dried with NaSO4, filtered and concentrated under
reduced pressure. The crude reside III-17 was used directly for next step.
184
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