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Chapter-I
A Flexible Enantioselective Total Synthesis of Diospongins A, B and their
Enantiomers Using Catalytic Hetero-Diel-Alder/Rh-catalyzed 1,4-Addition
and Asymmetric Transfer Hydrogenation Reactions as Key Steps.
Chapter I: A Flexible Enantioselective Total Synthesis of Diospongins A, B
and their Enantiomers Using Catalytic Hetero-Diels-Alder/Rh-catalyzed
1,4-Addition and Asymmetric Transfer Hydrogenation Reactions as Key
Steps.
Introduction
Cyclic ethers are a distinct class of molecules that are highly prevalent in nature. Many
such compounds, specifically those containing 2,6-disubstituted terahydropyran ring systems,
have been produced by microscopic living organisms.1 A variety of terahydropyran ring
systems have been isolated, slightly modified, and recognized as potential aids in the clinical
world. 2,6-disubstituted THPs are also synthetically useful intermediates in the production of
polysubstituted tetrahydropyran ring systems, such as those found in the pseudomonic acids
which are commonly used in skin antibiotics to fight infections including Staphylococcus
epidermidis.2 The wide variety of important applications of tetrahydropyran scaffolds
3 in the
biomedical world has made their synthesis a widely explored topic of research. Hence,
considerable attention has been focused on development of an efficient and stereocontrolled
synthetic routes to these key structural fragments.
Our group has embarked on the total synthesis of the substituted tetrahydropyran motif
containing natural products. It is worthwhile at this juncture to look briefly at a few
substituted tetrahydropyran molecules, which have been of paramount importance due to
their significant biological activity and also to the researchers who have been actively
involved in the synthesis of these natural products.
Phorboxazoles:
Phorboxazole A and B are the marine natural products isolated from a species of Indian
Ocean sponge (genus Phorbas sp.). Searlae and co-workers reported the isolation,
preliminary structural assignments and the results of initial bioassay of the phorboxazoles in
1995.4 Phorboxazole A is a C13 epimer of phorboxazole B. The complete structural
assignments for phorboxazoles A and B have resulted from the extensive NMR studies,
derivatisation and degradation-correlation studies. These substances were reported to be
extremely cytostatic towards the 60 tumor cell lines and having potent in vitro anti-fungal
activity against C. albicans and S. carlsbergensis. The complex and unique structures make a
distinction the phorboxazoles as a new class of natural products and they contain
unprecedented array of oxane, oxazole, polyene and macrolide moieties. The broad range of
activity against human cancer cell lines combined with cytostatic activity, structural novelty,
and limited availability make the phorboxazoles as important and challenging synthetic
targets (Figure 1).
O
OHMe
OMe
Br
OMe
O
NMe
O
Me
O
Me
N
O
O
X
Y
O
O
OH
Phorboxazole A: X = OH, Y = H Phorboxazole B: X = H, Y = OH
Figure 1, Phorboxazole A and B
(-)-Ratjadone:
In 1994, the polyketide ratjadone was isolated from cultures of Sorangium cellulosum strain
Soce360.5 Ratjadone displays potent in vitro antifungal activity with MIC values in the range
from 0.004 to 0.6 g/mL for Mucor hiemalis, Phytophthora drechsleri, Ceratocystis ulmi and
Monilia brunnea. Additionally, significant cytotoxicity in mammalian L929 cell lines (IC50
= 0.005 ng/mL) and Hela cell line KB3.1 (IC50 = 0.04 ng/mL) has been demonstrated6
(Figure 2).
O
OHO O
OH
Figure 2, (-)-Ratjadone
(-)-Zampanolide and (-)-Dactylolide:
In 1996 Higa and co-workers,7 isolated zampanolide (Figure 3) a novel macrolide that
exhibited significant activity against a variety of tumor cell lines. In particular, zampanolide
has proven to be active against the P388, A549, HT29 and MEL 28 cell lines with IC50
values ranging from 1 to 5 ng/mL.7 However, extensive biological tests have not been
performed because of the lack of material, as only 3.9 mg were isolated from 0.480 kg (wet
weight) of the marine sponge Fasciospongia rimosa. Riccio isolated a structurally related
compound, dactylolide (Figure 4) from the marine sponge Dactylospongia.8 However,
dactylolide only displayed a modest biological profile (63% and 40% inhibition of L1210 and
SK-OV-3 tumor cell lines at 3.2 g/mL) with respect to that of zampanolide, thus suggesting
that the N-acyl hemiaminal side-chain resident in zampanolide is required for the impressive
biological activity.
O
OO
OH
NH
OO
O
OO
OO
Figure 3, (-)-Zampanolide Figure 4, (-)-Dactylolide
(-)-Lasonolide A:
Lasonolide A, was isolated from shallow water Caribbean sponge; species of Forcepia.9 It
shows a potent activity against A-549 human lung carcinoma. Lee’s seminal synthetic work
included a correction of the structure and a reassignment of the absolute configuration.10
Lee
prepared the tetrahydropyran scaffold of lasonolide through a cyclisation with silyl ether.
Later, several other groups have synthesized the tetrahydropyran core of lasonolide A.11
Lasonolide A’s interesting structure, potent anticancer-activity and natural scarcity have
made it an attractive target for synthetic chemists (Figure 5).
O
OH
O
O
HO
OO
O
OH
Figure 5, (-)-Lasonolide A
(-)-Kendomycin:
(-)-Kendomycin, a novel macrocyclic polyketide first isolated in 1996 from Streptomyces
violaceoruber, possesses potent activity as both an endothelin receptor antagonist and an anti-
osteoporotic agent.12
Reisolation by the Zeeck group13
revealed, in addition, significant
antibacterial activity against multiresistant bacteria, including vancomycin–resistant strains
and remarkable cytotoxicity against a series of human tumor cell line (GI50 < 0.1 M). The
impressive biological profile, in conjunction with the challenging architecture, defined by X-
ray and Mosher ester analysis, triggered considerable synthetic efforts,14
culminating in 2004
with the first total synthesis.15
The structure of kendomycin comprises a unique quinone-
methide-lactol chromophore, attached to a densely substituted tetrahydropyran ring in
addition to an aliphatic ansa ring (Figure 6).
HO
O
O
O
HO
OH
Figure 6, (-)-Kendomycin
Polycarvernoside A:
Polycarvernoside A, a toxin isolated from the red alga Polycavernosatsudai.16
It is an unusual
13-membered macrolactone disaccharide assembled on a tetrahydropyran core bearing four
substituents each in an equatorial position (Figure 7). Three total syntheses of
polycarvernoside A have been achieved which utilize either a 6-epoxy cyclization of
protected trihydroxy-α,β-unsaturated esters17
or manipulation of a δ-lactone to construct the
THP core.18
A further valuable approach for the preparation of variously substituted THPs is
the acid-promoted Prins-type cyclization of an oxycarbenium ion generated in situ, from the
reaction of a homoallylic alcohol with an aldehyde or from a homoallylic acetal or α-acetoxy
ether. A number of reaction conditions have been employed to prepare C4 oxygenated THP
ring.19
O O
O
OO
O
HO
O
OMe
O
MeO
OMeOMe
OMe
Figure 7, Polycavernoside A
(+)-Neopeltolide:
(+)-Neopeltolide, is a marine macrolide belongs to the family Neopeltidae, and was isolated
by Wright et al. from a deep-water sponge collected off the northwest coast of Jamaica.20
Neopeltolide exhibits highly potent in vitro anti-proliferative activity against several cancer
cell lines with nano molar concentration (IC50 = 1.2, 5.1, and 0.56 nmol L-1
against the A-549
human lung adenocarcinoma, the NCI-ADR-RES human ovarian sarcoma, and the p388
murine leukaemia cells, respectively). Additionally, it also shows as potent antifungal activity
against pathogenic yeast Candida albicans. Kozmin and co-workers reported that
neopeltolide targets cytochrome bc1 complex and may inhibit mitochondrial ATP syntheses.21
The key structural features of neopeltolide include a 14-membered macrolactone ring,
containing a trisubstituted tetrahydropyran ring, and an oxazole-bearing unsaturated side
chain appended at C5 through an ester linkage. The complex macrolide structure and potent
biological activity of neopeltolide have stimulated a flurry of synthetic interest; as a result a
number of total syntheses 22
have been reported (Figure 8).
O
O
OO Me
OMe
Me
O
N
O
H H
HN
OOMe
1
5
9
13
Figure 8, (+)-Neopeltolide
(+)-Ambruticin:
Ambruticin is a novel antifungal agent that was isolated from fermentation extracts of the
myxobacterium Ployangium celluosum by Warner-lambert et. al. in 1977.36
It exhibits
pronounced activity against systemic medical pathogens such as Coccidioides immitis,
Histoplasma capsulatum, and Blastomyces dermatitidis.23
It is also displays potent inhibitory
activity against the yeast strain Hansenula anomala with an MIC of 0.03 µg/mL.24
The
relative stereochemistry of ambruticin have been established through a combination of
spectroscopic studies,25
chemical degradation, and single-crystal X-ray analysis.26
This
structurally intriguing molecule incorporates 10 stereocenters and 3 E-olefins within a
relatively small framework bearing a dihydropyran, a tetrahydropyran diol, and a
trisubstituted divinylcyclopropane unit unique to this family of natural products (Figure 9).27
The important structural features and potentially valuable biological activities have
stimulated considerable interest in the synthetic community28
and to date three total syntheses
have been reported.20-31
O
OH
OH
MeMe Me
O
Me
MeCO2H1
5
8
12 15
24
Figure 9, (+)-Ambruticin
(-)-Centrolobine:
(-)-Centrolobine, 6[β(p-hydroxyphenyl) ethyl]-2-(p-methyoxyphenyl) tetrahydropyran is a
crystalline substance isolated from the heartwood of Centrolobium robustum32
and from the
stem of Brosinum potabile33
in the amazon forest. (-)- Centrolobine is a 2,6-disubstituted
tetrahydropyran with antibiotic properties. Recently, (-)-centrolobine and related natural
products have been shown to be active against leishmania amazonenis promastigotes, a
parasite associated with leishmaniasis, a major health problem in Brazil. The basic structure
was elucidated in 1964 by total synthesis of the racemic methyl ether.32
The first
enantioselective total synthesis of (-)-centrolobine (Figure 10), which also served to elucidate
its absolute configuration by Colobert et. al.34
was appeared followed by several other
syntheses.35
O
MeO OH
Figure 10, (-)-Centrolobine
(-)-Diospongins:
(-)-Diospongin A and B are cyclic 1,7-diarylheptanoids, and they possess 2,6-cis and 2,6-
trans tetrahydro-2H pyran rings, respectively, and these rings are assumed to be formed by an
intramolecular cyclization of 5,7-dihydroxy-1,7-diphenyl-2-hepten-1-one, in their
biosynthesis (Figure 11).
Isolation & Biological activity:
Diospongin A and B (2 & 1) are isolated36
in 2003 from the rhizomes of Dioscorea spongiosa
along with Diospongin C 3 and three known lignans, piperitol 4, sesaminone 5 and (+)-
syringaresinol 6 (Figure 11). The water extracts of rhizomes of Dioscorea spongiosa was
chromatographed with a diaion HP-20 column, using a H2O-EtOH solvent system, to give
four (H2O and 30%, 60%, and 90% H2O-EtOH) fractions. They showed 11.2, 14.7, 86.7, and
89.5% stimulation of the proliferation of osteoblast-like UMR106 cell line at a concentration
of 200µg/mL, and all showed 100% inhibition of the formation of osteoclast-like
multinuclear cells at the same concentration. On the other hand, only the 90% H2O-EtOH
fraction inhibited the bone resorption induced by parathyroid hormone (PTH) in a bone organ
culture system at a concentration of 440µg/mL (82.8% inhibition). Thus this fraction was
further separated by a combination of normal and reversed-phase column chromatography
and preparative TLC, to afford 1 to 6 compounds.
O
O
O
O
HH
OCH3
OH
OO
O
CH2OHO
O
OO
O
HH
OCH3
OH
H3CO
HO
OCH3
OCH3
OR1 OR2 OR3 OR4
3, R1, R2, R3, R4 = H
3a, R1, R2 = H, R3, R4= C(CH3)3
3b, R1, R2, R3, R4 = C(CH3)3
O
N(CH3)2
3c, R3, R4 =
R3, R4 = C(CH3)3
O
OH
O
O
OH
O
(-)-Diospongin B, 1
(-)-Diospongin A, 2
4
5 6
7
5
3 1
7
5
3 1
Figure 11
Osteoporosis, the most frequent bone remodelling disease, is defined by a low bone mass
and high risk of fractures. It is caused by relative increase of osteoclastic bone resorption over
osteoblastic bone formation.37
Since ipriflavin (Figure 12) was approved for the treatment of
osteoporosis in the 1980’s, natural plants have been researched.
O
O
O
Figure 12, Ipriflavin
In traditional Chinese medicine, herbs that strengthen the kidney and bone can be used for
the treatment of bone diseases with the same symptoms as osteoporosis.38
The currently
available treatment, e.g., estrogen replacement treatment, is based on inhibition of bone
resorption to prevent further bone loss. Many osteoporotic patients, however, have already
lost a substantial amount of bone, and thus a method to increase bone mass by stimulating
new bone formation is needed.39
It is known that in bone formation, osteoblasts are the key
cell in bone matrix formation and calcification.40
Kadota and co-workers36
have screened
water and methanol extracts from 30 Chinese herbs that have effects on kidney and bone to
determine whether they influence the proliferation of the osteoblast like UMR 106 cell line.
As the excellent osteoporotic therapy should act on both formation and bone resorption, they
have also examined the effect of active extracts against the formation of tartrate-resistant acid
phosphatase (TRAP)-positive osteoclast-like multinucleated cells. Based on results of both
assays, the water extracts of rhizomes of Dioscorea spongiosa showed the strongest in vitro
antiosteoporotic activity. The same extract is used in traditional Chinese medicine for the
treatment of rheumatism, urethra, and renal infection.
Structural Elucidation:
OH
H
H
H
HO
H
Ph
H
H
7
6eq
6ax
5
4ax
4eq 3O H2'
H6'
Diospongin A, 2
Diospongin A, 2 showed a quasi-molecular ion, corresponding to the molecular formula
C19H20O3 on HR-FAB-MS. Its IR spectrum displayed the absorption of hydroxy (3450 cm-1
),
conjugated carbonyl (1695 cm-1
) functionalities including an aromatic ring (1610, 1495 cm-1
).
The 1H and
13C NMR spectra of 2 revealed the presence of three oxymethine, three
methylenes, two phenyl rings and a ketone carbonyl carbon. Extensive analysis of the 2D
NMR spectra suggested that 2 should be diarylheptanoid. The location of carbonyl carbon
was determined to be C-1 by the HMBC correlations between the aromatic protons H-2`, 6`
and the carbonyl carbon (δc = 198.4), while the HMBC correlations H-7 / C-2, 6 and H-2,
6/C-7 confirmed the other phenyl ring at C-7. The correlations H-3/C-7 and H-7 / C-3
indicated the presence of an ether linkage between C-3 and C-7. Thus, the structure of 2 was
determined as 1, 7-diphenyl-3, 7-epoxy-5-hydroxy-1-heptanone. The large coupling constants
between H-3 and H-4ax at δH = 1.67 (J = 11.2 Hz) and between H-7 and H-6ax at δH = 1.75
(J = 12.0 Hz) indicated that these protons should be axial while, H-5 was considered to be
equatorial form the small coupling constants with H2-4 and H2-6 (each J = 3.0 Hz). The
ROESY correlations H-3 / H-7, H-3/H4eq and H-4ax / H-6ax indicated that the pyran ring
had a chair conformation that H-3, H-4eq and H-7 are cis and that H-4ax and H-6ax are also
cis. Finally the absolute configuration at C-5 was determined to be S by the advanced Mosher
method. Thus the structure of diospongin A was established as (3R, 5S, 7S)-1,7-diphenyl-3,7-
epoxy-5-hydroxy-1-heptanone.
O
H
H
H
H
Ph
OH3
H
Ph
OH
H5
6eq
6ax 4ax
4eq
1
1
1
72
Diospongin B, 1
Correspondingly, the molecular formula of diospongin B, 1 was determined to be the same as
that of 2 by HR-FAB-MS. The 1H- and
13C-NMR spectra of 1 were very similar to those of 2,
except for slight differences in splitting patterns of H-4ax, H-5, H-6ax and H-7. Thus, 1 was
considered to be a diastereomer of 2, which was confirmed by the analysis of its 2D NMR
spectra. The coupling patterns of H-3, H-5 and H-7 indicated H-3 and H-5 to be axial and H-
7 to be equatorial. While the ROESY correlations H-3 / H-5, H-5 / H-6eq revealed that the
pyran ring should have a chair conformation. The analysis of the 1H-NMR spectra of its α-
methoxy- α-trifluoro methylphenylacetyl (MTPA) derivatives indicated the absolute
configuration at C-5 to be S. Thus, the structure of diospongin B, 1 was established as (3S,
5S, 7S)-1,7-diphenyl-3,7-epoxy-5-hydroxy-1-heptanone.
Contemporary works:
Jennings et al.41
not only achieved unambiguous total syntheses of both (-)-diospongins A, 2
and B, 1 but also validated the structures proposed by Kadota et. al..36
The synthetic protocol
along with preparation of key intermediate δ-lactone 11 is highlighted in Scheme 1. They
initially focused on the introduction of the bromoacetate functionality and consequently,
examined the stereoselective intramolecular Reformatsky lactone formation reaction
sequence. Thus, esterification of the free secondary hydroxyl of 742
(derived via a Keck
allylation of benzaldehyde in 92% ee) with bromoacetyl bromide in the presence of pyridine
provided 8. Ensuing oxidative cleavage via the modified Johnson-Lemieux protocol of the
terminal alkene in 8 furnished the extremely labile α-bromo acetyl aldehyde 9. Then, the
stage set for the intramolecular SmI2-mediated Reformatsky reaction.43
Accordingly, using
SmI2 generated Sm(III) enolate, which subsequently underwent an intramolecular aldol
reaction with a pendent aldehyde via a double six-membered transition state to furnish
selectively a β-hydroxylactone with exceptional diastereoselectivity44
in a low 32% yield
(Scheme 1).
OH
a) Br
O
Br
pyridine
O
O
Br
b) OsO4, NaIO4CHO
O
O
Br
c) SmI2
CHO
O
OSm(III)
O
O
OH
7 8 9
1011
OOSmIII
H
H
H
H
Scheme 1
Alternatively, a high yield synthetic strategy for the synthesis of the desired β-hydroxy
lactone 11 was developed based on their previous approach using same starting meterial.45
The alcohol 12 was coupled with acrylyl chloride under the standard protocol afforded the
dienic ester 13. Treatment of acrylate ester 13 with Grubbs catalyst 14 readily allowed for the
formation of lactenone 15 via a ring-closing olefin metathesis with a combined yield of 61%
over two steps from 12. An ensuing stereoselective epoxidation of the corresponding
lactenone intermediate 15 with basic hydroperoxide provided the epoxy-lactone 16 followed
by subsequent regioselective opening of the oxirane 16 with in situ generated PhSeH
provided the required intermediate 7 on a multigram scale (Scheme 2).
OHa) Cl
O
Et3N
O
O
O
O
O
O
O
N N
Ru
PCy3
Cl
ClPh
12 13
14
15
16
b) 18
c) H2O2
NaOH
d) PhSeH
11
a) TESCl, imid. O
O
OTES
O
OAc
OTES
b) DIBAL
c) Ac2O, Pyr.
d) BF3.OEt2
OTMS
O
O
OH
1
17 18
11
Scheme 2
Jennings and co-workers initially chose to investigate the synthesis (-)-diospongin B 1. As
delineated in Scheme 4, initial protection of the free hydroxyl moiety of 7 was with TESCl
and reduction of lactone 17 with DIBAL resulted in the formation of the lactol and
subsequent acetylation with Ac2O and pyridine gave 18.46
Treatment of intermediate 18 with
BF3.OEt2 generated oxocarbenium cation which was trapped with TMS enol ether (derived
from acetophenone) and concomitant removal of the TES group led to the target (-)-
diospongin B, 1 (Scheme 2).
The diastereomer (-)-diospongin A, 2 was synthesized using the same the lactone 11. The
reaction of lactone 11 with excess of allyl magnesium bromide furnished the lactol 19 as a
mixture of diastereomers which was readily reduced (TFA / Et3SiH) via the oxocarbenium
intermediates.
O
O
OH
a) allylMgBr O
OH
O
OH
TFA
H
O
OTES
H
+
HO
H
TESO+
X
11 19 18
OH+
Et3SiH
H-
H-
O
OTES
O
OTES
O
b) O3
c) PhMgBr
d) Dess-Martin O
OTES
O e) HCl
O
OH
O
20
21 22 2
Scheme 3
Ozonolysis of the alkene 20 followed by phenyl Grignard addition afforded the
corresponding secondary alcohol as a mixture of diastereomers, which was subsequently
oxidized to the ketone intermediate 22 by means of the Dess-Martin periodinane reagent.
Finally, deprotection of the TES ether furnished the diospongin A, 2 (Scheme 3).
Cossy’s Approach:
In 2006, Cossy and co-workers47
have reported the synthesis of (-)-diospongin A, 2 using two
enatioselective allylation to control the formation of two out of three steoreogenic centers
present in the molecule, followed by a cross-metathesis reaction and an intramolecular oxy-
Michael reaction. Thus, benzaldehyde was treated with allyltitanium complex (R, R)-Ti to
afford the corresponding allylic alcohol 23 with high enantioselectivity. After the protection
of 23 with TBSCl and was subsequent oxidative cleavage of terminal olefin produced the
corresponding aldehyde which is directly treated with titanium complex to afford 1, 3-syn
diol 24. The diol was then subjected to a cross-metathesis reaction with unsaturated ketone 25
in presence of Grubb’s catalyst furnished the desired 1,7-diarylheptanoid 26 with a E/Z ratio
95/5. Finally, cleavage of silylether and subsequent inramolecular oxy-Michael addition was
successfully achieved in one pot with TBAF to furnish (-)-diospongin A, 2 with an overall
yield of 29% (Scheme 4).
H
O
a) (R,R)-Ti, -78oC
OH
b) TBSCl, imid
c) OsO4, NaIO4
d) (R,R)-Ti, -78oC
OTBSOH
e) G II 5 mol %
23 24
O
25
OTBSOH O
O
OH
O
2
f ) TBAF, THF
26
Ti
O
O
PhPh
PhPh
O
O
(R,R)-Ti
N N
Ru
PCy3
Cl
ClPh
G II
Scheme 4
Uenishi’s Approach:
Uenishi and co-workers48
have synthesized both diospongins B, 1, A, 2 and their C5 epimers
using highly stereoselective Pd(II)-catlysed cyclization of chiral 1, 5, 7-trihydroxy-2-heptenes
and a regioselective Wacker oxidation as strategic reactions. The key intermediate 28 was
synthesized form the known aldehyde 27, which was readily derived from ethyl (R)-(-)-
mandelate (Scheme 5). Diastereoselective reductions of α, β-unsaturated ketone 28 with an
(S)-CBS reagent,49
at 0 oC gave the corresponding (R)-allylic alcohol 29a, followed by
deprotection with TBAF in THF afforded triol 30a in 90% yield. Meanwhile, the reduction of
28 with a (R)-CBS reagent49
gave 29b with 85% de and the deprotection of silyl ether
generated triol 30b in 94% yield (Scheme 5).
OTBS
CHO
OTBSOTBS O
27 28
OTBSOTBS OH
OTBSOTBS OH
OH
OH
HO
OH
OH
HO
29a
29b
30a
30b
a ,b, c, d
e
f
g
h
a) (+)-Ipc2Ballyl, E2tO, -78 oC, 62% b) O3, CH2Cl2, -78
oC 10 min then PPh3, rt c)
Ph3P=CHCOPh, THF, 80% (2 steps) d) TBSOTf, 2,6-lutidine, CH2Cl2, 86% e) (S)-CBS,
BH3.THF, THF, 0 oC, 1h, 92%, 87% de f) (R)-CBS, BH3.THF, THF, -40
oC, 1h, 98%, 85%
de g) TBAF, THF, rt, 3h, 90% h) TBAF, THF, rt, 3h, 94%
Scheme 5
The triol 30a containing 7% of 30b was treated with 10 mol% of PdCl2(CH3CN)2 in THF at 0
oC, the desired cis-tetrahydropyran 31a was obtained in 92% yield along with 31b in 6%
yield. Meanwhile, under the same conditions, triol 30b containing 8% of 30a gave the desired
trans-tetrahydropyran 31b in 86% yield and 31a in 5% yield. Treatment of alkene 31a with
50 mol% PdCl2 and CuCl under the microwave irradiation led to target 2 in moderate 57%
yield (Scheme 6).
OH
OH
HO
OH
OH
HO
30a
30b
O
OH
31a
O
OH
O
O
OH
31b
2
PdCl2(CH3CN)2
THF, 0 oC
PdCl2(CH3CN)2
THF, 0 oC
PdCl2, CuCl, O2
DMF+H2O
Scheme 6
The alcohol 31b was protected with MOMCl resulted in the compound 32 which was
subjected to Wacker oxidation led to the trans-hydropyran 33 in 55% yield under
conventional conditions. Final deprotection of MOM-ether with aq. HCl gave the desired 1 in
91% yield (Scheme 7).
O
OH
31b
O
OMOM
32
O
OMOM
O
O
OH
O
133
MOMCl, iPr2NEt
NaI, THF
PdCl2, CuCl
DMF+THF
HCl/THF
rt
Scheme 7
Ming Xian’s Approach:
Ming Xian and co-workers50
have reported the synthesis of diospongins A and B (1&2) using
a strategy which is based on the Smith-Tietze three-component linchpin coupling.51
The
syntheses started from the construction of the dihydropyranone intermediates 38 and 40
(scheme 8). The linchpin coupling of TBS-dithiane 34 with known epoxides (+)-35 and (+)-
36 provided alcohol (-)-37. Switching the order of epoxide addition under the same protocol
led to product (-)-39. Oxidative cleavage of dithiane group in (-)-37 and (-)-39 followed by
Dess-Martin oxidation, and acidic cyclization gave (+)-38 and (+)-40.
S S
TBS
t-BuLi
Et2O, -40 oC
a)O
Ph(+)-35
34
b) OOBn
(+)-36
TBSOSS
OBn
OH
(-)-37
c) HgCl2,CaCO3, H2O-MeCN, 60 oC
d) DMP, CH2Cl2, rt
e) TFA, CH2Cl2, rt
73% (for 3 steps)
O OBn
O
(+)-38
S S
TBS
t-BuLi
Et2O, -40 oC
a)
O
Ph(+)-35
34
b)
OOBn
(+)-36 SS
OBn
OTBS
(-)-39
c) HgCl2,CaCO3, H2O-MeCN, 60 oC
d) DMP, CH2Cl2, rt
e) TFA, CH2Cl2, rt
70% (for 3 steps)
O OBn
O
(+)-40
75%
74%
OH
Scheme 8
The key intermediate (+)-38 was on stereoselective Luche reduction provided alcohol (-)-41
(Scheme 9). The olefin hydrogenation and benzyl group deprotection of (-)-41 gave (-)-42 as
a single isomer. Next, the primary alcohol of (-)-42 was oxidized to aldehyde and addition of
PhMgBr furnished the compound 43. Then, the selective benzylic oxidation in 43 led to 5-
epi-diospongin A, (-)-44. Finally, the R-hydroxy group of (-)-44was converted into the S-
configuration under Mitsunobu conditions to complete the synthesis of diospongin A 2. The
Luche reduction of (+)-40 provided alcohol (+)-45 and hydrogenation with
Chlorotris(triphenylphosphine)rhodium(I) [Ph3P)3RhCl] under high pressure provided (+)-46
in modest yield along with stereoisomer (+)-47. Compound (+)-46 was then subjected the
same set of reactions as above afforded the diospongin B, 1 (Scheme 10).
O OBn
O
(+)-45
O OBn
OH
O OH
OH
O
OH
OH
O
OH
O
O
OH
O
(-)-2
(-)-48
(-)-4950
(-)-51
NaBH4, CeCl3, MeOH
-78 oC
H2, Pd(OH)2
72%
a) TEMPO, NaClO2, KBr
b) PhMgBr, THF, -78 oC
92%
DMP, CH2Cl2, rt
82%
1) DEAD, Ph3P,
4-bromobenzoic acid
2) K2CO3, MeOH
99%
Scheme 9
O OBn
O
(+)-40
O OBn
OH
O OBn
OH
O
OH
OH
O
OH
O
(-)-45
(-)-46
(-)-1
NaBH4, CeCl3, MeOH
-78 oC
b) TEMPO, NaClO2
c) PhMgBr
64%
DMP, CH2Cl2, rt
82%
(Ph3P)3RhCl
H2
200 psi
+
O OBn
OH
(-)-47
(-)-46
a) Pd/C, H2
Scheme 10
PRESENT WORK
While 1,7-diarylheptanoids are relatively simple molecules, they exhibit various
biological and pharmacological activities, such as anti-oxidant activity, anti-cancer activity,
inhibitory activity on nitric oxide production, anti-inflammatory activity, and DPPH-radical
scavenging activity. Particularly, cyclic 1,7-diarylheptanoids have been receiving
considerable attention. Among them, the intriguing C-aryl glycoside natural products
diospongins A, 2 and B, 1 contains six-membered cyclic ether structural unit with 2-aryl and
6-phenacyl substitution (Figure 11). Despite the fact that the both compounds indicate an
inhibitory activity against bone resorption induced by parathyroid hormone in a bone organ
culture, diospongin B shows more potent antiosteoporotic activity than that of diospongin A
due to their sterogenic variations at C3 and C7. Due to their antiosteoporotic activity coupled
with unique structure the diospongins have stimulated considerable interest in the synthetic
community.
Although considerable efforts has been devoted to the development of synthetic routes to
diospongins, there still exists a great need for a synthetic approach to these classes of
molecules that enables rapid and easy access to substrates, proceeds with excellent
stereosectivity in excellent yield, and requires mild reaction conditions compatible with
various functional groups. To date, most strategies rely on asymmetric induction resulting
from either chiral auxiliaries or resident chirality or enzymatic kinetic resolution of racemic
mixtures. Consequently, a synthetic sequence is preferred in which optical isomers are
excluded at the earliest possible stage through creation of chiral centers. A branch of
chemistry that has recently received much attention is that of organometallic catalysis. In a
view to develop a concise and viable route to this class of compounds, we have evaluated
organometallic catalytic processes. Organometallic catalysis is the acceleration of chemical
reactions with a sub-stoichiometric amount of an organic chiral compound which contain a
metal atom.
Keeping in mind all the valuable resources and with our continued interest in developing
catalytic routes to bioactive small molecules,52
we envisaged a flexible route for the
synthesis of the diospongins based on three catalytic steps: (a) catalytic asymmetric hetero-
Diels-Alder reaction, (b) diastereoselective rhodium(I)-catalyzed 1,4-addition, and (c)
catalytic asymmetric transfer hydrogenation (CATHy) reaction (Scheme 11).
+
O
OH
O
7
Keckhetero-Diels-Alder reaction
Rh-catalyzed1,4-addition
Catalytic Noyori's reduction
Diospongin B (1)
Me3SiO
OMe
+O
O
H
O
OPMB
O
O
OPMB
O
48 4950
5152
PO(OMe)2
OMe
3
5
Retrosynthetic analysis of Diospongin B, 1
Scheme 11
At the outset, we envisioned that this strategy in turn could be used to generate a library of
small molecules, in principle, by varying chirality inducing ligands of the above pivotal
reactions with perfect stereocontrol and a predictable absolute stereochemistry and
subsequently varying substitutions in the aromatic nucleus.
Results and Discussions:
In principle, the stereogenic center 3 in diospongin B 1 could be accessed through a catalytic
enantioselective hetero-Diels-Alder reaction that are either R or S selective by using
BINOL/Ti(OiPr)4 derived catalyst. The intermediate 52 would be equivalent to a masked
phenacyl moiety as well as we chose furyl moiety of 50 as a masked carboxaldehyde.
Further, the stereogenic center 7 could be realized through a rhodium (I)-catalyzed
stereoselective 1,4-addition of an arylboronic acid to a cyclic enone (Scheme 11).
Accordingly, the synthesis of diospongins initiated using catalytic asymmetric hetero-Diels-
Alder reaction between Danishefsky’s diene 48 and furfuraldehyde 49 with 10 mol % of the
(S)-BINOL / Ti(OiPr)4 derived catalyst, L1. A mixture of (S)-(+)-BINOL, Ti(OiPr)4 (1M),
CF3CO2H and 4Ao molecular sieves in ether was refluxed for 1 h. The aldehyde 49 and diene
48 was added successively at -78 oC, and the reaction mixture was stirred for 40 h at -20
oC.
After work up, and purification generated dihydropyranone 53 with 96% enantiomeric
excess.53
Further, single recrystallization of 53 from hexane:ether (2:1) solvent mixture
resulted in 99.9% enantiomeric excess with 60% yield (Scheme 12). The 1H NMR spectrum
of compound showed characteristic peaks as two doublets at δ 7.38 (J = 6.6 Hz), δ 5.47 (J =
3.6 Hz) integrating for one proton each and a triplet was appeared at δ 5.51 (J = 5.8 Hz)
integrating for one proton which can be assigned to furan attached carbon proton. Two sets of
doublet of doublet at δ 3.10 (J = 13.1, 16.8 Hz), 2.74 (J = 3.6, 16.8 Hz) integrates for one
proton each along with other peaks in their respective positions confirmed the desired
dihydropyranone formation. The required transformation also supported ESI spectral analysis
showing m/z peak at 165 [M + H]+. Similarly, 10 mol % of the (R)-BINOL / Ti(OiPr)4
derived catalyst, L2 generated ent-53 under otherwise identical conditions with the same
enantioselectivity and yield. The enantioselectivity and absolute configuration was assigned
based on optical rotation reported in the literature 53
and advanced further (Scheme 12).
O
O
O+48 49
53
10 mol% L1
-78 0C, 42h
CH2Cl2
60%
(96%ee)
(after recrstallization >99%ee)
O
O
O+48 49
ent -53
10 mol% L2
-78 0C, 42h
CH2Cl2
60%
(96%ee)
(after recrstallization >99%ee)
O
OTi
OiPr
OiPr
O
OTi
OiPr
OiPr
(S)-BINOL/Ti(OiPr)4 L1 (R)-BINOL/Ti(OiPr)4 L2
Scheme 12
The postulated mechanism for the proposed catalytic cycle is shown in scheme 13. Initially,
the silyoxydiene 48 on reaction with titanium complex L1 results the Ti-diene complex by
liberating TMSisoprpyl ether. Then, the Mukaiyama aldol53
adduct II was obtained through a
six-membered cyclic transition state I which involves the diene linked to the Ti-BINOL by
the C-3 oxygenated substituent and the aldehyde 49 associated to the metal by the carbonyl
oxygen followed by exchange of trimethylsilyl group from Danishefsky’s diene substrate to
the Mukaiyama aldol adduct II furnish the intermediate III and the Ti(IV) complex. Upon
treatment with trifluoroacetic acid generates the desired dihydropyranone.
TiLn-2O
O O
O
O
MeO
MeO
O OTiLn
O
OTiLn
OMe
BINOL_Ti(OiPr)2
48
TMSOiPr
OTMS
OMe
MeO
O OTMS
O
TFA
O
O
O
I
II
III*
Scheme 13: Mechanism of the Ti-BINOL catalyzed hetero-Diels-Alder reaction
With enantioenriched 53 in hand, we sought a flexible and appropriate means for introducing
a C-aryl group into the pyranose ring. To this end, we have examined the rhodium(I)-
catalyzed stereoselective 1,4-addition of an arylboronic acid to a cyclic enone, a protocol
developed by Miyaura,54a
Hayashi,54b
and Maddaford.55
Primarily, we have explored
Maddaford conditions. Accordingly, the reaction of 53 with phenylboronic acid in the
presence of 5 mol % of Rh(cod)2BF4 in dioxane/water was heated to 100 oC for 2 h.
Surprisingly, after workup, only a trace amount of the expected 1,4-addition product 54 was
isolated. However, the addition of 5 mol% of KOH to the reaction, under otherwise identical
conditions, furnished the product 54 in 70% yield. In another set of reactions, when the molar
ratio of the Rh catalyst was reduced to 2.5 mol% and the KOH loading was increased 2-fold
(1:2 catalyst:KOH), the reaction proceeded smoothly to yield the required product in 98%
(Scheme 14).55
2.5 mol% Rh(I)(cod)2BF4
PhB(OH)2
5 mol% KOH
Dioxane/H2O100 0C, 2h
98%(de = >99.9%)
54
O
O
O
53
2.5 mol% Rh(I)(cod)2BF4
PhB(OH)2
5 mol% KOH
Dioxane/H2O100 0C, 2h
98%(de = >99.9%)
ent-54
O
O
Oent-53
Scheme 14
The 1H NMR spectrum of product showed a doublet at δ 7.44 with a coupling constant 1.4 Hz
integrating for one proton which can be assigned for proton related to furan moiety. The
aromatic peak at δ 7.40-7.25 as multiplet integrating for five protons and a triplet at δ 4.74 (J
= 7.5 Hz) integrated for one proton could be attributed to phenyl attached carbon proton
proving the assigned structure of the product formation. The peak obtained in the ESI mass
spectra at m/z 243 (M + H)+
was an additional evidence for assigned structure. The de was
determined to be >99.9% by chiral HPLC (ODH column, 2% isopropanol in hexane, flow
rate 0.5 mL/min).
The highly diastereoselctive addition could be rationalized on the basis of proposed catalytic
cycle. As proposed,55
primarily, the pre-catalyst hydroxyl-Rh was generated by cataionic Rh
with KOH. Then, phenylboronic acid transmetallation resulted in organometallic species
ArRh(cod)2 II which inturn, proceeded from the less hindered Re-face addition of the enone
double bond and subsequent hydrolysis of Rh-O, III bond in the presence of H2O led to high
diastereoselective trans 2,6-disubstituted pyranone, 54 (Scheme 15).
Rh(cod)2BF4-
PhRh(cod)2
H2O
HORh(cod)2
PhB(OH)2
III
KOH
II
O
O
O
O
O
O
O
O
OPh
[Rh]
O
O
OPh
[Rh]
PhI
54
Scheme 15: Catalytic cycle
The stereochemistry of 54 was assigned α configuration at the anomeric center based on 1H
NMR data reported in the literature. Then, ent-53 was converted to ent-54 following the same
sequence of reaction conditions and the product ent-54 was characterized by 1H NMR, IR,
and Mass and corresponding data are placed under experimental section (Scheme 15). Under
anhydrous conditions, a low yield (<5%) of the 1,4-addition product was obtained, suggesting
need for H2O. Presumably, water serves to protonate the Rh-O bond. The role of hydroxide
(KOH which is added in the reaction mixture) could be facilitate the transmetalation, or it
could react with Rh(cod)2BF4 to generate precatalyst HORh(cod)2 or a combination of both.
Next, we focused on the reduction of the keto group of 54 (Scheme 16).
0.5 mol% cat. A
Et3N:HCO2H (5:2)
EtOAc, 50 0C, 3h
OO
OH
96%de = >99.9%
54
55
N
Ru
HNPh
PhTos
cat. A
N
Ru
HNPh
PhTos
cat. B
Scheme 16
Arrays of achiral and chiral reducing agents were screened for this transformation (Scheme
16) and the results are shown in Table 1. The achiral catalysts NaBH4 and DIBAL-H led to a
diastereomeric mixtures (entry 1 & 2, Table 1). Corey-shibaka chiral catalyst also furnished
55:45 diastereomeric mixture (entry 3, Table 1). While Noyori’s56
catalyst i.e., R,R-diamine-
Ru catalyst A, catalysed the reaction in high enantioselectivity with stable organic hydrogen
donor Et3N:HCO2H (entry 4, Table 1).
entry Reducing agent dr
ratio
%yield
1 NaBH4 55:45 90
2 DIBAL-H 60:40 92
3
N
B O
ArAr
Me
s
10mol% ; BH3.DMS
55:45
93
4
NRu
HNPh
PhTos
0.5mol% cat. A
>99.9
96
5
NRu
HNPh
PhTos
0.5mol% cat. B
60:40
94
Table 1: Reduction of ketone 54 with various reducing agents
The postulated mechanism is described in scheme 17. Initially, the [{RuCl2(p-cymene)}]
reacts with (S,S) or (R,R) TSDPEN ligand in the presence of KOH in CH2Cl2 at room
temperature to form orange colored catalyst precursor I. The precursor-I has acidic NH2
protons which undergoes facile elimination of HCl on treatment with 1eq of KOH to afford
the true catalyst II. This complex is a deep purple monomeric 16e-
species, which takes two
hydrogen atoms from a donor such as 2-propanol to produce yellow ruthenium hydride
species III by a rate-limiting step. The Ru-hydride in turn reduces the prochiral ketone via a
six-membered cyclic transition state to form highly enantioenriched product. This process
generates the catalyst which then re-enters the catalytic cycle to forward the reaction (Scheme
17).
Ph
Ph
N
NH2
Ru KOH, CH2Cl2 -H2O
-HCl
Ph
Ph
N
NH2
Ru
H
Ts
Cl
Ts
Ph
Ph
N
N
H
Ru
Ts HO H O
R1
HO H
R1
O
SubstrateProduct
Catalyst precursor-ITrue catalyst-II Hydride species-III
Scheme 17
Catalyst A (0.5 mol %) with the Et3N.HCO2H azeotropic mixture and heating at 50 oC for 3 h
afforded the alcohol 55 in 96% isolated yield with >99.9% diastereoselectivity The
diastereomeric ratio analyzed on chiral HPLC, ODH column, 10% isopropanol in hexane as
mobile phase at a flow rate of 0.5 mL/min (Scheme 16). The 1H NMR spectra showed a
characteristic peak of -CHOH at δ 4.03 ppm as multiplet and the furan attached carbon
proton appeared as triplet at δ 5.21 (J = 4.5 Hz). The aromatic protons appeared as multiplet
at δ 7.37-7.21 integrating for five protons confirming the product formation. The peak
obtained in the ESI mass spectra at m/z 267 (M + Na)+
was also corroborated the assigned
structure. The relative configuration of the hydroxyl group was assigned as R based on single
X-ray crystallography of 55 (Figure 18).
Figure 18: ORTEP representation of 55 with 50% probability
Our efforts to synthesize the C4 epimer of 55, by using substrate 54 employing S,S-diamine-
Ru catalyst B (0.5 mol %), under otherwise identical conditions resulted in a lower level of
diastereoselectivity (entry 5, Table 1). The R,R-diamine-Ru catalyst/ substrate 54 appears to
be a matched combination, which has overcome the inherent substrate bias, thus resulting in
high diastereoselectivity. On the other hand, S,S-diamine-Ru catalyst/substrate 54 is a
mismatched combination as evidenced by the modest level of diastereoselctivity. However,
the reduction of the keto group of ent-54 with R,R-diamine-Ru catalyst A (0.5 mol %), using
a Et3N.HCO2H azeotropic mixture, smoothly furnished the alcohol ent-55 in 98% yield.
Further, the optical rotation of ent-55 was found to be approximately equal in magnitude to
that of 55 but opposite in sign, indicating an enantiomeric relationship. Consequently, the
newly formed chirogenic center absolute configuration was assigned as S (Scheme 18). In
principle, the ent-55 should be achieved by employing the catalyst B. To our surprise, two
enantiomeric ketones 54 and ent-54 are reduced with the same enantiomer of catalyst A
leading to a pair of enantiomers, i.e., 55 and ent-55. These findings suggest that the
enantiomeric Ru-template catalyst A is efficiently differentiating diastereofaces of pro-chiral
ketone 54 and ent-54. However, these findings warrant a detailed investigation to establish
the plausible mechanism.
0.5 mol% cat. AEt3N:HCO2H (5:2)
EtOAc, 50 oC, 3hent -54
OO
OH
98%
(de = >99.9%)
ent-55
N
Ru
HNPh
PhTos
cat. A
Scheme 18
Having prepared the two enantiomeric tetrahydropyryl alcohols 55, ent-55 we next
proceeded to synthesise diospongin B 1 and its enatiomer ent-1. Proceeding further, the
hydroxy group of 55 was converted to PMB ether 50 by treating with 5.0eq of NaH and 4.0eq
of PMBCl at 0 oC to rt in THF for 6h in 98% yield. The product formation confirmed by
1H
NMR spectrum. In 1H NMR spectrum, the PMB protons appeared at δ 7.28 as a doublet (J =
8.0 Hz) and at 6.90 doublet (J = 8.8 Hz). The rest of the characteristic peaks showed at their
respective places. Then, the furyl group of 50 was oxidatively cleaved to acid (O3, 15 min,
DCM/MeOH, [1:1]), and the resulting acid on esterification with diazomethane (CH2N2,
ether, 0 oC to rt) gave methyl ester. The
1H NMR spectrum showed a peak at δ 3.81 as a
singlet integrated for three protons ensured the product formation. Then, the methyl ester was
subjected to reduction with 1.5eq of DIBAL-H at -78 oC for 1h lead to 51 in 88% yield (after
3 steps). The 1H NMR spectrum showing a peak corresponding to –CHO group at δ 10.01
ppm as a singlet and presence of all other proton signals in their respective positions
confirmed the compound 51 formation. The aldehyde 51 was then treated with the anion
derived from Horner-Emmons reagent 52 and subsequent hydrolysis of intermediate enol
ether resulted in 56 (75%).57
The presence of two doublet of doublets for each methylene
proton adjacent to keto group at δ 3.43 (dd, J = 6.6, 16.1 Hz), 3.27 (dd, J = 5.8, 16.1 Hz) in
the 1H NMR spectrum proved the product formation. Further evidence has come from ESI
spectrum exhibiting peak at m/z 439 [M+Na]+. Finally, compound 56 was exposed to 1.2eq of
DDQ in DCM/H2O (9:1) at 0 oC to rt for 1h furnished the target compound 1 in 92% isolated
yield (Scheme 19). The 1H NMR spectrum of 1 provided sample evidence for the formation
of product, with the devoid of PMB protons. A triplet at δ 5.19 (J = 4.4 Hz) integrated for one
proton corresponding to the carbon atom attached directly to phenyl group and the peaks at δ
2.51 (J = 3.8, 5.1, 13.4 Hz ) as doublet of doublet of doublet, δ 2.05 (J = 4.4, 8.9, 14.6 Hz) as
doublet of doublet of doublet, δ 1.92 (J = 5.0, 9.7, 13.5 Hz ) as doublet of doublet of doublet,
and δ 1.50 (J = 9.3, 12.3 Hz) as doublet of triplet integrating for one proton each indicating
the presence of two methylene groups adjacent to secondary hydroxyl carbon along with
other protons integrating at their respective values ensured the product formation. The ESI
mass spectral analysis, showing peak at m/z 319 [M+ Na]+ also supported the formation of
product 1 without any ambiguity. The chirooptical data of 1 were in full agreement with that
reported in the literature54
([α]23
D – 22.5, (c 0.2, CHCl3) {lit. 54
([α]23
D – 22.6, (c 0.0114,
CHCl3}).
OO
OPMB
DCM:MeOH (1:1)
ii) CH2N2, Et2O
0 oC to rt, 1hiii) DIBAL-H
toluene, -78 oC, 1h
O CHO
OPMB
Ph PO(OMe)2
OMe
n-BuLi, THF
-78 oC to rt, 3hO
OPMB
O
Cl3CCO2H/acetone
rt, 6h
50
5156
1
DDQ
DCM:H2O (9:1)
98%
88%( over 3 steps)75%
92%
i) O3, 15min.
PMBClNaH
THF, 0 oC to rt6h
55
60
0 oC to rt, 1h
Scheme 19
The 2, 6-trans enantiomer ent-1 was synthesized in 67% yield (over 6 steps) from ent-55
following the above mentioned conditions (Scheme 20). The corresponding experimental
data is all compounds are given in the experimental section.
ent-55
67%
OO
OH
(over 6 steps)
ent -1
O
O
OH
Scheme 20
Initially, the hydroxyl group of 55 was protected with TBDPS and carried out a
complete sequence. To our surprise, the final product 1H NMR and
13C data did not match to
reported data of 1. Consequently, changing the protecting group TBDPS to PMB followed by
the same set of reactions resulted in the expected product 1. The TBDPS protected 55 also
exposed to TBAF (10 equiv) but only deprotected compound 55 was recovered. To evaluate
the product formed from TBDPS, the C-5 hydroxyl group of diospongin B, 1 was converted
as TBDPS ether 57 (tBu(Ph)2SiCl, Et3N, DCM, 0 °C to rt, 6h). While subjecting deprotection
of the TBDPS group of compound 57 with 10eq of TBAF in THF at ambient temperature,
unexpectedly, furnished the product 2 in 86% yield. It was also noticed that the reaction did
not proceed with less than 10 equiv of TBAF. Using Aldrich supplied TBAF, reaction did not
initiate whereas, addition of 5 mol equiv of H2O (based on TBAF mole equivalent) to the
reaction under otherwise identical conditions yielded the expected product 2. However,
TBAF supplied by Spectochem.Pvt.Ltd., India without addition of H2O resulted in 2.
Further, the product 2 was unambiguously characterized by means of 1H NMR, IR and Mass
spectra. In 1H NMR spectrum, the peak at δ 4.90 (J = 1.5, 11.3 Hz) as doublet of doublet
integrating for one proton which can be assigned to phenyl attached carbon proton found to
characteristic. Two doublet of doublets at δ 3.39 (J = 5.3, 15.9 Hz), 3.04 (J = 7.5, 16.6 Hz)
accounting for one proton each of carbon atom directly attached to keto group, the peaks at δ
1.95 as multiplet, 1.67 as multiplet and absence of TBDPS and appearance of all other peaks
gave additional proof for the formation of the target molecule. Moreover, the optical data of 2
were in full agreement with that of diospongin A reported in the literature54
([α]23
D – 19.2, (c
1.2, CHCl3) {lit.54
([α]23
D – 19.6, (c 0.0084, CHCl3}). Also the 1H NMR and
13C NMR data
were in full accord with those reported for the natural product.
Under identical conditions ent-57 also resulted in ent-2. The structure of ent-2 was confirmed
by 1H and
13C NMR data. Furthermore, the optical rotation of ent-2 was found to be equal in
magnitude to 2, but opposite in sign and hence, was considered as enantiomer to 2 (Scheme
21).
ent -1 O
O
ent-2
O
OTBDPS
O
Et3N, DCM
i) tBu(Ph)2SiClexcess TBAF(10 equiv.)
THF, rt
57
ent-57
OTBDPS
0 oC to rt, 6hdiospongin B
1
diospongin A
2
92%
86%
O
O
OH
Scheme 21
The reaction could be rationalized on the basis of retro-Michael opening of pyran ring and the
subsequent intramolecular Michael reaction of the hydroxy nucleophile to the enone leads to
the thermodynamically more stable cis-conformer (Scheme 22).
O
H
Ph
H
H
H
Ph
O
OPH
H O
H
Ph
H
HPh
O
OHH
H
O
H OH
H
H
HPh
Ph
O
H
P = TBDPS
Scheme 22
In conclusion, we have accomplished the total synthesis of diospongins A, 2 and B, 1 and
their enantiomers employing achiral starting materials. To the best of our knowledge, the
synthesis of 2, 6-trans isomer ent-1 and 2, 6-cis isomer ent-2 are described here for the first
time. All three stereocenters are introduced by means of catalytic reactions and this strategy
in turn could be used to generate a library of small molecules with varying substitutions in
aromatic nucleus.
EXPERIMENTAL SECTION
(S)-2-(Furan-2-yl)-2, 3-dihydropyran-4-one (53):
O
O
O
A mixture of (S)-(+)-BINOL (0.276 g, 0.96 mmol), 1M Ti(OiPr)4 in CH2Cl2 (0.48 mL, 0.48
mmol), CF3CO2H (0.028 mL, 0.5 M in CH2Cl2), and flame dried powdered 4Ao molecular
sieves (1.86 g) in ether (20 mL) was heated at reflux for 1 h. The red-brown mixture was
cooled to room temperature, and furfuraldehyde 49 (0.460 g (0.39 mL, 4.83 mmol) was
added. The mixture was stirred for 5 min and cooled to -78 oC, Danishefsky’s diene 48 (1.0 g,
5.80 mmol) was added, and the reaction mixture was stirred for 10 min and then placed in a -
20 oC bath. After 40 h, saturated NaHCO3 (0.5 mL) was added, and the reaction mixture was
stirred for 1 h and then filtered through a plug of celite. The organic layer was separated, and
the aqueous layer was extracted with ether (3 x 20 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product
was dissolved in CH2Cl2 (60 mL) and cooled to 0 oC. To this solution was added CF3CO2H
(0.25 mL) and stirred for 1 h, saturated NaHCO3 (30 mL) was added, the reaction mixture
was stirred for 10 min, and the layers were separated. The aqueous layer was extracted with
CH2Cl2 (3 x 50 mL), and the combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by column chromatography on
silica gel (10% acetone in hexane), to afford product 53 as a crystalline solid. A single
recrystallization from 1:2 Et2O: hexanes gave white needle like crystals.
Yield : 1.05 g, 60 %.
M. P : 73-75 oC
[α]23
D : + 359.0 (c = 1.2, CH2Cl2).
IR (KBr) : 2923, 2852, 1724, 1595, 1268, 1114, 1039, 747 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.48 (d, J = 1.4 Hz, 1H), 7.38 (d, J = 6.6 Hz, 1H),
6.46 (d, J = 3.6 Hz, 1H), 6.42 (t, J = 1.4 Hz, 1H), 5.51
(t, J = 5.8 Hz, 1H), 5.47 (d, J = 3.6 Hz, 1H), 3.10 (dd,
J = 13.1, 16.8 Hz, 1H), 2.74 (dd, J = 3.6, 16.8 Hz, 1H).
13C NMR (100 MHz, CDCl3) : δ 191.3, 162.4, 149.9, 143.5, 110.5, 109.6, 107.3, 73.5,
39.4.
MS (ESI) : m/z 165 (M + H)+.
(2S, 6S)-2-(Furan-2-yl)-6-phenyl-tetrahydropyran-4-one (54):
O
O
O
A mixture of 53 (1.05 g, 6.40 mmol), phenyl boronic acid (1.56 g, 12.8 mmol),
Rh(I)(cod)2BF4 (0.052 g, 0.16 mmol), 1.0 mL of H2O, KOH (0.018 g, 0.32 mmol) and 20 mL
of dioxane was heated at reflux for 4 h. The reaction mixture was cooled to room temperature
and diluted with ethyl acetate (40 mL) and filtered through a pad of silica gel. The filtrate was
concentrated in vacuo and the residue was subjected to silica gel flash column
chromatography (5% EtOAc in hexane) to afford product 54 as a crystalline solid.
Yield : 1.51 g, 98 %.
M. P : 84-86 oC
[α]23
D : –10.0 (c = 0.5, CHCl3).
IR (KBr) : 2923, 2853, 1721, 1458, 1255, 1064, 1016, 752 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.44 (d, J = 1.5 Hz, 1H), 7.40-7.25 (m, 5H), 6.36 (t, J
= 5.3 Hz, 2H), 5.44 (dd, J = 3.0, 6.8 Hz, 1H), 4.74 (t,
J = 7.5 Hz, 1H), 2.96 (dd, J = 6.8, 15.1 Hz, 1H),
2.87 (dd, J = 3.02, 15.1 Hz, 1H), 2.72 (d, J = 7.5
Hz, 2H).
13C NMR (100 MHz, CDCl3) : δ 191, 151.1, 143.2, 140.2, 128.6, 128.1, 126.1, 110.2,
73.2, 69.0, 48.5, 43.4.
MS (ESI) : m/z 243 (M + H)+.
HRMS (ESI) : m/z 243.1026 (calcd for C15H15O3: 243.1016).
(2S, 4R, 6S)-2-(Furan-2-yl)-6-phenyl-tetrahydro-2H-pyran-4-ol (55):
O
OH
O
To a solution of 54 (1.51 g, 6.24 mmol) in anhydrous EtOAc (12 mL) under argon was added
Et3N: HCOOH (5:2) mixture (0.90 mL) followed by the addition of Ru-catalyst A (0.019 g,
0.031 mmol, 0.5 mol %) which was pre-dissolved in CH2Cl2 (2 x 1 mL). The resulting
reaction mixture was heated to 50 oC for 3 h. After cooling the reaction mixture to room
temperature diluted with ethyl acetate (20 mL) and filtered through a pad of silica gel. The
filtrate was concentrated in vacuo and the residue was subjected to silica gel flash column
chromatography (25% EtOAc in Hexane) to afford compound 55 as a crystalline solid.
Yield : 1.46 g, 96 %.
M. P : 65-68 oC
[α]23
D : –17.0 (c = 0.5, CHCl3).
IR (KBr) : 3404, 2925, 2856, 1451, 1366, 1060, 1011, 738 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.44 (d, J = 8.3 Hz, 1H), 7.37-7.21 (m, 5H), 6.32 (t, J
= 3.0 Hz, 1H), 6.29 (d, J = 3.7 Hz, 1H), 5.21 (t, J = 4.5
Hz, 1H), 4.66 (dd, J = 3.7, 9.0 Hz, 1H), 4.03 (m, 1H),
2.48 (dt, J = 4.5, 13.5 Hz, 1H), 2.13 (dt, J = 3.7, 12.8
Hz, 1H), 2.02-1.95 (m, 2H).
13C NMR (100 MHz, CDCl3) : δ 154.3, 142.2, 140.1, 128.6, 127.2, 126.3, 110.2,
106.9, 72.3, 65.8, 64.1, 37.4, 36.8.
MS (ESI) : m/z 267 (M + Na)+.
HRMS (ESI) : m/z 267.1000 (calcd for C15H16O3Na: 267.0997).
(2S, 4R, 6S)-2-(Furan-2-yl)-4-(4-methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran
(50):
O
OPMB
O
To a solution of 55 (1.46 g, 5.98 mmol) in DMF (30 mL) was added 60 % dispersion sodium
hydride (0.718 g, 29.9 mmol) at 0 oC. After the solution was stirred for 30 min at the same
temperature, 4-Methoxybenzyl chloride (3.74 g, 23.9 mmol) was added. The resulting
reaction mixture was stirred for 12 h at room temperature under argon. The reaction mixture
was quenched with water and extracted with EtOAc (3 X 30 mL). The organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue
was purified by flash chromatography (10% EtOAc in hexane) to afford product 50 as a
colourless oil.
Yield : 2.13 g, 98 %.
[α]23
D : –36.5 (c = 0.7, CHCl3).
IR (KBr) : 3448, 2929, 2860, 1612, 1513, 1248, 1089, 1035, 816,
737 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.46-7.34 (m, 6H), 7.28 (d, J = 8.0 Hz, 2H), 6.90 (d, J
= 8.8 Hz, 2H), 6.36 (t, J = 3.6 Hz, 1H), 6.34 (d, J = 3.6
Hz, 1H), 5.29 (t, J = 4.4 Hz, 1H), 4.65 (dd, J = 3.6,
10.2 Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.51 (d, J =
11.7 Hz, 1H), 3.82 (s, 3H), 3.78 (m, 1H), 2.59 (m, 1H),
2.23 (m, 1H), 2.07 (m, 2H).
13C NMR (100 MHz, CDCl3) : δ 159.2, 154.2, 142.1, 140.2, 130.5, 129.2, 128.6,127.1,
126.4, 113.8, 110.1, 106.6, 72.8, 70.4, 69.6, 65.9, 55.2,
34.9, 33.8.
MS (ES) : m/z 387 ( M + Na)+.
HRMS (ES) : m/z 387.1588 (calcd for C23H24O4Na: 387.1572).
(2S, 4R, 6S)-Methyl 4-(4-methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-
carboxylate:
O
OPMB
OMe
O
Ozone was passed for 10 min through a cooled (-78 oC) solution of 50 (2.13 g, 5.85 mmol) in
150 mL MeOH:CH2Cl2 (1:1), Me2S (0.725 g, 11.7 mmol) was added to the reaction mixture
and further stirring was continued for 30 min at -78 oC and 1 h at room temperature. The
solvent was removed under reduced pressure. The crude residue was dissolved in diethyl
ether (10 mL) and cooled to 0 oC in an ice bath. To this, etheral solution of diazomethane (10
equiv) (Caution: Liquid diazomethane is an explosive compound and explosions may occur
in the gaseous state if the substance is dry and undiluted) was added and resulting reaction
mixture stirred for 1 h (the reaction progress was monitored by TLC). Then, the reaction
mixture was allowed to stand overnight to escape the left over diazomethane in a well
ventilated fuming cupboard. The residual solvent was removed under reduced pressure and
the crude residue was purified by column chromatography (15% EtOAc in hexane) to yield
methyl ester as a colourless oil.
Yield : 1.79 g, 86 %.
[α]23
D : –32.1 (c = 0.7, CHCl3).
IR (KBr) : 2923, 2853, 1746, 1512, 1246, 1173, 1034, 819,
755 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.41-7.32 (m, 5H), 7.27 (d, J = 8.8 Hz, 2H), 6.89 (d, J
= 8.8, 2H), 5.38 (dd, J = 2.2, 10.2 Hz, 1H), 4.54 (d, J =
11.7 Hz, 1H), 4.50 (dd, J = 0.7, 2.2 Hz, 1H), 4.40 (d, J
= 11.7 Hz, 1H), 3.88 (m, 1H), 3.81 (s, 3H), 3.67 (s, 3H),
2.52 (m, 2H), 2.06 (m, 1H), 1.89 (m, 1H).
13C NMR (100 MHz, CDCl3) : δ 172.9, 158.9, 141.8, 128.8, 128.3, 127.4, 126.2,
113.7, 113.6, 70.4, 70.0, 69.8, 69.6, 55.2, 51.9, 36.8,
30.4.
MS (ESI) : m/z 379 (M+Na)+.
HRMS (ESI) : m/z 379.1542 (calcd for C21H24O5Na: 379.1521).
(2S,4R,6S)-4-(4-Methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-carbaldehyde
(51):
O
OPMB
CHO
To a solution of methyl ester (1.79 g, 5.02 mmol) in CH2Cl2 (20 mL) was added DIBAL-H
(1.07 g, 7.54 mmol, 1M solution in toluene) at -78 oC. The reaction mixture was stirred for 1
h at the same temperature and then quenched with saturated sodium potassium tartarate
solution. The aqueous layer extracted with CH2Cl2 (3 x 25 mL). The combined organic layers
were washed with brine solution, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (10%
EtOAc in hexane) to yield product 51 as a colourless oil.
Yield : 1.47 g, 90 %.
[α]23
D : –86.5 (c = 1.0, CHCl3).
IR (KBr) : 3444, 2929, 1729, 1610, 1512, 1248, 1089, 1034, 822,
757, 700 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 10.01 (s, 1H), 7.41- 7.24 (m, 7H), 6.89 (d, J = 8.2 Hz,
2H), 5.23 (dd, J = 3.0, 11.2 Hz, 1H), 4.48 (d, J = 11.2
Hz, 1H), 4.33 (d, J = 11.2 Hz, 1H), 4.28 (dd, J = 2.2,
6.7 Hz, 1H), 3.89 (m, 1H), 3.81 (s, 3H), 2.42 (m, 1H),
2.01 (m, 2H), 1.83 (m, 1H).
13C NMR (100 MHz, CDCl3) : δ 203.3, 159.1, 141.7, 130.1, 129.2, 128.4, 127.7,
126.0,113.8, 76.8, 70.4, 69.6, 69.4, 55.2, 36.9, 29.5.
MS (ESI) : m/z 349 ( M + Na)+.
HRMS (ESI) : m/z 349.1421 (calcd for C20H22O4Na: 349.1415).
(2-((2S, 4S, 6S)-4-(4-Methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-
phenylethanone) (56):
O
OPMB
O
To a -78 oC stirred solution of 52 (1.14 g, 4.96 mmol) in THF (40 mL) was slowly added n-
BuLi (0.316 g, 4.96 mmol, 3.0 mL, 1.6 M solution in hexane). After stirring the solution for
15 min, a solution of 51 (1.47 g, 4.50 mmol) in THF (25 mL) was added, then stirred for 1 h.
The reaction mixture was warmed to room temperature, and resulting solution was carefully
concentrated to 1/3 of original volume under reduced pressure. To the resulting reaction
mixture, acetone solution (0.8 M) of Cl3COOH (25 mL) was added and resulting reaction
mixture stirred at room temperature for 6 h. The reaction mixture was neutralized by addition
of saturated aq NaHCO3 until gas evolution subsides and extracted with EtOAc (3 x 50 mL).
The combined organic layers were washed with brine solution and dried over anhydrous
Na2SO4, then concentrated under reduced pressure. The crude residue was purified by flash
column chromatography over silica gel (10% EtOAc in hexane) to afforded product 56 as
colourless oil.
Yield : 1.40 g, 75 %.
[α]23
D : –45.5 (c = 1.0, CHCl3).
IR (KBr) : 3061, 2926, 2854, 1683, 1598, 1513, 1448, 1250,
1068, 755, 698 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.96 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H),
7.45 (t, J = 7.3 Hz, 2H), 7.31-7.21 (m, 7H), 6.86 (d, J =
8.8 Hz, 2H), 5.14 (t, J = 5.1 Hz, 1H), 4.50 (m, 2H),
4.28 (m, 1H), 3.80 (s, 3H), 3.72 (m, 1H), 3.43 (dd, J =
6.6, 16.1 Hz, 1H), 3.27 (dd, J = 5.8, 16.1 Hz, 1H), 2.39
(ddd, J = 3.6, 8.0, 13.2 Hz, 1H), 2.05 (ddd, J = 3.6, 8.0,
13.2 Hz, 1H), 1.95 (m, 1H), 1.58 (m, 1H).
13C NMR (100 MHz, CDCl3) : δ 198.4, 140.6, 137.2, 133.1, 130.6, 129.2, 128.5,
128.4, 128.2, 127.1, 126.3, 126.1, 113.8, 71.9, 70.7,
69.8, 67.3, 55.3, 44.4, 36.4, 34.4.
MS (ESI) : m/z 439 (M+Na)+.
HRMS (ESI) : m/z 439.1888 (calcd for C27H28O4Na: 439.1885).
Diospongin B (1):
O
OH
O
To a stirred solution of 56 (1.40 g, 3.37 mmol) in CH2Cl2:H2O (9:1) (70 mL) was added DDQ
(0.919 g, 4.05 mmol) at 0oC and the reaction mixture was stirred at room temperature for 1 h.
The reaction mixture was quenched with saturated NaHCO3 solution and extracted with
EtOAc (3 x 20 mL). The combined organic layers were washed with H2O followed by brine
solution and dried over anhydrous Na2SO4, then concentrated under reduced pressure. The
crude residue was purified by flash column chromatography (30% EtOAc in hexane) to
afford the product 1 as an amorphous solid.
Yield : 0.91 g, 92 %.
[α]23
D : –22.5 (c = 0.2, CHCl3).
IR (KBr) : 3624, 2925, 2857, 2312, 1740, 1682, 1515, 1452, 1174
753 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.98 (d, J = 8.9 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H),
7.47 (t, J = 8.2 Hz, 2H), 7.34 (m, 5H), 5.19 (t, J = 4.4
Hz, 1H), 4.23 (m, 1H), 4.02 (m, 1H), 3.45 (dd, J = 7.0,
15.7 Hz, 1H), 3.17 (dd, J = 5.9, 15.7 Hz, 1H), 2.51
(ddd, J = 3.8, 5.1, 13.4 Hz, 1H), 2.05 (ddd, J = 4.4, 8.9,
14.6 Hz, 1H), 1.92 (ddd, J = 5.0, 9.7, 13.5 Hz, 1H),
1.50 (dt, J = 9.3, 12.3 Hz, 1H).
13C NMR (100 MHz, CDCl3) : δ 198.3, 140.2, 137.2, 133.2, 128.6, 128.5, 128.3,
127.1, 126.3, 72.3, 66.9 64.2, 44.6, 40.1, 36.7.
MS (ESI) : m/z 319 (M + Na)+.
HRMS (ES) : m/z 319.1301 (calcd for C19H20O3Na: 319.1310).
[2-((2S, 4S, 6S)-4-(tert-Butyldiphenylsilyloxy)-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-
phenylethanone] (57):
O
OTBDPS
O
To a stirred solution of 1 (0.5 g, 1.68 mmol) in CH2Cl2 (15 mL) was added Et3N (0.341 g,
3.37 mmol) at 0 oC. After stirring the solution for 15 min, tert-Butyldiphenylsilyl chloride
(0.927 g, 3.37 mmol) and DMAP (0.020 g, 0.16 mmol) was sequentially at the same
temperature. The resulting reaction mixture was stirred at room temperature for 6 h,
quenched with saturated NH4Cl solution and extracted with CH2Cl2 (3 x 20 mL). The
combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude residue was purified by flash column chromatography (10% EtOAc in
hexane) to afford the product 57 as a colourless oil.
Yield : 0.853 g, 95 %.
[α]23
D : –31.0 (c = 0.25, CHCl3).
IR (KBr) : 3068, 2927, 2855, 1681, 466, 1215, 1110, 760,
701 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.94 (d, J = 7.3 Hz, 2H), 7.71 (d, J = 6.7 Hz, 2H),
7.62 (m, 3H), 7.47-7.36 (m, 8H), 7.05 (d, J = 4.8, Hz,
3H), 6.71 (t, J = 4.8 Hz, 2H), 4.97 (t, J = 3.7 Hz, 1H),
4.03 (m, 1H), 3.94 (m, 1H), 3.37 (dd, J = 7.0, 15.7 Hz,
1H), 3.01 (dd, J = 5.9, 15.7 Hz, 1H), 2.11 (m, 1H),
2.00 (m, 1H), 1.86 (m, 1H), 1.65 (m, 1H), 1.05 (s, 9H).
13C NMR (100 MHz, CDCl3) : δ 198.3, 139.8, 137.0, 135.9, 135.7, 134.0, 133.7,
133.0, 129.7, 129.6, 128.5, 128.2, 128.1, 127.7, 127.6,
126.6, 126.1, 72.2, 66.8, 65.4, 44.7, 40.2, 36.5, 26.9.
19.0.
MS (ESI) : m/z 557 (M + Na)+.
HRMS (ES) : m/z 535.2692 (calcd for C35H39O3 Si: 535.2668).
Diospongin A (2):
O
OH
O
To a stirred solution of 57 (0.853 g, 1.59 mmol) in THF (15 mL) was added TBAF
(Specrochem Pvt.Ltd., India) (15.7 mL 15.9 mmol, 1M solution in THF) at 0 oC and the
reaction mixture was stirred at room temperature over night. The reaction mixture was
quenched with H2O and extracted with EtOAc (3 x 20 mL). The combined organic layers
were washed with brine solution and dried over anhydrous Na2SO4, then concentrated under
reduced pressure. The crude residue was purified by column chromatography over silica gel
(26% EtOAc in hexane) to afford product 2 as an amorphous solid.
Yield : 0.238 g, 86 %.
[α]23
D : –19.2 (c = 1.2, CHCl3).
IR (KBr) : 3624, 2925, 2857, 2312, 1740, 1682, 1515, 1452, 1174,
753 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.97 (d, J = 6.8 Hz, 2H), 7.53 (t, J = 6.8 Hz, 1H),
7.43 (t, J = 7.5 Hz, 2H), 7.22 (m, 5H), 4.90 (dd, J = 1.5,
11.3 Hz, 1H), 4.60 (m, 1H), 4.34 (t, J = 2.3 Hz, 1H),
3.39 (dd, J = 5.3, 15.9 Hz, 1H), 3.04 (dd, J = 7.5, 16.6
Hz, 1H), 1.95 (m, 2H), 1.67 (m, 2H).
13C NMR (100 MHz, CDCl3) : δ 198.3, 142.8, 137.5, 133.0, 128.5, 128.3, 128.2,
127.2, 125.8, 73.8, 69.1, 64.7, 45.2, 40.4, 38.8.
MS (ESI) : m/z 319(M + Na)+.
HRMS (ESI) : m/z 319.1319 (calcd for C19H20O3Na: 319.1310).
(R)-2-(Furan-2-yl)-2, 3-dihydropyran-4-one (ent-53):
O
O
O
Same procedure was used for preparation of compound ent-53 as used for 53 by using (R)-
(+)-BINOL catalyst gave white needle like crystals. [a single recrystallization from 1:2
Et2O:hexanes].
[α]23
D : –352 (c = 1.0, CH2Cl2).
IR (KBr) : 2923, 2852, 1724, 1595, 1268, 1114, 1039, 747 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.48 (d, J = 1.46 Hz, 1H), 7.38 (d, J = 5.8 Hz, 1H),
6.46 (d, J = 2.9 Hz, 1H), 6.42 (dd, J = 2.2, 3.6 Hz, 1H),
5.50 (dd, J = 5.8, 7.3 Hz, 1H), 5.47 (d, J = 4.39 Hz,
1H), 3.10 (dd, J = 12.4, 16.8 Hz, 1H), 2.74 (dd, J = 3.6,
16.8 Hz, 1H).
13C NMR (100 MHz, CDCl3) : δ 191.4, 162.4, 149.4, 143.5, 110.5, 109.6, 107.3, 73.5,
39.4.
MS (ESI) : m/z 165 (M+H)+.
(2R, 6R)-2-(Furan-2-yl)-6-phenyl-tetrahydropyran-4-one (ent-54):
O
O
O
Same procedure was used for preparation of compound ent-54 as used for 54.
[α]23
D : + 10.9 (c = 0.5, CHCl3).
IR (KBr) : 2923, 2853, 1721, 1458, 1255, 1064, 1016, 752 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.44 (d, J = 1.5 Hz, 1H), 7.39-7.29 (m, 5H), 6.37 (d, J
= 3.5 Hz, 1H), 6.36 (t, J = 1.4 Hz, 1H), 5.44 (dd, J =
3.5, 7.1 Hz, 1H), 4.74 (dd, J = 5.6, 7.8 Hz, 1H), 2.96
(dd, J = 6.3, 14.8 Hz, 1H), 2.87 (dd, J = 2.8, 15.5 Hz,
1H), 2.72 (m, 2H).
13C NMR (100 MHz, CDCl3) : δ 205.5, 151.9, 143.2, 140.2, 128.6 128.1, 126.1, 110.2,
73.2 68.9, 48.4, 43.4.
MS (ESI) : m/z 243 (M + H)+.
HRMS (ESI) : m/z 243.1009 (calcd for C15H15O3: 243.1016).
(2R, 4S, 6R)-2-(Furan-2-yl)-6-phenyl-tetrahydro-2H-pyran-4-ol (ent-55):
O
OH
O
Same procedure was used for preparation of compound ent-55 as used for 55.
[α]23
D : +18.5 (c = 1.0, CHCl3).
IR (KBr) : 3404, 2925, 2856, 1451, 1366, 1060, 1011, 738 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.49 (d, J = 8.0 Hz, 1H), 7.42-7.27 (m, 5H), 6.37 (t, J
= 1.5 Hz, 1H), 6.34 (d, J = 2.9 Hz, 1H), 5.26 (t, J = 4.4
Hz, 1H), 4.72 (dd, J = 3.6, 8.7 Hz, 1H), 4.10 (m, 1H),
2.53 (dt, J = 4.4, 13.1 Hz, 1H), 2.19 (dt, J = 4.4, 13.2
Hz, 1H), 2.02 (m, 2H).
13C NMR (100 MHz, CDCl3) : δ 154.3, 142.2, 140.2, 128.7, 127.3, 126.4, 110.4,
107.0, 72.2, 65.8, 64.2, 37.4, 36.9.
MS (ESI) : m/z 267 (M + Na)+.
HRMS (ESI) : m/z 267.1011 (calcd for C15H16O3Na: 267.0997).
(2R,4S,6R)-2-(Furan-2-yl)-4-(4-methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran (ent-
50):
O
OPMB
O
Same procedure was used for preparation of compound ent-50 as used for 50.
[α]23
D : +37.0 (c = 0.9, CHCl3).
IR (KBr) : 3447, 2927, 2865, 1611, 1514, 1248, 1035, 816 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.44-7.33 (m, 6H), 7.27 (d, J = 8.4 Hz, 2H), 6.89 (d, J
= 8.8 Hz, 2H), 6.35 (t, J = 2.9 Hz, 1H), 6.32 (d, J = 2.9
Hz, 1H), 5.28 (t, J = 3.6 Hz, 1H), 4.63 (dd, J = 2.9,
10.2 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.50 (d, J =
11.0 Hz, 1H), 3.81 (s, 3H), 3.78 (m, 1H), 2.58 (m, 1H),
2.24 (m, 1H), 2.05 (m, 2H).
13C NMR (100 MHz, CDCl3) : δ 159.1, 154.5, 142.1, 142.0, 130.5, 129.1, 128.6,127.2,
126.4, 113.8, 110.2, 108.2, 72.6, 71.4, 69.5, 65.9,
55.3, 34.9, 33.8.
MS (ESI) : m/z 387 (M + Na)+.
HRMS (ESI) : m/z 387.1582 (calcd for C23H24O4Na: 387.1572).
(2R,4S,6R)-Methyl-4-(4-methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-
carboxylate:
O
OPMB
OMe
O
[α]23
D : + 2.4 (c = 0.3, CHCl3).
1H NMR (400 MHz, CDCl3) : δ 7.41-7.32 (m, 5H), 7.27 (d, J = 8.8 Hz, 2H), 6.89 (d, J
= 8.8 Hz, 2H), 5.38 (dd, J = 2.9, 11.0 Hz, 1H), 4.54 (d,
J = 11.7 Hz, 1H), 4.50 (dd, J = 0.7, 2.2 Hz, 1H), 4.40
(d, J = 11.0 Hz, 1H), 3.88 (m, 1H), 3.81 (s, 3H), 3.67
(s, 3H), 2.52 (m, 1H), 2.06 (m, 2H), 1.91 (m, 1H).
13C NMR (100 MHz, CDCl3) : δ 173.1, 159.0, 141.8, 128.8, 128.4, 127.5, 126.2,
113.8, 113.7, 70.5, 70.0, 69.8, 69.7, 55.2, 51.9, 36.8,
30.4.
MS (ESI) : m/z 379 (M + Na)+.
HRMS (ESI) : m/z 379.1535 (calcd for C21H24O5Na: 379.1521).
(2R,4S,6R)-4-(4-Methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-carbaldehyde
(ent-51):
O
OPMB
CHO
Same procedure was used for preparation of compound ent-51 as used for 51.
[α]23
D : + 74.3 (c = 1.5, CHCl3).
IR (KBr) : 3443, 2928, 1728, 1611, 1512, 1245, 1034, 822 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 9.98 (s, 1H), 7.37-7.25 (m, 5H), 7.19 (d, J = 8.3 Hz,
2H), 6.83 (d, J = 9.1 Hz, 2H), 5.18 (dd, J = 2.3, 10.6
Hz, 1H), 4.45 (d, J = 11.3 Hz, 1H), 4.26 (d, J = 11.3
Hz, 1H), 4.20 (dd, J = 2.3, 6.8 Hz, 1H), 3.84 (m, 1H),
3.79 (s, 3H), 2.40 (m, 1H), 1.96 (m, 2H), 1.76 (m, 1H).
13C NMR (100 MHz, CDCl3) : δ 203.4, 159.2, 141.7, 130.2, 129.2, 128.4, 127.6,
126.0, 113.9, 77.5, 70.5, 69.7, 69.5, 55.3, 37.0, 29.6.
MS (ESI) : m/z 349 (M + Na)+.
HRMS (ESI) : m/z 349.1420 (calcd for C20H22O4Na: 349.1415).
2-((2R,4R,6R)-4-(4-Methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-
phenylethanone (ent-56):
O
OPMB
O
Same procedure was used for preparation of compound ent-56 as used for 56.
[α]23
D : + 47.2 (c = 0.8, CHCl3)
IR (KBr) : 3061, 2926, 2854, 1683, 1598, 1513, 1448, 1250, 1068,
755, 698 cm-1
.
1H NMR (300 MHz, CDCl3) : δ 7.96 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H),
7.45 (t, J = 6.6 Hz, 2H), 7.31-7.22 (m, 7H), 6.86 (d, J =
8.8 Hz, 2H), 5.14 (t, J = 5.1 Hz, 1H), 4.50 (m, 2H),
4.28 (m, 1H), 3.80 (s, 3H), 3.73 (m, 1H), 3.43 (dd, J =
6.6, 16.1 Hz, 1H), 3.27 (dd, J = 5.8, 16.1 Hz, 1H), 2.43
(ddd, J = 3.6 8.0, 13.2 Hz, 1H), 2.10 (ddd, J = 6.3, 8.0,
13.2 Hz, 1H), 1.97 (m, 1H), 1.63 (m, 1H).
13C NMR (100 MHz, CDCl3) : δ 198.4, 140.6, 137.2, 133.0, 130.5, 129.2, 128.5,
128.4, 128.2, 127.0, 126.3, 126.1, 113.8, 71.9, 70.7,
69.8, 67.3, 55.2, 44.4, 36.4, 34.4.
MS (ESI) : m/z 439 (M + Na)+.
HRMS (ESI) : m/z 439.1907 (calcd for C27H28O4Na: 439.1885).
2-((2R,4R,6R)-4-hydroxy-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-phenylethanone (ent-
1):
O
OH
O
Same procedure was used for preparation of compound ent-1 as used for 1.
[α]23
D : + 23.3 (c = 0.2, CHCl3).
IR (KBr) : 3624, 2925, 2857, 2312, 1740, 1682, 1515, 1452, 1174,
753 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.98 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H),
7.49 (t, J = 8.8 Hz, 2H), 7.38-7.23 (m, 5H), 5.18 (t, J =
4.4 Hz, 1H), 4.22 (m, 1H), 4.00 (m, 1H), 3.45 (dd, J =
6.6, 15.4 Hz, 1H), 3.16 (dd, J = 5.9, 16.1 Hz, 1H), 2.15
(ddd, J = 3.7, 7.3, 13.2 Hz, 1H), 2.04 (m, 1H), 1.91
(ddd, J = 3.7, 5.1, 8.8 Hz, 1H), 1.50 (dt, J = 9.5, 12.4
Hz, 1H).
13C NMR (100 MHz, CDCl3) : δ 198.4, 140.2, 137.1, 133.1, 128.5, 128.4, 128.2,
127.0, 126.3, 72.3, 66.9, 64.0, 44.6, 40.0, 36.6.
MS (ESI) : m/z 319 (M + Na)+.
HRMS (ES) : m/z 319.1297 (calcd for C19H20O3Na: 319.1310).
2-((2R, 4R, 6R)-4-(tert-Butyldiphenylsilyloxy)-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-
phenylethanone (ent-57):
O
OTBDPS
O
Same procedure was used for preparation of compound ent-57 as used for 57.
[α]23
D : + 36.0 (c = 0.25, CHCl3)
IR (KBr) : 3068, 2927, 2855, 1681, 1466, 1215, 1110, 760,
701 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.94 (d, J = 6.6 Hz, 2H), 7.72 (t, J = 6.7 Hz 4H), 7.65
(d, J = 6.7 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44-
7.36 (m, 7H), 7.05 (t, J = 2.9 Hz, 2H), 6.71 (t, J = 2.9
Hz, 2H), 4.97 (t, J = 3.7 Hz, 1H), 3.98 (m, 2H), 3.39
(dd, J = 7.4, 15.5 Hz, 1H), 3.05 (dd, J = 5.9, 16.2 Hz,
1H), 2.15 (m, 2H), 1.74 (m, 2H), 1.07 (s, 9H).
13C NMR (100 MHz, CDCl3) : δ 198.3, 142.9, 135.8, 35.7, 134.1, 132.9, 130.3, 129.8,
129.7, 128.5, 128.4, 128.3, 128.1, 127.6, 127.0, 126.4,
125.7, 73.9, 69.6, 66.1, 45.3, 40.6, 38.4, 27.0, 19.3.
MS (ESI) : m/ 557 (M + Na)+.
HRMS (ESI) : m/z 535.2685 (calcd for C35H39O3 Si: 535.2668).
2-((2R,4R,6S)-4-Hydroxy-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-phenylethanone (ent-
2):
O
OH
O
Same procedure was used for preparation of compound ent-2 as used for 2.
[α]23
D : +18.9 (c = 1.8, CHCl3).
IR (KBr) : 3622, 2922, 2854, 1681, 1598, 1452, 1058, 751 cm-1
.
1H NMR (400 MHz, CDCl3) : δ 7.97 (d, J = 6.9 Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H),
7.43 (t, J = 7.7 Hz, 2H), 7.26-7.22 (m, 5H), 4.90 (dd, J
= 1.9, 12.0 Hz, 1H), 4.60 (m, 1H), 4.34 (t, J = 3.0, 1H),
3.39 (dd, J = 5.7, 16.0 Hz, 1H), 3.04 (dd, J = 6.8, 16.0
Hz, 1H), 1.94 (m, 2H), 1.75-1.60 (m, 2H).
13C NMR (100 MHz, CDCl3) : δ 198.3, 142.5, 137.0, 133.1, 128.5, 128.2, 127.2,
125.8, 73.7, 68.9, 64.6, 45.0, 39.8, 38.3.
MS (ESI) : m/z 319 (M + Na)+.
HRMS (ESI) : m/z 319.1325 (calcd for C19H20O3Na: 319.1310).
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