Copyright by Benjamin Perry Fauber 2006 · The first total synthesis of galanthamine was reported...
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Copyright by Benjamin Perry Fauber 2006
Transcript of Copyright by Benjamin Perry Fauber 2006 · The first total synthesis of galanthamine was reported...
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Copyright
by
Benjamin Perry Fauber
2006
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The Dissertation Committee for Benjamin Perry Fauber Certifies that this is the
approved version of the following dissertation:
STUDIES DIRECTED TOWARD THE SYNTHESES OF THE
BIOLOGICALLY ACTIVE ALKALOIDS
(-)-GALANTHAMINE AND (-)-LEMONOMYCIN
Committee:
Philip D. Magnus, Supervisor
Richard A. Jones
Sean M. Kerwin
Michael J. Krische
Hung-wen Liu
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STUDIES DIRECTED TOWARD THE SYNTHESES OF THE
BIOLOGICALLY ACTIVE ALKALOIDS
(-)-GALANTHAMINE AND (-)-LEMONOMYCIN
by
Benjamin Perry Fauber, B.S.
Dissertation
Presented to the Faculty of the Graduate School of
The University of Texas at Austin
in Partial Fulfillment
of the Requirements
for the Degree of
Doctor of Philosophy
The University of Texas at Austin
December, 2006
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Dedication
Laura, Richard, Jill, Dan, Frank, and Sallie — for all of your support and encouragement
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Acknowledgements
I am indebted to Professor Philip D. Magnus for the mentoring and guidance he
provided in solving the complex problems associated with my projects. Additionally, I
would like to thank Dr. Vincent Lynch for his assistance with X-ray crystallography and
structural elucidation, as well as the members of the P. D. Magnus and S. F. Martin
research groups for their helpful insight and discussions.
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STUDIES DIRECTED TOWARD THE SYNTHESES OF THE
BIOLOGICALLY ACTIVE ALKALOIDS
(-)-GALANTHAMINE AND (-)-LEMONOMYCIN
Publication No._____________
Benjamin Perry Fauber, Ph.D.
The University of Texas at Austin, 2006
Supervisor: Philip Douglas Magnus
Despite the enormous amount of work devoted to the synthesis of the
anticholinesterase Amaryllidaceae alkaloid, (-)-galanthamine, and the diversity of the
various strategies employed, the para-alkylation of an appropriately substituted phenol to
generate the cross-conjugated 2,4-cyclohexadienone has not been reported. As discussed
in this dissertation, the successful implementation of the intramolecular phenolate
alkylation strategy avoids the low yielding phenolic oxidation reaction used previously to
generate similar intermediates. The resultant product requires a reductive amination of
the aromatic aldehyde and latent aliphatic aldehyde to arrive at racemic narwedine, a
biogenetically related and validated synthetic precursor to (-)-galanthamine.
A methodology for the construction of enantio-enriched hydroisoquinolines was
also developed, with potential application toward the synthesis of the
tetrahydroisoquinoline antitumor antibiotic (-)-lemonomycin. Several approaches are
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discussed, with the key step being an asymmetric reduction of 1-substituted and
1,3-disubstituted isoquinolines to yield enantio-enriched hydroisoquinoline products.
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Table of Contents
List of Abbreviations ...............................................................................................x
PART A: STUDIES DIRECTED TOWARD THE SYNTHESIS OF THE BIOLOGICALLY ACTIVE ALKALOID (-)-GALANTHAMINE 1
Chapter 1: The Amaryllidaceae Alkaloids and Galanthamine ................................2
1.0 Introduction...............................................................................................2
1.1 Galanthamine ............................................................................................6
1.2 References...............................................................................................16
Chapter 2: Studies Toward the Synthesis of (-)-Galanthamine .............................21
2.0 Double Condensation Strategy ...............................................................21
2.1 Benzoazepine Strategy............................................................................24
2.2 Pummerer Strategy..................................................................................33
2.3 Ether Alkylation Strategy .......................................................................38
2.4 Amination of the Cross-Conjugated Dienone.........................................51
2.5 References...............................................................................................64
PART B: STUDIES DIRECTED TOWARD THE SYNTHESIS OF THE BIOLOGICALLY ACTIVE ALKALOID (-)-LEMONOMYCIN 73
Chapter 3: The Tetrahydroisoquinoline Alkaloids and Lemonomycin .................74
3.0 Introduction.............................................................................................74
3.1 Lemonomycin and Prior Synthetic Studies.............................................79
3.2 Previous Work within the Magnus Research Group...............................84
3.3 Summary of Previous Efforts Toward Lemonomycin............................87
3.4 References...............................................................................................89
Chapter 4: Studies Toward the Synthesis of (-)-Lemonomycin ............................94
4.0 Background on the Asymmetric Synthesis of Isoquinolines ..................94
4.1 Asymmetric Reduction Strategy .............................................................97
4.2 Bischler-Napieralski Strategy ...............................................................118
4.3 References.............................................................................................128
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PART C: EXPERIMENTAL CONDITIONS AND COMPOUND DATA 138
Chapter 5: Experimental Conditions and Compound Data..................................139
5.0 General Information..............................................................................139
5.1 Experimental Conditions and Compound Data for Chapter 2 ..............141
5.2 Experimental Conditions and Compound Data for Chapter 4 ..............184
5.3 References.............................................................................................232
Appendix A: X-ray Data for the Biaryl Dimer (36) ............................................234
Appendix B: X-ray Data for the Cross-Conjugated Dienone (79) ......................241
Appendix C: X-ray Data for the Tetracyclic Pyranone (84)................................247
Appendix D: X-ray Data for the Multicyclic Tertiary Amine (93) .....................255
Appendix E: X-ray Data for the Lactone Enone (103) ........................................261
Appendix F: X-ray Data for the Aldehyde Lactol (105)......................................269
Appendix G: X-ray Data for the Acetal Ether (107)............................................277
Appendix H: X-ray Data for the Isoquinoline Amide (39)..................................283
Appendices References........................................................................................288
Bibliography ........................................................................................................290
Vita.......................................................................................................................317
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List of Abbreviations
1,2-DCE 1,2-dichloroethane
1,2-DME 1,2-dimethoxyethane
Å ångström
Ac acetyl
Ar aryl or argon (dependent upon the context)
atm atmosphere
BHT 2,6-di-tert-butyl-4-methyl-phenol
binap 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
biphep 2,2'-bis(diphenylphosphino)-1,1'-biphenyl
Bn benzyl
Boc tert-butylcarbonyl
bs broad singlet
Bu butyl
c concentration
CAN ammonium cerium(IV) nitrate
Cbz benzyloxycarbonyl
m-CPBA m-chloroperbenzoic acid
cod 1,5-cyclooctadiene
CSA 10-camphorsulfonic acid
Cy cyclohexyl
d doublet
D sodium D-line, 589 nm
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DABCO 1,4-diazabicyclo[2.2.2]octane
dba dibenzylideneacetone
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC N,N'-dicyclohexylcarbodiimide
DCE dichloroethane
DCM dichloromethane
dd doublet of doublets
DEAD diethyl azodicarboxylate
DIAD diisobutyl azodicarboxylate
DIBAL-H diisobutylaluminum hydride
DIEA N,N-diisopropylethylamine
diop 4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane
dioxane 1,4-dioxane
DMAP 4-N,N-dimethylaminopyridine
DMF N,N-dimethylformamide
DMP Dess-Martin periodinane
DMSO dimethyl sulfoxide
dppp 1,3-bis(diphenylphosphino)propane
dr diastereomeric ratio
dt doublet of triplets
EDC N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide
ee enantiomeric excess
er enantiomeric ratio
Et ethyl
g gram
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Gly glycosyl
HOBt 1-hydroxybenzotriazole
HPLC high-pressure liquid chromatography
HRMS high-resolution mass spectrometry
IR infrared
kg kilogram
L-selectride lithium tri-sec-butylborohydride
LDA lithium diisopropylamide
m multiplet
m meta
M molar
Me methyl
ml milliliter
mmol millimole
mol mole
MOM methoxymethyl
M.p. melting point
Ms methanesulfonyl
MTBE methyl-tert-butyl ether
NBS N-bromosuccinimide
ng nanogram
nm nanometer
NMR nuclear magnetic resonance
o ortho
p para
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Ph phenyl
Piv pivaloyl
ppm parts per million
PPSE polyphosphoric acid trimethylsilyl ester
Pr propyl
prep preparatory
psi pounds per square inch
py pyridine
q quartet
qd quadruplet of doublets
R generic functional group
s singlet
t triplet
TBAF tetrabutylammonium fluoride
TBDMS tert-butyldimethylsilyl
td triplet of doublets
Tf trifluoromethanesulfonyl
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
THP tetrahydropyran
TIPS triisopropylsilyl
TLC thin-layer chromatography
TMS trimethylsilyl
Troc 2,2,2-trichloroethoxycarbonyl
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Ts toluenesulfonyl
p-TsOH p-toluenesulfonic acid
X halogen
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1
PART A: STUDIES DIRECTED TOWARD THE
SYNTHESIS OF THE BIOLOGICALLY ACTIVE
ALKALOID (-)-GALANTHAMINE
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Chapter 1: The Amaryllidaceae Alkaloids and Galanthamine
1.0 INTRODUCTION
The Amaryllidaceae alkaloids comprise a unique group of tertiary amine bases
which have been found almost exclusively within the title family. The Amaryllidaceae
family includes (but is not limited to) the Amaryllis, Crinum, Galanthus, Haemanthus,
Hymenocallis, Hypoxis, Leucojum, Lophiola, Lycorus, Narcissus, Sceletium, Vallota, and
Zephyranthes genera.1,2 Members of this family are found terrestrially, throughout the
globe, with the plants being most prevalent in tropical and subtropical regions.3 The
alkaloids isolated from plants of the Amaryllidaceae family are often most abundant in
the buds and bulbs, giving rise to 0.1-2% total alkaloid content versus raw plant
material.4
N
O
O
HO
lycorine (1)
O
OH
O
N
galanthamine (3)
O
O N
OH
crinine (2)
membrenone (4)
NH
O
O
pancratistatin (6)
O
OHOH
OHO
O N
O
OH
montanine (5) OHN
HO
OO HO
Figure 1.01. Some representative Amaryllidaceae alkaloids
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3
The Amaryllidaceae alkaloid family is distinguished by the elaboration of a
15 carbon nucleus ― of which there is typically an aromatic unit and a reduced aromatic
unit.5 The greater than 500 alkaloids found in the family can be attributed to the diversity
that results from minor variations in the degree of oxidation, aromatic substitution,
hydrogenation, and ring connectivity of the parent C-15 skeleton (Figure 1.01). 6,7
The similarities of the Amaryllidaceae alkaloids are best rationalized through their
biosynthetic pathways. The alkaloids arise via alternative modes of norbelladine (9)
oxidative coupling. Norbelladine is generated through the reductive condensation of
3,4-dihydroxybenzaldeyde (7) with tyramine (8), and both of these precursors are the
products of phenylalanine and tyrosine metabolites, respectively. Three structural types
can be generated through the different modes of phenolic oxidation coupling of 4'-O-
methylnorbelladine (10) ― para-ortho' (A), para-para' (B), and ortho-para' (C) (Scheme
1.01). These three oxidative coupling modes give rise to the respective skeletal
frameworks of lycorine (1), crinine (2), and galanthamine (3).8 Subsequent redox of the
crinine core results in the formation of the membrenone (4), montanine (5), and
pancratistatin (6) skeletons.
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N
O
O
HO
lycorine (1)
O
OH
O
Ngalanthamine (3)
O
O N
OH
crinine (2)
L-PheHO
HOO + NH2 OH
L-Tyr
tyramine (8)
HO
HONH
norbelladine (9)
S-methyl adenosine
O
HOHN
HO
OOH
NH
OH
O
NH
OH
HO
(7)
(10) (10)(10)
B CA
OH
reductive condensation
Scheme 1.01. Biosyntheses of the Amaryllidaceae alkaloid skeletons
The medicinal properties of the Amaryllidaceae family have long been exploited
by natives of the high-mountain Caucasus region of Russia, where teas made from the
plant’s constituents are used to treat a variety of ailments.9 Modern research efforts have
revealed the individual Amaryllidaceae alkaloid components to be potent medicinal
agents, with a wide range of biological activity. Noteworthy examples include the highly
explored antineoplastic pancratistatin (6), which inhibits murine P388 lymphomic
leukemia and human cancer cell lines with double-digit ng/ml activity.10
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5
Membrenone (4), and its oxidative related derivatives, have received notable synthetic
activity due to their action as serotonin uptake inhibitors.7 Additionally,
(-)-galanthamine (3) has been thoroughly explored as a symptomatic treatment for
Alzheimer’s disease, due to its activity as an acetylcholinesterase inhibitor. The
following subchapter discusses the background, synthetic studies, and biological activity
of galanthamine in more detail.
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1.1 GALANTHAMINE
The alkaloid (-)-galanthamine (3) is a tertiary amine base which has been isolated
from a number of species in the Amaryllidaceae family. Galanthamine was first reported
as a constituent of the Caucasian snowdrop (Galanthus woronowii) in 1952.11 Its
structure was confirmed, utilizing degradation studies, by Uyeo and Kobayashi in 1957.9
The absolute configuration of the structure was determined after Barton and Kirby
reported the first total synthesis of (-)-galanthamine in 1960.12
Several genera produce galanthamine, with most yielding approximately
10-100 mg of galanthamine per kilogram of raw plant material through a costly
extraction process (approximately US$50,000 per kilogram of galanthamine).13 Due to
the high cost of extraction, several synthetic routes to galanthamine, and the related
oxidized enone, narwedine (11), have been explored (Scheme 1.02).
O
ON
O
O
O
OH
N
(-)-galanthamine (3) (-)-narwedine (11)
O
O
OH
N
(-)-lycoramine (12)
Scheme 1.02. The structures of (-)-galanthamine, (-)-narwedine, and
(-)-lycoramine
The first total synthesis of galanthamine was reported by Barton and Kirby in
1960.12 They completed a biomimetic route, in which 4'-O-N-dimethylnorbelladine (13)
was subjected to phenolic oxidation coupling conditions, giving rise to a symmetrical
dienone intermediate (14), which was then trapped by the adjacent phenol, yielding
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(±)-narwedine (11), the proposed biogenetic precursor to galanthamine. The carbonyl of
narwedine was reduced with LiAlH4 to yield a mixture of (±)-galanthamine (3), and
(±)-epigalanthamine (15) (Scheme 1.03).
O
ON
O
O
O
OH
N
(±)-(11)
OOH
N
OH
(13)
O
O
OH
N+
HO
ON
O
(14)
K3[Fe(CN)6]
NaHCO3H2O/CHCl30.9% yield
LiAlH4
Et2Oreflux
(±)-(3)39% yield
(±)-(15)39% yield
Scheme 1.03. Barton and Kirby’s synthesis of (±)-galanthamine
While the yield of the phenolic oxidation step was 0.9%, the Barton and Kirby
approach demonstrated the plausibility of utilizing a phenolic oxidation strategy to
generate the galanthamine core. Additionally, feeding experiments involving 14C-labeled
4'-O-N-dimethylnorbelladine, and subsequent incorporation of the labeled carbon unit
into galanthamine and narwedine, further supported the hypothesis for the biosynthesis of
galanthamine from norbelladine (9) intermediates, just as Barton and Kirby had used in
their synthesis.14
Zenk and co-workers reported a detailed study on the biosynthesis of
galanthamine and found that 13C-labeled 4'-O-methylnorbelladine was 27% incorporated
into galanthamine, and 31% incorporated into N-demethylgalanthamine (18), through
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feeding experiments with the Snowflake Lily (Leucojum aestivum).15 Furthermore, they
established that N-demethylgalanthamine was N-methylated in the final step of the
biosynthesis, which was in contrast to the biosynthetic hypothesis of Barton and Kirby.
Thus, Zenk and co-workers concluded that norbelladine (9) reacted within the Snowflake
Lily to form N-demethylnarwedine (17), which was reduced to N-demethylgalanthamine
(18), and N-methylated to form galanthamine (3) (Scheme 1.04).
O
ONH
O
O
O
OH
NH
(17)
OOH
NH
OH
(9)
HO
ONH
O
(16)
(18)
O
O
OH
N
(-)-(3)
Scheme 1.04. Zenk’s postulated biosynthetic pathway for galanthamine
Interestingly, in a process first reported by Barton and Kirby in their 1962 full
paper detailing the synthesis of (-)-galanthamine (3), (–)-narwedine (11) was converted,
in high optical purity, to (+)-narwedine by trace amounts of (-)-galanthamine during
recrystallization from hot ethanol (Scheme 1.05).16 This method was exploited to
generate (-)-narwedine, by resolving (±)-narwedine with catalytic amounts of
(+)-galanthamine, which upon further reduction yielded (-)-galanthamine.
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O
ON
O
(-)-(11)
O
O
OH
N
(-)-(3)
MnO2
CHCl323 °C
EtOH recrx.O
ON
O
(+)-(11)
trace of(-)-galanthamine
80% yield38% yield
Scheme 1.05. Barton and Kirby’s resolution of (–)-narwedine to
(+)-narwedine
The dynamic resolution of narwedine was improved upon by the scientists at
Ciba-Geigy, utilizing catalytic amounts of (+)-galanthamine to resolve (±)-narwedine
(11) into (-)-narwedine in high optical yield and purity on kilogram scale (Scheme
1.06).17
O
ON
O
O
ON
O
(+)-galanthamine(1 mol %)
95% EtOH/NEt3 (9:1)80 → 25 °C90% yield
(±)-(11) (-)-(11)
HO
ON
O
(14)
Scheme 1.06. The Ciba-Geigy dynamic resolution of (±)-narwedine
The Ciba-Geigy team went on to explore the details of the resolution and found
that no isolable, or spectrally identifiable, conglomerate or covalent pair of narwedine
and galanthamine was detected in the solution or solid states. The Ciba group explained
the resolution event as a “spontaneous resolution of stereoisomers,” in which the
crystallization of a single enantiomer of (-)-narwedine drove the dynamic resolution
event to completion through the symmetrical dienone intermediate (14). The scientists at 9
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Ciba-Geigy also solved the problem of epigalanthamine (15) contamination during the
reduction of narwedine to galanthamine by utilizing L-selectride as the reducing agent to
generate (-)-galanthamine in 99% yield. It should also be noted that (±)-narwedine can
be resolved via a classical chiral acid resolution with di-p-toluoyl-D-tartaric acid.18
The syntheses that followed Barton and Kirby’s initial studies of galanthamine (3)
have focused on generating the quaternary carbon center, while simultaneously forming
the bond between the two six-membered rings of the target. The synthetic efforts to form
the aforementioned carbon-carbon bond can be categorized into two different methods ―
those which utilize a phenolic oxidation strategy and those which utilize a Heck
coupling19 strategy (Scheme 1.07).13
O
O
OH
NO
R'
YPO
XRphenolic oxidation Heck coupling
(3) (20)
O
HON
OH
(19)X
Scheme 1.07. The two major strategies to form the galanthamine core
The biggest contribution to improving the yield of the phenolic oxidation
coupling, over that of the 0.9% yield initially reported by Barton and Kirby, came from
the research of Kametani and co-workers. They made use of a para-blocking group (in
the form of a halide) (26), which promoted the desired ortho-para' coupling, to generate
the galanthamine core (27) in 40% yield. Subsequent treatment with refluxing LiAlH4
removed the aromatic halide blocking group and reduced the enone carbonyl to produce a
mixture of (±)-galanthamine (3) and (±)-epigalanthamine (15) (Scheme 1.08).20
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O
HON
OH
(26) BrO
O
ON
O
(±)-(27)
K3[Fe(CN)6]
NaHCO3H2O/CHCl3
60 °C40% yield
Br
O
ON
OH
BnO
MeNH2NaOH
H2O BnO
HNCl
O O91% yield
LiAlH4
THFreflux
98% yieldBnO
HN
BnO
O Br
COCl
10% NaOH(aq)CHCl3, 23 °C
O
BnON
OBn
(25) BrO
(21) (22)(23)
(24)
48% HBr(aq)
EtOHreflux
55% yield(2 steps)
LiAlH4
THFreflux
(±)-(3)50% yield
O
ON
OH
(±)-(15)40% yield
+
Scheme 1.08. Kametani’s synthesis of (±)-galanthamine
The Kametani research group and others have also explored the effects of various
phenolic oxidation reagents and substitution on the amine/amide tether, in attempts to
improve the yield of the phenolic oxidation step (c.a. 0.9-60% yield).21 The effects of
asymmetric centers on the amine tether, in efforts to promote formation of a single
narwedine-type enantiomer, have also been examined.22
Reports concerning the Heck coupling strategy to form the galanthamine core
structure often involved the formation of a 2-haloarylether, which was then cyclized to
yield the tricyclic galanthamine core. The research groups of Fels,23 Parsons,24 and
Guillou/Thal25 independently reported this approach on nearly identical model substrates,
which was built upon by the Trost research group.26 The Trost approach utilized an
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asymmetric allylic alkylation27 (30), followed by the Heck coupling step, to generate the
tricyclic core of galanthamine as a single enantiomer (33) (Scheme 1.09).
OO
O
CN
O
ON
OH
(-)-(3)
(33)
OO Br
O
(30)
O
OO Br
O
(32)
CN
OO Br
O(31)
OH
O
1) p-TsOH, (MeO)3CH MeOH
2) DIBAL-H, -78 °C toluene 85% yield
O
1) Acetonecyanohydrin PPh3, DIAD, Et2O
2) p-TsOH, H2O, THF76% yield96% ee
Pd(OAc)2, dpppAg2CO3
PhCH3107 °C
91% yield
SeO2NaH2PO4
1,4-dioxane150 °C
57% yield10:1 dr
OO
O
CN
(34)
HO1) MeNH2, MeOH2) DIBAL-H3) NaH2PO4(aq)
4) NaBH3CN
O
O
BrOH O O
OTroc+
(28) (29)
[(η3-C3H5)PdCl2]ligand*
NEt3, DCM23 °C
72% yield88% ee
Scheme 1.09. Trost’s synthesis of (-)-galanthamine
Although the yield for the Heck coupling reaction, which generated the
quaternary carbon center, was higher than the respective phenolic oxidation reaction, the
resulting spirocyclic cyclohexene product (33) required an allylic oxidation to install the
allylic alcohol (34) present in galanthamine. Unfortunately, allylic oxidation reactions
are often unselective,24 and the yields are less than 50%, as exemplified in the formation
of the allylic alcohol product (34), highlighting a significant drawback to the Heck
coupling approach. Moreover, the low yielding oxidation reaction brought the overall
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yield of the synthesis to a comparable level versus the phenolic oxidation strategy (c.a.
10% overall yield).
A recent publication from the Tu research group discussed a new approach to
galanthamine,28 which was analogous to their earlier work toward lycoramine (12).29 The
key step introduced the quaternary center of the target via a semi-pinacol rearrangement
of a secondary alcohol (35). Electrophilic bromination of the olefin promoted the aryl
migration, which quenched the bromonium ion, resulting in the formation of the bicyclic
aldehyde (36). Removal of the silylether revealed the phenol, which displaced the
secondary bromide under basic conditions, to yield the tricyclic core of
galanthamine (37) (Scheme 1.10).
OH
O
OO
(35)
NBS
DCM0 °C
95% yieldOTBDMS
OO
OTBDMSO
O
BrDBU
DMSO95 °C
90% yield
(±)-(36)
O
O
O
(±)-(37)
OO
O
O(±)-(38)
O
OO O
O(±)-(39)
O
OO
1) LDA, TMSCl THF, -78 °C
2) Pd(OAc)2 Na2CO3 CH3CN
63% yield
O
O(±)-(40)
NHO
HO
O
ON
OH
(±)-(3)
LiAlH4
1,2-DMEreflux
76% yield
(CH2O)nTFA
1,2-DCE82% yield
O
ON
OH
(±)-(41)
O
Scheme 1.10. Tu’s synthesis of (±)-galanthamine
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14
Additional transformations homologated the aldehyde and revealed the ketone,
generating the cyclohexanone intermediate (38). The oxidation of the ketone to the
enone (39) proceeded in low yield, highlighting a drawback to this approach. Subsequent
reduction of the enone carbonyl, followed by deprotection and oxidation of the aldehyde,
generated the Pictet-Spengler cyclization30 precursor (40). Under identical conditions
utilized by Hoshino in his synthesis of (±)-lycoramine,31 the amide was treated with a
formaldehyde equivalent to form the N-acyliminium ion, which was quenched by the
adjacent aromatic ring to form the benzoazepine ring system (41). Reduction of the
amide with LiAlH4 yielded (±)-galanthamine in 14 steps from commercially available
starting materials.
Research efforts have also revealed galanthamine to be an acetylcholinesterase
inhibitor which enhances cholinergic function. In patients diagnosed with Alzheimer’s
disease, (–)-galanthamine was well tolerated and produced significant improvement in
attention and performance, leading to its FDA approval in 2001 under the RazadyneTM
trade name.32 Sales of Alzheimer’s disease treatments, such as RazadyneTM, were in
excess of 3.8 billion dollars (US) in fiscal year 2005, illustrating the demand for large
quantities of (-)-galanthamine.33
RazadyneTM is distributed in the United States by Ortho-McNeil Pharmaceuticals,
a Johnson & Johnson subsidiary. Sano Chemia AG of Hungary claims to be the
exclusive manufacturer and supplier of (-)-galanthamine to Johnson & Johnson. The
Sano Chemia synthetic approach to galanthamine borrowed heavily from the previous
work of Carroll and co-workers,21e which was based on the phenolic oxidation strategy
pioneered by Barton and Kirby. Although the Sano Chemia route was highly-optimized,
it still required 13 steps in a nine pot process, with a calculated overall yield of 13%
-
(Scheme 1.11).34 Clearly, there is room to improve on the synthesis of (-)-galanthamine
(3) with regards to an effective and high-yielding process.
O
O
O Br2
MeOHreflux
91% yield
O
O
O
Br
95% H2SO4(aq)
90 °C68% yield
HO
O
O
Br
1) tyramine EtOH, reflux
2) NaBH4 H2O, 5 °C
92% yield
HO
O Br
NH
dioxane/DMF(30:1)reflux
85% yield
HO
O Br
N
O
K3[Fe(CN)6]K2CO3
toluene/H2O(5:1)60 °C
47% yield
O
O
N
O
O
HO OH
p-TsOH (cat.)toluenereflux
80% yield
ON
O
O
OO
1) LiAlH4, THF, 60 °C
2) 15% NaOH(aq), reflux3) 4M HCl(aq), 60 °C
85% yield
O
O
N
O
(-)-narwedine(1 mol %)
EtOH/NEt3 (9:1)reflux → 40 °C
75% yield
O
O
N
O
OHHCO2Et
HCO2H (cat.)
OH
1) L-selectride THF, -15 °C
2) 48% HBr(aq), 10 °C98% yield
ON
O(-)-(3)·HBr
HO
H
Br
Br Br
(42) (43) (44)
(45)(46)
(±)-(47) (±)-(48)
(±)-(11) (-)-(11)
Scheme 1.11. The Sano Chemia (-)-galanthamine·HBr (RazadyneTM) synthesis
15
-
16
1.2 REFERENCES
1) Cordell, G. A. Introduction to the Alkaloids: A Biogenetic Approach; John
Wiley & Sons, Inc.: New York, 1981; pg. 533.
2) Fernald, M. L. Gray’s Manual of Botany, 8th edition; American Book
Company: NY, 1950; pg. 452.
3) Raffauf, R. F. Plant Alkaloids: A Guide to Their Discovery and Distribution;
Haworth Press, Inc.: Binghamton, NY, 1996; pg. 13.
4) Harvey, A. L. The Pharmacology of Galanthamine and its Analogues.
Pharmac. Ther. 1995, 68, 113.
5) Pelletier, S. W. Chemistry of the Alkaloids; Van Nostrand Reinhold Company:
New York, 1970; pg. 151.
6) Hoshino, O. The Alkaloids: Chemistry and Biology; Cordell, G. A., editor;
Academic Press: San Diego, CA, 1998; vol. 51, pg. 324.
7) Zhong, J. Amaryllidaceae and Sceletium Alkaloids. Nat. Prod. Rep. 2005, 22,
111.
8) Dewick, P. M. Medicinal Natural Product: A Biosynthetic Approach; Second
ed.; John Wiley & Sons, LTD: West Sussex, 2002.
9) Wildman, W. C. The Alkaloids: Chemistry and Physiology; Manske, R. H. F.,
editor; Academic Press: New York, 1960; vol. 6, pg. 289.
10) Rinner, U.; Hudlicky, T. Synthesis of Amaryllidaceae Constituents – An
Update. Synlett 2005, 3, 365.
11) Proskurnina, N. F.; Yakovleva, A. P. Alkaloids of Galathus woronowi. II.
Isolation of a New Alkaloid. Zhur. Obshchei. Khim. 1952, 22, 1899.
-
17
12) Barton, D. H. R.; Kirby, G. W. The Synthesis of Galanthamine. Proc. Chem.
Soc. 1960, 392.
13) Marco-Contelles, J.; Carreiras, M. C.; Rodriguez, C.; Villarroya, M.; Garcia,
A. G. Synthesis and Pharmacology of Galanthamine. Chem. Rev. 2006, 106,
116.
14) Barton, D. H. R.; Kirby, G. W.; Taylor, J. B.; Thomas, G. M. Phenol
Oxidation and Biosynthesis. Part VI. The Biogenesis of Amaryllidaceae
Alkaloids. J. Chem. Soc. 1963, 4545.
15) Eichhorn, J.; Takada, T.; Kita, Y.; Zenk, M. H. Biosynthesis of the
Amaryllidaceae Alkaloid Galanthamine. Phytochem. 1998, 49, 1037.
16) Barton, D. H. R.; Kirby, G. W. Phenol Oxidation and Biosynthesis. Part V.
The Synthesis of Galanthamine. J. Chem. Soc. 1962, 806.
17) Shieh, W.-C.; Carlson, J. A. Asymmetric Transformation of Either
Enantiomer of Narwedine via Total Spontaneous Resolution Process, a
Concise Solution to the Synthesis of (-)-Galanthamine. J. Org. Chem. 1994,
59, 5463.
18) Chaplin, D. A.; Johnson, N. B.; Paul, J. M.; Potter, G. A. Dynamic
Diastereomeric Salt Resolution of Narwedine and its Transformation to
(-)-Galanthamine. Tetrahedron Lett. 1998, 39, 6777.
19) Heck, R. F. Palladium-Catalyzed Reactions of Organic Halides with Olefins.
Acc. Chem. Res. 1979, 12, 146.
20) Kametani, T.; Yamaki, K.; Yagi, H.; Fukumoto, K. Modified Total Synthesis
of (±)-Galanthamine Through Phenol Oxidation. Chem. Comm. 1969, 425.
21) A) Kametani, T.; Yamaki, K.; Yagi, H.; Fukumoto, K. Studies on the
Syntheses of Heterocyclic Compounds. Part CCCXV. Modified Total
-
18
Synthesis of (±)-Galanthamine through Phenol Oxidation. J. Chem. Soc. (C),
1969, 2602. B) Kametani, T.; Seino, C.; Yamaki, K.; Shibuya, S.; Fukumoto,
K.; Kigasawa, K.; Satoh, F.; Hiiragi, M.; Hayasaka, T. Studies on the
Syntheses of Heterocyclic Compounds. Part CCCLXXXVI. Alternative Total
Syntheses of Galanthamine and N-Benzylgalanthamine Iodide. J. Chem. Soc.
(C), 1971, 1043. C) Kametani, K.; Shishido, K.; Hayashi, E.; Seino, C.;
Kohno, T.; Shibuya, S.; Fukumoto, K. Studies on the Syntheses of
Heterocyclic Compounds. CCCXCVI. An Alternative Total Synthesis of
(±)-Galanthamine. J. Org. Chem. 1971, 36, 1295. D) Holton, R. A.; Sibi, M.
P.; Murphy, W. S. Palladium-Mediated Biomimetic Synthesis of Narwedine.
J. Am. Chem. Soc. 1988, 110, 314. E) Szewczyk, J.; Lewin, A. H.; Carroll, F.
I. An Improved Synthesis of Galanthamine. J. Heterocycl. Chem. 1988, 25,
1809. F) Vlahov, R.; Krikorian, D.; Spassov, G.; Chinova, M.; Vlahov, I.;
Parushev, S.; Snatzke, G.; Ernst, L.; Kieslich, K.; Abraham, W.-R.; Sheldrick,
W. S. Synthesis of Galanthamine and Related Alkaloids – New Approaches. I.
Tetrahedron 1989, 45, 3329. G) Szewczyk, J.; Wilson, J. W.; Lewin, A. H.;
Carroll, F. I. Facile Synthesis of (±)-, (+)-, and (-)-Galanthamine. J.
Heterocycl. Chem. 1995, 32, 195. H) Chaplin, D. A.; Fraser, N.; Tiffin, P. D.
A Concise, Scaleable Synthesis of Narwedine. Tetrahedron Lett. 1997, 38,
7931. I) Kita, Y.; Arisawa, M.; Gyoten, M.; Nakajima, M.; Hamada, R.;
Tohma, H.; Takada, T. Oxidative Intramolecular Phenolic Coupling Reaction
Induced by a Hypervalent Iodine(III) Reagent: Leading to Galanthamine-Type
Amaryllidaceae Alkaloids. J. Org. Chem. 1998, 63, 6625. J) Krikorian, D.;
Tarpanov, V.; Parushev, S.; Mechkarova, P. New Achievements in the Field
of Intramolecular Phenolic Coupling Reactions, Using Hypervalent (III)
-
19
Iodine Reagent: Synthesis of Galanthamine. Synth. Commun. 2000, 30, 2833.
K) Node, M.; Kodama, S.; Hamashima, Y.; Baba, T.; Hamamichi, N.;
Nishide, K. An Efficient Synthesis of (±)-Narwedine and (±)-Galanthamine
by an Improved Phenolic Oxidative Coupling. Angew. Chem. Int. Ed. 2001,
40, 3060.
22) A) Shimizu, K.; Tomioka, K.; Yamada, S.; Koga, K. A Biogenetic-Type
Asymmetric Synthesis of Optically Active Amaryllidaceae Alkaloids: (+)- and
(-)-Galanthamine from L-Tyrosine. Heterocycles 1977, 8, 277. B) Kodama,
S.; Hamashima, Y.; Nishide, K.; Node, M. Total Synthesis of
(-)-Galanthamine by Remote Asymmetric Induction. Angew. Chem., Int. Ed.
2004, 43, 2659.
23) Pilger, C.; Westermann, B.; Florke, U.; Fels, G. A New Stereoselective
Approach Towards the Galanthamine Ring System via an Intramolecular
Heck Reaction. Synlett 2000, 1163.
24) Parsons, P. J.; Charles, M. D.; Harvey, D. M.; Sumoreeah, L. R.; Shell, A.;
Spoors, G.; Gill, A. L.; Smith, S. A General Approach to the Galanthamine
Ring System. Tetrahedron Lett. 2001, 42, 2209.
25) Guillou, C.; Beunard, J.-L.; Gras, E.; Thal, C. An Efficient Total Synthesis of
(±)-Galanthamine. Angew. Chem. Int. Ed. 2001, 40, 4745.
26) Trost, B. M.; Tang, W. An Efficient Enantioselective Synthesis of
(-)-Galanthamine. Angew. Chem. Int. Ed. 2002, 41, 2795.
27) Trost, B. M.; Toste, F. D. Asymmetric O- and C-Alkylation of Phenols. J. Am.
Chem. Soc. 1998, 120, 815.
28) Hu, X.-D.; Tu, Y. Q.; Zhang, E.; Gao, S.; Wang, S.; Wang, A.; Fan, C.-A.;
Wang, M. Total Synthesis of (±)-Galanthamine. Org. Lett. 2006, 8, 1823.
-
20
29) Fan, C.-A.; Tu, Y.-Q.; Song, Z.-L.; Zhang, E.; Shi, L.; Wang, M.; Wang, B.;
Zhang, S.-Y. An Efficient Total Synthesis of (±)-Lycoramine. Org. Lett. 2004,
6, 4691.
30) A) Pictet, A.; Spengler, T. Über die Bildung von Isochinolin-derivaten durch
Einwirkung von Methylal auf Pheny-äthylamine, Phenyl-alanin und Tyrosin.
Chem. Ber. 1911, 44, 2030. B) Cox, E. D.; Cook, J. M. The Pictet-Spengler
Reaction: A New Direction for an Old Reaction. Chem. Rev. 1995, 95, 1797.
31) Ishizaki, M.; Ozaki, K.; Kanematsu, A.; Isoda, T.; Hoshino, O. Synthetic
Approaches Toward Spiro[2,3-dihydro-4H-1-benzopyran-4,1'-cyclohexan]-
2-one Derivatives via Radical Reactions: Total Synthesis of (±)-Lycoramine.
J. Org. Chem. 1993, 58, 3877.
32) Lilienfeld, S. Galanthamine – A Novel Cholinergic Drug with a Unique Dual
Mode of Action for the Treatment of Patients with Alzheimer’s Disease. CNS
Drug Rev. 2002, 8, 159.
33) Whalen, J. Britain Stirs Outcry by Weighing Benefits of Drugs Versus Price.
The Wall Street Journal, Nov. 22, 2005, pg. A1.
34) Küenburg, B.; Czollner, L.; Fröhlich, J.; Jordis, U. Development of a Pilot
Scale Process for the Anti-Alzheimer Drug (-)-Galanthamine Using
Large-Scale Phenolic Oxidative Coupling and Crystallization-Induced Chiral
Conversion. Org. Proc. Res. Dev. 1999, 3, 425.
-
Chapter 2: Studies Toward the Synthesis of (-)-Galanthamine
2.0 DOUBLE CONDENSATION STRATEGY
There have been several reported syntheses of galanthamine (1) and/or narwedine
(2). Most of the syntheses are in excess of ten steps and almost all suffer from
debilitating low yields at the key step (c.a. 40-55%).1 The low yields are often due to the
use of phenolic or allylic oxidation chemistry, which results in overall yields of
approximately 10%. In the syntheses of galanthamine and narwedine, the central issue
has been the generation of a carbon-carbon bond, of which one carbon is a quaternary
center, between the two six-membered rings of the carbon skeleton. A majority of
previous syntheses have formed this bond via phenolic oxidation methods, with the
remainder utilizing Heck-type couplings, as discussed in Chapter 1.1.
O
ON
O
O
O
OH
N
(-)-galanthamine (1) (-)-narwedine (2)
O
O
OH
N
(-)-lycoramine (3)
Figure 2.01. The structures of (-)-galanthamine, (-)-narwedine, and
(-)-lycoramine
My initial strategy, designed to enhance the efficiency of galanthamine synthesis
and provide access to the Amaryllidaceae family, involved the generation of a substituted
benzofuranone (4), which would be functionalized at the α-carbon and reduced to the
21
-
lactol (5) (Scheme 2.01). A double aldol condensation could generate the enone ring
system (6), followed by a Pictet-Spengler cyclization, as described by Martin and
Garrison in their synthesis of (±)-lycoramine (3),2 to generate the benzoazepine ring
structure and (±)-narwedine (2). The established resolution of (±)-narwedine into the
desired single optical isomer3 made the racemate a sensible target intermediate in route to
(-)-galanthamine.
O
O
OO
ON
(±)-(2)
O
OH
O
O
NR
O
O
O
(6)(5)(4)
NR
O
CO2R
Scheme 2.01. The double aldol condensation approach to (±)-narwedine
Synthesis of the substituted benzofuranone (4) was envisioned as originating from
the C-arylation of a dialkyl malonate. There are no examples reported in the literature in
which 2-halo-6-methoxy-phenols successfully participate in the arylation of a malonate.
Therefore, it was not surprising that 2-bromo-6-methoxy-phenol4 was unreactive under a
variety of copper(I)-mediated arylation conditions which produced related
benzofuranones,5 but yielded none of the desired benzofuranone (4) and only trace
amounts of the mixed phenol/alkyl malonate esters. Additionally, palladium catalyzed
conditions similar to those described by Hartwig,6 Buchwald,7 and Miura8 were also
unsuccessful in forming the substituted benzofuranone. Arylation was achieved with
2,6-dibromophenol9 (7) under copper(I) bromide conditions as reported by Konopelski,10
to yield the 7-bromo-benzofuranone (8) (Scheme 2.02). Attempts to convert the
22
-
aryl-bromide to an aryl-methoxy (9) under copper(I) chloride and sodium methoxide
conditions11 yielded an intractable mixture of products.
OH
Br BrO
O CO2Me
O
(9)
OBr CO2Me
O
(8)
NaH, CuBrMeCO2CH2CO2Me
dioxane, reflux51% yield
(7)
CuCl
NaOMe/MeOHDMF, reflux
X
Scheme 2.02. Formation of the benzofuranone core
The multi-step conversion of o-vanillin into the 7-methoxy-3H-benzofuran-2-one
was also considered,12 but was not pursued due to the lengthy synthesis required to
generate the unstable benzofuranone core.13 Ultimately, efforts toward the
benzofuranone/double condensation route were halted due to the inefficiency of the
synthetic pathway. In the following subchapter, an alternative strategy is discussed.
23
-
2.1 BENZOAZEPINE STRATEGY
The use of an intramolecular phenolate alkylation to generate a cross-conjugated
cyclohexa-2,5-dienone and a quaternary carbon center was first described in 1957 by
Winstein and Baird.14 Masamune utilized this method to establish the quaternary center
of a divergent intermediate15 (13) in his 1964 syntheses of the diterpenes kaurene (15),16
garryine,17 and atisine18 (Scheme 2.03). It was noted that only alkylbromide 12 cyclized
to the dienone (13), while alkylbromide 11 did not react due to the steric repulsion of the
axial C8 proton and the tetrahydropyranyl (THP) ether in the alkylation transition state.
BnO
CO2H(10)
HO
(11) OTHP
Br
HO
OTHP
Br
(12)
KOtBu
tBuOHreflux
OTHP
O (13)
(-)-kaurene (15)
H
H
OH
O (14)
H3O+
H
H
H
H
30% yieldfrom 10
8
8
8+
8
6 steps
Scheme 2.03. Masamune’s application of an intramolecular phenolate
alkylation toward the synthesis of (-)-kaurene
The most recent review of intramolecular phenolate alkylations describes the
scope and limitations of this reaction.19 A majority of syntheses utilizing this method
have been directed toward steroidal targets, but to our knowledge only one report has
showcased this reaction’s utility in the synthesis of a non-terpenoid alkaloid.20
24
-
The cross-conjugated dienone and quaternary carbon center of (±)-narwedine (2)
maps well onto a strategy involving an intramolecular phenolate alkylation. Furthermore,
an approach using this method would allow for an entirely new, and potentially efficient,
synthetic entry into the Amaryllidaceae alkaloid family. With the overall goal of
enhancing the efficiency of galanthamine (1) synthesis while providing access to the
Amaryllidaceae alkaloid family, we envisioned a new approach to the target which
originated from a functionalized biaryl compound (16) (Scheme 2.04).
R1O
O
O
O
O
OH
NO
ON
O
(±)-(2) (-)-(1)
R1O
ON
O
NR1O
O
OH
N
X
(19)
(18)(17)
R1O
O
OH
(16)
R2
Scheme 2.04. Benzoazepine approach to (-)-galanthamine
Installation of the basic-nitrogen side-chain would introduce the tethered
electrophile to the biaryl phenol (17). The electrophilic side-chain could exist in
equilibrium between the open form and the aziridinium ion (18) via neighboring group
participation of the nitrogen lone-pair21 and displacement of the primary leaving group.
The phenol(ate) could cyclize onto the electrophilic carbon and/or the symmetrical
aziridinium to generate the benzoazepine framework (19) of (±)-narwedine. Removal of
25
-
the phenolic protecting group would allow for conjugate addition of the phenol to the
dienone, yielding (±)-narwedine (2). As mentioned earlier, the established resolution of
(±)-narwedine into the desired single optical isomer3 made the racemate a sensible target
intermediate in route to (-)-galanthamine (1).
Synthesis of the functionalized biaryl intermediate originated from the
commercially available 2-bromo-3-hydroxy-4-methoxy-benzaldehyde (20), which was
transformed to the methoxymethyl ether product (21) under conditions similar to those
described by Fuchs and co-workers (Scheme 2.05).22 The protected aldehyde was
coupled with a commercially available boronic acid (22), under Suzuki conditions,23 to
yield the biaryl aldehyde (23). The aldehyde was subjected to reductive amination
conditions with 2-(methylamino)-ethanol and NaBH(OAc)3 to install the basic-nitrogen
side-chain (24).
O
MOMOO
Br
O
MOMOO
OH
O
HOO
Br K2CO3MOMCl
acetone50 °C
99% yield
Pd(PPh3)4 (2 mol %)
2M Na2CO3(aq)EtOH/1,2-DME
reflux73% yield
(HO)2B OH
O
MOMON
OH
HOHN
OH
NaBH(OAc)3, AcOH1,2-DCE, reflux
89% yield
(20) (21)
(22)
(23) (24)
Scheme 2.05. Construction of the functionalized biaryl intermediate
26
-
The biaryl diol (24) contained all the required functionality to attempt a
dehydration and cyclization to the cross-conjugated dienone and benzoazepine core
structure (19). Initial attempts to utilize Dean-Stark dehydration conditions resulted in
recovered starting material. Heating the diol (24) under refluxing conditions in the
presence of a variety of othroformates resulted in the loss of the primary alcohol, and
incorporation of the corresponding orthoformate alcohol to form a primary ether (25).
This process is exemplified in Scheme 2.06 with triisopropyl orthoformate.
O
MOMON
OH
HO (iPrO)3CH
reflux65% yield
O
MOMON
OH
O
(24) (25)
Scheme 2.06. Attempted dehydration and cyclization to the dienone
The biaryl diol (24) was also subjected to Mitsunobu dehydration conditions.24 An
interesting result occurred under the Mitsunobu conditions in which the cross-conjugated
dienone (19) did not form, but instead, the parent biaryl aldehyde (23) was generated in
high yield. This reaction pathway was rationalized through the mechanism shown in
Scheme 2.07 in which the primary alcohol reacted with the activated phosphonium ion
(26) to generate the primary leaving group. Then, the diethyl hydrazodicarboxylate anion
revisited the molecule to remove the benzylic hydrogen (27), resulting in N-methylimine
formation (28) and loss of the side-chain in the form of ethylene gas and
triphenylphosphine oxide. It was assumed that the imine was hydrolyzed upon aqueous
workup to produce the biaryl aldehyde (23). Raising or lowering the reaction
27
-
temperature and altering the solvent concentration had no effect on the final product
distribution.
O
MOMON
OH
HO
O
MOMO
OH
O
DEAD, PPh3
DCM, 0 °C98% yield
(24) (23)
O
MOMON
OH
HO
(26)
O
MOMON
OH
(27)O
MOMON
OH
(28)
NEtO2CHN
Ph3P
OEt
O
HNHCO2EtN
EtO O
-C2H4
-Ph3P(O)
H2O
O PPh3
Scheme 2.07. Attempted Mitsunobu dehydration of the biaryl diol
Dialkyl azodicarboxylates have been reported as oxidants in the conversion of
primary alcohols to the corresponding aldehydes,25 but when the biaryl diol (24) was
subjected to diethyl azodicarboxylate, in the absence of triphenylphosphine, the diol was
unreactive and only the starting material was recovered.
Upon analysis of the results from the attempted dehydration of the biaryl diol
(24), it was determined that a better leaving group than water might facilitate formation
of the cross-conjugated dienone (19). Revisiting the biaryl aldehyde intermediate (23)
allows for a change in the order of reactions to arrive at the new cyclization precursor. In
the new scheme, the phenol of the biaryl aldehyde (23) was protected as a
28
-
triisopropylsilyl ether (29), followed by reductive amination with 2-methylamino-ethanol
and NaBH(OAc)3 to install the basic-nitrogen side-chain (30) (Scheme 2.08).
O
MOMON
OTIPS
HO
O
MOMOO
OH
TIPSClimidazole
1,2-DCEreflux
97% yieldO
MOMOO
OTIPS
HN
OH
NaBH(OAc)3, AcOH1,2-DCE, reflux
92% yield
(23) (29) (30)
Scheme 2.08. Synthesis of the silyl-protected biaryl alcohol
Treatment of the primary alcohol (30) with methanesulfonyl chloride (MsCl) and
iPr2NEt in dioxane at 23 °C resulted in a mixture of the primary mesylate (31) and the
primary chloride (32). It was presumed that the primary mesylate was generated upon
treatment with MsCl and a base, but the diisopropylethylamine hydrochloride salt did not
appear to precipitate from the dioxane. Therefore, the chloride ion was still in solution,
allowing it to displace the mesylate and form the primary chloride. The primary chloride
was the exclusive product when the reaction mixture was heated at reflux under identical
reaction conditions (Scheme 2.09).
MsCliPr2NEt
dioxanereflux
91% yieldO
MOMON
OTIPS
HO
(30)O
MOMON
OTIPS
MsO
O
MOMON
OTIPS
Cl
(31) (32)
Scheme 2.09. Synthesis of the biaryl primary chloride
29
-
If the primary mesylate (31) was desired, the primary alcohol (30) was treated
with MsCl and iPr2NEt in toluene at 23 °C, in which the diisopropylethylamine
hydrochloride salt formed a visible precipitate, thereby removing the chloride ion from
the equilibrium upon salt formation. The primary chloride (32) was selected as the
intermediate of choice over the primary mesylate (31) due to the chloride’s superior
stability during storage.
The biaryl primary chloride (32) contained the requisite framework to attempt the
intramolecular phenolate alkylation reaction to generate the cross-conjugated dienone
(19). It was postulated that the removal of the silyl ether would result in phenolate
formation, followed by an intramolecular alkylation. When the biaryl chloride (32) was
treated with tetrabutylammonium fluoride (TBAF) in THF at 0 °C, or heated under
reflux, the resulting product was the same new single spot by TLC. Attempts to isolate
and characterize this product resulted in an intractable mixture with no carbonyl
resonances upon IR analysis. A broad O–H stretch was seen in the IR, thus it was
rationalized that the tetrabutylammonium fluoride reaction resulted in hydrodesilation
and formation of the phenol (33), which decomposed upon dissolution on the rotary
evaporator (Scheme 2.10).
O
MOMON
OTIPS
Cl
O
MOMON
OH
Cl
(32) (33)
TBAF
THF
Scheme 2.10. Attempted desilation and cyclization to the
cross-conjugated dienone
30
-
Treatment of the biaryl primary chloride (32) with silver(I) fluoride or AgBF4 in
either THF, DMF, or CH3CN at 23 °C, or heating under reflux, also resulted in
hydrodesilation (33). There was no evidence for the formation of the cross-conjugated
dienone product (19) by IR or NMR analysis.
The use of anhydrous powdered cesium fluoride with anhydrous DMSO or DMF
at 23 °C resulted in the formation of a product other than the hydrodesilated product. The
NMR and IR data indicated that the isolated compound did not contain resonances for the
dienone protons or a carbonyl resonance, respectively. The spectral data, along with the
mass spectrograph, correlated with the dimerization of the phenolate intermediate (34).
X-ray crystallography confirmed the dimeric structure (36). It appeared that the use of
cesium fluoride in DMSO or DMF formed the phenolate, but the intermediate reacted
inter-, instead of intra-molecularly, to yield the dimer (Scheme 2.11).
O
OMOM
OO
MOMO
O
N
N
O
MOMON
OTIPS
Cl
O
MOMON
OMOMO
ON
O
Cl
(32) (34)
(35)
(36)69% yield
X
DMSO23 °C
CsF
Cs
Scheme 2.11. Attempted cyclization to the cross-conjugated dienone and
resultant dimerization
31
-
32
Dimerization reactions simlar to that of the biaryl primary chloride (32) are
precedented in reports of intramolecular phenolate alkylation substrates dimerizing,
instead of forming the intramolecular phenolate alkylation product, presumably due to
poor molecular overlap in the alkylation transition state.26 Attempts to avert the
dimerization pathway by altering the solvent concentration and reaction temperature had
no effect on the product distribution. As a result, it was postulated that the desired
intramolecular alkylation to form the benzoazepine ring system was unlikely to occur
under the described reaction conditions and an alternative intramolecular phenolate
alkylation strategy was pursued.
-
33
2.2 PUMMERER STRATEGY
In an attempt to facilitate the intramolecular phenolate alkylation strategy for the
synthesis of (-)-galanthamine (1), new cyclization conditions were conceived. In the
studies described in Chapter 2.1, the intramolecular phenolate alkylation substrate reacts
inter-, instead of intra-molecularly. The exact reason(s) for this preference are unknown,
but it is reasonable to assume that the undesired intermolecular alkylation pathway might
have a more favorable molecular orbital overlap in the transition state than the desired
intramolecular alkylation pathway, thereby giving rise to the dimeric product (36). Thus,
it was hypothesized that changing the nature of the electrophile from an sp3 hybridized
carbon to an sp2 hybridized carbon might enhance the molecular orbital overlap of the
desired reaction pathway, and as a result, change the overall product distribution.
To test the hypothesis of utilizing a sp2 hybridized electrophilic carbon, a strategy
involving a Pummerer reaction27 was envisioned. The use of a functionalized biaryl
intermediate (16), similar to that originally used in the benzoazepine strategy, would
allow for a rapid exploration of the Pummerer strategy (Scheme 2.12). The cyclization
substrate would originate from an amidosulfoxide (37), which could be activated to the
electrophilic sulfonium ion (38). The sulfonium ion could be attacked by the
para-carbon of the phenolic ether, followed by loss of the phenolic protecting group and
formation of the cross-conjugated dienone core (39) of narwedine. The use of this
strategy would also require the reductive cleavage of the phenyl sulfide and amide
carbonyl groups after the dienone cyclization event to arrive at (±)-narwedine (2).
-
O
R1O N
OR3
O
(37)
SO
Ph
O
R1O N
OR3
O
(38)
SPhX
R1O
ON
O
(39)
OSPh
O
ON
O
(±)-(2)
R1O
O
OH
(16)
R2
Scheme 2.12. Pummerer cyclization approach to (±)-narwedine
Synthesis of the amidosulfoxide cyclization precursor (37) originated from the
aforementioned biaryl aldehyde (23). Silyl ether formation with the biaryl phenol (40),
followed by reductive amination of the pendant aldehyde with methyl amine, produced
the biaryl secondary amine (41) (Scheme 2.13). The use of methanolic sodium
borohydride and aqueous methyl amine suppressed appreciable formation of the benzyl
alcohol byproduct encountered under Borch reductive amination conditions.28 Acylation
of the amine with phenylsulfanyl-acetyl chloride,29 under basic conditions, yielded the
amidosulfide (42). Oxidation of the sulfide with m-CPBA generated the amidosulfoxide
(43) Pummerer cyclization precursor.
34
-
O
MOMONH
OTBDMS
O
MOMOO
OTBDMS
NaBH4, MeOH23 °C
73% yield
40% H2NMe(aq)
Cl
OSPh
iPr2NEt1,2-DCE
23 °C78% yield
O
MOMON
OTBDMS
OSPh
O
MOMOO
OH
TBDMSClimidazole
1,2-DCEreflux
95% yield
(23) (40) (41)
(42)
m-CPBA
THF, 0 °C86% yield
O
MOMON
OTBDMS
OSO
Ph
(43)
Scheme 2.13. Synthesis of the amidosulfoxide for exploration of the
Pummerer cyclization conditions
Treatment of the amidosulfoxide (43) with trifluoroacetic anhydride (TFAA) to
generate the sulfonium ion, and thus allow for the cyclization to the cross-conjugated
dienone, resulted in the formation of a vibrant yellow-green oil with spectral properties
unlike those expected for the desired product. Upon further analysis, it was determined
that the formation of the sulfonium ion had proceeded, but rather than be attacked by the
para-carbon of the phenolic ether, it had been intercepted by the adjacent aromatic ring
(44), resulting in the formation of a hydroisoquinolone skeleton (45) (Scheme 2.14). The
hydroisoquinolone went on to lose a benzylic proton, resulting in the expulsion of the
phenyl sulfide group and increased π-system conjugation of the isoquinolone structure
(46). A similar result was reported by Yonemitsu and Oikawa, who utilized a Pummerer
cyclization to synthesize functionalized 2-naphthols.30 The unstable isoquinolone (46)
was the only identifiable component of a complex mixture of products from the
Pummerer cyclization reaction. IR spectroscopy of the crude reaction mixture did not
35
-
indicate the presence of a cross-conjugated dienone carbonyl resonance (c.a. 1660 cm-1).
Raising or lowering the reaction temperature and altering the solvent concentration had
no effect on the product distribution.
O
HON
OTBDMS
TFAA
1,2-DCE23 °C
53% yieldOO
MOMON
OTBDMS
OSO
Ph
(43)(46)
O
RON
OTBDMS
OS
Ph
O2CCF3
(44)R = MOM, H
O
RON
OTBDMS
OPhS(45)
R = MOM, H
H
H O2CCF3
Scheme 2.14. Attempted Pummerer cyclization to generate the core
structure of narwedine
Identical results were also observed the amidosulfide (42) was subjected to Lewis
acid promoted Pummerer cyclization conditions.31 Under these conditions, the
amidosulfide was treated with N-chlorosuccinimide (NCS) to form the α-chlorosulfide
intermediate (47), which was reacted in situ with SnCl4 to promote formation of the
sulfonium ion (Scheme 2.15). The sulfonium ion intermediate was trapped in the same
manner as in Scheme 2.14 to produce the highly fluorescent and unstable isoquinolone
product (46).
36
-
O
HON
OTBDMS
OO
MOMON
OTBDMS
OSPh
(42)(46)
O
MOMON
OTBDMS
OSPh
(47)
NCS
PhCl0 °C
SnCl4
Cl
52% yield
Scheme 2.15. Lewis acid promoted Pummerer cyclization conditions
After exploring the sp2 hybridized electrophilic carbon center (Pummerer)
strategy and arriving at an interesting, yet undesired, result, a new strategy involving the
use of an intramolecular phenolate alkylation was devised. In the following subchapter,
the exploration of an alternative strategy is discussed.
37
-
38
2.3 ETHER ALKYLATION STRATEGY
In an attempt to avert the dimerization discussed in Chapter 2.1 (36) and the
cyclization to the isoquinolone addressed in Chapter 2.2 (46), an alternative cyclization
strategy was devised in which the phenolate would cyclize onto an electrophile to
generate a six-membered ring intermediate. In the previous intramolecular phenolate
alkylation strategies, the electrophile had been tethered at the benzylic position of the
highly-substituted aromatic ring (17, 38). In the updated strategy, the electrophile was
appended to the phenol, which was previously protected as a methoxymethyl ether. It
was postulated that tethering the electrophile to the oxygen would not allow it to cyclize
onto the adjacent positions because they were already substituted, thereby promoting
cyclization onto the para-carbon of the phenolate. Additionally, removal of the
methoxymethyl ether protecting group from the synthesis could facilitate a shorter route
to (±)-narwedine (2) due to the deletion of steps required for the installation and removal
of the methoxymethyl ether.
Thus, the ether alkylation strategy was envisioned as originating from a similar
biaryl intermediate (48) similar to the one utilized in the previously discussed
approaches. Installation of the ether side-chain, which contained a two-carbon tether
terminated by an electrophile, would generate the intramolecular phenolate alkylation
precursor (49) (Scheme 2.16). Removal of the phenolic protecting group on the distal
aromatic ring would form the phenolate (50), allowing it to cyclize onto the electrophile
to form the cross-conjugated dienone (51) and the full carbon framework of galanthamine
(1) and narwedine (3). Cleavage of the acetal (Y = OR) should allow the molecule to
form the tricyclic dialdehyde (52). Reaction of the dialdehyde with methyl amine under
double reductive amination conditions would yield the final ring required for the
-
synthesis of (±)-narwedine (2). As with the previous strategies, the established resolution
of (±)-narwedine into the desired single optical isomer3 made the racemate a sensible
target intermediate in route to (-)-galanthamine (1).
O
OX
Y
O
O
O
O
O
O
YO
ON
O
(±)-(2)
O
O
OR
O
XY
(49) (50)
(51)
O
O
O
(52)O
O
O
HO
OR
O
(48)
Scheme 2.16. Ether alkylation approach to (±)-narwedine
Synthesis of the substituted biaryl intermediate (48) required a different protecting
group scheme than the approach used with the previously discussed strategies. The
revised biaryl synthesis originated from commercially available 4-bromophenol (53).
Triisopropylsilyl ether formation (54), followed by halogen-metal exchange and
quenching with freshly distilled triisopropyl borate, yielded the boronic acid (Scheme
2.17). The boronic acid was a gummy white solid that was stable for about one week on
the bench top. Toluene azeotrope of the boronic acid yielded a boroxine (55) (the
boronic acid trimer), which existed as a free-flowing white solid that was stable on the
bench top for multiple months. Thus, the boroxine was the preferred intermediate over
the boronic acid.
39
-
OH
Br
TIPSCl
imidazole1,2-DCE
23 °C99% yield
OTIPS
Br76% yield
1) nBuLi THF, -78 °C
2) (iPrO)3B THF, -78 °C
OTIPS
BOO
BO
B(53) (54)
(55) OTIPSTIPSO
Scheme 2.17. Synthesis of the silyl-protected boroxine
After establishing a route to the silyl-protected boroxine (55), the focus turned to
the Suzuki coupling reaction. The coupling reaction employed the commercially
available 2-bromo-3-hydroxy-4-methoxy-benzaldehyde (20) and the silyl-protected
boroxine (55), which was available in two steps from the commercially available phenol.
Since multiple steps were required to synthesize the boroxine, Suzuki reaction conditions
were explored in which the boroxine was the limiting reagent. These conditions are in
contrast to the numerous reports of Suzuki coupling reactions in which the boronic acid
component is used in excess and the aryl-halide is the limiting reagent. 23
The Suzuki cross-coupling conditions which were successful in the formation of
the MOM-protected biaryl (23) were employed in the coupling of the silyl-protected
boroxine (55) and the commercially available bromo-aldehyde (20). The reaction
conditions resulted in the formation of numerous products and a 38% yield of the desired
biaryl aldehyde (56). Some of the isolated byproducts included the hydro-deboronation
product (57), the hydro-dehalogenated aldehyde (58), and the oxidized boronic acid
phenol product (59) (Scheme 2.18).32
40
-
O
HOO
OTIPS
O
HOO
BrOTIPS
BOO
BO
BAr Ar
(55) (56)
(20)
O
HOO
OTIPS
(57) (58)
+
OTIPS
(59)
+
OH
+Pd(PPh3)4 (2 mol %)
2M Na2CO3(aq)EtOH/1,2-DME
reflux
Scheme 2.18. Synthesis of the biaryl aldehyde and unwanted byproducts
Although phenyl transfer from triphenylphosphine (PPh3) to the palladium
catalyst, and ultimately incorporation into the biaryl cross-coupling product, has been
documented,33 no phenyl transfer was detected under the conditions screened.
Regardless, the highly-effective tricyclohexylphosphine (PCy3) ligand34 was substituted
for PPh3 to avoid the possibility of the aforementioned phenyl transfer complication. As
a result of the modification in phosphine ligand, the catalyst was also changed to the
commercially available and bench top stable [Pd2(dba)3] in place of the less stable
Pd(PPh3)4.35 Catalyst loadings of 1-2 mol % were feasible, but resulted in yields of 30%
and 51%, respectively. Slightly higher catalyst loadings of 3-4% resulted in higher
yields. Attempts to conduct the reaction in the absence of phosphine with Pd(OAc)2,
similar to the conditions reported by Novak36 and Hirao,37 resulted in approximately 50%
yield of the biaryl aldehyde (56). Nickel catalysis38 was also explored, but that only
produced an 18% yield of the biaryl product. After screening multiple catalysts and
ligands, [Pd2(dba)3] and PCy3 were deemed the optimal combination.
A judicious choice of base in the reaction suppressed the formation of the hydro-
deboronation product (57). A strong mineral base promoted the formation of the hydro-
deboronated product, while too weak of a mineral base resulted in sluggish rates of biaryl
aldehyde (56) formation. The rationale for this observation is illustrated in Scheme 2.19,
41
-
in which the boronic acid (63) interacts with a base during a Suzuki coupling reaction to
form the reactive boronate ion (64). When the boronate ion is too reactive (i.e. as a result
of a strong base), the formation of the hydro-deboronation product (65) predominates
over the biaryl coupling pathway (68). If the base is too weak, then the formation of the
activated boronate ion is sluggish (64), which in turn slows the overall rate of the biaryl
coupling reaction (68). After screening multiple hydroxide, carbonate, and bicarbonate
mineral bases, aqueous K2CO3 was selected as the optimal base for the cross-coupling
reaction.
LnPd(0)
Pd(II)L
LAr1 X
Pd(II)L
LAr1 Ar2
Pd(II)Ar2
LAr1 L
Ar1 X
Pd(II)L
LAr1 O
RH
HO R
X
O
R
Pd(II)L
LAr1 H
Pd(II)H
LAr1 L
Ar1 H
Ar2 B(OH)3B(OH)3
Ar2 H
H2O
Ar2 B(OH)2HO
Ar1 Ar2
(60)
(62)
(61)
(63)(64)
(65)
(66)
(67)
(68)
(70)(69)
(71)
(72)
(73)
(74)
Scheme 2.19. Generalized Suzuki biaryl coupling reaction pathways
Exploration of the Suzuki biaryl coupling conditions also revealed that the
removal of ethanol from the solvent system suppressed the formation of the hydro-
dehalogenated aldehyde (58). It has been reported that Pd(II) species (62), which have
42
-
43
undergone oxidative insertion with aryl halides (61), can go on to react with primary
alcohols, in a hydride transfer process (70), to form palladium hydrides (72) (Scheme
2.19).39 These metal hydrides can then undergo reductive elimination to expel the
reduced arene (74) and regenerate the Pd(0) species (60).
Thus, after considerable examination, a set of reaction conditions were established
which consistently produced a 60-72% yield of the desired biaryl product (56), with the
remainder of the material characterized as the oxidized boronic acid phenol byproduct
(59). Similar oxidation byproduct distributions are also reported in the chemical
literature where close inspection of the Suzuki biaryl coupling products have been
conducted.40 In an attempt to solve this oxidation problem, the solvent was rigorously
degassed by bubbling argon through the reaction mixture, prior to catalyst addition.
Unfortunately, this method did little to absolutely suppress the oxidation byproduct
profile. Thus it was determined that two options were available — subject the solvent
system to a time consuming freeze-pump-thaw degassing regimen41 prior to running the
Suzuki coupling reaction, or add an oxygen scavenger to the reaction mixture. The latter
option was chosen due to its ease of operation upon scale-up. The oxygen scavenger,
2,6-di-tert-butyl-4-methyl-phenol (BHT), was chosen due to its effective role as a
stabilizing agent in laboratory-grade THF and its low cost. The use of 30-50 mol % of
BHT suppressed any appreciable formation of the oxidation byproduct, allowing for use
of the silyl-protected boroxine (55) as the limiting reagent in the Suzuki cross-coupling
reaction with only 1.05 equivalents of the aryl-halide coupling partner (20). Under
[Pd2(dba)3] catalyzed conditions, the two components were coupled to produce the biaryl
aldehyde (56) in high yield (Scheme 2.20).
-
O
HOO
OTIPSO
HOO
Br
[Pd2(dba)3] (4 mol %)
P(Cy)3, BHT, K2CO3dioxane/H2O, reflux
96% yield
OTIPS
BOO
BO
BAr Ar
(55) (56)
(20)
Scheme 2.20. Optimized Suzuki biaryl cross-coupling conditions
After optimization of the Suzuki cross-coupling reaction, conditions for the
intramolecular phenolate alkylation were investigated. The biaryl aldehyde (56) was
treated with chloroacetyl chloride and triethylamine to yield the biaryl α−chloro ester
(75) (Scheme 2.21).
O
OO
OH
O
Cl
O
OO
OTIPS
O
Cl fluoride
(75) (76)O
HOO
OTIPS
(56)
ClCl
O
NEt31,2-DCE
23 °C92% yield
heat
Scheme 2.21. Attempt to generate the dienone intermediate from the
biaryl α-chloro ester
Treatment of the α-chloro ester product with TBAF in refluxing dioxane, or
cesium fluoride in refluxing DMSO, yielded only the hydrodesilated product (76) with no
evidence of the intramolecular phenolate alkylation product (51). Incorporation of
sodium iodide or tetrabutylammonium iodide into the reaction to promote a Finkelstein
44
-
process42 allowed for halogen exchange, but it did not facilitate the desired cyclization
reaction. Likewise, treatment of the hydrodesilated product (76) with sodium hydride or
potassium tert-butoxide yielded no cyclization product.
The inability of the phenolate to cyclize onto the α-chloro ester under the
described reaction conditions might be a result of the increased rigidity of the two-carbon
tether due to the presence of the ester carbonyl, as noted in the studies of Masamune.16 As
a modification of this approach, the α−halo acetal, as opposed to the ester, was pursued.
There is precedent for the cyclization of an enolate onto an α-bromo acetal to form a
six-membered ring product, as demonstrated in Fuchs and co-workers’ efforts toward the
synthesis of the diterpenoid (±)-bruceantin.43 Based on this precedent, 1,2-dibromo-1-
ethoxy-ethane was generated in situ by dropwise addition of ethyl vinyl ether to a 0 °C
solution of bromine in dichloromethane. A dichloromethane solution of the biaryl phenol
(56) and iPr2NEt was added to the reaction pot, resulting in alkylation of the phenol and
formation of the primary halide acetal (77) (Scheme 2.22).
OEt
Br2, iPr2NEtDCM, 0 °C99% yield O
OO
OTIPS
EtO
Br
O
HOO
OTIPS
(56) (77)
Scheme 2.22. Installation of the α-bromo acetal
Treatment of the biaryl α-bromo acetal (77) with cesium fluoride in refluxing
dioxane, toluene, acetonitrile, or 1,2-DCE did not facilitate cyclization to the
cross-conjugated dienone (51) and only resulted in hydrodesilation. It was presumed that
45
-
these solvents failed to generate the dienone because they were unable to reach
temperatures high enough to promote the cyclization event, thus DMSO was explored.
When the biaryl α-bromo acetal was treated with cesium fluoride in anhydrous DMSO at
130 °C, cyclization and formation of the cross-conjugated dienone (79) occurred to
produce the quaternary center and carbon framework of narwedine (2) (Scheme 2.23).
Although a 65% yield of the desired product was isolated, there was a considerable
amount of dark baseline material observed during column chromatography. Reaction
temperatures below 130 °C with the CsF/DMSO conditions resulted in hydrodesilation
(78) and no evidence of cyclization to the cross-conjugated dienone.
O
OO
OTIPS
EtO
Br CsF
DMSO130 °C
65% yield O
OO
EtOO
(77) (79)O
OO
O
EtO
Br
(78)
Scheme 2.23. Cyclization to the cross-conjugated dienone
Under the CsF/DMSO cyclization conditions, an aroma similar to dimethyl
sulfide was detected. It was considered that the dimethyl sulfide evolution may be due to
a Kornblum oxidation44 of the α-bromo acetal (77). If the primary halide was displaced
by the DMSO oxygen (80), followed by the loss of dimethyl sulfide (81), it could give
rise to an aldehyde byproduct (82) (Scheme 2.24). Although the hypothetical aldehyde
intermediate was never isolated under the DMSO reaction conditions, trace amounts of
the biaryl diphenol (83) were isolated, which could have resulted from the decomposition
of the dialdehyde acetal (82).
46
-
O
OO
OTIPS
EtO
Br CsF
DMSO130 °C
(77) O
OO
O
EtO
(80)
Br
OS
O
OO
O
EtO
O
(81)
S
H
-Me2S
O
OO
OH
EtO
O
(82)
OAr
decomposition
O
HOO
OH
(83)
CsCs
Scheme 2.24. Potential Kornblum reaction with the α-bromo acetal
The use of DMF in place of DMSO was explored in order to achieve a
high-boiling polar solvent medium which could also facilitate the cyclization to the
cross-conjugated dienone without the potential to participate in the Kornblum oxidation
side reaction. Since the use of wet DMF was unsuccessful in the aforementioned attempt
to generate the cross-conjugated dienone (79), anhydrous DMF was examined. The DMF
was stored over activated 4 Å molecular sieves and anhydrous cesium fluoride was also
used to mitigate the presence of water. The DMF was decanted from the sieves, but
during the process, molecular sieve dust entered the reaction. When the reaction was
conducted in the presence of the sieve dust, none of the cross-conjugated dienone product
(79) was formed, but a tetracyclic pyranone racemate (84) of similar polarity to that of
the dienone was generated (Scheme 2.25). After column chromatography, the pyranone
was the only identifiable product isolated. The tetracyclic pyranone racemate was
47
-
isolated as an oil, which later crystallized into small plates, allowing for confirmation of
the structure by X-ray analysis.
O
OO
OTIPS
EtO
Br CsF
4Å molecular sieve dustDMF
130 °C24% yield(77) (84)
OO
EtO
O
O
HH
Scheme 2.25. Cyclization conditions to form the dienone in the presence
of 4 Å molecular sieve dust, resulting in the generation of the pyranone
Since the pyranone byproduct was observed when the reaction was conducted in
the presence of the molecular sieve dust, it was hypothesized that the sieves and their
contents played a role in the byproduct formation. Molecular sieves are known to be
mildly acidic,45 and the sieve dust within the reaction mixture would contain some water
that was absorbed from the DMF during the drying process. Thus, it was proposed that
the tetracyclic pyranone (84) potentially arose from an acid-catalyzed rearrangement of
the cross-conjugated dienone intermediate (79) (Scheme 2.26). The formation of the
tetracyclic pyranone could result from the hydration of the cross-conjugated dienone (79),
followed by a retro-aldol reaction to yield the ring-opened product (86). The ring-opened
product could then participate in a cyclization reaction to yield the tetracyclic carbon
skeleton (87). A 1,3-proton shift can generate the lactone (88), followed by a
dehydration and another 1,3-proton shift to bring the styrene olefin into conjugation with
the enone, resulting in the full conjugation of the α-pyranone olefins with the aromatic
ring (84). It is hypothesized that the α-pyranone forms in preference to the γ-pyranone
due to the increased aromaticity of the α-pyranones over the γ-pyranones.46 Additionally, 48
-
the formation of the α-pyranone allows for the full conjugation of the olefins within the
molecule, whereas the γ-pyranone would isolate one of the olefins from the π-system
unless the γ-pyranone were to exist in its higher energy pyrylium salt isomer.
O
OO
OTIPS
EtO
Br CsF
sieve dustDMF
130 °C(77)
(84)
OO
EtO
O
O
HH
O
OO
EtO
(79) O
O
EtO
O
OH
OHO
O
O
EtOH
O OH
OH
O
O
EtOH
O OH
OH
(85) (86)
O
O
EtOH
O O
OH
(87) (88)
1,3-protonshift
-H2OH
H
Scheme 2.26. Postulated pathway for the formation of the tetracyclic
pyranone racemate in the presence of 4 Å molecular sieve dust
Anhydrous DMF, which had been dried over activated 4 Å molecular sieves, but
allowed to settle and carefully decanted to minimize the carry-over of sieve dust, was
combined with anhydrous cesium fluoride at 130 °C to produce the cross-conjugated
dienone (79) in an improved yield over that achieved with DMSO. Furthermore, the
reaction proceeded with no sign of oxidation or rearrangement byproducts. Thus, it
appeared that a temperature of approximately 130 °C and anhydrous conditions (in the
absence of sieves and sieve dust) were required for a successful intramolecular phenolate
cyclization reaction with the biaryl α-bromo acetal (77) (Scheme 2.27). Drying the
49
-
cesium fluoride under high vacuum, and a toluene azeotrope of the biaryl α-bromo acetal
(77) prior to conducting the reaction resulted in a modest improvement in the yield.
O
OO
OTIPS
EtO
Br CsF
DMF130 °C
90% yield O
OO
EtOO
(77) (79)
Scheme 2.27. Improved cyclization conditions to form the dienone
The successful implementation of the intramolecular phenolate alkylation strategy
avoided the low yielding phenolic oxidation reaction used previously to generate similar
intermediates. The cyclization to the cross-conjugated dienone (79) formed the
quaternary carbon center and the dienone ring required for the synthesis of narwedine (2)
and galanthamine (1). The reductive amination of the aromatic aldehyde and latent
aliphatic aldehyde to arrive at (±)-narwedine and (-)-galanthamine is discussed in the
following subchapter.
50
-
2.4 AMINATION OF THE CROSS-CONJUGATED DIENONE
The successful intramolecular phenolate alkylation to generate the
cross-conjugated dienone, discussed in Chapter 2.3, formed the carbocyclic framework of
(-)-galanthamine (1). To complete the synthesis, incorportation of methylamine was
required at the carbons bearing the aromatic aldehyde and the ethyl acetal. Since both
carbons were at the aldehyde oxidation state (89), it was envisioned that a reductive
amination would allow for introduction of the methyl amine and subsequent formation of
the narwedine (2) and galanthamine benzoazepine skeletons (Scheme 2.28).
O
O
O
O
HOO
ON
O
(±)-(2)(89)
O
O
O
(52)O
OO
OO
EtOO
(79)
Scheme 2.28 Postulated reductive amination of the cross-conjugated
dienone to arrive at narwedine
A stepwise approach toward the amination was initially explored in an effort to
closely monitor and understand each step of the process. Borch reductive amination
conditions28 were considered to install the methylamine. The stability of the
cross-conjugated dienone toward ethanol and NaBH3CN was explored since it contained
multiple carbons at the aldehyde/ketone oxidation state which carry the risk of
over-reduction with promiscuous reducing agents. After stirring the cross-conjugated
dienone (79) with NaBH3CN in ethanol for one hour at 23 °C, there was no reaction by
51
-
TLC. Upon heating the reaction at reflux for an additional hour, none of the carbonyls
had been reduced, but the ethyl acetal of the aldehyde had formed (90) (Scheme 2.29).
O
OO
EtOO
O
O
O
OEtO
(79)(90)
NaBH3CN
OEtEtOHreflux
68% yield
Scheme 2.29. Exposure of the cross-conjugated dienone to NaBH3CN
Since ethanol, in combination with the Borch reducing agent, generated the
tetracyclic diethyl acetal product (90), the methylamine was installed via the application
of NaBH(OAc)3 reductive amination conditions.47 The reaction resulted in the formation
of a tetracyclic tertiary amine racemate (91) which existed as a mixture of diastereomers
in an approximate ratio of 1:1, as determined by 1H NMR (Scheme 2.30). The acetal of
the tetracyclic tertiary amine (91) was hydrolyzed to generate the lactol (92) in situ, but
instead of remaining in the lactol form, or opening to the phenol and aldehyde, the lactol
oxygen performed a conjugate addition onto the enone, resulting in the formation of the
multicyclic tertiary amine acetal racemate (93) as a single diastereomer. The relative
stereochemistry of the multicyclic tertiary amine acetal was determined by X-ray
crystallography.
52
-
O
OO
EtOO
O
O
O
N
H2NMeNaBH(OAc)3
THF23 °C
EtO 3M HCl(aq)
dioxanereflux
53% yield(2 steps)
NO
O
O
O
(79)(91)
(93)O
O
O
NHO
(92)
H
Cl
Scheme 2.30. Amination and hydrolysis to form the multicyclic tertiary
amine intermediate
The secondary amine multicyclic acetal (95) was formed in a similar manner as
the tertiary amine multicyclic acetal (92). The cross-conjugated dienone (79) was treated
with ammonium formate and NaBH(OAc)3 in refluxing ethanol to produce the tetracyclic
secondary amine (94) as a mixture of diastereomers (Scheme 2.31).
NHO
EtO
O
OO
OO
OEtO
NHO
O
O
O
HCO2NH4NaBH(OAc)3
ethanolreflux
94% yield
3M HCl(aq)
dioxanereflux
84% yield(79)
(94) (95)
Scheme 2.31. Amination and hydrolysis to form the multicyclic
secondary amine intermediate
53
-
Ammonium formate was a suita
