Enantioselective syntheses of corynanthe alkaloids by Chiral Br?nsted acid and palladium catalysis

Article abstract of DOI:10.1002/chem.201103150

Synergistic catalysis: Three indole alkaloids (-)-corynantheidine, (+)-corynantheine and (+)-dihydro-corynantheine were prepared following a short and common strategy based on the binol phosphoric acid catalyzed enantioselective Pictet-Spengler reaction,

Full text of DOI:10.1002/chem.201103150

DOI: 10.1002/chem.201103150
Enantioselective Syntheses of Corynanthe Alkaloids by Chiral Brønsted Acid
and Palladium Catalysis
Martin J. Wanner, Elise Claveau, Jan H. van Maarseveen,* and Henk Hiemstra*[a]
Dedicated to Professor Barry M. Trost on the occasion of his 70th birthday
Over the last decade, enantioselective organocatalysis has
become an integral part of the catalysis field. Meanwhile,
several enantioselective organocatalysis-based total synthe-
ses have been reported.[1] Recently, we have published an
enantioselective organocatalytic approach to tetrahydro-b-
carbolines using an asymmetric binol phosphoric acid-cata-
lyzed Pictet–Spengler reaction as the key step,[2] culminating
in a short total synthesis of (À)-arboricine.[2c] Herein, we
report total syntheses of the corynanthe indole alkaloids
(À)-corynantheidine 1, (+)-corynantheine, 2 and (+)-dihy-
drocorynantheine 3 by a combination of enantioselective or-
ganocatalysis and a novel variant of the palladium-catalyzed
allylic alkylation reaction.
racemic and partial enantioselective syntheses of corynan-
theidine 1 and its C20-epimer (+)-dihydrocorynantheine 3
have been published, but only a few enantioselective total
syntheses have appeared.[6] (+)-Corynantheine 2 contains a
C20-vinyl substituent, and although it is the most frequently
described member of the corynanthe family, no enantiose-
lective total synthesis of 2 has been reported yet. Most of
the existing corynanthe syntheses share tryptophan as the
chiral source in a Pictet–Spengler reaction thus requiring ad-
ditional steps to remove the carboxyl group. It would be ad-
vantageous to use tryptamine as the starting material in
combinaton with a catalytic asymmetric Pictet–Spengler re-
action.[7] Recently, Jacobsenꢀs and our group developed cata-
lytic asymmetric versions differing in the tryptamine precur-
sor and catalyst type. Jacobsenꢀs approach requires unsubsti-
tuted tryptamine in an acyl Pictet–Spengler reaction, in
combination with a peptidic thiourea catalyst.[8] Our ap-
proach involves the direct use of Nb-alkyl-substituted trypta-
mines in combination with binol phosphoric acid-type cata-
lysts.[2]
In Scheme 1 we present the synthetic strategy toward the
corynanthe alkaloids 1–3, based on this binol phosphoric
acid-promoted enantioselective Pictet–Spengler reaction be-
tween the tert-butyl carbonate of 2-butenyl-functionalized
tryptamine and methyl 5-oxo-2,2-(dialkylthio)pentanoate as
the aldehyde. The D-ring of the indoloACTHNUTRGNEUNG[2,3-a]quinolizidine
ring system was envisaged to be formed by an unprecedent-
ed Pd-catalyzed allylic alkylation with an a-ketoester anion
The alkaloids 1–3 were all isolated from the stem bark of
the African tree Pseudocinchona africana.[3,4] Pharmacologi-
cal evaluation showed that corynantheidine 1 antagonizes m-
opioid receptors,[5] whereas 2 and 3 serve as inhibitors of
Leishmania major promastigotes.[4] Over the years several
[a] M. J. Wanner, Dr. E. Claveau, Dr. J. H. van Maarseveen,
Prof. Dr. H. Hiemstra
Vanꢁt Hoff Institute for Molecular Sciences
University of Amsterdam, Science Park 904
1098 XH Amsterdam (The Netherlands)
Fax : (+31)205255604
E-mail: j.h.vanmaarseveen@uva.nl
h.hiemstra@uva.nl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103150.
Scheme 1. Retrosynthetic analysis of the corynanthe alkaloids.
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Chem. Eur. J. 2011, 17, 13680 – 13683

COMMUNICATION
as the nucleophile, immediately followed by a Wittig reac-
tion to construct the b-methoxyacrylate unit. In contrast to
the previously published approaches, this novel method
would give direct access to the vinyl-substituted indoloACTHNUTRGNEU[GN 2,3-
a]quinolizidine ring system as present in 2.
The synthesis commenced with the Nb-functionalization of
tryptamine with a tert-butyl carbonate-protected butenyl
side chain by alkylation of p-nosyl-tryptamine (6) with bro-
mide 5, in a Fukuyama protocol, to give 7 in 89% yield
(Scheme 2).[9] Bromide 5, free from its Z isomer, was pre-
Next, the crucial a-ester carbonyl had to be liberated by
thioacetal hydrolysis. The Boc group was first introduced to
prevent irreversible ring closure of the indole nitrogen onto
the a-ketoester once formed, and to protect the indole ring
against oxidation during dithioacetal hydrolysis. Still, one-
pot hydrolysis of the electron-poor thioacetal under several
standard conditions was not possible. After extensive experi-
mentation a reliable two-step procedure was found in which
at first, after AgOTf treatment in dry dichloromethane at
room temperature, the stable pyrrolidinium salts 11a and
11b were formed from 10a and 10b as a mixture of diaste-
reomers. Treatment of 11a and 11b with aqueous DMSO at
elevated temperature gave the desired hydrolysis of the N,S-
acetal providing ketone 12 in overall yields of 65% from
10a, and 68% from 10b.
Now the scene was set for the closure of the final ring by
trapping of a p-allyl complex with the ketoester-derived
enolate. Treatment of 12 with 5 mol% {[PdACTHNUTRGNEUNG
(h3-C3H5)]Cl}2 in
the presence of base gave 13, showing the correct C14–C20
cis stereochemistry for the corynantheidine skeleton, and 14
with the trans configuration required for the corynantheine
series. By using
(DiPEA)/Cs2CO3 as a base, a maximum cis/trans ratio of 4:1
was obtained. However, using 1,8-diazabicyclo[5.4.0]undec-
a mixture of diisopropylethylamine
AHCTUNGTRENNUNG
7-ene (DBU) as the base, the cis and trans diastereomers
were obtained in equal amounts. The a-ketoester protons
are less acidic than for example, b-ketoesters or malonates,
but more acidic then the corresponding methyl ketone,
which was not reactive in this allylic alkylation
(Scheme 3).[12]
Scheme 2. Enantioselective synthesis of the tetrahydro-b-carboline skele-
ton through the enantioselective Brønsted-acid catalyzed Pictet–Spengler
reaction. DMAP=4-dimethylaminopyridine; brsm=based on recovered
starting material.
pared in a single step from commercially available (E)-1,4-
dibromobut-2-ene (4). The subsequent Pictet–Spengler reac-
tion was initially carried out with the previously described
aldehyde 8a,[10] in which the ketone carbonyl was protected
as a diphenylthioacetal. Protection of the ketone was re-
quired to avoid rearrangement of the intermediate iminium
species to the enamine forming a stable and isolatable con-
jugated system with the enolized ketone (not shown). After
screening several binol phosphoric acid-type catalysts[11] it
was found that (R)-3,3’-bis(triphenylsilyl)-octahydrobinol-
phosphoric acid (9) gave the best results providing, after a
one-pot indole-N protection with
a tert-butoxycarbonyl
(Boc) group, tetrahydro-b-carboline 10a isolated in 73%
yield but with an unsatisfactory 74% enantiomeric excess
(ee). Fortunately, both the yield and ee value could be im-
proved by replacing the diphenyl thioacetal for a diethyl thi-
oacetal giving 10b in a yield of 82% and with 86% ee. It is
worth mentioning that only 2% of catalyst was required to
give complete conversion in a reaction time of 48 h at room
temperature. Previous work has shown that (R)-binol phos-
phoric acid catalysts are required for obtaining the (S)-con-
figured tetrahydro-b-carboline, which corresponds with the
(S)-configuration at C3 in the corynanthe alkaloid series.[2]
Scheme 3. Closure of the final ring by trapping of a Pd-p-allyl complex
with an a-ketoester-derived enolate. dppe=1,2-bis(diphenylphosphino)-
ethane.
A second asset of the a-ketoester moiety in 13 became
clear in the construction of the b-methoxyacrylate unit,
adding a valuable method to the commonly used ester anion
formylation/methylation sequence.[6b] Wittig reaction of 13
with (methoxymethylene)triphenylphosphorane selectively
gave the Z enol ester 15 isolated in 80% yield as a solid of
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J. H. van Maarseveen, H. Hiemstra et al.
which the optical purity could be increased to 98% ee by re-
crystallization. We were pleasantly surprised that the subse-
quent acidic removal of the Boc protecting group was ac-
companied by complete isomerization of the Z enol ether to
the desired E isomer. Final Pd(C)-catalyzed hydrogenation
of the vinylic double bound gave (À)-corynantheidine 1 in
83% yield. Starting from tryptamine we thus accomplished
the enantioselective synthesis of corynantheidine in 10 steps
in 9% overall yield (Scheme 4).
theine. The binol phosphoric acid-catalyzed Pictet–Spengler
condensation between an N-substituted tryptamine and a
masked a-ketoester efficiently introduced the required
enantioselectivity.
Acknowledgements
The National Research School Combination-Catalysis (NRSC-C) is
gratefully acknowledged for financial support. J. A. J. Geenevasen is very
appreciated for his help with NMR characterization. J. W. H. Peeters is
kindly acknowledged for mass spectrometric analyses.
Keywords: alkaloids
·
allylation
·
Brønsted acids
·
enantioselectivity · palladium
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Scheme 4. The final steps towards (À)-corynantheidine (1).
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phenylphosphorane now gave a mixture of the Z/E isomers
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Selective Pd(C)-catalyzed hydrogenolysis of 2 furnished
(+)-dihydrocorynantheine (3) in 90% yield (Scheme 5).
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of three corynanthe alkaloids, with an a-ketoester playing a
major role as nucleophile in an intramolecular Tsuji–Trost-
type allylic alkylation and as Wittig precursor in the con-
struction of b-methoxyacrylates. In particular, the Pd-cata-
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produced the vinyl substituent as it is present in corynan-
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Scheme 5. The final steps towards (+)-dihydro-corynantheine (2) and
(+)-corynantheine (3).
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Enantioselective Syntheses of Corynanthe Alkaloids
COMMUNICATION
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Received: October 6, 2011
Published online: November 8, 2011
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