Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for the Total Synthesis of (?)-17-nor-Excelsinidine

Article abstract of DOI:10.1002/anie.201802610

We report the first total synthesis of (?)-17-nor-excelsinidine, a zwitterionic monoterpene indole alkaloid that displays an unusual N4?C16 connection. Inspired by the postulated biosynthesis, we explored an oxidative coupling approach from the geissoschizine framework to forge the key ammonium–acetate connection. Two strategies allowed us to achieve this goal, namely an intramolecular nucleophilic substitution on a 16-chlorolactam with the N4 nitrogen atom or a direct I₂-mediated N4?C16 oxidative coupling from the enolate of geissoschizine.

Full text of DOI:10.1002/anie.201802610

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Accepted Article
Title: Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton
for the Total Synthesis of (-)-17-nor-Excelsinidine
Authors: Maxime Jarret, Aurélien Tap, Cyrille Kouklovsky, Erwan
Poupon, Laurent Evanno, and Guillaume Vincent
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802610
Angew. Chem. 10.1002/ange.201802610
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Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton
for the Total Synthesis of (–)-17-nor-Excelsinidine
Maxime Jarret, [‡,a] Aurélien Tap, [‡,a] Cyrille Kouklovsky,[a] Erwan Poupon,[b] Laurent Evanno*[b] and
Guillaume Vincent*[a]
Abstract: We report the first total synthesis of (–)-17-nor-
excelsinidine, a zwitterionic monoterpene indole alkaloid, which
displays an unusual N4-C16 connection. Inspired by the postulated
biosynthesis, we explored an oxidative coupling approach from the
geissoschizine framework to forge the key ammonium-acetate
connection. Two strategies allowed us to achieve this goal: an
intramolecular nucleophilic substitution of the N4-nitrogen on a 16-
chlorolactam or a direct I2-mediated N4-C16 oxidative coupling from
the enolate of geissoschizine.
These umpolungs involve the C16 carbon of the formyl methyl
ester[2] and respectively the N1-nitrogen for mavacuran alkaloids
(e. g. pleiocarpamine), the C7-carbon for akuammilan alkaloids (e.
g. rhazimal, rhazimol, akuammiline and strictamine) or the N4-
nitrogen for the recently discovered zwitterionic excelsinidine and
17-nor-excelsinidine, also known as singaporentinidine as its
protonated form (Scheme 1).[3]
All the interconnections and mechanisms between these families
of alkaloids are not completely understood or proven. While
divergent direct oxidative couplings between C16 and N1 or C7
or N4 are possible,[2a] it has also been postulated that the
akuammilan skeleton could be the biogenetic precursor of both
the mavacuran[2c] and the excelsinidine frameworks.[3d] The
akuammilans have been the subject of very intense synthetic
efforts and several members of this family have succumbed to
total synthesis in the last decade.[4,5] The synthesis of mavacurans
have also been well studied over the years.[6]
Geissoschizine seems, intuitively, to be at the common
biosynthetic origin of several families of monoterpene indole
alkaloids[1] via unsolved oxidative cyclizations.
Scheme 1. Postulated biosynthesis of the mavacurans, akuammilans and
excelsinidines.
[a]
Mr. Maxime Jarret,[‡] Dr. Aurélien Tap,[‡] Prof. Cyrille Kouklovsky, Dr.
Guillaume Vincent
[‡] These authors contributed equally.
Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO),
Equipe MSMT
Univ. Paris Sud, CNRS, Université Paris-Saclay
15, rue Georges Clémenceau, 91405 Orsay, Cedex, France
E-mail: guillaume.vincent@u-psud.fr
[b]
Prof. Erwan Poupon, Dr. Laurent Evanno
Pharmacognosie et chimie des substances naturelles, BioCIS
Univ. Paris-Sud, Université Paris-Saclay, CNRS
92290 Châtenay-Malabry, France
Scheme 2. Divergent oxidative couplings for the formation of the N1-C16, C7-
C16 or N4-C16 bonds.
E-mail: laurent.evanno@u-psud.fr
The key bioinspired oxidative couplings have been achieved
synthetically in few occasions (Scheme 2). Sakai, in its pioneering
Supporting information for this article is given via a link at the end of
the document.
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work, adopted a two-stage approach to form the N1-C16 bond of
3.[6a,b] Oxidative chlorination of the C16 carbon of 1, followed by a
nucleophilic substitution of 2 was performed on a substrate
lacking the CD-ring junction in order to have more flexibility. More
recently, Ma developed a direct strategy via deprotonation of both
a malonate and the NH of the indole of 4 followed by an oxidation
of the resulting dianion with I2 into a biomimetic bis-radical
intermediate.[5] Importantly, to favor the C7-C16 oxidative
coupling (e.g. 5 from 4 with R = H), a free alcohol is required to
form a chelated-anion at C7.[5b] Otherwise, the N1-C16 bond is
formed (e.g. 6 from 4 with R = TBS and 8 from 7).[5b,6d] In contrast,
no synthetic work has been reported towards the excelsinidines,
which contain a bridged bicyclic ammonium moiety. Therefore, in
line with our interest in the chemistry of monoterpene indole
alkaloids,[7] we would like to report our endeavors towards the
total synthesis of these natural products with an emphasis on the
formation of the key N4-C16 bond over the N1-C16 and C7-C16
bonds. We sought to study the intrinsic selectivity of the
intramolecular oxidative coupling between C16 and N1 or N4 or
C7 directly from complete geissoschizine skeleton 9 (Scheme 2)
since Sakai, Ma and Zhu have achieved oxidative cyclizations on
C3-N4 seco or C13-N14 seco or acyclic unconstrained
substrates.[8]
the ester were connected by forming 7-membered-lactam (–)-
21.[9a] The oxidative process was effected in two stages. First, the
C16-carbon was subjected to umpolung by
a
highly
diastereoselective chlorination, leading to -chlorolactam 22.[14,15]
Then, addition of sodium carbonate, in wet methanol, induced the
nucleophilic substitution of the chlorine by the quinolizidinic
nitrogen[16] and the cleavage of the lactam to form selectively the
expected N4-C16 bond of the bridged-ammonium bicycle,
delivering enantiopure (–)-17-nor-excelsinidine in 68% yield in
two steps.
In order to rapidly access 16-desformyl-geissoschizine 9,[8a,9] as a
platform for our study, we evaluated the nickel-mediated 1,4-
intramolecular addition of vinyl iodide (±)-12 onto
itsunsaturated methyl ester (Scheme 3).[9d,f] The latter was
obtained by a Pictet-Spengler-like reaction from tryptamine
derivative 10 and methyl propiolate[10] followed by DIBAL-H
reduction and olefination of ester (±)-11. Unfortunately, the high
yielding intramolecular radical 1,4-addition of (±)-12 produced the
undesired (±)-trans-9 compound as the major diastereoisomer in
a 1.8:1 ratio.
To overcome this issue, we decided to perform this key cyclization
with a C5-benzyloxycarbonyl substituent, which will control the
stereoselectivity of the nickel-mediated 1,4-addition as
demonstrated by Cook.[9d,11] Therefore, starting from enantiopure
D-tryptophan instead of tryptamine will allow us to perform a
diasteroselective synthesis leading to an enantiopure final
product.11 The Mannich addition, developed by Martin, of vinyl
ketene acetal 14 onto dihydro--carboline (–)-13 delivered
stereoselectively trans-tetrahydro--carboline (–)-15.[9c,12] The 2-
iodoprop-2-ene moiety was then introduced via a nucleophilic N4-
substitution with allyl bromide 16. In presence of Ni(COD)2, the
Scheme 3. Synthesis of (±) and (+)-16-desformyl-geissoschizine (9).
radical cyclization of (+)-17 occurred, with
a
2:1
diastereoselectivity in favor of the desired diastereoisomer (–)-cis-
18 which could be isolated in 55% yield.[9d,11]] The benzyl ester
was then removed in a classical sequence:[9c,d] debenzylation into
acid (+)-19, formation of
a
phenylselenoester 20 and
decarboxylation in reductive radical conditions to yield the
expected enantiopure (+)-16-desformyl-geissoschizine (9) in 8
steps in the longest linear sequence.
Having the required scaffold in hands, the stage was set to
explore the key oxidative cyclization. Several attempts to achieve
this transformation directly from (+)-9 were unsuccessful.[13] At this
point, we believed that accessing a rigid framework would bring
closer the potential reactive centers, which should allow us to
perform the expected intramolecular coupling with selectivity
(Scheme 4). Therefore, the indole nitrogen and the carbonyl of
Scheme 4. Completion of the total synthesis of (–)-17-nor-excelsinidine.
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Very pleased to have achieved the first synthesis of 17-nor-
excelsinidine with a selective two steps N4-C16 coupling, we
wondered if a direct oxidative cyclization from geissoschizine
would be possible.[17] Unfortunately, this approach failed from
desformyl-geissoschizine (+)-9, however we reasoned that the
presence of the formylester function of geissoschizine itself
should be more reactive (Scheme 5). Therefore, geissoschizine
was prepared from (+)-9 by a known formylation step.[9]
25 and 26 would lead, respectively, to the mavacurans and the
akuammilans. However, we should remain cautious on this
hypothesis until proven by feeding experiments or identification of
enzymes responsible for these oxidative couplings.[22,23]
This latter was then deprotonated with KHMDS and the
corresponding dianion was then submitted to oxidation with I2
leading selectively, after aqueous work-up with sodium
metabisulfite, to (–)-17-nor-excelsinidine methyl ester (23)
(Scheme 5) in 25% yield.[18,19] Methyl ester (–)-23 was then
saponified to (–)-17-nor-excelsinidine in 73% yield.
Scheme 6. Alternative biosynthesis of the mavacurans and akuammilans.
In conclusion, we discovered two oxidative cyclization strategies
of the complete geissoschizine skeleton, which led to the selective
formation of the N4-C16 bond encountered in the excelsinidine
alkaloids over the C7-C16 and N1-C16 bonds of the akuammilan
and mavacuran alkaloids. The -electrophilic chlorination of a 7-
membered-ring lactam and its ring rearrangement via
a
nucleophilic substitution led to the first total synthesis of (–)-17-
nor-excelsinidine. Alternatively, the cyclization of geissoschizine
itself via a direct oxidative coupling delivered (–)-17-nor-
excelsinidine methyl ester (23) which could be saponified into (–)-
17-nor-excelsinidine
Scheme 5. Direct oxidative cyclization of geissoschizine leading to (–)-17-nor-
excelsinidine.
Acknowledgements
A plausible mechanistic hypothesis for this oxidative cyclization
involves the oxidation of the aliphatic nitrogen into N-
iodoammonium A which would be substituted by the C16-
enolate.[20] While it is less likely to us, we cannot exclude that this
cyclization proceeds by the heterocoupling of a N4,C16-bis-
radical generated via two single electron transfers (SET), related
to the original Ma’s coupling[5,6d] or by a nucleophilic substitution
of the aliphatic tertiary amine onto a 16-iodo ester.[6d]
The Zhu and Ma previous studies (Scheme 2) and this selective
chemical transformation of geissoschizine into the excelsinidine
skeleton over the akuammilan and mavacuran ones could raise
questions about their respective biosynthesis from chemo-
divergent oxidative annulations. Indeed, specific enzymes
(oxidases) could induce selective couplings between C16 and N1
or N4 or C7 from geissoschizine as classically proposed.[2]
However considering the constrained structure of the mavacurans
and the akuammilans, it might also be postulated that the key N1-
C16 and C7-C16 couplings could occur prior to the formation of
the N4-C21 bond (Scheme 6). One can envision that these bond
formations could arise from the open form 24b of aglycon 24a
after deglycolysation of strictosidine, the common precursor of all
monoterpene indole alkaloids, as previously proposed.[21]
Subsequently, cyclization, via reductive amination, of compounds
We gratefully acknowledge the ANR (ANR-15-CE29-0001;
“Mount Indole”), the Université Paris-Sud and the CNRS for
financial support.
Keywords: monoterpene indole alkaloids • oxidative coupling •
excelsinidine • biosynthesis • geissoschizine
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COMMUNICATION
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Maxime Jarret, Aurélien Tap, Cyrille
Kouklovsky, Erwan Poupon, Laurent
Evanno* and Guillaume Vincent*
Selectivity! Two unprecedented oxidative cyclization strategies from the complete
geissoschizine skeleton allow to selectively achieve the first total synthesis of the
monoterpene indole alkaloid 17-nor-excelsinidine over the mavacuran and
akuammilan alkaloids.
Page No. – Page No.
Bioinspired Oxidative Cyclization of
the Geissoschizine Skeleton for the
Total Synthesis of (–)-17-nor-
Excelsinidine
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