Bioinspired Divergent Oxidative Cyclizations of Geissoschizine: Total Synthesis of (–)-17-nor-Excelsinidine, (+)-16-epi-Pleiocarpamine, (+)-16-Hydroxymethyl-Pleiocarpamine and (+)-Taberdivarine H

Article abstract of DOI:10.1002/ejoc.202000962

We report a full account of our efforts towards bioinspired oxidative cyclizations of geissochizine and analogs to mimic the biosynthesis of the mavacuran, akuammilan, and excelsinidine groups of monoterpene indole alkaloids. The construction of the A,B,C,D ring system of geissoschizine was first achieved by merging two known syntheses of this alkaloid. Modified Ma's oxidative conditions (KHMDS/I₂) applied directly to geissoschizine induced formation of the N4–C16 bond encountered in the excelsinidines core. Identical conditions applied to C16-dimethylmalonate-containing N4-quaternized substrates ended in the formation of the mavacurans core (N1–C16 bond). With this unified oxidative cyclization strategy: (–)-17-nor-excelsinidine, (+)-16-epi-pleiocarpamine, (+)-16-hydroxymethyl-pleiocarpamine, 16-formyl-pleiocarpamine and (+)-taberdivarine H were synthetized. We also report a shortened total synthesis of 16-epi-pleiocarpamine compared to our preliminary communication from a C16-monoester analog. Alternatively, 17-nor-excelsinidine was synthesized via an intramolecular nucleophilic substitution of a 7-membered ring α-chlorolactam prepared from 16-desformyl-geissoschizine.

Full text of DOI:10.1002/ejoc.202000962

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Bioinspired divergent oxidative cyclizations of geissoschizine:
total synthesis of 17-nor-excelsinidine, 16-epi-pleiocarpamine,
16-hydroxymethyl-pleiocarpamine and taberdivarine H
Authors: Maxime Jarret, Aurélien Tap, Victor Turpin, Natacha Denizot,
Cyrille Kouklovsky, Erwan Poupon, Laurent Evanno, and
Guillaume Vincent
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000962
Link to VoR: https://doi.org/10.1002/ejoc.202000962
01/2020

10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
Bioinspired divergent oxidative cyclizations of geissoschizine:
total synthesis of (–)-17-nor-excelsinidine, (+)-16-epi-
pleiocarpamine, (+)-16-hydroxymethyl-pleiocarpamine and (+)-
taberdivarine H
Maxime Jarret,[a] Aurélien Tap,[a] Victor Turpin,[b] Natacha Denizot, [a] Cyrille Kouklovsky,[a] Erwan
Poupon,*[b] Laurent Evanno*[b] and Guillaume Vincent*[a]
In memory of Robert M. Williams
[a]
[b]
Dr. Maxime Jarret, Dr. Aurélien Tap, Dr. Natacha Denizot, Prof. Cyrille Kouklovsky and Dr. Guillaume Vincent
Institute de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO)
Université Paris-Saclay, CNRS
91405 Orsay, France
E-mail: guillaume.vincent@universite-paris-saclay.fr
Victor Turpin, Prof. Erwan Poupon and Dr. Laurent Evanno
Biomolécules: Conception, Isolement et Synthèse (BioCIS).
Université Paris‐Saclay, CNRS, BioCIS,
92290 Châtenay‐Malabry, France
E-mail: erwan.poupon@universite-paris-saclay.fr; laurent.evanno@universite-paris-saclay.fr
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: We report a full account of our efforts towards bioinspired
oxidative cyclizations of geissochizine and analogues to mimic the
biosynthesis of the mavacuran, akuammilan and excelsinidine groups
of monoterpene indole alkaloids. The construction of the A,B,C,D ring
system of geissoschizine was first achieved by merging two known
syntheses of this alkaloid. Modified Ma’s oxidative conditions
(KHMDS/I2) applied directly to geissoschizine induced formation of
the N4-C16 bond encountered in the excelsinidines core. Identical
conditions applied to C16-dimethylmalonate-containing N4-
quaternized substrates ended to the formation of the mavacurans
core (N1-C16 bond). With this unified oxidative cyclization strategy:
divergent biosynthetic routes from 2 or 3 lead to a large diversity
of pentacyclic frameworks (Scheme 1).[1] On one hand from 2,
cyclization between the C17-aldehyde and the unsaturated
iminium (or the corresponding dienamine) furnishes the
heteroyohimban (ajmalicine) and yohimban (yohimbine 4,
reserpine) alkaloids.[2] On the other hand, reduction of the
N4=C21 iminium of 2 delivers geissoschizine (3) which is central
to generate structural diversity via divergent oxidative cyclizations.
The C16-formyl ester moiety is pivotal in these oxidative couplings.
The formation of the C5-C16 bond yields the sarpagan alkaloids
such as polyneuridine aldehyde (5) via an oxidation of the N4-
quinolizidine into a N4=C5 iminium.[3] Alternatively, oxidation of
this N4-tertiary amine could also forge the N4-C16 bond and lead
to the recently discovered excelsinidines (6, 7).[4]
Oxidative cyclizations between the C16 formyl ester and two
different positions of the indole nucleus, leading either to a C-C or
a C-N bond formation are also possible. [5,6] The coupling with the
C7-indolic position delivers the akuammilan alkaloids (rhazimal 8,
rhazimol 9, akuammiline 10, strictamine 11) which are currently
popular synthetic targets.[7] Importantly, the strychnan framework
(–)-17-nor-excelsinidine,
(+)-16-epi-pleiococarpamine,
(+)-16-
hydroxymethyl-pleiocarpamine, 16-formyl-pleiocarpamine and (+)-
taberdivarine H were synthetized. We also report a shortened total
synthesis of 16-epi-pleiocarpamine compared to our preliminary
communication from a C16-monoester analog. Alternatively, 17-nor-
excelsinidine was synthetized via an intramolecular nucleophilic
substitution
of
a
7-membered
ring
-chlorolactame prepared from 16-desformyl-geissoschizine.
(akuammicine 12) is postulated to arise from
a skeletal
rearrangement of the akuammilan scaffold,[8] thus constituting the
main biosynthetic continuum of the monoterpene indole
alkaloids.[1] Coupling of C16 with the N1-indolic position results in
the formation of the mavacuran skeleton.[9,10] After the formation
of the N1-C16 bond and postulated biosynthetic intermediate 13,
reduction of the aldehyde and desformylation would furnished 16-
hydroxymethyl-pleiocarpamine (14) and pleiocarpamine (15). The
indolyl-ester stereocenter of the latter could be epimerized into
16-epi-pleiocarpamine (16). Some members of the mavacurans
such as C-mavacurine (17) and taberdivarine H (18) display a N4-
methyl ammonium.
Introduction
Monoterpene indole alkaloids are a structurally diverse family of
more than 3000 known molecules, originating from strictosidine
(1) as the single biosynthetic precursor (Scheme 1).[1] At a very
early stage of the biosynthetic route, a deglucosylation of 1
release a reactive C-21 aldehyde. Then, condensation with the
N4-secondary amine and the isomerization of the terminal
C18=C19 double bond lead to the corynanthe-type skeleton
[4,21-dehydrogeissoschizine (2) and geissoschizine (3)]. The
tetracyclic corynanthe skeleton plays a pivotal biosynthetic role as
1
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10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
Scheme 1. Pivotal role of geissoschizine in the biosynthesis of several families of monoterpene indole alkaloids
Among those compounds, pleiocarpamine (15) is a particularly
Scheme 2. Our synthetic approach based on bioinspired oxidative cyclizations
of geissoschizine.
appealing synthetic target since it is found as a subunit of several
of multimeric indole alkaloids (eg villalstonine 19, pleiocraline 20,
voacalgine A 21 or bipleiophylline 22).[11]
Actually, in 2017 we accomplished the bioinspired hemisyntheses
of voacalgine A (21) and bipleiophylline (22) from pleiocarpamine
(15) isolated from natural sources (Scheme 2).[12] In order to
accomplish a full total synthesis of bipleiophylline which is a
particularly intricate bis-indole alkaloid, we embarked in the total
synthesis of pleiocarpamine (15).[13] Following an approach
inspired by its biosynthesis, we sought to study the oxidative
cyclization of the complete geissoschizine scaffold.[14]
In relation with our interest in the bioinspired synthesis of
monoterpene indole alkaloids,[8a,15] we would like to describe here,
a full account of our efforts towards this goal. Our collaborative
work recently led to the total synthesis of (–)-17-nor-excelsinidine
(7),[16] (+)-16-epi-pleiocarpamine (16), (+)-16-hydroxy-methyl-
pleiocarpamine (14) and (+)-taberdivarine H (18).[17]
Several synthetic studies mimicking the key oxidative couplings
of the biosynthesis presented in scheme 1 were reported but on
incomplete scaffolds.[18,19] A rare number of approaches were
performed on the complete geissoschizine skeleton (Scheme 3).
During the hemisynthesis of 16-epi-pleiocarpamine (16), Sakai
and Shinma had to cleave the C3-N4 bond of 23 before effecting
a nucleophilic substitution of 16-chloroester 24 by the indolic N1-
nitrogen, and then reconstructed the C3-N4 bond.[13c,d] Harley-
Mason used a similar strategy a few years later.[13e]
The sarpagan skeleton was accessed by van Tamelen and Martin
via a biomimetic addition of an aldehyde or its corresponding enol
ether onto a N4=C5 iminium (27).[20] However, the latter was not
generated by selective oxidation of geissoschizine but from the -
amino-acid moiety of tryptophan (van Tamelen)[20b] or the
[20a]
corresponding -aminonitrile 26 (Martin)
methylvellosimine (29).
leading to (+)-N-
Martin effected the first straightforward oxidative cyclization of the
geissoschizine scaffold which resulted in the selective formation
of akuammicine [(12), strychan skeleton].[21] Electrophilic
chlorination of 16-desformyl-geissoschizine (30) in the presence
of SnCl4, was followed by the deprotonation of the C16-ester to
induce the addition of the generated enolate onto 7-
chloroindolenine 31. It is debatable, whether the enolate adds
2
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10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
Scheme 4. Hydrolysis of geissospermine (32).
directly to the C2 imine or to the C7-chloride accompanied with a
skeletal reorganisation.
However, due to a limited stock of the latter, the supply line of
geissoschizine (3) was secured by synthesis. Several efficient
total syntheses of enantioenriched geissoschizine (3) are indeed
known.[24] The nickel-mediated reductive Heck reaction from vinyl
iodide 35a[25] employed by Cook is an attractive feature to
introduce stereoselectively the E-ethylidene in 36a (Scheme
5).[24d] To bypass the use of tryptophan as starting material and
the necessity to remove its carboxylate after the key reaction, we
used tryptamine 37 as starting material (Scheme 5). After
coupling with allylmesylate 38a,[26] allylated tryptamine 39 was
added to methylpropiolate in a 1,4-fashion.[27] Then, addition of
TFA induced a Pictet-Spengler type reaction via an iminium to
generate -tetrahydrocarboline rac-40 in a racemic form. It is
reasonable to think that an enantioselective Pictet-Spengler
reaction could be implemented.[28] The ester of rac-40 was then
converted to a ,-unsaturated ester via reduction of the aldehyde
followed by a Horner-Wadsworth-Emmons olefination.
Scheme 3. Previous approaches to the oxidative cyclizations of the
geissoschizine framework.
Results and Discussion
Access to the geissoschizine scaffold
In order to evaluate our oxidative cyclization strategies, we first
needed to have geissoschizine in hands. A first batch of about
100 mg of geissoschizine (3) itself was produced by the hydrolysis
of the natural product geissospermine (32, Scheme 4).[22]
Geissoschizoline (33), the second subunit released was valorized
for the biomimetic assembly of leucoridine A (34).[23]
Scheme 5. Initial attempts for the synthesis of geissoschizine.
Disappointingly, the nickel-mediated intramolecular 1,4-addition
of the vinyl iodide of rac-35c to the -unsaturated ester led to a
1.8:1 mixture of diastereoisomers of rac-30 with the undesired
trans product as the major compound. Evidently, it seems that the
carboxylate
in
35a
from
tryptophan
controls
the
diastereoselectivity of the reductive Heck reaction. From the work
of Wei and Yang, the presence of a PMB group on the indolic
nitrogen of 35b could also direct the cis-selectivity (Scheme 5),
however introduction and removal of the PMB group would
lengthen the synthetic sequence.[24f]
With this information in mind, we thus decided to reproduce the
nickel-mediated reaction of Cook on D-tryptophan-derived vinyl
iodide 35a. To improve the access of the latter, we reproduced
3
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10.1002/ejoc.202000962
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the Martin’s trans-selective vinylogous Mannich addition of silyl
ketene acetal 43 onto dihydro--carboline 42 derived from
D-tryptophan (41, Scheme 6).[24c] Nucleophilic substitution of allyl
bromide 38b with the N4-secondary amine allowed to intercept
Cook’s intermediate 35a. Indeed, the reductive Heck reaction
allowed to isolate the desired cis-isomer 36a as the major product
in a useful yield of 55%. Nevertheless, it should be noted that the
diastereoselectivity is moderate with a cis/trans ratio of 2:1.
Removal of the carboxylate was achieved as previously described
in three steps: a reductive debenzylation and formation of a
selenoester were followed by a tributyltin hydride-mediated
decarboxylation. Useful quantities of pivotal 16-desformyl-
geissoschizine 30 were thus secured in an efficient manner in
several batches, building on the previous Martin’s and Cook’s
works. Geissoschizine (3) itself was accessed by a known direct
formylation of the ester at C16 in presence of LDA. We also
wanted to get a hand on malonate analog 45 of geissoschizine.
In this case, the direct carboxylation resulted in the formation of
the additional unwanted indolic methyl carbamate. Therefore, the
indole ring was protected with a Boc group, before the formation
of the C16-malonate with methyl cyanoformate and LDA and,
finally deprotected with TFA to yield 45.
deprotonation of a C16-malonate and of the NH indole with
LiHMDS, followed by addition of I2 as oxidant to presumably form
a bis-radical intermediate. This oxidative coupling is substrate
dependent since in the cases of 49 and 50, coupling of the C16-
malonate with the N1 indolic nitrogen was observed respectively
by Ma[18b] and Zhu.[19a]
Scheme 7. Ma’s indole-malonate intramolecular oxidative coupling.
Table 1. Oxidative cyclization of geissoschizine into 17-nor-excelsinidine methyl
ester 51.
Entry
1
Substrate
Base then Oxidant
Yield 51[a]
3
KHMDS (2.2 equiv.)
then I2 (1.05 equiv.)
25%
2
3
4
5
6
7
3
KHMDS (1.1 equiv.)
then I2 (1.05 equiv.)
23%
3
LiHMDS (2.4 equiv.)
then I2 (1 equiv.)
not
detected
3
No base
I2 (1 equiv.)
not
detected
3
KHMDS (2.2 equiv.)
then PIFA (1.05 equiv.)
not
detected
30
45
KHMDS (2.2 equiv.)
then I2 (1.05 equiv.)
not
detected
KHMDS or LiHMDS (2.2 equiv.)
then I2 (1.05 equiv.)
not
detected
Scheme 6. Synthesis of the geissoschizine scaffold based on Martin’s and
Cook’s work.
[a] Isolated yield.
Since at that time, we did not have LiHMDS in hand, we used
KHMDS as base instead which was decisive to observe any
oxidative cyclization (Table 1, entry 1). Deprotonation of
geissoschizine (3) with 2.2 equivalents of KHMDS, followed by
addition of 1.05 equivalent of I2 did not lead to pleiocarpamine or
strictamine as planned but to the methyl ester of 17-nor-
excelsnidine (51) via an N4-C16 unexpected bond formation and
desformylation at C16.[29] While this result was not what we have
Direct oxidative cyclization of geissoschizine: total synthesis
of (–)-17-nor-excelsinidine
With geissoschizine in hand, the stage was set to study its
bioinspired oxidative cyclization. It seemed logical to try the
process first described by Ma to form the C7-C16 bond of the
akuammilan alkaloids on simplified substrates 46 leading to 47 or
48 (Scheme 7).[18] This oxidative coupling proceeds via the double
4
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10.1002/ejoc.202000962
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expected, it was still a useful discovery since the excelsinidine
skeleton was accessed for the first time. The indole moiety being
not involved in this oxidative coupling, the deprotonation of this
heterocycle may probably not be needed. Indeed, with only 1.1
equivalent of KHMDS, a similar yield of 23% was obtained (entry
2). Curiously, when we switched from KHMDS to LiHMDS, the
base of the original Ma’s condition, no oxidative coupling was
observed (entry 3). The absence of base did not allow the
oxidative cyclization to proceed either (entry 4). Replacing I2 as
oxidant by PIFA did not lead to a favorable outcome (entry 5).[19]
Intriguingly, the oxidative cyclization is specific to geissoschizine
itself: 16-desformylgeissoschizine (30) and malonate analog 45 in
presence of LiHMDS or KHMDS and I2 as oxidant could not lead
to any pentacyclic scaffold (Table 1, entries 6, 7).
in a nucleophilic substitution by the nucleophilic N4-tertiary amine.
This last hypothesis is less likely based on the observation of
Zhu.[19] We believe that the spontaneous and biomimetic
desformylation of intermediate D occurs during the aqueous
workup with sodium metabisulfite used to reduce the excess of I2.
Addition of water to the aldehyde of D would generate formic acid.
Otherwise, reduction of the aldehyde of D into primary alcohol E
with sodium metabisulfite would be associated with release of
formaldehyde.
Finally, methyl ester 51 was saponified to complete the first total
synthesis of zwitterionic (–)-17-nor-excelsinidine (7) in 11 steps
from 41 (Scheme 8).
Rearrangement of a seven-membered ring lactam: total
Retrospectively, the formation of the N4-C16 bond is not
surprising. NMR conformation studies have demonstrated that
geissoschizine adopts a C3-N4 trans conformation in which the
C16-formyl ester or the N4 nitrogen are in proximity.[30] More
importantly, the N4-tertiary amine of 3 is more reactive than in
previous substrates 46 in which the lone pair of the nitrogen is
sequestered.
synthesis of (–)-17-nor-excelsinidine
The direct oxidation of geissoschizine does not lead to the
mavacurans for, among hypothetical reasons, conformational
considerations. We consequently planned to overcome this issue
by bringing the N1 indolic nitrogen and the C16-carbon in close
proximity to favor their coupling (Scheme 9). We were inspired by
the synthesis of vincamine (55) for which the 6-membered E ring
was formed by the ring contraction of the 7-membered-ring -
ketolactam 54 under the action of sodium methoxide.[32]
Accordingly, our retrosynthesis to obtain pleiocarpamine, implied
protonation of the hydroxyl group of 52 and stereoselective
addition of a hydride into the more accessible face of the resulting
carbocation. 16-Hydroxy-pleiocarpamine 52 would, indeed, arise
from the ring contraction of keto-lactam 53.
Scheme 9. Ring contraction approach towards pleiocarpamine from -
ketolactam 53.
The first task to study this ring contraction approach consisted in
the synthesis of -ketolactam 53. Two routes were envisioned to
access this target (Scheme 10). Cyclization of tetracyclic
ketoester 56 seemed to be a reasonable approach. The latter was
Scheme 8. Total synthesis of (–)-17-nor-excelsinidine by oxidative cyclization
of geissoschizine.
sought to be accessed either via
a palladium-catalyzed
intramolecular -vinylation of the tricyclic keto-ester 57 with a
iodopropenyl moiety[33] or a 6-exo-dig cyclization of enol ether 58
onto the propynyl functionality (Conia-ene-type reaction) with a
cationic gold catalyst[34] to ensure the stereoselective formation of
the E-ethylidene via intermediate F. As an alternative,
lactamization of 16-desformyl-geissoschizine 30 into 59 could be
followed by -oxidation into ketolactam 53.
We could postulate than reaction of tertiary amine with I2 would
lead to N-iodoamonium A which could succumb to the addition of
the C16-potassium enolate to complete the cyclization into D
(Scheme 8).[31] It is also possible to envision that the N4-amine
and the C16-enolate could be oxidized into respectively a radical
cation and a free radical (intermediate B) that would associate to
form the N4-C16 bond. Alternatively, the C16-enolate could react
with I2 to form 16-iodoformylester C which can then be engaged
5
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Scheme 10. Retrosynthesis to access 7-membered ring ketolactam 53.
We first tried to access tetracyclic -ketoester rac-56 via
palladium-catalyzed cyclization of vinyliodide rac-57 (Scheme 11).
The latter was obtained in a racemic manner using a Pictet-
Spengler reaction between N-functionalized tryptamine 39[33a] and
aldehyde 60[35] which contains an -dimethoxyester. After
protection of the indolic nitrogen, the acetal was hydrolyzed with
iron(III) chloride hexahydrate. Unfortunately, all our attempts to
effect the intramolecular -vinylation of ketoester rac-57 or of the
corresponding enol ethers rac-62a/b failed (see SI for details).
Most of the times, Claisen-type dimerization of rac-57 or
deallylation of the N4-amine were observed. It is in stark contrast
with the reported successful -vinylation of a very similar
substrate bearing
ketoester.[33a]
a
C16-methylketone instead of the
Scheme 12. Attempts towards the synthesis of tetracyclic rac-56 via Au-
catalyzed cyclization of propynyl-containing enolethers rac-58.
Unfortunately, various cationic gold catalysts were evaluated
without success (see SI for details).[34a-c] The enol ether moiety
derived from the -ketoester is not nucleophilic enough to add to
the gold-activated alkyne and instead, we unexpectedly obtained
the 8-membered ring-containing indole rac-66. Despite the
presence of an electron-withdrawing group on the nitrogen, the
indole added to the alkyne (G) leading to carbocation H.
Rearomatization was possible, inducing cleavage of the C2-C3
bond and, leading to the dienamine part of rac-66. Such a
transformation has rarely been observed.[36]
Scheme 11. Attempts towards the synthesis of tetracyclic rac-56 via Pd-
catalyzed intramolecular -vinylation of ketoester rac-57.
We thus turned to our second option to access rac-56 using a
Conia-ene-type reaction (Scheme 12). Pictet-Spengler reaction
between propargylated tryptamine 63 and aldehyde 60 yielded
acetal rac-64. Then, hydrolysis catalyzed by para-toluene sulfonic
acid in acetone, released -ketoester rac-65. The corresponding
silylenol ethers rac-58a/b were then formed in order to test the 6-
exo-dig cyclization leading to rac-56.
Since the silyl enol ethers of rac-58a/b are not reactive enough to
intramolecularly add to the alkyne, we envisioned to replace it by
the aldehyde-derived silyl enol ethers rac-70. Aldehyde rac-69
was prepared via the Pictet-Spengler reaction between 63 and
6
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mono-protected dialdehyde 67[37] and hydrolysis of dimethyl
acetal rac-68. Despite several attempts, we were unable to
convert the aldehyde into its silyl enol ethers rac-70. We also
unsuccessfully, turned our attention towards the generation of an
enamine intermediate with a secondary amine to induce the gold-
catalyzed direct -addition of the aldehyde to the alkyne.[34d] Only
dimerization was observed via aldolization/crotonisation (see SI
for details). The use of an indium or copper catalyst gave similar
results. [34e,f]
-Chloration of lactam 59 was first undertaken via the formation
of an enolate with LiHMDS and trapping with TsCl which was
previously developed for the -chlorination of ketones (Table
2).[41] A 2:1 mixture of the targeted -chlorolactam 73 with its
dichloro analogue 74 was obtained with 1.2 equivalent of TsCl
(entry 1). Counterintuitively, a large excess of TsCl (3 equivalents,
entries 2,3) allowed to dramatically improve the selectivity in favor
of the monochloro compound 73. It could be explained by the fact
that if the trapping of enolate I with the chlorinating reagent is too
Facing the impossibility to obtain ketoester 56, we believed that
-ketolactam 53 could be obtained by -oxidation of lactam 59
(Scheme 13). The latter was indeed obtained by cyclization of 16-
desformylgeissoschizine 30. Saponification of the latter was
followed by the formation of an activated mixed anhydride in
presence of trifluoroacetic anhydride (TFAA) to promote
lactamization into 59. Due to the poor solubility of the carboxylic
acid resulting from 30 in pure TFAA, addition of trifluoroacetic acid
was required to ensure reproducibility of the cyclization. We were
unable to obtain 53 by direct oxidation of 59,[38] we therefore
turned towards a two-step procedure previously used in the
synthesis of vincamine.[32a] Oxidation of lactam 59 with t-butyl
nitrite delivered crude -ketoxime ester 72.[39] Despite several
attempts, hydrolysis of the latter into 53 did not meet with success.
slow, persistent enolate I could deprotonate the formed
monochlorolactam 73 to generate -chloro enolate J which could
react with TsCl and lead to dichlorolactam 74. Fast addition of an
excess of the electrophilic chlorine reagent allows to rapidly trap
the totality of enolate I before the latter could transform 73 into J.
A single but undetermined C16-diastereoisomer of 73 was formed.
Therefore, it seems logical to assume that an α-chlorination on
the convex face of the pentacyclic framework occurred.
Table 2. -chloration of lactam 59.
Entry
LiHMDS
1.2 equiv.
1.0 equiv.
1.2 equiv.
TsCl
Yield 73+74[a]
73%
ratio 73/74
2:1
1
2
3
1.2 equiv.
3.0 equiv.
3.0 equiv.
54%
> 95:5
> 95:5
69%
Scheme 13. Attempts to form ketolactam 53 from 16-desformylgeissoschizine
(30).
[a] Isolated yield based on 59.
Everything was in place to test the ring contraction step in
methanol with sodium carbonate in presence of traces of water
(Scheme 15). Unlike what we expected, the contraction of the
7-membered ring lactam into a 6-membered ring related to
pleiocarpamine (15) did not take place despite the proximity of the
N1 indolic nitrogen and the C16 carbon. Instead, we obtained
directly (–)-17-nor-excelsinidine (7) and we, therefore,
accomplished our second total synthesis of this natural product in
12 steps from 41. We believe that a methoxide or a hydroxide
adds on the carbonyl of the lactam to break the amide bond and
form -chloro ester 75 or -chloro acid 76. Nucleophilic
substitution of the chloride by the N4-tertiary amine delivered
either directly (–)-17-nor-excelsinidine (7) or its methyl ester 51
that is in-situ saponified into the natural product. While this
synthesis necessitates one more step than the direct oxidation of
geissoschizine, the overall yield from 16-desformygeissoschizine
(30) is better (30% instead of 17%). It should be noted that in order
to shortcut this overall sequence, we attempted, but failed, to
directly chlorinate 16-desformylgeissoschizine 30 into 75.
Having failed to produce -ketolactam 53, another revision of our
strategy was needed which involved a formal aza-Favorskii-type
rearrangement.[40] It became apparent to us that performing the
ring contraction on -chlorolactam 73 could be advantageous
over the ketoester strategy by saving few steps (Scheme 14).
Oxidation of 59 into -chlorolactam 73 should require a single
step and the ring contraction of 73 should deliver directly
pleiocarpamine as we would not have to reduce 16-hydroxyl-
pleiocarpamine 52 (see Scheme 9).
Scheme 14. Ring contraction approach towards pleiocarpamine from
-chlorolactam 73.
7
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10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
reasoned that quaternization of the aliphatic nitrogen N4 into 81
would inhibit its reactivity and more importantly would lock the
required C3-N4 cis-conformation of geissochizine in order to
access pentacycle 82 (Scheme 17).
Scheme 15. Total synthesis of (–)-17-nor-excelsinidine (7) via rearrangement
of -chlorolactam 73.
Oxidative cyclization of N4-geissoschizinium salts: total
synthesis of (+)-16-hydroxymethyl-pleiocarpamine, (+)-16-
epi-pleiocarpamine and (+)-taberdivarine H.
Scheme 17. Quaternization/oxidation strategy from geissoschizine
Considering the results of Ma and Zhu, we believed that the
I2/KHMDS-induced coupling of the C16 carbon with the indole
nucleus of 3 was still possible.[18,19]
At first, we attempted to in-situ complex the N4 nitrogen of 3 with
Lewis acids such as boron trifluoride etherate or tin tetrachloride
(Scheme 18). Unfortunately, the oxidative coupling conditions
resulted either in the recovery of the starting material or to the
formation of 17-nor-excelsinidine methyl ester 51. Protonation of
the N4-tertiary amine was sought when we subjected
geissoschizine to Mn(OAc)3 in acetic acid but without success.
Performing the oxidation with PIFA in HFIP which is able to induce
hydrogen-bond interactions was also disappointing. Formation of
geissoschizine N-oxide was then envisioned. Unprotected 3,
reacts cleanly with m-CPBA, but the reaction product could not be
purified by flash chromatography.
Helpfully, Eckermann and Gaich demonstrated that benzylation of
geissoschizine (3) with 4-bromobenzyl bromide effectively lock
the C3-N4 cis-conformation of 83a and insure proximity between
the C16 carbon and the indole nucleus.[43] We thus applied the
oxidative conditions (KHMDS, then I2) to ammonium 83a. The
mavacuran skeleton was selectively formed as a mixture of 84a
and deformyl counterpart 85a via the expected N1-C16 bond
formation. Unfortunately, the 4-bromobenzyl removal by
methanolysis was inoperative, thus, we turned to quaternization
of geissochizine (3) with a PMB group. The N1-C16 oxidative
coupling performed on 83b, resulted on similar results and a
mixture of 84b and 85b was obtained. The reaction revealed to
be stereoselective but, careful NMR analysis done on the mixture
of products 84b and 85b indicated that both presents an 16-epi-
At first sight, sequestration of the lone pair of the N4-tertiary amine
should avoid its reaction with the C16-formyl ester: switching from
a tertiary amine to an amide functionality at N4 seemed
appropriate. Therefore, we decided to attempt the oxidative
cyclization on tetracyclic lactam rac-78 which synthesis was
described by Martin through the Michael addition of dimethyl
malonate onto ,-unsaturated lactam rac-77 (Scheme 16).[42]
Unfortunately, no oxidative cyclization to rac-79 was observed in
various conditions. Complementary to this approach, we also
observed that rac-79 couldn’t be obtained via the intramolecular
Michael addition from -indolyester rac-80 which aroused from
the N-alkylation of rac-77 with bromomethylacetate.[42]
pleiocarpamine-type
stereochemistry
rather
than
the
Scheme 16. Attempts of cyclisation of tetracyclic lactams.
pleiocarpamine one. The quaternary amine was then restored by
the action of TMS iodide on the mixture of 84b and deformyl 85b
which delivered 16-epi-pleiocarpamine (16) and 16-epi-16-formyl-
pleiocarpamine (86). More efficient and convenient deprotection
conditions were found latter during the improvement of the
synthesis.
Obviously, masking the reactivity of the N4-tertiary amine is not
the only hurdle to overcome to permit the formation of the key N1-
C16 bond from a tetracyclic geissoschizine analog. It is also
important to consider conformational parameters.
Geissochizine, as above mentioned, adopts in solution a C3-N4
trans-conformation 3a suitable for the selective formation of the
N4-C16 bond of the excelsinidines core.[30] However, a cis-
conformation 3b is needed to bring closer the C16-formyl ester
and the indole nucleus to favor their oxidative coupling. We
8
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10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
Scheme 18. Synthesis of 16-epi-pleiocarpamine (16) by oxidative cyclization of
N-PMB geissoschizine.
Scheme 19. Total synthesis of 16-formyl-pleiocarpamine (13), (+)-16-
hydroxymethyl-pleiocarpamine (14) and (+)-16-epi-pleiocarpamine (16).
Despite the efficiency of the N1-C16 coupling step, the
uncontrolled deformylation of 84b eroded the reaction yield. To
circumvent this, cyclization of symmetrical diester 45 was
envisioned with also the aim to fix the C16 stereochemistry at a
later stage (Scheme 19). The same N4-benzylation and N1-C16
cyclization sequence applied to malonate 45 afforded the
mavacuran-type product 88 with a very satisfying 76% yield over
2 steps. The PMB removal was improved with the use of BBr3, to
give 89 with a 53% yield. To reach pleiocarpamine (15) our initial
synthetic target, we reasoned that the lesser hindered α-ester of
89 could selectively be modified. At first, a diastereoselective
As the 16-epi-type stereochemistry and a N4-ammonium are
encountered in the structure of taberdivarine H (18), its synthesis
seemed well suited to our strategy (Scheme 20). This time,
malonate 45 was strategically N-methylated and then the
KHMDS/I2 conditions were applied to 91 furnishing the cyclized
product 92 with a 75% yield over two steps. Double saponification
and decarboxylation of 92 by sodium hydroxide in a mixture of
THF and water at reflux completed the total synthesis of (+)-
taberdivarine H (18) in 14 steps from 41.
decarboxylation
strategy
was
envisioned.
Krapcho
decarboxylation of 89 with KCN delivered (+)-16-epi-
pleiocarpamine (16) in 15 steps from 41. We assumed that
cyanide effectively reacts with the expected α-ester but, the
transient enol formed during the decarboxylation is converted to
the more thermodynamically stable epimer 16. This hypothesis
was confirmed when the α-ester of 89 was selectively saponified,
into acid 90. Again, decarboxylation of 90 ended to 16. At this
stage, the synthesis of 16-hydroxymethyl-pleiocarpamine (14)
was targeted as Quirion claimed that its deformylation produced
pleiocarpamine (15).[9c] Reduction of 89 by DIBAL-H selectively
delivered 16-formyl-pleiocarpamine (13) which is postulated to be
the direct product of oxidative cyclization of geissoschizine and
the biosynthetic precursor of pleiocarpamine (15). In a second
reduction step, aldehyde 13 was reduced with NaBH4 into (+)-16-
hydroxymethyl-pleiocarpamine (14) in 16 steps from 41.
Compounds 13 and 14 present a C16 stereochemistry matching
with pleiocarpamine (15) and deformylation or retro-aldolization
were performed on both compounds. Heating 13 in methanol in
the presence of K2CO3 and heating 14 in toluene at reflux under
the action of NaH both ended to (+)-16-epi-pleiocarpamine (16).
Contrary to Quirion’s report, release of the carbon C17 was
accompanied with the isomerization of the transient enolate into
16.
Scheme 20. Total synthesis of (+)-taberdivarine H (18).
Simultaneously to our work in 2019, Takayama reported the
access to the mavacurans via a rhodium-catalyzed insertion of a
carbenoid intermediate into the indolic N1-H bond (Scheme
21).[13a] Analogous to our strategy, blocking the cis-conformation
via formation of aminoborane rac-93 was key to the success of
the cyclization. Oxidative cleavage of the aminoborane delivered
rac-16-epi-pleiocarpamine (16) as the major compound and rac-
pleiocarpamine (15) as the minor constituent as racemic mixtures.
9
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10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
In order to bring in close proximity, the indolic N1 nitrogen and the
C16 carbon, a ring contraction strategy from a seven-membered
ring -chlorolactam, was therefore adopted and also resulted in
the total synthesis of (–)-17-nor-excelsinidine. Realizing that the
nucleophilicity of the N4-tertiary amine needed to be masked and
that geissoschizine required to be blocked in its cis-conformation,
alkylation of geissoschizine malonate was performed. The N4-
ammonium obtained was then engaged in the oxidative
cyclization with KHMDS and I2 to successfully form the
mavacuran skeleton. After diastereoselective reductions and/or
decarboxylation, we completed the total synthesis of (+)-16-epi-
pleiocarpamine, (+)-16-hydroxymethyl-pleiocarpamine and (+)-
taberdivarine H. Performing the oxidative coupling with a C16-
monoester instead of a C-16 malonate allowed to shorten the
synthetic sequence towards (+)-16-epi-pleiocarpamine.
Scheme 21. Total synthesis of rac-pleiocarpamine (15) and rac-16-epi-
pleiocarpamine (16) by Takayama.
Acknowledgements
Finally, we aimed to shorten our access to the mavacuran
skeleton. Accordingly, we recently wandered if the N1-C16
oxidative cyclization could be effected with a C16-monoester
instead of a C16-malonate and what would be the outcome of the
stereochemistry at C16 (Scheme 22). 16-Desformyl-
geissoschizine 30 was thus transformed into ammonium 94 which
was subjected to our optimized oxidative coupling conditions.
Pleasantly, we were able to obtain a modest 30% yield of 85b.
This result is in contrast with the precedent from Ma or Zhu for
which a soft dicarbonyl enolate is required. However, we were not
able to obtain the pleiocarpamine stereochemistry at C16.
Nevertheless, removal of the PMB group and restoration of the
N4-tertiary amine yielded (+)-16-epi-pleiocarpamine (16) in 25%.
This strategy allowed us to avoid 4 steps: 3 steps to transform 16-
desformyl geissoschizine 30 into the corresponding malonate 45
and 1 step for the Krapcho decarboxylation of 89. This approach
shortens the longest linear sequence to 11 steps from 41 but was
balanced by a lower overall yield.
We gratefully acknowledge the ANR (ANR-15-CE29-0001;
“Mount Indole”), the Université Paris-Sud, the Université Paris-
Saclay and the CNRS for financial support.
Keywords: Indole • Oxidative coupling • Monoterpene Indole
Alkaloids • Total synthesis • Biomimetic
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10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Total Synthesis
To synthetize excelsinidines and mavacurans alkaloids, bio-inspired oxidative cyclizations of (+)-geissochizine and analogues mediated
by KHMDS/I2 were studied. Applied to geissoschizine, the N4-C16 bond formation led to excelsinidines core. Quaternization of the
aliphatic nitrogen was necessary to access the mavacurans core (N1-C16 bond). Alternatively, 17-nor-excelsinidine was synthetized
via an intramolecular nucleophilic substitution of an -chlorolactame.
@MaximeJarret; @turpinvictor1; @erwan_poupon; @LaurentEvanno; @gvincentUPSUD
@BioCIS; #ICMMO
12
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10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
Maxime Jarret completed his Master degree
in 2016 from Université de Nantes (France)
with a one-year internship at GSK (Les Ulis,
France) with Dr. Nicolas George. Then, he
continued his education under the
supervision of Dr. Guillaume Vincent at
Université Paris-Saclay (France), focusing
on the total synthesis of monoterpene
indole alkaloids, and received his PhD in
2019. In 2020, he joined the group of Prof.
Alois Fürstner, at the Max-Planck-Institut für
Kohlenforschung (Mülheim/Ruhr, Germany), as a postdoctoral associate.
His research interest include polyketide total synthesis.
Aurélien Tap is since 2017 a Research
Chemist at Oncodesign (Villebon-sur-Yvette,
France) designing kinase inhibitors. After a
Bachelor degree in 2008 and a M. Sc
degree in 2010 from Université Pierre et
Marie Curie Paris-6 (France with internships
at Sanofi, Rueil-Malmaison, France and with
Dr. Sylvain Rolland, Institut Parisien de
Chimie Moléculaire, France), he was
awarded his PhD under the direction of Prof.
Janick Ardisson at Université Paris-
Descartes in 2013 on studies in total synthesis. He was then a postdoctoral
researcher at the Max-Planck Institut für Kholenforschung (Germany) with
Prof. Benjamin List from 2014 to 2016 in organocatalysis and at Institut de
Chimie Moléculaire et des Matériaux d’Orsay of Université Paris-Saclay
(France) with Dr. Guillaume Vincent in 2016-2017 in total synthesis.
Victor Turpin received his M.Sc. degree in
Pharmaceutical Chemistry from Université
Paris-Sud (France) in 2017 with a six-month
internship at Sanofi with Dr. Baptiste Ronan
and graduated in Pharmacy (Pharm.D
degree) from Université Paris-Saclay
(France) in 2019. He is now PhD student
under the supervision of Prof. Erwan
Poupon and Dr. Laurent Evanno at the
Laboratoire BioCIS (Biomolécules:
Conception, Isolement, Synthèse) of
Université Paris-Saclay.
13
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10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
Natacha Denizot obtained her bachelor
degree of chemistry from Université
d’Avignon et Pays du Vaucluse (France) in
2009. She then was awarded her M.Sc.
degree from Université Joseph Fourier,
Grenoble (France) in 2012 with an internship
at Givaudan (Switzerland) with Dr. Philip
Kraft. In November 2015, she completed her
PhD from Université Paris-Saclay in the
group of Prof. Cyrille Kouklovsky and Dr.
Guillaume Vincent on the synthesis of
natural products. After a Master in project management from CESI (Lyon,
France) in 2018, she is currently consulting project manager at Mi-GSO
(Lyon, France).
Cyrille Kouklovsky was born in Paris,
France, and educated at Université Paris-
Sud, Orsay (France). He defended his PhD
in 1989 under the supervision of Prof. Y.
Langlois (CNRS, Gif-Sur-Yvette, France),
working on the cationic asymmetric Diels-
Alder reaction. Then he moved to a
postdoctoral position in Prof. Steven V.
Ley's research group (University of
Cambridge, UK), working on the total
synthesis of rapamycin. In 1995, he was
appointed as a CNRS research fellow at Université Paris-Sud working on
asymmetric dipolar cycloaddition reactions and their synthetic applications.
He was promoted as Professor of Chemistry in 2003 and he is currently
the MSMT team leader at the Institut de Chimie Moléculaire et des
Matériaux d’Orsay of Université Paris-Saclay. His research interests are in
the field of synthetic methodology, asymmetric synthesis and peptide
synthesis. He was president of the Organic Chemistry Division of the
French Chemical Society from 2015 to 2019.
Erwan Poupon is a full professor of Natural
Product Chemistry at Université Paris-
Saclay (France). He obtained his PharmD
from the University of Rennes in 1996 and
his PhD from Paris-Descartes University in
2000 under the guidance of Pr Henri-
Philippe Husson and Dr. Nicole Kunesh.
After a post-doctoral period in the group of
Pr Emmanuel Theodorakis (University of
California in San Diego, USA), he joined the
faculty at Paris-Sud University. He is
particularly interested in biomimetic strategies in total synthesis and in
understanding the intimate mechanisms involved in the biosynthetic
pathways of specialized metabolites. Other interests include the discovery
of new natural products from plants, marine invertebrates and micro-
organisms as well as natural product-based drug design.
14
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10.1002/ejoc.202000962
European Journal of Organic Chemistry
FULL PAPER
Laurent Evanno received his PhD degree in
2007 from Université Pierre et Marie Curie,
Paris (France), working on total synthesis
under the supervision of Dr Bastien Nay at
the ‘Muséum National d'Histoire Naturelle’.
He then undertook postdoctoral research
with Professor Petri Pihko at Helsinki
University of Technology – TKK (Finland) in
2008 and with Professor Janine Cossy at
ESPCI – Paris Tech (France) in 2009. Since
2010, he has been an assistant professor at
Paris-Saclay University (France) and his research interests encompass
biomimetic synthesis.
Guillaume Vincent graduated from CPE
Lyon (2002) with a one-year internship at
Dupont Pharma (Wilmington, DE, USA) with
Dr. Patrick Y. S. Lam. He obtained his
Master (2002) and PhD (2005) degrees from
Université Lyon-1 (France) with Prof. Marco
A. Ciufolini. After two postdoctoral
experiences with Prof. Robert M. Williams at
Colorado State University (USA) and with
Prof. Louis Fensterbank and Prof. Max
Malacria at Université Pierre et Marie Curie Paris-6 (France), he was
recruited as a CNRS researcher in 2007 (“Chargé de Recherche” and then
“Directeur de Recherche” since 2019) at the Institut de Chimie Moléculaire
et des Matériaux d’Orsay (ICMMO) of Université Paris-Sud which is now
Université Paris-Saclay (France). He obtained in 2018, the Jean-Marie
Lehn Prize (Advanced Researcher Prize) from the Organic Chemistry
Division of the French Chemical Society.
15
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