Bioinspired Divergent Oxidative Cyclization from Strictosidine and Vincoside Derivatives: Second-Generation Total Synthesis of (?)-Cymoside and Access to an Original Hexacyclic-Fused Furo[3,2-b]indoline

Article abstract of DOI:10.1002/chem.202003758

The second-generation synthesis of (?)-cymoside as well as the formation of a new hexacyclic-fused furo[3,2-b]indoline framework is reported. After a Pictet–Spengler condensation between secologanin tetraacetate and tryptamine, the course of the cyclization of the 7-hydroxyindolenine intermediate, generated by oxidation with an oxaziridine, depended on the stereochemistry of the 3-position. The 3-(S)-strictosidine stereochemistry delivered efficiently the scaffold of cymoside via intramolecular coupling with the C16–C17 enol ether, while the 3-(R)-vincoside stereochemistry directed towards the reaction with the C18–C19 terminal alkene and the formation of the unexpected caged compound.

Full text of DOI:10.1002/chem.202003758

Accepted Article
Accepted Article
Title: Bioinspired Divergent Oxidative Cyclization from Strictosidine
and Vincoside Derivatives: Second Generation Total Synthesis of
Cymoside and Access to an Original Hexacyclic-Fused Furo[3,2-
b]indoline
Authors: Yingchao Dou, Cyrille Kouklovsky, and Guillaume Vincent
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To be cited as: Chem. Eur. J. 10.1002/chem.202003758
Link to VoR: https://doi.org/10.1002/chem.202003758
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10.1002/chem.202003758
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Bioinspired Divergent Oxidative Cyclization from Strictosidine
and Vincoside Derivatives: Second Generation Total Synthesis of
(–)-Cymoside and Access to an Original Hexacyclic-Fused
Furo[3,2-b]indoline
Yingchao Dou,[a] Cyrille Kouklovsky[a] and Guillaume Vincent*[a]
Dedication ((optional))
[a]
Mr. Yingchao Dou, Prof. Dr. Cyrille Kouklovsky and Dr. Guillaume Vincent
Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO)
Université Paris-Saclay, CNRS
91405 Orsay, France
E-mail: guillaume.vincent@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 our second generation synthesis of (–)-cymoside
as well as the formation of a new hexacyclic-fused furo[3,2-b]indoline
framework. After
a
Pictet-Spengler condensation between
secologanin tetraacetate and tryptamine, the course of the cyclization
of the 7-hydroxyindolenine intermediate generated by oxidation with
an oxaziridine, depends on the stereochemistry of the 3-position. The
3-(S)-strictosidine stereochemistry delivered efficiently the scaffold of
cymoside via intramolecular coupling with the C16-C17 enol ether,
while the 3-(R)-vincoside stereochemistry directed towards the
reaction with the C18-C19 terminal alkene and the formation of the
unexpected caged compound.
Introduction
Scheme 1. Biosynthesis of cymoside.
Cymoside (–)-1 is one of the 3000 known monoterpene indole
alkaloids[1] and it possess a highly unusual and intricate structure
with a fused-hexacyclic skeleton encompassing a furo[3,2-
b]indoline moiety.
This natural product was isolated from the tropical tree Chimarrhis
cymosa (Rubiaceae) found in Martinique in the French Antilles
and its structure was elucidated by Kritsanida, Grougnet and co-
workers.[2] Cymoside biosynthetically arises from a rare direct
oxidative cyclization of strictosidine (2), the common biosynthetic
precursor of all monoterpene indole alkaloids, which itself has for
origin an enzymatic Pictet-Spengler reaction between tryptamine
(3) and secologanin (4) (Scheme 1).
In line with our interest in furoindoline moieties[3] and in the total
synthesis of monoterpene indole alkaloids,[3a,4] we recently
performed the total synthesis of cymoside (–)-1[5] by mimicking
the biosynthetic intramolecular oxidative coupling[6] between the
indole nucleus and the enol ether part of the terpenic
dihydropyrane to complete the furo[3,2-b]indoline core (Scheme
2).[7-9]
The N-p-nitrophenylsulfonyl ethylether aglycone of racemic
strictosidine (±)-6 was subjected to oxidation with oxaziridine 7 to
presumably form 7-hydroxyindoline A with assistance of the N-
sulfonyl group to control the diastereoselectivity.[10] Subsequent
(3+2) annulation proceeds via successive addition of the enol
ether to the imine and interception of the incipient oxocarbenium
B by the hydroxy group.
However, this first generation total synthesis suffers from some
downsides. We synthesized secologanin aglycon derivative (±)-5
in a racemic manner by reproducing the work of Tietze via a
Knoevenagel condensation and hetero Diels-Alder cycloaddition
sequence.[11] This aldehyde was engaged in a Pictet-Spengler
reaction with tryptamine to deliver strictosidine aglycon derivative
(±)-6a with a modest diastereoselectivity. The fact that the key
bioinspired cyclization was performed on the racemic aglycon
derivative (±)-6a is the major drawback since only half of this
material could lead to the enantiopure natural product. After a low
1
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yielding hydrolysis of the acetal part of (±)-8, the glycosylation with
the enantiopure (D)-glucose derivative 9 was effected on the
racemic cymoside aglycon (±)-8 leading to a mixture of two major
-glucosylated diasteroisomers: cymoside precursor 10a and the
coupling product 10b from the enantiomeric skeleton of cymoside.
Two minor diastereoisomers, resulting from an inefficient
stereocontrol at the anomeric positions, were also obtained.
Overall, cymoside (–)-1 was obtained in a 1.7% yield from the
racemic ethyl ether secologanin aglycone (±)-5.
enantioselective synthesis, could greatly improve the efficiency of
the enantioselective synthesis of cymoside (–)-1 (Scheme 3).
Pictet-Spengler reaction with tryptamine should deliver
enantiopure protected stritosidine 15a which would be submitted
to our biosinspired oxidative cyclization and therefore avoid the
low yielding hydrolysis of the acetal and glycosylation steps at a
late stage of our first generation synthesis. More importantly, half
of the cymoside aglycon would not be lost as it is the case in the
racemic approach. In addition, obtaining the C3-epimer 15b
would also be an opportunity to study its oxidative cyclization.
Scheme 3. Our first generation synthesis of cymoside (–)-1 via a racemic
synthesis of the cymoside backbone (–)-8.
In order to improve the efficiency of the synthesis of cymoside (–)-
1, it is, indeed, desirable to effect the bioinspired oxidative
cyclization on an enantiopure strictosidine derivative and if
possible already containing the -(D)-glucose moiety. When we
started to study the synthesis of cymoside, no enantioselective
syntheses of secologanin (4) or strictosidine (2) were known,
despite their pivotal role in the biosynthesis of monoterpene indole
alkaloids.
However, at the end of our endeavour, the research group of
Ishikawa filled this important gap and reported the first
enantioselective synthesis of secologanin (–)-4 (Scheme 3).[12]
The authors cleverly took advantage of an organocatalyzed trans-
selective Michael addition developed by Hong of aldehyde 12
onto 1-thioester acrylate 11.[13] Reduction of the thioester,
glycosylation of 13, hydroboration and sulfoxide elimination
delivered secologanin tetraacetate (–)-14 and then secologanin
(–)-4.
Scheme 3. Synthetic approach towards the enantioselective synthesis of the
cymoside backbone.
While we were finishing this second generation synthesis of
cymoside (–)-1, Ishikawa published the realization of a similar
approach for the total synthesis of cymoside (–)-1 (Scheme 3).[14]
He employed (R)--cyano tryptamine (–)-16 for the Pictet-
Spengler reaction with (–)-14, in order to ensure a high
diastereoselectivity and the oxidative cyclization was performed
on protonated strictosidine (–)-17 with m-CPBA after prior
Therefore, after the completion of our first generation synthesis of
cymoside (–)-1, it appeared evident to us that using enantiopure
secologanin tetraacetate (–)-14, produced by the Ishikawa
2
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protonation of the N4 amine. Reduction of the aminonitrile of (–)-
18 and deacetylation delivered cymoside (–)-1. The very recent
publication of Ishikawa urged us to report our own approach
herein.
15b into unexpected hexacyclic-fused compound (–)-19 in 42%
yield which represent a 72% yield from 15b. 2D NMR analysis of
this compound (Figure 1, see SI for details), notably showed
HMBC correlations between the C18 and C19 atoms of the former
terminal double bond with the C2 and C7 atom of the indoline ring.
We were therefore able to assign the intricate furo[3,2-b]indoline-
containing structure to (–)-19, which is the product of an oxidative
cyclization between the indole moiety and the C18-C19 terminal
alkene of 15b.
Results and Discussion
We started our study by the synthesis of secologanin tetraacetate
(–)-14 with slight modifications of the Ishikawa procedures (see
SI). We then studied the Pictet-Spengler cyclization between
tryptamine and secologanin tetraacetate (–)-14 (Scheme 4).[15]
The presence of the glucose moiety on (–)-14 had an impact on
the efficiency of the reaction in comparison with aglycon (±)-5
since a low conversion was observed with 1.5 equivalent of TFA
as in our previous conditions. The tetraacetateglycosyl of (–)-14
offers several chemical functions which could be protonated and
thus compete with activation of the imine to induce the Pictet-
Spengler reaction. The reactivity was restored by increasing the
amount of TFA to 8 equivalents with an excess of 3 and after one-
pot nosylation of the N4-secondary amine, a 76% yield was
obtained of a mixture of protected strictosidine 15a and protected
vincoside 15b, its C3-epimer in a 1:1.4 ratio in favour of the latter.
It is known that a diastereoselective Pictet-Spengler reaction
could be performed in presence of the enzyme strictosidine
synthase to obtain selectively the stereochemistry of
strictosidine.[16] However this chemoenzymatic approach is not
yet easily available to most organic chemistry labs.
Therefore, we envisioned to induce a diastereoselective Pictet-
Spengler reaction with non-racemic chiral catalysts that are
known
to
promote
enantioselective
Pictet-Spengler
cinchona-derived
reactions.[17,18] Unfortunately, neither
a
thiourea[17b,c,18] nor a squaramide,[17d,e,18] nor a binol-derived
phosphoric acid[17f,18] were able to promote the conversion of the
reaction. It is probably due to the presence of competitive
protonatable functional groups. Mimicking strictosidine synthase
with
a
simple organocatalyst able to induce
a
highly
diastereoselective Pictet-Spengler reaction between tryptamine
and secologanin remains a challenge. Ishikawa devised an
elegant and efficient alternative by using -cyanotryptamine (–)-
16 instead of tryptamine (see Scheme 3). Nevertheless, the latter
is synthesized in three steps from tryptophan and the cyano group
needs to be removed afterwards.
While the diastereoselectivity is not what we expected, this
procedure from tryptamine is very straightforward and represents
a fast access to protected strictosidine 15a to pursue the total
synthesis of cymoside (–)-1. In addition, the access to protected
vincoside 15b offered us an opportunity to study its oxidative
cyclization.
Scheme 4. Divergent oxidative cyclization of 15a and 15b: total synthesis of
cymoside (–)-1 and synthesis of (–)-20.
The 1:1.4 diastereomeric mixture of 15a/b was then subjected to
the oxidative cyclization that we developed with oxaziridine 7
(Scheme 4).[5] We were delighted to observe that the presence of
the glycosyl moiety at this stage did not affect the efficiency of the
key bioinspired oxidative cyclization and the furo[3,2-b]indoline-
containing hexacyclic fused-skeleton 10a of cymoside was
obtained in 30% yield from the mixture of diastereoisomers which
represent a 73% yield from protected strictosidine 15a. In fact,
compound 10a was an intermediate of our first generation total
synthesis of cymoside (–)-1, that we intercepted in a much more
efficient manner in this second generation approach. We were
also thrilled to observe the transformation of protected vincoside
3
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Figure 1. Key HMBC correlation of 19 and 20.
The same deprotective sequence of two steps was also applied
to (–)-19 to deliver (–)-20. Worthy of note, we did not observe any
lactamisation between the methyl ester at C16 and the N4-
secondary amine after the removal of the nosyl group in basic
conditions.
While the unique structure of (–)-20 is not presently known among
natural products, it is not unconceivable that it could be produced
by Nature via an oxidative cyclization related to the one that we
have uncovered (Scheme 5). Indeed, unlike (–)-20, most of the
monoterpene indole alkaloids possess a (S)-configuration at the
C3 position arising from strictosidine. However, there are few
examples of monoterpene indole alkaloids that display a (R)-
configuration at this position such as vincosamide or reserpine.
In analogy with the formation of the cymoside skeleton (see
Scheme 2), we can postulate that the indole moiety is oxidized
into 7-hydroxyindolenine C (Scheme 5). We assume that to
minimize steric interactions, the nosyl group blocks the face
opposite to the one bearing the monoterpene part at C3. As a
result, the oxidation is directed into the latter face which can allow
the oxidative cyclization to happen. In contrast to the formation of
the cymoside scaffold 10a from protected strictosidine 15a, the
inversion of the configuration at C3 in vincoside derivative 15b
precludes the addition of the enol part to the C2-position.
Alternatively, the terminal position of the C18-C19 alkene is
poised to add onto the C2-iminium of C leading to the formation
of the seven-membered ring of tertiary carbocation D. The latter
would then be intercepted by the hydroxyl group at C7 to complete
the synthesis of the five-membered ring of the furo[3,2-b]indoline
moiety of (–)-19.
Conclusion
We significantly improved the synthesis of cymoside (–)-1 that we
published earlier this year by starting from enantiopure
secologanin tetraacetate instead of its racemic aglycon. After the
Pictet-Spengler reaction, the key bioinspired oxidative cyclization
of strictosidine derivative 15a between the indole and the C16-
C17 enol ether proceeded well in presence of the glucose moiety.
Cymoside (–)-1 was synthesized in 4 steps and 18% yields from
secologanin tetraacetate 14 obtained according to the synthesis
of Ishikawa, while our first generation synthesis required 6 steps
and 1.7 % yields from racemic secologanin aglycon (±)-5. In a
divergent manner, the oxidation of the vincoside derivative 15b,
the 3-epimer of 15a, yielded a new fused hexacyclic furo[3,2-
b]indoline structure 20 via reaction with the terminal C18-C19
alkene instead of the C16-C17 enol ether. It was obtained in 4
steps and 25% yields from secologanin tetraacetate 14. While
unexpected, we think that this new skeleton is the more
interesting part of our report since it expands the molecular
diversity
and
complexity
accessible
from
the
Scheme 5. Mechanistic hypothesis for the synthesis of (–)-19.
strictosidine/vincoside skeleton. The mechanism of its formation
might also be relevant from a biosynthetic point of view.
All what remained, was to achieve the two deprotection steps
(Scheme 4). Attempts to effect this double deprotection in the
same pot did not succeeded, therefore it was performed
uneventfully in two steps. The nosyl group was removed from the
secondary amine with thiophenol in presence of potassium
carbonate and in a second operation the four acetyl groups were
removed from the glucose moiety with potassium carbonate in
methanol to finally deliver cymoside (–)-1 in 78% yield. All spectra
data of this synthetic cymoside (–)-1 were in strong agreement
with the ones of the natural substance as well as the synthetic
products of our first generation synthesis as well as the Ishikawa
synthesis. Slight differences of the 1H and 13C signals at positions
in proximity of the N4 secondary amine were observed (see SI).
It might be explained by the fact that traces of acid could influence
the NMR chemical shifts of protons or carbons closed to the
nitrogen lone pair. The optical rotation of the product obtained in
this second generation synthesis ([]D -29.5 c 0.475 in MeOH) is
also similar to the ones of our first generation ([]D -26.3, c 0.015
in MeOH)5 and the Ishikawa ([]D -28.9, c 0.3 in MeOH)14
syntheses. These three values significantly differ from the optical
rotation reported in the isolation paper ([]D +190, c 0.011 in
MeOH)2 which we believe is not accurate.
Acknowledgements
YD thanks the China Scholarship Council (CSC) for his PhD
fellowship. We also gratefully acknowledge the ANR (ANR-15-
CE29-0001; “Mount Indole”), the Université Paris-Saclay and the
CNRS for financial support. We would like to thank Dr. Marina
Kritsanida and Dr. Raphaël Grougnet from the Faculty of
Pharmacy of Université Paris-Descartes for fid data of all NMR of
natural cymoside and helpful discussions as well as Dr. Laurent
Evanno and Prof. Erwan Poupon from the Faculty of Pharmacy of
Université Paris-Saclay for helpful discussions.
Keywords: Total synthesis • Monoterperne indole alkaloids •
Cymoside • Oxidative cyclisation • Furoindoline
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Entry for the Table of Contents
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The oxidative cyclization of an enantiopure strictosidine derivative lead to the total synthesis of (–)-cymoside, while the corresponding
3-epimeric vincoside derivative deliver a new hexacyclic-fused furo[3,2-b]indoline framework.
@GVincentUPSUD
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