Enantioselective total syntheses of leuconolam-leuconoxine-mersicarpine group monoterpene indole alkaloids

Article abstract of DOI:10.1021/ja4115192

A unified strategy allowing enantioselective total syntheses of (-)-mersicarpine, (-)-scholarisine G, (+)-melodinine E, (-)-leuconoxine, and (-)-leuconolam from a common cyclohexenone derivative was reported. The Suzuki-Miyaura reaction was used to couple

Full text of DOI:10.1021/ja4115192

Communication
pubs.acs.org/JACS
Enantioselective Total Syntheses of Leuconolam−Leuconoxine−
Mersicarpine Group Monoterpene Indole Alkaloids
Zhengren Xu, Qian Wang, and Jieping Zhu*
Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fed
́ ́
erale de
Lausanne, EPFL-SB-ISIC-LSPN, BCH 5304, CH-1015 Lausanne, Switzerland
S
* Supporting Information
reported from the groups of Banwell8a and Hoye,8b
respectively.
In the context of our continuous interest in the construction
of indole rings at the late stage of total synthesis,9 we devised a
unified strategy to reach different skeletons of aforementioned
alkaloids from the same intermediate. As shown in Scheme 1,
ABSTRACT: A unified strategy allowing enantioselective
total syntheses of (−)-mersicarpine, (−)-scholarisine G,
(+)-melodinine E, (−)-leuconoxine, and (−)-leuconolam
from a common cyclohexenone derivative was reported.
The Suzuki−Miyaura reaction was used to couple two
simple fragments incorporating the key elements for total
synthesis, and unprecedented oxidation/reduction/cycliza-
tion processes were developed that converted the
substituted cyclohexenone to either a mersicarpine or
leuconoxine skeleton. In a reverse biomimetic synthesis
fashion, (+)-melodinine E was converted to (−)-leucono-
lam under acidic conditions.
Scheme 1. Unified Strategy for the Total Syntheses of
Leuconolam−Leuconoxine−Mersicarpine Group
Monoterpene Indole Alkaloids
he class of monoterpene indole alkaloids, comprising
Tcurrently over 2000 members with broad skeleton
diversity and important bioactivities, has attracted the attention
of synthetic chemists for over a century.1 Specifically, the
leuconolam−leuconoxine−mersicarpine triad is a subfamily of
Aspidosperma alkaloids. Although sharing the same biogenetic
origin from vincadifformine, these polycyclic alkaloids have
completely different ring connectivities.1a (−)-Mersicarpine
(1), having a fused 6/5/6/7 ring system centered around a
hemiaminal carbon, was isolated from the Kopsia genus in 2004
by Kam.2 It is characterized by an unprecedented tetrahydro-
2H-azepine ring system, together with a contiguously arranged
imine, hemiaminal, and a quaternary carbon motif. Three total
syntheses were achieved in the groups of Kerr,3a Fukuyama,3b
and Tokuyama,3c,d and two formal syntheses were reported
from the groups of Zard4a and Han.4b (−)-Scholarisine G (also
named as leuconodine B) (2),5a,b recently isolated from the
bark of Alstonia scholaris by Luo, has a pentacyclic structure
with three contiguous quaternary stereogenic centers and a
labile aminal function. Related natural products included
(+)-melodinine E (3)5c and (−)-leuconoxine (4), the latter
being isolated by Abe and Yamauchi in 1994 from Leuconotis
eugenifolius.5d It is interesting to note that similar structures
were obtained before the isolation of this class of natural
products, either by oxidative rearrangement of vincadifformine
(e.g., oxymetavincadifformine)6a,b or by acid treatment of
leuconolam (e.g., 6-chlorodiazaspiroleuconolam).6c-6d How-
ever, no total synthesis of these natural products has been
reported until now. Isolated by Goh from Leuconotis plants L.
griffithii, (−)-leuconolam (5)7 is a tetracyclic alkaloid
containing an unusual nine-membered lactam and a 1,5-
dihydro-2H-pyrrol-2-one unit. Two total syntheses were
both leuconoxine and mersicarpine skeletons were thought to
be elaborated from the same functionalized amino diketone 6
by controlling the chemoselectivity of the cyclization mode.
Bis-imine formation by selective condensation of N1 to C21
and N4 to C7 would lead to the mersicarpine skeleton, while
addition of both N1 and N4 onto C21 would afford the
spiroaminal motif found in the leuconoxine skeleton.10 Amino
diketone 6, unstable due to its multiple reactivity-matched
functional groups, could be generated in situ from substituted
cyclohexenone 7, which could in turn be prepared by the
Received: November 12, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4115192 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Suzuki−Miyaura coupling reaction between enantiomerically
enriched vinyl iodide 8 and 2-nitrophenyl boronic acid (9). By
utilizing the acid lability of the aminal function, we planned to
prepare leuconolam (5) by acid-promoted fragmentation of
melodinine E (3), a reverse process of the biosynthesis
pathway.11
Our total synthesis commenced with palladium-catalyzed
enantioselective decarboxylative allylation of β-ketoester 10
(Scheme 2). Using conditions developed by Stoltz and co-
of Ac2O and Et3N, afforded the diketone ester 15 in 92%
overall yield.16 After having surveyed different reducing agents,
we found that hydrogenation of diketone 15 in the presence of
Pd/C (3 mol % based on Pd) directly provided (−)-mersi-
carpine (1), albeit in only 23% yield. The major product was
the unstable hexahydroazepino[3,2-b]indole 16 (50% yield).
Being aware of the easy oxidation of the 3-aminoindoles,3b−d,17
a one-pot protocol allowing the direct conversion of 15 to
(−)-mersicarpine (1) was developed. Hydrogenation of
diketone ester 15 in the presence of Pd/C (10 mol % based
on Pd) gave 16, which underwent lactamization to tetracycle 17
upon addition of potassium hydroxide. Purging the reaction
mixture with argon followed by oxygen afforded presumably
peroxide 18 which, upon addition of dimethyl sulfide, was
reduced to (−)-mersicarpine (1) in 75% overall yield. We stress
that workup was not needed in the conversion of 15 to
(−)-mersicarpine (1) and the entire transformation was
realized in EtOH by sequential addition of reagents (KOH,
oxygen, and then Me2S).
a
Scheme 2. Synthesis of Substituted Cyclohexenone 7
The high synthetic efficiency observed in the conversion of
15 to (−)-mersicarpine (1) under such simple reaction
conditions indicated that compound 15, after release of two
latent amino groups, was instructed to undergo the highly
chemo- and regioselective cyclization. It is reasonable to assume
that the C21 carbonyl is more reactive than the C7 carbonyl,
the latter being a vinylogous amide.18 Intramolecular
nucleophilic attack of aniline onto C21 would lead to 3H-
indol-3-one 19, which could evolve in two directions.
Condensation of primary amine to the C7 carbonyl group
would produce bisimine 20 corresponding to the mersicarpine
skeleton (path a, Scheme 4), while intramolecular nucleophilic
a
Reagents and conditions: (a) Pd2(dba)3, (S)-t-BuPhox, THF, 25 °C,
90% yield, 92% ee; (b) disiamyl borane, THF, 0 °C to rt, then NaI,
NaOAc, Chloramine-T, MeOH, H2O, 80%; (c) NaN3, DMF, rt,
overnight, 92%; (d) IBX, DMSO, 80 °C, 12 h, 70%; (e) I2, DMAP,
CCl4/Py (1:1), 95%; (f) 2-NO2C6H4B(OH)2 (9), Pd2(dba)3,
JohnPhos, Ba(OH)2·8H2O, THF, H2O, 75%.
workers,12 10 was converted to the known (S)-2-allyl-2-ethyl
cyclohexanone (11) in 90% yield with 92% ee. A hydro-
boration−iodination sequence13 converted 11 to alkyl iodide
12 that was subsequently transformed to alkyl azide 13 under
standard conditions. Enone 14 could be obtained in 70% yield
by treatment of 13 with an excess of IBX (6.0 equiv) in
DMSO.3b,14 Iodination of 14 afforded cleanly the vinyl iodide 8
in 95% yield, which underwent the Suzuki−Miyaura coupling
with 2-nitrophenyl boronic acid (9) to give the functionalized
cyclohexenone 7 in 75% yield.15
Scheme 4. Tuning the Cyclization Mode of Diamino
Diketone Ester 6
With key intermediate 7 in hand, the stage was set for the
construction of natural products by a planned skeleton
rearrangement process. The total synthesis of (−)-mersicarpine
is shown in Scheme 3. Ozonolysis of the enone 7 in CH2Cl2/
MeOH buffered with NaHCO3 at −78 °C, followed by addition
Scheme 3. Total Synthesis of (−)-Mersicarpine (1)
addition of the primary amine (N4) to the imine would furnish
spiroindolin-3-one 21 (path b, Scheme 4). Due to the
reversibility of both steps, the reaction was presumably under
thermodynamic control leading to a more stable compound 20
(path a), which was in situ reduced to indole 16.
For the total synthesis of the leuconoxine skeleton from the
same diamino diketone 6, we need to orient the nucleophilic
addition of N4 to the iminyl carbon C21 instead of the
B
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Journal of the American Chemical Society
Communication
carbonyl carbon C7. Noting the higher nuclophilicity of the
aliphatic primary amine (N4), we assumed that a chemo-
selective N4-acetylation under the hydrogenation conditions
should be possible. In addition, it was envisioned that formation
of a highly reactive, cyclic N-acyl iminium ion 23 could then
undergo intramolecular attack by the acetamide to give aminal
24, a compound presumed to be more thermodynamically
stable than 21.
conditions found consisted of performing the reaction in
THF at −50 °C in the presence of an excess amount of t-BuOK
followed by quenching the reaction mixture with acetic acid at
−78 °C. Under these conditions, (−)-scholarisine G (2) was
isolated in 73% yield. It is worth noting that using an excess
amount of t-BuOK (8.0 equiv) was crucial, as the desired
product appeared only after addition of around 6 equiv of t-
BuOK. Quenching the reaction with acetic acid at low
temperature is also important, as significant degradation was
observed when the reaction was quenched with H2O, MeOH,
or saturated aqueous NH4Cl. There are small discrepancies in
Putting principle into practice, the total synthesis of
(−)-scholarisine G (2) is accomplished as detailed in Scheme
5. Hydrogenation of diketone 15 in the presence of Pd/C and
1
the H NMR spectrum between our synthetic sample and
natural (−)-scholarisine G (2),5a,b due probably to the presence
of varying amounts of water. However, its structure was
unequivocally confirmed by single crystal X-ray analysis of our
synthetic sample. As a result, our synthesis also confirmed the
absolute configuration of (−)-scholarisine G (2), previously
assigned based on the biosynthetic hypothesis.
Scheme 5. Total Synthesis of (−)-Scholarisine G (2)
Conversion of (−)-scholarisine G (2) to other members of
the leuconoxine group was straightforward (Scheme 6). O-
Scheme 6. Further Structure Diversification: From
(−)-Scholarisine G (2) to (+)-Melodinine E (3),
(−)-Leuconoxine (4), and (−)-Leuconolam (5)
acetic anhydride (5.0 equiv) afforded indolin-3-one 25. Under
these conditions, the N4 was selectively acetylated and its
condensation with C7 carbonyl was effectively inhibited.
Without isolation, compound 25 was directly oxidized to the
unstable indol-3-one 22 upon purging the reaction mixture with
argon followed by oxygen. Addition of potassium hydroxide
into the above reaction mixture afforded 2-ethoxyindoline-3-
one 26 as a mixture of two diastereomers (dr = 2:1). The lack
of diastereoselectivity in the hemiaminal formation is of no
consequence since it will be converted to the N-acyliminium
ion in the next step. To our delight, treatment of the crude
mixture of 26 with TFA in CH2Cl2 afforded the desired
tetracycle 24 as the only diastereomer whose structure was fully
determined by X-ray analysis. The intramolecular nucleophilic
addition of amide NH to the in situ generated N-acyliminium
ion took place therefore from the side opposite to the
neighboring ethyl group. It is interesting to note that both
piperidine rings in 24 adopted the boat conformation in its
solid state. An intramolecular aldolization of 24 will complete
the synthesis of (−)-scholarisine G (2). This reaction was
found to be quite sensitive to the choice of base, solvent, and
quenching process. For example, using potassium ethoxide in
ethanol resulted in the ring opening of the aminal to afford 2-
ethoxyindoline-3-one 26. After many trials, the optimum
Mesylation of the tertiary hydroxy group in (−)-scholarisine G
(2) followed by DBU-promoted elimination afforded (+)-mel-
odinine E (3) in 75% yield. Reduction of the double bond in
(+)-melodinine E (3) by hydrogenation is highly diastereose-
lective furnishing (−)-leuconoxine (4) in 85% yield. The
spectroscopic data of synthetic (+)-melodinine E (3)5c and
(−)-leuconoxine (4)5d,19 were identical to those reported in the
literature. Furthermore, the structure of leuconoxine was
confirmed by X-ray analysis.
(−)-Leuconolam (5) was proposed to be a biogenetic
precursor of leuconoxine type alkaloids,2 and the chemical
conversion of 5 to melodinine derivatives in the presence of
conc HCl has been reported.6c,d Reasoning that this conversion
might be an equilibrium process going through an N-
acyliminium ion intermediate 27, we thought that it should
be possible to drive the equilibrium toward the formation of
leuconolam (5) by intermolecular addition of water to 27.
C
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Journal of the American Chemical Society
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nitrophenyl boronic acid (9) afforded a functionalized
cyclohexenone derivative 7 that was subsequently diversified
into different natural products by controlled oxidation/
reduction/polycyclization sequences. Key to the success of
the structure diversification is the fine-tuning of the
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philicity of the C7 carbonyl vs C21 iminyl groups in the
putative 3H-indol-3-one intermediate. This deceptively simple
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experiment procedures, spectroscopic data, copies of the H
and 13C NMR spectra, and X-ray structural data (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jieping.zhu@epfl.ch
Notes
■
rhazinilam and was named diazaspiroleuconolam; see: Dec
Bellocq, D.; Thoison, O.; Lekieffre, N.; Chiaroni, A.; Ouazzani, J.;
Cresteil, T.; Gueritte, F.; Baudoin, O. Bioorg. Med. Chem. 2006, 14,
1558−1564.
́
or, A.;
́
The authors declare no competing financial interest.
(20) (a) Hoffmann, R. W. Synthesis 2006, 3531−3541. (b) Young, I.
S.; Baran, P. S. Nat. Chem. 2009, 1, 193−205.
ACKNOWLEDGMENTS
■
We thank EPFL (Switzerland), Swiss National Science
Foundation (SNSF) for financial support. We thank Prof.
Olivier Baudoin for providing us copies of the NMR spectra of
leuconoxine (diazaspiroleuconolam). We are grateful to Dr.
Rosario Scopelliti for performing the X-ray crystallographic
analysis.
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