Concise asymmetric total synthesis of 9-epi-sessilifoliamide J

Article abstract of DOI:10.1021/ol202140y

A 10-step asymmetric synthesis of 9-epi-sessilifoliamide J (20), together with sessilifoliamide J (6), has been accomplished from the key chiral building block 11 via a threo-selective vinylogous Mannich reaction and a Ley oxidation-SmI2-mediated coupling

Full text of DOI:10.1021/ol202140y

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5270–5273
Concise Asymmetric Total Synthesis
of 9-epi-Sessilifoliamide J
Shi-Chuan Tuo,† Jian-Liang Ye,† Ai-E Wang,† Su-Yu Huang,† and
Pei-Qiang Huang*,†,‡
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian
Province, College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, P. R. China, and State Key Laboratory of Bioorganic and
Natural Products Chemistry, 354 Fenglin Lu, Shanghai 200032, P. R. China
pqhuang@xmu.edu.cn
Received August 6, 2011
ABSTRACT
A 10-step asymmetric synthesis of 9-epi-sessilifoliamide J (20), together with sessilifoliamide J (6), has been accomplished from the key chiral
building block 11 via a threo-selective vinylogous Mannich reaction and a Ley oxidation-SmI2-mediated coupling lactonization. The absolute
configuration of the natural sessilifoliamide J was established.
The extracts of roots and leaves of Stemonaceae plants
have been used in traditional Chinese medicine as cough
suppressants and domestic insecticides.1 More than 100
alkaloids have been isolated from these plants.2 Due to the
challengingstructures, these alkaloids haveattracted much
attention from many synthetic chemists, so that numerous
ingenious total syntheses of stemona alkaloids,3 including
(ꢀ)-stemoamide (1),4 (þ)-croomine (2),5 (ꢀ)-stemonine
(3),6 (ꢀ)-tuberostemonine (4),7 (ꢀ)-stemospironine (5),8
† Xiamen University.
‡ State Key Laboratory of Bioorganic and Natural Products Chemistry.
(1) (a) Sakata, K.; Aoki, K.; Chang, C.-F.; Sakurai, A.; Tamura, S.;
Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457–463. (b) Ye, Y.; Qin,
G.-W.; Xu, R.-S. Phytochemistry 1994, 37, 1205–1208.
(2) For a comprehensive review, see: Greger, H. Planta Med. 2006,
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D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989, 111, 1923–1925.
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1999, 121, 6990–6997.
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Mori, M. J. Org. Chem. 1996, 61, 8356–8357. (b) Jacobi, P. A.; Lee, K.
J. Am. Chem. Soc. 2000, 122, 4295–4303. (c) Gurjar, M. K.; Reddy, D. S.
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Synlett 2004, 1211–1214. (e) Olivo, H. F.; Tovar-Miranda, R.; Barragan,
E. J. Org. Chem. 2006, 71, 3287–3290. (f) Torssell, S.; Wanngren, E.;
Somfai, P. J. Org. Chem. 2007, 72, 4246–4249. For a racemic synthesis,
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ꢀ
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r
10.1021/ol202140y
Published on Web 08/31/2011
2011 American Chemical Society

(20) and the establishment of the absolute configuration of
the natural product by characterization of minor diaster-
eomer (ꢀ)-sessilifoliamide J (6).
Our retrosynthetic analysis for (3S,9S,9aS,11R,14S,16S)-
6 is displayed in Scheme 1. The spirolactone moiety was
envisioned to be built via the SmI2-mediated coupling of
methacrylate with ketone 7,14,15 while the other lactone ring
by a vinylogous Mannich reaction (VMR)5b,c,16,17 on bi-
cyclic N,O-acetal 8. The indolizidinone core 8 was avaibable
from the chiral building block 1113eꢀg via the regio- and
diastereoselective reductive alkylation.13
Scheme 1. Retrosynthetic Analysis of Sessilifoliamide J 6
Figure 1. The structure of some stemona alkaloids.
and their diastereomers9 have been reported.10 Sessilifo-
liamide J (6) (Figure 1) is a new stemona alkaloid isolated
in 2008 from the roots of Stemona sessilifolia (Miq.) Miq.
(Stemonaceae).11 Its structure and relative stereochemistry
were established by single crystal X-ray crystallography
analysis; however, the absolute configuration remained
unknown. Different from all other known stemona alka-
loids, (ꢀ)-sessilifoliamide J (6) contains a unique fused
piperidin-2-one core. To date, no synthetic study toward
sessilifoliamide J (6) has been reported. In continuation
with our efforts in developing 3-hydroxyglutarimide-based
synthetic methodology,12,13 we were engaged in the devel-
opment of a novel strategy for the total synthesis of ses-
silifoliamide J. Preliminary results of this study are reported
herein, which include the synthesis of 9-epi-sessilifoliamide J
The synthesis started from a stepwise reductive alkyla-
tion13 of the known glutarimide derivative 11,13eꢀg readily
available from D-glutamic acid in four steps with a 56%
overall yield.13e Treatment of a CH2Cl2 solution of 11
with a freshly prepared Grignard reagent 12 in THF
at 0 °C, followed by BF3 OEt2-mediated reductive dehy-
droxylation of the resultant regio- and diastereomeric
3
mixture of hemiaminal with Et3SiH (ꢀ78 °C to rt),
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L.-X.; Huang, P.-Q. Chirality 2005, 17, 595–599. (b) Wei, B.-G.; Chen,
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Y.; Li, Z.-Y.; Xu, W.-X.; Huang, P.-Q. Tetrahedron 2009, 65, 9765–
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afforded the concomitantly O-desilylated 2-piperidinone
13 in 56% yield over two steps, along with the C-6 adduct
as a diastereomeric mixture in 12% yield (Scheme 2). The
diastereomeric ratio of lactam 13 was determined to be
96:4by HPLC analysis. Althoughwewereunabletoisolate
the minor cis-diastereomer for a comparison,18 the stereo-
chemistry of the major diastereomer was assigned as trans
based on the observed small vicinal coupling constant
between H-5 and H-6 (J5,6 = 3.2 Hz), and by analogy
with the similar reductive alkylation reactions of glutar-
imide derivative 11.13eꢀg This assignment was confirmed
by the X-ray analysis of compound 19 (vide infra). Treat-
Scheme 3. Vinylogous Mannich Reaction of N,O-Acetal 8
ment of 13 with 5 mol % of RhCl3 xH2O in refluxing
3
n-propanol for 3 h,19 followed by refluxing in a mixture of
AcOHꢀH2O (v/v = 1/10) for 3 h, gave the deprotected
lactam 10 in 81% yield.
We next focused on the vinylogous Mannich reaction
between 2-methylsilyloxyfuran 9and N,O-acetal 8(Scheme 3).
Among the Lewis acids tested (TMSOTf, BF3 OEt2,
Scheme 2. Synthesis of Indolizidinone 8
3
InCl3, Bi(OTf)3, ZnCl2, Et2AlCl), TMSOTf gave optimal
results. Thus, by treating 8 (1.0 equiv) with 9 (1.5 equiv)
and TMSOTf (1.0 equiv) in CH2Cl2 at ꢀ78 °C, and
allowing the reaction to warm to room temperature and
stir for 1 h, two fractions 15a/15b and 16a/16b were
isolated. 1H NMR analysis showed that the ratio of
15a/15b was 78:22 and that of 16a/16b was 93:7. The
stereochemistry of the major diastereomer 15a was deter-
minedtobe threoata latterstage (videinfra), whereasthose
ofthe minor isomer 15b, 16a, and 16b were not determined.
The observed threo-diastereoselection is in agreement with
most vinylogous Mannich reactions involving cyclic imi-
nium ion intermediates.16,17 A plausible DielsꢀAlder tran-
sition state17e is displayed in Figure 2. Noteworthy is that
the efficiency of the vinylogous Mannich reaction on our
ring system using N,O-acetal 8 has been improved com-
pared with the original one utilizing an R-amino acid as a
precursor of the iminium ion intermediate.5b,c
Oxidation of 10 with IBX in DMSO20 produced indo-
lizidinone 14 in 80% yield, which was acetylated [DMAP
(cat.), Ac2O, NEt3, CH2Cl2] to give the N,O-acetal 8 as a
68:32 diastereomeric mixture (1H NMR) in a combined
yield of 85%. Because the subsequent vinylogous Mannich
reaction would involve an N-acyliminium intermediate,21
which could be generated from either diastereomer of 8,
this diastereomeric mixture was used in the next step with-
out further separation.
Figure 2. Proposed transition state for the threo-selective VMR
of N,O-acetal 8 with 2-methylsilyloxyfuran 9.
(18) For the 6-substituted piperidin-2-one derivatives of type 13, the
5,6-trans-isomer generally exhibits a smaller vicinal coupling constant
between H-5 and H-6 (e.g., J5,6 = 1.5 Hz;12d 2.3 Hz;12f 2.4 Hz13e) than
the cis-isomer does (e.g., J5,6 = 4.5 Hz;12e 4.5 Hz12f).
(19) Zacuto, M. J.; Xu, F. J. Org. Chem. 2007, 72, 6298–6300.
(20) (a) Corey, E. J.; Palani, A. Tetrahedron Lett. 1995, 36, 7945–
7948. (b) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999,
64, 4537–4538.
Reduction of the diastereomeric mixture 15 with NaBH4/
NiCl217b,c,22 in methanol gave compound 17 in 60% yield,
(21) For recent reviews on the chemistry of N-acyliminium ions, see:
(a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3871–
3856. (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431–1628. (c) Royer, J. Chem.
Rev. 2004, 104, 2311–2352. (d) Yazici, A.; Pyne, S. G. Synthesis 2009,
339–368. (e) Yazici, A.; Pyne, S. G. Synthesis 2009, 513–541.
(22) Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971, 19,
817–820.
(23) Although the direct conversion of 15 to 18 by hydrogenolysis
(Pd/C, H2, MeOH) afforded a higher yield, compound 18 could not be
separated from other stereoisomers.
5272
Org. Lett., Vol. 13, No. 19, 2011

20
rotation data {synthetic 6: [R]D ꢀ71 (c 0.15, CHCl3);
along with three other diastereomers (dr = 9:30:61) in
20% yield.23 On the basis of these results, the diastereoselec-
tivity in the hydrogenation of threo-15a was estimated to be
at least 10:1, which is in accordance with literature precedent
for similar systems.5b,c,9c,10e,17b,c O-Debenzylation of the
major diastereomer 17 under catalytic hydrogenolytic con-
ditions [10% Pd/C, H2, MeOH] produced alcohol 18 in 90%
yield. To determine the stereochemistry of 18, its tosylate
derivative 19 was prepared. Single crystal X-ray analysis
revealed that 19 possessed the structure shown in Scheme 4.
Thus the relative stereochemistries of 17 and 18 were con-
firmed, and the major diastereomer (15a) obtained from the
vinylogous Mannich reaction was established as threo.
sessilifoliamide J (6):11 [R]D ꢀ73 (c 0.13, CHCl3)} and
26
spectral data for the synthetic product (6) are in good
agreement with those reported for the natural product.11
Thus the absolute configuration of the natural (ꢀ)-sessili-
foliamide J (6) is 3S,9S,9aS,11R,14S,16S.
Scheme 5. Final Synthesis of 9-epi and (ꢀ)-Sessilifoliamide J
Scheme 4. Synthesis of Alcohol 18
To the best of our knowledge, among various synthetic
approaches for the synthesis of stemona alkaloids, this is
the first example utilizing the SmI2-mediated coupling to
install the spirolactone moiety.
In summary, we have demonstrated that the chiral build-
ing block 11 can serve as a powerful platform for the rapid
assembly of the tetracyclic skeletal framework of sessilifo-
liamide J. Using this novel strategy, the first asymmetric
synthesis of 9-epi-sessilifoliamide J (20) has been achieved in
only 10 steps with a 4.3% overall yield. Meanwhile sessili-
foliamide J (6) was obtained as a minor diastereomer, which
allowed the establishment of the absolute configuration of
the natural sessilifoliamide J as 3S,9S,9aS,11R,14S,16S.
Considering the complexity of the molecule with six chiral
centers, our asymmetric approach is remarkably concise.
Work is currently in progress in our laboratories for improv-
ing the selectivity in the asymmetric total synthesis of sessi-
lifoliamide J, and the results will be reported in due course.
Now, we were in a position to install the spiro lactone
moiety. Swern oxidation24 followed by SmI2-mediated
coupling gave eight diastereomers, which implied that
partial epimerization at C-9a might have occurred during
Swern oxidation. However, when the Ley oxidation25 was
used, only four isomers were observed, in a ratio of
53:21:20:6 (Scheme 5). Extensive NMR experimentation
(see Supporting Information) indicated that the major
component had the structure assigned as 9-epi-sessilifoli-
amide J (20), the minor component 6 was the natural
product, and the other diastereomers had the structures
assigned as 21 and 22, respectively. The stereochemical
outcome of the SmI2-mediated lactonization reaction is
attributable to the approach of methyl acrylate from the
more accessible convex face of the ketyl radical intermedi-
ate, initially formed from the ketone and SmI2. Optical
Acknowledgment. The authors are grateful to the Na-
tional Basic Research Program (973 Program) of China
(Grant No. 2010CB833200), the NSF of China (20832005,
21072160), and the NSF of Fujian Province of China (No.
2011J01056) for financial support.
Supporting Information Available. Full experimental
1
procedures; H and 13C NMR spectra of all new com-
pounds; NOESY spectra of compounds 20ꢀ22; X-ray
crystallographic data (CIF) of compound 19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Mancuso, A. J.; Swern, D. Synthesis 1992, 165–185.
(25) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625–1627. (b) Ley, S. V.; Norman,
J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639–666.
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