Enantioselective total synthesis of (-)-walsucochin B

Article abstract of DOI:10.1021/ol500553x

The first enantioselective total synthesis of the structurally unique nortriterpenoid (-)-walsucochin B has been accomplished through the cationic polyolefin cyclization initiated by chiral epoxide. The core framework and the stereocenters in the natural

Full text of DOI:10.1021/ol500553x

Letter
pubs.acs.org/OrgLett
Enantioselective Total Synthesis of (−)-Walsucochin B
Shiyan Xu,† Jixiang Gu,† Huilin Li,† Donghui Ma,† Xingang Xie,*,† and Xuegong She*,†,‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University Lanzhou
730000, P. R. China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: The first enantioselective total synthesis of the structurally unique nortriterpenoid (−)-walsucochin B has been
accomplished through the cationic polyolefin cyclization initiated by chiral epoxide. The core framework and the stereocenters in
the natural product were all constructed in this step. A site-selective, late-stage free-radical halogenation and Seyferth−Gilbert
homologation was adopted to install the acetylene moiety to synthesize the phenylacetylene. The absolute configuration of
walsucochin B was confirmed through enantioselective total synthesis.
alsucochins A and B (Figure 1, 1 and 2) are the first
examples of C24 nortriterpenoids featuring a phenyl-
Due to the unique structure and interesting biological
properties of these molecules, we investigated these synthesis
by a strategy that uses a cationic polyolefin cyclization initiated
by chiral epoxide. This has led to the first enantioselective total
synthesis of (−)-walsucochin B (2).
W
Our retrosynthetic analysis of (−)-walsucochin B (2) is
outlined in Scheme 1. It was envisaged that the target molecule
2 could be obtained from the tetracyclic precursor 3 via
oxidation and deprotection. Aldehyde 4 would be converted to
3 through a Seyferth−Gilbert homologation reaction. Aldehyde
4 could be obtained by site-selective bromination and oxidation
of the methyl group in the tetracyclic precursor 5. Considering
the potential of cationic polyolefin cyclization in the assembly
of polycyclic ring systems,2 we envisaged that the unique 6/5/
6/6 tetracyclic skeleton with a carbonyl group in the six-
membered C ring could be constructed by a cation-initiated
polyolefin cyclization. To our knowledge, the application of
cationic polyolefin cyclization to synthesize such a 6/5/6/6
tetracyclic skeleton has been seldom reported previously.3 The
BCD rings would thus be produced in only one step in an
efficient and concise way. The key polyolefin precursor epoxide
6 could be formed from compound 7, which could be prepared
from 8 and 9 by an allylation reaction in a convergent pathway.
Our synthesis began with the stepwise preparation of
dithiane 8 and allylic bromide 9 (Scheme 2). Bromination4 of
the commercially available 2,3-dimethylanisole (10) afforded
the aryl bromide 11 in 98% yield, which was subsequently
treated with n-BuLi and reacted with ethylene oxide in THF at
−78 °C to give the desired phenylethanol 12 in 82% yield.5
Figure 1. Structures of (+)-walsucochin A (1) and (−)-walsucochin B
(2).
acetylene moiety fused onto a contracted five-membered ring.
They were isolated from the leaves and twigs of Walsura
cochinchinensis by Yue and co-workers in 2007.1 The fused
tetracyclic ABCD frameworks of the walsucochins not only
include a common A/B ring but also a C/D ring system typical
of the apotirucallane-type triterpenoids. The B/C ring is also
trans-fused, which makes the whole molecules more torsionally
inflexible and difficult to synthesize. Walsucochin B also has a
6/5/6/6 fused ring system with four continuous stereocenters
(including two quaternary carbon centers) and a chiral hydroxyl
group. The CD exciton chirality method was applied to
determine the absolute configuration of walsucochin A, but the
CD spectrum of walsucochin B did not provide convincing
evidence that allowed assignment of its absolute configuration.
Biogenetically, walsucochin A and B coexist in the same plant
and are probably produced via the same plausible biosynthetic
pathway. The absolute configuration of walsucochin B is
proposed to be the same as walsucochin A for biogenetic
reasons. The two novel C24 nortriterpenoids exhibit significant
cell protecting activity against H2O2-induced PC12 cell damage.
Received: February 20, 2014
Published: March 26, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol500553x | Org. Lett. 2014, 16, 1996−1999

Organic Letters
Letter
gave (R)-6,7-epoxynerol (20), which was then converted to the
desired allylic bromide 9 via the corresponding mesylate. This
allylic bromide 9 was also used in the next step without further
purification.
Scheme 1. Retrosynthetic Analysis of (−)-Walsucochin B (2)
Having efficiently synthesized the necessary fragments, we
turned our efforts toward the coupling of allylic bromide 9 with
the organolithium reagent derived from treatment of dithiane 8
with n-BuLi and afforded the desired polyolefin epoxide 7 in
86% yield (Scheme 3).10 Subsequent dedithianation of 7 with I2
Scheme 3. Synthesis of the Key Step Precursor 6 of the
Cationic Polyolefin Cyclization
Scheme 2. Synthesis of the Fragments 8 and 9
and CaCO3 at 0 °C gave the α,β-unsaturated ketone 21 in 82%
yield, and the epoxy group survived. Asymmetric reduction of
the ketone 21 with the R-CBS reagent afforded the alcohol 22
in 71% yield.11 1H NMR analysis indicated that 22 was an
inseparable diastereomeric mixture (R/S = 1:4). Alcohol 22 was
protected with an acetyl group to give the desired key
cyclization precursor 6 as an inseparable mixture (R/S = 1:4)
in 98% yield.12
With the stage set for our key cascade reaction, a variety of
Lewis acids were used to probe the cationic polyolefin
cyclization.13 Pleasingly, the inseparable diastereomeric mixture
of 6a and 6b could be converted to the corresponding core
tetracyclic framework 5 as a single diastereomer via cationic
polyolefin cyclization in the presence of Et2AlCl in dichloro-
methane for 10 h at −78 °C in 62% yield (Scheme 4).14 The
proposed cyclization proceeds via a favored chair conformation.
Notably, the cascade cyclization of 6a gave the tetracycle
skeleton as a single diastereomer, while the minor diastereomer
6b could not undergo the cascade cyclization to give the
corresponding product. This cascade reaction formed three C−
C bonds, the 5/6/6 tricycle, and four contiguous stereocenters
(two of which are all-carbon quaternary centers) established in
one step. The tetracyclic alcohol 5 was subsequently reacted
with 4-bromobenzoyl chloride (p-BrC6H4COCl) to give
tetracyclic ester 23 in 93% yield. The structure and the relative
configuration were confirmed by single-crystal X-ray diffraction
analysis.15
Oxidation of the primary hydroxy in 12 with Dess−Marin
periodinane (DMP) followed by a Wittig olefination with
methyl propionate ylide 13 delivered the α,β-unsaturated
methyl ester 14 with high stereoselectivity (E/Z >99:1)6 in
88% yield over two steps. The α,β-unsaturated ester 14 was
reduced with DIBAL-H, and the allylic alcohol 15 was obtained
in high yield. Oxidation of the allylic alcohol 14 with DMP
produced an unstable α,β-unsaturated aldehyde, which was
used in the next step without further purification. The aldehyde
was immediately treated with 1,3-propanedithiol in the
presence of BF3·Et2O at 0 °C, which led to dithiane 87 in
83% yield over two steps.
Since we had constructed the core skeleton, only functional
group interconversions remained to complete the synthesis of
(−)-1 (Scheme 5). Alcohol 5 was protected with TBSOTf, and
ether 24 was obtained in 96% yield.16 An initial attempt to
directly transform 24 to aldehyde 4 by site-selective oxidation17
of the requisite methyl group on the aromatic ring (CuSO4,
Protection of geraniol (16) with p-nitrobenzoyl chloride (p-
NO2BzCl) gave the ester 17, and a subsequent Shi asymmetric
epoxidation8 using the sugar-derived catalyst 189 afforded the
epoxide 19 in 84% yield with 91% ee. Saponification of ester 19
1997
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Letter
In summary, we have accomplished the first enantioselective
total synthesis of the (−)-walsucochin B (2) and confirmed its
absolute configuration. A convergent pathway was used to
arrive at the cyclization precursor. The cationic polyolefin
cyclization constructed the core architecture 3 as a single
diastereomer. Site-selective, late-stage free-radical halogenation
and oxidation were utilized to accomplish oxidation of one of
the two methyl groups on the aromatic ring. A Seyferth−
Gilbert homologation installed the acetylene moiety to
construct the phenylacetylene. Additional efforts to apply the
strategy to (+)-walsucochin A (1) along with other related
natural products are currently being pursued in our laboratory
and will be reported in due course.
Scheme 4. Synthesis of the Core Tetracyclic Framework 5
via Cationic Polyolefin Cyclization
ASSOCIATED CONTENT
■
S
* Supporting Information
Descriptions of experimental procedures for compounds and
analytical characterization.This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Scheme 5. Completion of the Synthesis of (−)-Walsucochin
B (2)
Corresponding Authors
*E-mail: xiexg@lzu.edu.cn.
*E-mail: shexg@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21125207, 21102062,
and 21372103), the MOST (2010CB833203), PCSIRT
(IRT1138), the FRFCU (lzujbky-2013-49 and lzujbky-2013-
ct02), and Program 111.
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