A short enantioselective total synthesis of the fundamental pentacyclic triterpene lupeol

Article abstract of DOI:10.1021/ja906335u

(Chemical Equation Presented) The first enantioselective synthesis of lupeol has been developed by applying two carefully crafted cation-π cyclization stages to generate the pentacyclic structure with complete stereocontrol. The synthesis (Scheme 1) is no

Full text of DOI:10.1021/ja906335u

Published on Web 09/09/2009
A Short Enantioselective Total Synthesis of the Fundamental Pentacyclic
Triterpene Lupeol
Karavadhi Surendra and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received July 28, 2009; E-mail: corey@chemistry.harvard.edu
The direct, one-step pentacyclizaion of (S)-2,3-oxidosqualene to
the pentacyclic triterpene lupeol (1, Scheme 1)1 is a remarkable
example of biosynthetic efficiency. The chemical emulation of this
elegant biosynthetic conversion remains an elusive challenge in
modern synthesis. In fact, there has not even been a successful
multistep enantioselective synthesis of lupeol, the closest ap-
proximation being a relay synthesis2 of racemic lupeol via an
oxidation product3 of natural lupeol. Described herein is a simple
enantioselective solution to the longstanding challenge posed by
the lupeol molecule. Our enantioselective synthesis of lupeol
required the careful choice of substrate for stereocontrolled cation
olefin polycyclization and was facilitated by recent studies.4 We
also discuss herein a related matter of biosynthetic interest, the
further one-step conversion of lupeol to the naturally occurring
pentacyclic triterpenes germanicol, δ-amyrin, 18-epi-ꢀ-amyrin,
taraxasterol, ψ-taraxasterol, and R-amyrin via cationic intermediates.
The first step in the synthesis of lupeol (see Scheme 1) was the
position-selective, copper-promoted coupling of the readily available
(S)-epoxy acetate 24,5 with Grignard reagent 3 to form cleanly the
primary-primary coupling product 4. Various other coupling
procedures, for example using Pd catalysis, proved to be unsatisfac-
tory because of low position selectivity and yield. Lewis acid
activation of the chiral epoxide 4 provided after TBAF treatment
the required tetracycle product 5 in acceptable yield (ca. 80% per
ring formed). This step occurs stereoselectively and also solves the
difficult problem of putting in place the angular methyl group at
the C/D ring juncture (C(14) position in 1). Selective catalytic
hydrogenation of the disubstituted double bond in 5 and subsequent
methylation afforded the tertiary alcohol 6, which upon sequential
exposure to acid and base provided the R,ꢀ-enone 7 in good yield.
Reduction of the R,ꢀ-double bond in 7, basic stereoequilibration,
and silylation gave the desired trans-antitrans-antitrans saturated
ketone 8, alkylation and reduction of which produced the alcohol
10. Cyclization of 10 to the lupeol ether 11 occurred spontaneously
under mesylation conditions and led to lupeol itself after desilylation
(64%) along with the noncyclized 1,2-elimination product (bac-
chara-12,21-dien-3ꢀ-ol, 16%). Synthetic and natural samples of
Scheme 1. Synthesis of Lupeol (1)
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13928 J. AM. CHEM. SOC. 2009, 131, 13928–13929
10.1021/ja906335u CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
1
Scheme 2
products was monitored by H NMR at 500 MHz by comparison
1
with reference H NMR data for lupeol, germanicol, ꢀ-amyrin,
δ-amyrin (13,18-double bond isomer of ꢀ-amyrin), 18-epi-ꢀ-amyrin,
R-amyrin, ψ-taraxasterol, and taraxasterol.8 After 60 min only 18%
of lupeol remained, the rest having been converted to germanicol
(12%), δ-amyrin (16%), 18-epi-ꢀ-amyrin (12%), R-amyrin (6%),
ψ-taraxasterol (38%), and taraxasterol (5%). The relative amounts
of these compounds after 2 h were (respectively): 0%, 12%, 18%,
12%, 8%, 42%, and 5%. After 12 h, they were (respectively): 0%,
15%, 12%, 17%, 10%, 29% and 10%. At near equilibrium (24 h),
0% lupeol 15% germanicol, 12% δ-amyrin, 17% 18-epi-ꢀ-amyrin,
10% R-amyrin, 29% ψ-taraxasterol, and 10% taraxasterol were
present. As anticipated from the recent results,7 further backbone
rearrangement in the direction of friedelin, which is sharply higher
in terms of conformational energetics, does not happen under the
conditions of our experiments. The amazing ability of a pentacyclic
triterpene synthase to channel the cyclization of (S)-2,3-oxi-
dosqualene to a particular pentacyclic triterpene product is a
consequence of (1) the precise positioning on the protein of a single
proton accepting group and (2) driving force for backbone rear-
rangement that results from a faVorable total energy for the
combination of enzyme and bound cationic substrate. The results
summarized above on the facile conversion of lupeol to other
pentacyclic triterpenes carry synthetic meaning since they imply
that any projected chemical route to lupeol that relies on protic
acid catalyzed formation of this target is problematic.
The enantioselective synthetic pathway described herein is
noteworthy not only for its brevity and stereocontrol but also for
its inclusion of two unusually interesting ring-forming steps. First,
the conversion of 4 to tetracycle 5 depends on the careful choice
of the substituents on the aromatic ring to (1) activate that ring for
a sterically difficult cyclization, (2) channel the cyclization to a
single tetracyclic product, (3) establish functionality in 5 that allows
rapid execution of the final steps of the synthesis, and (4) minimize
the possibility of Lewis acid coordination to the electron supplying
groups (which would deactivate the aromatic ring). Second, the
unusually facile cationic conversion of 10 to 11 under essentially
nonacidic conditions is highly instructive.
Supporting Information Available: Experimental procedures and
characterization data for all reactions and products, including copies
lupeol were identical spectroscopically and by measurements of
optical rotation, mp and mixed mp.
1
of H NMR and 13C NMR spectra. Time course studies of the triflic
acid catalyzed rearrangement of lupeol to other naturally occurring
pentacyclic triterpenes. This material is available free of charge via
the Internet at http://pubs.acs.org.
Although the synthesis of lupeol described above is very different
from the process used in biosynthesis, it shares the use of cationic
cyclization to simplify and shorten the synthesis. It is important to
note, however, that in a chemical setting careful choice of the
substrates for cyclization is absolutely crucial for success. A
previous study provided essential guidance.4
We have also examined the transformation of lupeol Via cationic
intermediates to other pentacyclic triterpenes.6 This research was
motivated in part by recent work in our laboratory on the
conformational energetics of backbone rearrangement of pentacyclic
triterpenes,7 and specifically by the finding that the conformational
energetics for the conversion of the lupanyl cation to the germanicyl
and oleanyl (ꢀ-amyrin) cations favor rearrangement. Consequently,
we performed some simple experiments with lupeol to clarify the
tendency of the lupanyl cation to rearrange under minimal acidic
conditions.
References
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(4) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 8865–8869.
(5) (a) Corey, E. J.; Noe, M. C.; Shieh, W.-C. Tetrahedron Lett. 1993, 34, 5995–
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(7) Ku¨rti, L.; Chein, R.-J.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 9031–
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(8) For the details of the 1H NMR data and time course studies of the acid-
catalyzed rearrangement of lupeol, see: Supporting Information.
Thus, lupeol was treated with a 20 mM solution of triflic acid in
CDCl3 at 23 °C, and the appearance of the resulting rearrangement
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