A short total synthesis of (+)-omaezakianol via an epoxide-initiated cationic cascade reaction

Article abstract of DOI:10.1021/ol100213e

Figure Presented (+)-Omaezaklanol was synthesized in only three steps from racemic chlorohydrin 4 by Shi epoxidatlon followed by cascade cyclization and reduction.

Full text of DOI:10.1021/ol100213e

ORGANIC
LETTERS
2
010
Vol. 12, No. 7
512-1514
A Short Total Synthesis of
1
(+)-Omaezakianol via an
Epoxide-Initiated Cationic Cascade
Reaction
,
†
†
Zhaoming Xiong,* Robert Busch, and E. J. Corey
‡
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc.,
00 Ridgebury Road, Ridgefield, Connecticut 06877, and Department of Chemistry and
9
Chemical Biology, HarVard UniVersity, 12 Oxford Street, Cambridge, Massachusetts 02138
zhaoming.xiong@boehringer-ingelheim.com
Received January 29, 2010
ABSTRACT
(+)-Omaezakianol was synthesized in only three steps from racemic chlorohydrin 4 by Shi epoxidation followed by cascade cyclization and
reduction.
Natural products constitute a remarkably diverse and valuable
collection of biologically active compounds. However, they
(+)-Omaezakianol (1), a member of the oxasqualenoid
family of squalene-derived triterpene polyethers, was re-
1
5
are often not available in amounts needed for study or
development as biological reagents or medicines. In such
instances, total chemical synthesis becomes indispensable to
both research and further development. Often, nature uses
cationic “cascade”-type polycyclization processes to produce
topologically complex structures. As demonstrated many
times over the past five decades, this strategy is also very
useful in the design of short, simple, and aesthetically
cently isolated in milligram amounts from the red alga
Laurencia omaezakiana Masuda. These triterpene polyethers
6
are believed to be biosynthesized from squalene via poly-
5
,7
epoxide intermediates by cascade cyclizations. Although
there is no report on the biological activity on 1, it is expected
to have ionophoric functions as recent studies have shown
that oligotetrahydrofuranyl derivatives have strong interac-
8
9
tions with metal cations. The cytotoxicities exhibited by
some members of this family may be linked to their
2
pleasing chemical syntheses. Despite numerous elegant
8
a
examples in the synthetic literature, much remains to be
learned about the application of cascade-type chemistry for
complex molecular synthesis. We report herein the use of
ionophoric functions. The unique nonsymmetric structure
with four cis-THF rings anti to each other combined with
3
,4
(3) For previous work using epoxide-initiated cationic cascade reactions
an epoxide-initiated cationic cascade reaction to achieve
for the synthesis of squalene-derived triterpene polyethers, see: (a) Xiong,
Z.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 4831–4832. (b) Xiong, Z.;
Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9328–9329.
an efficient total synthesis of (+)-omaezakianol (1).
†
Boehringer Ingelheim Pharmaceuticals, Inc.
Harvard University.
(4) For a recent review, see: Vilotijevic, I.; Jamison, T. Angew. Chem.,
Int. Ed. 2009, 48, 5250–5281.
‡
(
1) For recent reviews, see: (a) Li, J. W.-H.; Vederas, J. C. Science 2009,
25, 161–165. (b) Rishton, G. M. Am. J. Cardiol. 2008, 101, 43D–49D.
c) Itokawa, H.; Morris-Natschke, S. L.; Akiyama, T.; Lee, K.-H. J. Nat.
(5) For reviews, see: (a) Connolly, J. D.; Hill, R. A. Nat. Prod. Rep.
2003, 20, 640–659. (b) Fern a´ ndez, J. J.; Souto, M. L.; Norte, M. Nat. Prod.
Rep. 2000, 17, 235–246.
3
(
Med. 2008, 62, 263–280. (d) Baker, D. D.; Chu, M.; Oza, U.; Rajgarhia,
V. Nat. Prod. Rep. 2007, 24, 1225–1244. (e) Wilson, R. M.; Danishefsky,
S. J. J. Org. Chem. 2006, 71, 8329–8351. (f) Newman, D. J.; Cragg, G. M.;
Snader, K. M. J. Nat. Prod. 2003, 66, 1022–1037.
(6) Matsuo, Y.; Suzuki, M.; Masuda, M.; Iwai, T.; Morimoto, Y. HelV.
Chim. Acta 2008, 91, 1261–1266.
(7) (a) Hoye, T. R.; Suhadolnik, J. C. Tetrahedron 1986, 42, 2855–
2862. (b) Rudi, A.; Yosief, T.; Schleyer, M.; Kashman, Y. Tetrahedron
1999, 55, 5555–5566. (c) Kashman, Y.; Rudi, A. Phytochem. ReV. 2004,
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10.1021/ol100213e  2010 American Chemical Society
Published on Web 03/10/2010

Scheme 1. Hypothetical Biogenesis of 1
Scheme 2. Synthetic Strategy
the interesting biogenesis and potential biological activity
made it an interesting target for total synthesis. Recently,
Morimoto and co-workers reported the first total synthesis
As outlined in Scheme 3, the synthesis started with (()-
2,3-oxidosqualene (6), which was easily prepared in two
steps from squalene (2) by a reported procedure. Treatment
10
11
of this compound and established its absolute configuration.
The synthesis was accomplished in 24 steps from farnesol.
In this paper, we describe a total synthesis of 1 which
requires only six steps from squalene via a biomimetic
epoxide-opening cascade reaction.
of epoxide 6 with HCl in ether gave a 1:1 mixture of
1
2
chlorohydrin 4 and its regioisomer 7 in 92% yield. The
mixture was easily separated by flash column chromatog-
raphy, and compound 7 could be converted back to epoxide
6 in 94% yield by treatment with potassium carbonate in
methanol. Asymmetric epoxidation of 4 with Shi catalyst
Our synthetic strategy was inspired by the hypothetical
biosynthethic pathway of 1, which involves a regioselective
asymmetric epoxidation of five out of six double bonds of
squalene (2) followed by a subsequent cascade cyclization
of the pentaepoxide 3 to give 1 (Scheme 1). Mimicking this
biogenesis through the chemical synthesis presents two
challenges: regioselective asymmetric pentaepoxidation of
squalene (2) and unidirectional cascade cyclization of the
pentaepoxide 3. Our approach relied on squalene-derived
chlorohydrin 4 as the key intermediate (Scheme 2). We
expected the chlorohydrin group in 4 to serve not only as a
masking group for the terminal double bond to achieve
regioselective pentaepoxidation but also as the initiating
1
3
8
(3 equiv, 60 mol % per double bond) gave pentaepoxide
5. Without purification, compound 5 was treated with
camphorsulfonic acid (CSA) in acetone to induce an epoxide-
opening cascade cyclization which afforded the pentacyclic
compound 9 in 21% overall yield from 4 after chromato-
3
a
graphic purification on silica gel column. Since racemic 4
was used, 9 was obtained as a 1:1 mixture of two diaster-
1
14
eomers as shown by the H NMR spectrum. Reduction of
this diastereomeric mixture 9 with sodium in refluxing ether
generated the terminal double bond and opened the tethered
3,4
group (3-hydroxyl group) for the epoxide-opening cascade
cyclization. Since the chlorohydrin moiety in 4 serves as a
masking group for the olefin in 1, the chirality at the
(11) (a) Ceruti, M.; Balliano, G.; Viola, F.; Cattel, L.; Gerst, N.; Schuber,
F. Eur. J. Med. Chem. 1987, 22, 199–208. (b) van Tamelen, E. E.; Curphey,
T. J. Tetrahedron Lett. 1962, 3, 121–124. (c) van Tamelen, E. E.; Sharpless,
K. B. Tetrahedron Lett. 1967, 8, 2655–2659.
3-position is of no consequence and the racemic mixture can
(12) The preparation of (S)-4 (69% ee) has been reported in two steps
with 46% yield from racemic 6; see: Raina, S.; Singh, V. K. Tetrahedron
be used.
1
995, 51, 2467–2476.
(
13) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
(
8) (a) Morimoto, Y.; Iwai, T.; Yoshimura, T.; Kinoshita, T. Bioorg.
Soc. 1997, 119, 11224–11235.
Med. Chem. Lett. 1998, 8, 2005–2010. (b) Bellenie, B. R.; Goodman, J. M.
Tetrahedron Lett. 2001, 42, 7477–7479. (c) Tsukube, H.; Takagi, K.;
Higashiyama, T.; Iwachido, T.; Hayama, N. Inorg. Chem. 1994, 33, 2984–
(14) The 1HNMR of the diastereomeric mixture of 9 shows two sets of
two singlets of the two methyl groups attached to C-2 with 1:1 integration
ratio indicating the diastereomeric ratio is 1:1.
2
987. (d) Schultz, W. J.; Etter, M. C.; Pocius, A. V.; Smith, S. J. Am. Chem.
(15) (a) Bromidge, S. M.; Sammes, P. G.; Street, L. J. J. Chem. Soc.,
Perkin Trans. 1 1985, 1725–1730. (b) Chen, B.; Ko, R. Y. Y.; Yuen,
M. S. M.; Cheng, K.-F.; Chu, P. J. Org. Chem. 2003, 68, 4195–4205. (c)
Geng, Z.; Chen, B.; Chiu, P. Angew. Chem., Int. Ed. Engl. 2006, 45, 6197–
6201.
Soc. 1980, 102, 7981–7982. (e) Wagner, H.; Harms, K.; Koert, U.; Meder,
S.; Boheim, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 2643–2646.
(
9) (a) Suzuki, T.; Suzuki, M.; Furusaki, A.; Matsumoto, T.; Kato, A.;
Imanaka, Y.; Kurosawa, E. Tetrahedron Lett. 1985, 26, 1329–1332. (b)
Morita, H.; Kishi, E.; Takeya, K.; Itokawa, H.; Iitaka, Y. Phytochemistry
(16) Suzuki, M.; Matsuo, Y.; Takeda, S.; Suzuki, T. Phytochemistry
1993, 33, 651–656.
1
993, 34, 765–771.
10) Morimoto, Y.; Okita, T.; Kambara, H. Angew. Chem., Int. Ed. 2009,
8, 2538–2541.
(
(17) Morimoto, Y.; Okita, T.; Takaishi, M.; Tanaka, T. Angew. Chem.,
Int. Ed. Engl. 2007, 46, 1132–1135.
4
Org. Lett., Vol. 12, No. 7, 2010
1513

THF ring to give the natural product (+)-omaezakianol (1)
1
5
1
13
in 76% yield. The HRMS and H and C NMR of 1 match
Scheme 3. Total Synthesis of (+)-Omaezakianol (1)
6
,10
very well with those reported
addition, the optical rotation of our synthetic 1 ([R]
17.1 (c ) 1.0, CHCl
the natural product 1 ([R]
and that of synthetic 1 by Morimoto and co-workers ([R]
for (+)-omaezakianol. In
2
3
D
)
+
3
)) is also in agreement with that of
2
0
6
D
3
) +15.8 (c ) 0.57, CHCl ))
2
9
D
1
0
)
+17.7 (c ) 0.59, CHCl
3
)).
In summary, we have developed a short and efficient total
synthesis of tetracyclic oxasqualenoid (+)-omaezakianol (1)
in only six steps from squalene via a biomimetic epoxide-
opening cascade reaction. The key feature of the synthesis
is the use of a chlorohydrin function to mask the terminal
olefin, which allows the utilization of the Shi asymmetric
epoxidation as well as an epoxide-opening cascade reaction
to construct rapidly the four THF-ring subunits with the
required stereochemistry in both regio- and stereoselective
fashion. This synthetic strategy resulted in a simple total
synthesis of (+)-omaezakianol (1) and provided another
example of the power of cascade reactions for the efficient
synthesis of a complex natural product. This strategy could
also find application for the total synthesis of other natural
products in the oxasqualenoid family with an olefinic or
olefin-derived terminal group such as, for example, intri-
1
6,17
catetraol.
Acknowledgment. We thank Scott Pennino and Dr.
Fenghe Qiu (Boehringer Ingelheim Pharmaceuticals) for the
determination of HRMS. R.B. was a participant in a
Boehringer Ingelheim partnered Pilot MS Program in
Organic Synthesis at the University of Connecticut.
Supporting Information Available: Experimental details
for the synthesis and characterization data of compound 1.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100213E
1514
Org. Lett., Vol. 12, No. 7, 2010