ORGANIC
LETTERS
2011
Vol. 13, No. 12
3028–3031
Total Synthesis of (À)-Salinosporamide A
Nobuhiro Satoh, Satoshi Yokoshima, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received April 5, 2011
ABSTRACT
A concise and stereoselective total synthesis of (À)-salinosporamide A (1), a potent inhibitor of the 20S proteasome that is in
clinical development as an anticancer drug candidate, has been accomplished in 14 steps with 19% overall yield from 4-pentenoic
acid. Our synthesis features a stereoselective alkylation utilizing a chiral auxiliary, formation of a pyrrolidine unit, and oxidation of
the pyrrolidine to a γ-lactam. To demonstrate the scalability of our synthesis, (À)-salinosporamide A has been synthesized on a
gram scale.
(À)-Salinosporamide A (1, NPI-0052, marizomib) was
isolated by Fenical and co-workers from a marine actino-
mycete Salinospora tropica that is distributed in ocean
sediments around the Bahamas.1 Salinosporamide A is a
potent inhibitor of the 20S proteasome and is currently
being tested as an anticancer drug candidate to treat
patients with multiple myeloma.2 In addition to its potent
bioactivity, the highly functionalized structure of 1, pos-
sessing a β-lactone, R,R-disubstituted amino acid moiety,
cyclohexene ring, and five contiguous stereogenic centers,
has attracted the attention of a number of synthetic
chemists. Intensive efforts have therefore been made to
establish efficient synthetic routes to 1.2e,3À6 In this com-
munication, we report a concise and enantioselective
synthesis of this natural product.
As illustrated in Scheme 1, salinosporamide A would be
derived from 2 by differentiation of the diester and cleav-
age of the lactol. We envisioned that 2 could in turn
be derived from acyclic amino ketone 3 in a stereo-
selective manner upon sequential cyclization. In the event,
(3) For enantioselective syntheses, see: (a) Reddy, L. R.; Saravanan,
P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230. (b) Endo, A.;
Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 8298. (c) Ling, T.;
Macherla, V. R.; Manam, R. R.; McArthur, K. A.; Potts, B. C. M. Org.
Lett. 2007, 9, 2289. (d) Takahashi, K.; Midori, M.; Kawano, K.;
Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed. 2008, 47, 6244.
(e) Fukuda, T.; Sugiyama, K.; Arima, S.; Harigaya, Y.; Nagamitsu, T.;
Omura, S. Org. Lett. 2008, 10, 4239. (f) Nguyen, H.; Ma, G.; Romo, D.
Chem. Commun. 2010, 46, 4803. (g) Sato, Y.; Fukuda, H.; Tomizawa,
M.; Masaki, T.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. Heterocycles
2010, 81, 2239. (h) Nguyen, H.; Ma, G.; Gladysheva, T.; Fremgen, T.;
Romo, D. J. Org. Chem. 2011, 76, 2. (i) Kaiya, Y.; Hasegawa, J.;
Momose, T.; Sato, T.; Chida, N. Chem.;Asian J. 2011, 6, 209.
(4) For racemic syntheses, see: (a) Mulholland, N. P.; Pattenden, G.;
Walters, I. A. S. Org. Biomol. Chem. 2006, 4, 2845. (b) Ma, G.; Nguyen,
H.; Romo, D. Org. Lett. 2007, 9, 2143.
(1) (a) Felig, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355. For the
ꢀ
studies on biosynthesis, see: (b) Eustaquio, A. S.; Moore, B. S. Angew.
Chem., Int. Ed. 2008, 47, 3936. (c) McGlinchey, R. P.; Nett, M.;
ꢀ
Eustaquio, A. S.; Asolkar, R. N.; Fenical, W.; Moore, B. S. J. Am.
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Chem. Soc. 2008, 130, 7822. (d) Liu, Y.; Hazzard, C.; Eustaquio, A. S.;
Reynolds, K. A.; Moore, B. S. J. J. Am. Chem. Soc. 2009, 131, 10376.
(2) (a) Chauhan, D.; Catley, L.; Li, G.; Podar, K.; Hideshima, T.;
Velankar, M.; Mitsiades, C.; Mitsiades, N.; Yasui, H.; Letai, A.; Ovaa,
H.; Berkers, C.; Nicholson, B.; Chao, T.-H.; Neuteboom, S. T. C.;
Richardson, P.; Palladino, M. A.; Anderson, K. C. Cancer Cell 2005, 8,
407. (b) Macherla, V. R.; Mitchell, S. S.; Manam, R. R.; Reed, K. A.;
Chao, T.-H.; Nicholson, B.; Deyanat-Yazdi, G.; Mai, B.; Jensen, P. R.;
Fenical, W.; Neuteboom, S. T. C.; Lam, K. S.; Palladino, M. A.; Potts,
B. C. M. J. Med. Chem. 2005, 48, 3684. (c) Fenical, W.; Jensen, P. R.;
Palladino, M. A.; Lam, K. S.; Lloyd, G. K.; Potts, B. C. Bioorg. Med.
Chem. 2009, 17, 2175. (d) Singh, A. V.; Palladino, M. A.; Lloyd, G. K.;
Potts, B. C.; Chauhan, D.; Anderson, K. C. Br. J. Hamaetol. 2010, 140,
550. For a review, see: (e) Gulder, T. A. M.; Moore, B. S. Angew. Chem.,
Int. Ed. 2010, 49, 9346.
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(5) For formal syntheses, see: (a) Caubert, V.; Masse, J.; Retailleau,
P.; Langlois, N. Tetrahedron Lett. 2007, 48, 381. (b) Margalef, I. V.;
Rupnicki, L.; Lam, H. W. Tetrahedron 2008, 64, 7896. (c) Momose, T.;
Kaiya, Y.; Hama, N.; Hasegawa, J.; Sato, T.; Chida, N. Synthesis 2009,
2983. (d) Mosey, R. A.; Tepe, J. J. Tetrahedron Lett. 2009, 50, 295. (e)
Struble, J. R.; Bode, J. W. Tetrahedron 2009, 65, 4957. (f) Ling, T.; Potts,
B. C.; Macherla, V. R. J. Org. Chem. 2010, 75, 3882.
(6) For reviews of the syntheses, see: Shibasaki, M.; Kanai, M.;
Fukuda, N. Chem.;Asian J. 2007, 2, 20 and ref 2f.
r
10.1021/ol200886j
Published on Web 05/17/2011
2011 American Chemical Society