ORGANIC
LETTERS
2007
Vol. 9, No. 12
2289-2292
Enantioselective Total Synthesis of
)-Salinosporamide A (NPI-0052)
(−
Taotao Ling, Venkat R. Macherla,* Rama Rao Manam, Katherine A. McArthur, and
Barbara C. M. Potts
Nereus Pharmaceuticals, Inc., 10480 Wateridge Circle, San Diego, California 92121
Received March 12, 2007
ABSTRACT
A novel enantioselective total synthesis of 20S proteasome inhibitor Salinosporamide A (NPI-0052; 1) is presented. Key features include
intramolecular aldol cyclization of 6 to simultaneously generate the three chiral centers of advanced intermediate 5, cyclohexene ring addition
using B-2-cyclohexen-1-yl-9-BBN, and inversion of the C-5 stereocenter by oxidation followed by enantioselective enzymatic reduction.
Salinosporamide A (NPI-0052; 1), a secondary metabolite
of the marine actinomycete Salinispora tropica, is a potent
inhibitor of the 20S proteasome that is currently in clinical
trials for the treatment of cancer.1-3 Structurally, 1 comprises
a γ-lactam-â-lactone bicyclic ring system substituted with
methyl, cyclohex-2-enylcarbinol, and chloroethyl substituents
that give rise to specific and mechanistically important
interactions within the proteasome active site.4 Clinical
supplies and analogues of 1 have been generated by saline
fermentation,3,5,6 and the results of SAR studies of these and
other analogues prepared by semisynthesis have been
reported previously.3,6 However, the number of analogues
accessible through semisynthesis is limited by the labile
nature of the â-lactone ring. We therefore designed a novel
total synthesis of 1 to provide access to a broader suite of
analogues. To date, several total syntheses of 1 have been
reported,7-10 with all routes progressing toward an aldehyde
intermediate through which the cyclohexene ring is installed
via the Corey strategy7 and converging upon a common
sequence of steps.11 The enantioselective routes employ
stepwise introduction of the C-2, C-3, and C-4 chiral centers.
In contrast, we envisioned a novel enantioselective method
(Scheme 1) that involves intramolecular aldol cyclization to
generate key intermediate 5 using the self-regeneration of
stereocenters (SRS) principle developed by Seebach et al.12
to simultaneously generate these three chiral centers. Specif-
(1) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355-357.
(2) 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, 407-419.
(3) 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, 3684-3687.
(4) Groll, M.; Huber, R.; Potts, B. C. M. J. Am. Chem. Soc. 2006, 128,
5136-5141.
(5) Williams, P. G.; Buchanan, G. O.; Feling, R. H.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. J. Org. Chem. 2005, 70, 6196-6203.
(6) Reed, K. A.; Manam, R. R.; Mitchell, S. S.; Xu, J.; Teisan, S.; Chao,
T.-H.; Deyanat-Yazdi, G.; Neuteboom, S. T. C.; Lam, K. S.; Potts, B. C.
M. J. Nat. Prod. 2007, 70, 269-276.
(7) (a) Reddy, L. R.; Saravanan, P.; Corey, E. J. Am. Chem. Soc. 2004,
126, 6230-6231. (b) Reddy, L. R.; Fournier, J.-F.; Reddy, B. V. S.; Corey,
E. J. Org. Lett. 2005, 7, 2699-2701.
(8) Endo, A.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 8298.
(9) (a) Caubert, V.; Masse, J.; Retailleau, P.; Langlois, N. Tetrahedron
Lett. 2007, 48, 381-384. (b) Caubert, V.; Langlois, N. Tetrahedron Lett.
2006, 47, 4473-4475.
(10) Mulholland, N. P.; Pattenden, G.; Walters, I. A. S. Org. Biomol.
Chem. 2006, 4, 2845-2846.
(11) Shibasaki, M.; Kanai, M.; Fukuda, N. Chem. Asian J. 2007, 2, 20-
38.
(12) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708-2748.
10.1021/ol0706051 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/12/2007