ORGANIC
LETTERS
2
004
Vol. 6, No. 16
729-2731
Stereocontrolled Total Synthesis of
Potent Immunosuppressant FR901483
2
Toshiyuki Kan, Teppei Fujimoto, Shigeru Ieda, Yusuke Asoh,
Haruka Kitaoka, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received May 20, 2004
ABSTRACT
A total synthesis of the potent immunosuppressant FR901483 (1) has been accomplished. The key feature of our convergent synthesis is the
stereoselective incorporation of the p-methoxybenzyl and methylamino groups within the core moiety 10. Tricycle 10 was itself constructed
by an intramolecular aldol reaction of the symmetrical keto-aldehyde 7.
FR901483 (1) is a novel immunosuppressant isolated from
the fermentation broth of the Cladobotryum species by
researchers at the Fujisawa Pharmaceutical Company. The
carbonyl groups to append the requisite p-methoxybenzyl
and methylamino groups at C(1) and C(10), respectively.
The synthesis of 2 would be accomplished using an intra-
molecular aldol reaction on the symmetrical keto-aldehyde
7 as a key step.
As shown in Scheme 2, the cyclization precursor 7 was
readily prepared by an eight-step sequence from inexpensive
nitromethane (3) and methyl acrylate (4). Upon treatment
of 3 and 3 equiv of 4 with 5 mol % DBU, the desired Michael
reaction proceeded smoothly to afford the triester. Subsequent
reduction of the nitro group and concomitant ester-amide
exchange proceeded to provide 5, which possessed the
required quaternary carbon. After Dieckmann condensation
1
promising biological activity and intriguing structure of this
compound has made it an attractive target for total synthe-
2,3
sis. Although four total syntheses of 1 have been reported
4
to date, none are completely stereoselective. Herein, we
describe a stereocontrolled total synthesis of racemic 1 that
could potentially lead to a range of diverse analogues. The
heart of our synthetic plan is illustrated in Scheme 1; it would
involve the intermediacy of tricycle 2 and use its multiple
(
1) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37.
2) For a review of biomimetic synthesis of this family compounds,
see: Takayama, H. J. Synth. Org. Chem. Jpn. 2002, 60, 350.
3) For the synthetic studies, see: (a) Fujimoto, T.; Kitaoka, H.; Ieda,
(
(
S.; Kan, T.; Fukuyama, T. Abstract of papers, 79th Symposium on Organic
Synthesis, Japan; The Society of Synthetic Organic Chemistry, Japan:
Tokyo, June 2001; p 17. (b) Suzuki, H.; Yamazaki, N.; Kibayashi, C.
Tetrahedron Lett. 2001, 42, 3013. (c) Brummond, K. M.; Lu, J. L. Org.
Lett. 2001, 3, 1347. (d) Wardrop, D. J.; Zhang, W. M. Org. Lett. 2001, 3,
Scheme 1. Structure and Synthetic Strategy of 1
2
001. (e) Puigbo, G.; Diaba, F.; Bonjoch, J. Tetrahedron 2003, 59, 2657.
f) Bonjoch, J.; Diaba, F.; Puigbo, G.; Peidro, E.; Sole, D. Tetrahedron
Lett. 2003, 44, 8387.
4) For total syntheses, see: (a) Snider, B. B.; Lin, H. J. Am. Chem.
(
(
Soc. 1999, 121, 7778. (b) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew.
Chem., Int. Ed. 2000, 39, 4593. (c) Ousmer, M.; Braun, N. A.; Bavoux, C.;
Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7543. (d) Maeng,
J.; Funk, R. L. Org. Lett. 2001, 3, 1125.
1
0.1021/ol049074w CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/10/2004