ORGANIC
LETTERS
2009
Vol. 11, No. 3
777-779
Total Synthesis of FR901483
Cheryl A. Carson and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London, Ontario,
Canada N6A 5B7
Received December 12, 2008
ABSTRACT
The architecturally sophisticated skeleton of the immunosuppressive alkaloid FR901483 was assembled via a process relying on the reaction
of an in situ generated imine with a suitably disposed donor-acceptor cyclopropane. A short sequence of functional group transformations
provided the natural product in an efficient manner.
FR901483 (1, Figure 1) is a potent immunosuppressive
alkaloid isolated from the fermentation broth of Cladobot-
ryum sp.1 As an inhibitor of purine biosynthesis with a novel
mode of action compared to leading immunosuppressive
agents cyclosporin A and FK-506 (both of which display
significant toxicity at high doses), FR901483 has garnered
significant attention from the synthetic community due to
its biological activity and unique aza-tricyclic structure. This
has resulted in the publication of a number of inventive total
Figure 1. Structure of FR901483.
syntheses2 and ongoing synthetic efforts.3
(1) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37–44.
(2) (a) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121, 7778–7786.
(b) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem., Int. Ed. 2000,
39, 4593–4596. (c) Ousmer, M.; Braun, N. A.; Ciufolini, M. A. Org. Lett.
2001, 3, 765–767. (d) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.;
Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534–7538. (e) Maeng, J.-
H.; Funk, R. L. Org. Lett. 2001, 3, 1125–1128. (f) Kan, T.; Fujimoto, T.;
Ieda, S.; Asoh, Y.; Kitaoka, H.; Fukuyama, T. Org. Lett. 2004, 6, 2729–
2731. (g) Brummond, K. M.; Hong, S.-P. J. Org. Chem. 2005, 70, 907–
916. (h) Ieda, S.; Asoh, Y.; Fujimoto, T.; Kitaoka, H.; Kan, T.; Fukuyama,
T. Heterocycles 2008, PrePress.
(3) (a) Wardrop, D. J.; Zhang, W. Org. Lett. 2001, 3, 2353–2356. (b)
Suzuki, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2001, 42, 3013–
3015. (c) Bonjoch, J.; Diaba, F.; Puigbo, G.; Peidro, E.; Sole, D. Tetrahedron
Lett. 2003, 44, 8387–8390. (d) Kropf, J. E.; Meigh, I. C.; Bebbington,
M. W. P.; Weinreb, S. M. J. Org. Chem. 2006, 71, 2046–2055. (e) Kaden,
S.; Reissig, H.-U. Org. Lett. 2006, 8, 4763–4766. (f) Gotchev, D. B.;
Comins, D. L. J. Org. Chem. 2006, 71, 9393–9402. (g) Asari, A.; Angelov,
P.; Auty, J. M.; Hayes, C. J. Tetrahedron Lett. 2007, 48, 2631–2634. (h)
Simila, S. T. M.; Martin, S. F. J. Org. Chem. 2007, 72, 5342–5349. (i)
Seike, H.; Sorensen, E. J. Synlett 2008, 695–701.
Our interest in FR901483 was piqued as part of our
research program aimed at the synthesis of complex pyrro-
lidine ring systems via ring-opening/annulation reactions of
cyclopropanes.4 At the outset, we envisioned two potential
deconstructive routes (Scheme 1). Retrosynthetic route A
would have as a late-stage step an intramolecular aldol
reaction where the substrate would be spiroheterocycle 2,
in turn assembled via an intermolecular imine/cyclopropane
formal cycloaddition between substrates such as 3 and 4.4b,5
Route B, on the other hand, would reverse the order of the
(4) (a) Young, I. S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7,
953–955. (b) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242–
8244. (c) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am.
Chem. Soc. 2008, 130, 4196–4201.
(5) Kang, Y.-B.; Tang, Y.; Sun, X.-L. Org. Biomol. Chem. 2006, 4,
299–301
.
10.1021/ol802870c CCC: $40.75
Published on Web 01/12/2009
2009 American Chemical Society