Synthetic studies toward the immunosuppressant FR901483: Facile construction of the azatricyclic skeleton

ORGN 745

Suvi T. Simila, suvisimila@mail.utexas.edu, Department of Chemistry & Biochemistry, The University of Texas, 1 University Station A5300, Austin, TX 78712 and Stephen F. Martin, sfmartin@mail.utexas.edu, Department of Chemistry and Biochemistry, University of Texas at Austin, 1 University Station A5300, Austin, TX 78712.
A potent immunosuppressant, FR901483, was isolated from the fermentation broth of the fungal strain Cladobotryum sp. No. 11231, by Fujisawa Pharmaceutical Company in Japan during a program exploring alternative immunosuppressants to replace currently used cyclosporine A and tacrolimus (FK-506). Herein, we describe a unique approach to FR901483 and a successful application of the underlying chemistry to construct the azatricyclic core. The approach features an addition of a functionalized allylsilane (2) to an acyl iminium ion to provide an intermediate that undergoes a ring-closing metathesis to generate a spirocycle (3). Stereoselective hydroboration of the resultant olefin and lactonization provides a fused lactone (4). Base promoted lactone-lactam rearrangement then delivers the azatricyclic core (5). Application of this strategy and the progress towards FR901483 are also described.

 

Total Synthesis, Materials, Molecular Recognition, Process R&D, and Physical Organic Chemistry
8:00 PM-10:00 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Division of Organic Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006