Abstract
The first synthesis of the immunosuppressant (−)-FR901483 (1) has been accomplished in 2% overall yield from O-methyltyrosine methyl ester (31) in 22 steps establishing the absolute stereochemistry of the natural product. A 1,3-dipolar cycloaddition of nitrone 5b with ethyl acrylate gave predominantly isoxazolidine 4b that was hydrogenated to give azaspirolactam 3b with the correct absolute and relative stereochemistry for the synthesis of 1. Elaboration of 3b to keto aldehyde 38 and an intramolecular aldol reaction gave tricyclic keto alcohol 40 with reasonable selectivity using KO-t-Bu in t-BuOH. Further elaboration afforded (−)-1 in 9 steps with spectral data identical to that of the natural product.