TOTAL SYNTHESIS OF FK-506 .1. CONSTRUCTION OF THE C16-C34 FRAGMENT

The C23-C27 1,3-diol was constructed via either Brown's crotylation - osmylation or regio- and stereoselective opening of an 2,3-anhydro-bet a-ribofuranoside derived from D-xylofuranose. Lewis acid catalyzed epo xide opening with a protected lithiofurfural alcohol followed by oxida tive spiroketalization established the C21-C24 spiroketal as a masked alpha'-allyl aldol. The C19-C20 tri-substituted olefin was synthesized via zirconium catalyzed carboalumination - in situ transmetalation wi th a higher order cuprate, followed by stereoselective conjugate addit ion to a spiroenone. The C27-C28 tri-substituled olefin was formed eit her via coupling of a methyl cuprate with an enoltriflate, mediated by sonication, or via direct coupling between the C17-aldehyde and the C 28-vinyl magnesium bromide. (C) 1997 Elsevier Science Ltd.