A UNIFIED TOTAL SYNTHESIS OF THE IMMUNOMODULATORS (-)-RAPAMYCIN AND (-)-27-DEMETHOXYRAPAMYCIN - CONSTRUCTION OF THE C(21-42) PERIMETERS

A total synthesis of the potent, naturally occurring immunomodulators (-)-rapamycin (1) and (-)-27-demethoxyrapamycin (2) has been achieved via a unified, highly convergent synthetic strategy. Both targets were elaborated from common building blocks A-E, the latter available in d ecagram quantities. Herein we present the construction of the ABC nort hern perimeters of 1 and 2. The accompanying paper describes the prepa ration of the southern perimeter DE segment, triene and deprotection m odel studies, and completion of the synthetic venture. Notable feature s of the approach include stereoselective sigma-bond constructions of trisubstituted olefins and the union of advanced intermediates via eff icient dithiane couplings.