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 decagram quantities. Herein we present the construction of the ABC northern perimeters of 1 and 2. The accompanying paper describes the preparation of the southern perimeter DE segment, triene and deprotection model studies, and completion of the synthetic venture. Notable features of the approach include stereoselective sigma-bond constructions of trisubstituted olefins and the union of advanced intermediates via efficient dithiane couplings.