A Unified Total Synthesis of the Immunomodulators (−)-Rapamycin and (−)-27-Demethoxyrapamycin:  Construction of the C(21−42) Perimeters

Abstract

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 σ-bond constructions of trisubstituted olefins and the union of advanced intermediates via efficient dithiane couplings.