A Unified Total Synthesis of the Immunomodulators (−)-Rapamycin and (−)-27-Demethoxyrapamycin:  Assembly of the Common C(1−20) Perimeter and Final Elaboration

Abstract

The potent, naturally occurring immunomodulators (−)-rapamycin ( 1 ) and (−)-27-demethoxyrapamycin ( 2 ) have been synthesized via a unified and highly convergent strategy. In the preceding paper we discussed the construction of common building blocks A−C and their linkage to provide the C(21−42) segments of 1 and 2 . Herein we describe model studies of triene generation and hydroxyl deprotection, the preparation and coupling of building blocks D and E, a two-step protocol for macrocycle formation via union of the ABC and DE subtargets, and completion of the total syntheses. The synthesis of 27-demethoxyrapamycin ( 2 ) confirmed the assigned structure.