Total Synthesis of Rapamycin

摘要

Rapamycin (1) is a macrocyclic natural product first isolated in 1975 from Streptomyces hygroscopicus from a soil sample collected on Easter Island (Rapa Nui).[1], [2] While its initial biological activity as an antifungal agent[3] attracted little attention, it soon became recognized as a potent immunosuppressive agent, which was launched commercially by Wyeth in 1999 for clinical usage following organ transplantation.[4] Not surprisingly, the interesting architecture and important biological profile of rapamycin (1) attracted interest from the organic synthesis community and cumulated in four total syntheses in the 1990s.[5], [6] Several molecules related to rapamycin, such as FK506,[7] L-685-818,[8] meridamycin,[9] ascomycin,[10] and the antascomicins,[11] have also been characterized and extensively studied. Over the years, the detailed biology and the molecular targets for these fascinating compounds have gradually been revealed. Despite the importance and obvious value of the immunomodulating effects,[12] more extensive studies are delineating whole new fundamental signaling pathways that have significant biological ramifications, especially for cancer chemotherapy. Indeed, new analogues of rapamycin, such as CCI-779, RAD001, and AP23573, have been developed and are rapidly progressing through clinical trials for applications as antitumor agents.[13], [14]