Total Synthesis of Rapamycin

Abstract

Abstract Rapamycin (1) is a macrocyclic natural product, established as a potent immunosuppressant and currently of interest to the scientific community as the framework for a series of novel anticancer drugs. Extensive studies have culminated in a new convergent total synthesis of 1 , which features a number of group‐derived methodologies and an unusual catechol‐templating strategy for the construction of the challenging macrocyclic core. magnified image For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro‐etherification/catechol‐templating strategy for construction of the macrocyclic core of this natural product.