Total Synthesis of Rapamycin
Ley SV., Tackett MN., Maddess ML., Anderson JC., Brennan PE., Cappi MW., Heer JP., Helgen C., Kori M., Kouklovsky C., Marsden SP., Norman J., Osborn DP., Palomero MÁ., Pavey JBJ., Pinel C., Robinson LA., Schnaubelt J., Scott JS., Spilling CD., Watanabe H., Wesson KE., Willis MC.
AbstractRapamycin (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 imageFor 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.