K. Nicolaou, T. Chakraborty, A. Piscopio
May 1, 1993
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Journal
Journal of the American Chemical Society
Abstract
Rapamycin (1)lJ is a novel, naturally occurring substance, with potent antibiotic, cytotoxic, and immunosuppressive activity. Isolated from Streptomyces hygroscopicus found in an Easter Island soil sample, this synthetically challenging molecule is currently under intense investigation as a rival to the immuno-suppressive agents FK506 and cyclo~porin.~ Herein we report the first total synthesis of rapamycin (1) in its naturally occurring enantiomeric forms4 Rapamycin (1) with its 31-membered ring, plethora of asymmetric and geometrical centers, and sensitive functionality presents to thesyntheticchemist a formidablechallenge. A rather daring approach to this target is outlined in Scheme I. According to this strategy, rapamycin (1) was to be constructed by a single operation from a fully functionalized acyclic precursor (2), via a " stitching-cyclization " process that would bring in the two missing carbons as the central olefinic unit (C19420) of the triene moiety. The bridging unit, enedistannane 3,5 was expected to bring together the two terminal vinyl iodides of precursor 2 in a Stille-t~pe6.~ coupling-cyclization reaction to furnish the natural product in a single step. Such a strategy would ensure a direct approach to 1 and avoid instability problems, deprotection steps, and late stage oxidation state adjustments. Precursor 2 was expected to be derived from advanced key intermediates 4 and 5 (Scheme I). Coupling of advanced intermediates 48 and 59 in the presence of 1-hydroxybenzotriazole and diisopropylcarbodiimide proceeded