Highly chemoselective trichloroacetimidate-mediated alkylation of ascomycin: A convergent, practical synthesis of the immunosuppressant L-733,725

L-733,725, a new immunosuppressant drug candidate, was prepared by a highly chemoselective alkylation of the macrolide ascomycin at the C32 hydroxy po sition with the imidazolyl trichloroacetimidate 16. The trichloroacetimidat e-activated side chain 16 was prepared by an efficient four-step sequence i n 42% overall yield. The high chemoselectivity in the alkylation of the C32 hydroxy group of the unprotected ascomycin was the result of the synergeti c effects of the electron-donating protecting group on the imidazole 16, th e polar, moderately basic solvent, and the strong acid catalyst. N,N-Dimeth ylpivalamide mixed with acetonitrile was found to be the best solvent and t rifluromethanesulfonic acid the best catalyst. This synthesis coupled with a resin column purification of L-733,725 followed by crystallization of its tartrate salt has been used to make multikilogram quantities of the bulk d rug with consistent and high purity.