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

Zhiguo Song, Anthony DeMarco, Mangzhu Zhao, Edward G. Corley, Andrew S. Thompson, James McNamara, Yulan Li, Dale Rieger, Paul Sohar, David J. Mathre, David M. Tschaen, Robert A. Reamer, Martha F. Huntington, Guo Jie Ho, Fuh Rong Tsay, Khateeta Emerson, Richard Shuman, Edward J.J. Grabowski, Paul J. Reider

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

L-733,725, a new immunosuppressant drug candidate, was prepared by a highly chemoselective alkylation of the macrolide ascomycin at the C32 hydroxy position with the imidazolyl trichloroacetimidate 16. The trichloroacetimidate-activated side chain 16 was prepared by an efficient fourstep sequence in 42% overall yield. The high chemoselectivity in the alkylation of the C32 hydroxy group of the unprotected ascomycin was the result of the synergetic effects of the electron-donating protecting group on the imidazole 16, the polar, moderately basic solvent, and the strong acid catalyst. N,N-Dimethylpivalamide mixed with acetonitrile was found to be the best solvent and trifluromethanesulfonic 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 drug with consistent and high purity.

Original languageEnglish (US)
Pages (from-to)1859-1867
Number of pages9
JournalJournal of Organic Chemistry
Volume64
Issue number6
DOIs
StatePublished - Mar 19 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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