Total synthesis and asymmetric formal synthesis of manzacidin D

ORGN 752

D. Bruce Mackay1, Roch M. A. Lavigne2, Christian Drouin2, and Jacqueline C. S. Woo2. (1) Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, QC H9H 3L1, Canada, (2) Merck Frosst Canada, Ltd, 16711 TransCanada Highway, Kirkland, QC H9H 3L1, Canada
We have developed the first total synthesis of manzacidin D. This synthesis features a highly diastereoselective iodocyclization of an olefinic isothioureas, and a novel method for conversion of an appropriately substituted thiourea to the corresponding formamidine. Subsequent to our racemic synthesis, we investigated a formal asymmetric synthesis of manzacidin D. Using Maruoka's asymmetric phase transfer catalyst, we were able to form the first stereocenter in high ee. Proceeding with the same synthetic sequence to the iodocyclization step showed no loss of enantiomeric excess, thus constituting a formal enantioselective synthesis of manzacidin D.