Short, enantioselective total synthesis of okaramine N

The first enantioselective total synthesis of a member of the okaramine family of bis-indole alkaloids, okaramine N (1), has been accomplished via intermediates 2-7, as outlined. The N-prenylated derivative of (S)-tryptophan methyl ester (2) was coupled with Fmoc-protected N-tert-prenylated tryptophan (3) to form the amide 4 in 70% yield. Pd(II)-mediated cyclization/rearrangement, a key step in the synthesis, transformed 4 into the indoloazacine 5 (44%), which was deprotected and cyclized in a single step to give the hexacyclic diketopiperazine 6 (95%). In the following novel and key sequence, 6 was transformed into 1: (1) selective ene reaction with N-methyltriazolinedione, (2) photooxidation of the remaining tert-prenylated indole subunit to provide 7, and (3) thermal retroene reaction of 7 to afford okaramine N (70% from 6). Copyright © 2003 American Chemical Society.