Total Synthesis of (+)-Brefeldin C, (+)-nor-Me Brefeldin A and (+)-4-epi-nor-Me Brefeldin A

• Published in: European Journal of Organic Chemistry 2010-03, Vol.2010 (7), p.1364-1380
• Main Authors: Archambaud, Sylvie, Legrand, Frédéric, Aphecetche-Julienne, Karine, Collet, Sylvain, Guingant, André, Evain, M.
• Format: Article
• Language: English
• Subjects: Asymmetric synthesis; Brefeldin A analogues; Chemistry; Condensed Matter; Desymmetrization; Exact sciences and technology; G protein; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Macrocycles; Macrolactoni­zation; Materials Science; Organic chemistry; Physics; Preparations and properties; Total synthesis
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200901233

A total synthesis of (+)‐brefeldin C (BFC) and two brefeldin A (BFA) analogues – (+)‐nor‐Me BFA and (+)‐4‐epi‐nor‐Me BFA – has been developed. Key features of the syntheses include desymmetrization of meso anhydrides, a Carreira reaction to control the absolute configuration at C4 of BFC, a Suzuki–Miyaura cross‐coupling reaction to create the C11–C12 bond and a Yamaguchi reaction to form the 13‐membered lactone ring. Brefeldin A (BFA) inhibits activation of the G protein Arf1 by its protein effector (GEF) by stabilizing an abortive complex between Arf1‐GDP and GEF; this might represent an original tool for cellular pathway inhibition. To study the elements of BFA involved in its binding we prepared three analogues. The formation of the C11–C12 and C3–C4 bonds is unusual in BFA synthesis.