International audienceA 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

A new synthesis of (+)-brefeldin C featuring a Bolm desymmetrisation reaction, a B-alkyl Suzuki-Miyaura cross-coupling and a Carreira alkynylation reaction as the key steps is reported.Brefeldin A (BFA) 1 (Scheme 1) is a naturally occurring 16-membered macrolide antibiotic first isolated 1 from Penicillium decumbens and subsequently identified as a metabolite from several other ascomycetes sources. 2 BFA exhibits a diversity of biological activities, which include antiviral and antitumor effects. 3 BFA is also an important tool for cell biologists due to its dramatic effects on the structure and functioning of intracellular organelles, particularly the Golgi apparatus. 4 Therefore, BFA, and its direct biosynthetic precursor brefeldin C (BFC), offer promising opportunities for the development of structural analogs useful for biological evaluation and study of intracellular vesicular trafficking.Herein, we report a new synthesis of natural (+)-BFC featuring the construction and union of three principal fragments resulting from the sequential disconnection of the C1-O s-bond as well as the C3-C4 and C11-C12 sbonds of the macrocyclic lactone as outlined in Scheme 2.As depicted in Scheme 2 and Scheme 3, union of fragments 1 and 2 was envisaged via a palladium-mediated Balkyl Suzuki-Miyaura cross-coupling reaction. 5 We planned to synthesise fragment 1 (5) from acid-ester 6, the synthesis of which was already reported 6 through a desymmetrisation process of meso anhydride 7, whereas the synthesis of fragment 2 was envisaged via opening of commercially available (S)-2-methyl-oxirane with an organometallic species. After functional group transformation (ester to aldehyde), application of the recently developed Carreira protocol 7 for the enantioselective synthesis of propargylic alcohols was envisioned for the attachment of fragment 3 with concomitant control of the absolute configuration at C4.Our synthesis of fragment 1 (Scheme 4) thus commenced with the desymmetrisation reaction of anhydride 7 available in multi-gram quantities from b-keto ester 8 through a three-step sequence of known reactions (59% overall yield). 8 Applying the Bolm protocol 6 to 7 afforded acidester 6 in 99% yield and with 94% ee, in complete agreement with the reported data. To establish the future C5 chiral centre of BFC with proper stereochemistry, acidester 6 was cleanly epimerised to 9 upon treatment with potassium tert-butoxide in THF (92% yield). Chemoselective acid to aldehyde transformation was best accomplished in a two-step sequence (BH 3 overreduction to an alcohol, followed by oxidation under Swern conditions) to provide aldehyde-ester 10 in 58% overall yield. To complete the synthesis of 5 (fragment 1), aldehyde 10 was subjected to the conditions of the Takai reaction (excess chromium chloride in a 1:6 THF-dioxane mixture for 72 h) 9 to afford the vinylic iodide 5 in 75% isolated yield and in excellent selectivity (E:Z isomer ratio = 97:3).

The 2005 Spring Meeting of the Swiss Chemical Society was held at the University of Bern on March 10th, 2005. The one-day symposium was dedicated to recent advances in chemical biology and synthesis. The four speakers, Dennis P. Curran, Johann Mulzer, Scott Miller, and Samuel Danishefsky covered a wide range of modern organic chemistry emphasizing "the formidable power of chemical synthesis" (Danishefsky) to investigate biologically relevant problems.