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

Abstract

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 Short Synthesis of (+)‐Brefeldin C through Enantioselective Radical Hydroalkynylation

“…The first synthesis of the racemic brefeldin A was reported by Corey and Wollenberg in 1976 followed by around 40 total and formal syntheses . Brefeldin C was prepared for the first time by total synthesis in 1988 by Schreiber and Meyers followed by Takano, Guingant (along with aspects of the biological properties of BFA) and Tsunoda . Following the pioneer work of Corey and Wollenberg, the majority of the syntheses of brefeldin A and C accessed the 13‐membered ring lactone in high yields by macrolactonization .…”

“…In analogy to the work of Kobayashi in his syntheses of brefeldin A and of macrosphelides A and B, the 3‐carboxyacryloyl chain (carbon C1–C4) will be prepared by oxidative opening of the furan ring of II . The pentan‐4‐ol‐1‐yl side chain (carbon atoms C12–C16) will be inserted by a Suzuki–Miyaura cross‐coupling process starting from iodide III in analogy to the work of Guingant . The ( E )‐iodide III will be obtained from the alkyne IV by a hydrozirconation–iodination process .…”

A Short Synthesis of (+)-Brefeldin C via Enantioselective Radical Hydroalkynylation

“…The unique biological profile of brefeldin A, C, and analogues [10] has attractedalot of interest in the synthetic organic chemistry community.T he first synthesis of the racemic brefeldin Aw as reported by Corey and Wollenberg [11] in 1976 followed by around 40 total and formal syntheses. Brefeldin Cw as prepared for the first time by total synthesis in 1988 by Schreiber and Meyers [52] followed by Ta kano, [25] Guingant (along with aspects of the biological properties of BFA) [48,53] and Tsunoda. [54] Following the pioneer work of Corey and Wollenberg, [11] the majority of the syntheses of brefeldin Aa nd C accessed the 13-membered ring lactone in high yields by macrolactonization.…”

“…[11] In analogyt ot he work of Kobayashi in his syntheses of brefeldin A [35] and of macrosphelides Aa nd B, [74,75] the 3-carboxyacryloyl chain (carbon C1-C4)w ill be prepared by oxidative openingo f the furan ring of II.T he pentan-4-ol-1-yl side chain (carbon atoms C12-C16)w ill be inserted by aS uzuki-Miyaura crosscoupling process startingf rom iodide III in analogyt ot he work of Guingant. [48,53] The (E)-iodide III will be obtained from the alkyne IV by ah ydrozirconation-iodination process. [76] The planed key reactiono fo ur approachi st he enantioselective and diastereoselective hydroalkynylation of 1-furanylcyclopentene V that has to be designed based on our previous work.…”

“…[77] With the TIPS-protected alkyne 2b in hand, we next focused on the introduction of the C12-C16 chain by Suzuki-Miyaura couplingi na nalogy to work of Guingant (Scheme 3). [48] The pmethoxybenzyl (PMB) (S)-configurated protected alkenol 4 was conveniently accessible in two steps from (S)-propylene epoxide [48,83] and it was convertedt o5 by hydroboration with 9borabicyclo[3.3.1]nonane (9-BBN). Due to its volatility and instability, the deprotected alkyne 3 obtainedb yt reatment of 2b with tetra-n-butylammonium fluoride( TBAF) was immediately converted into the vinyl iodide 6 by hydrozirconation using the Schwartz reagent followed by treatment with iodine.…”