A New Total Synthesis of (+)-Brefeldin C

Abstract

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).

Concise Total Syntheses of (+)‐Brefeldin A, Diastereomers and Analogs and Their Biological Activity

“…Intramolecular nucleophilic substitution with nitrile anions, [10h] Michael addition/enolate alkylation, [10e] tandem lithium‐iodine exchange/cyclization reaction, [10i] Dieckmann cyclization, [10j] norbornenone Baeyer‐Villiger oxidation, [10k] intramolecular metal‐catalyzed allylic substitution, [10l,m] cycloisomerization, [10n] intramolecular Mukaiyama aldol addition, [10o] epoxide opening, [10f,p,q] or [3+2] cycloaddition steps [10r,s] were applied as key steps for the formation of functionalized cyclopentane precursors. Transformation of substituted cyclopentane rings like [2+2] cycloaddition with cyclopentadiene, [10t] conjugate addition of γ‐crotonolactone enolate, [10u] cyclopentadiene oxidation [10v] also exist for BFA and BFC [10x–z] . The northern side chain was typically connected by acetylide or vinyllithium addition, [10f,g,l,s,w] Horner‐Wadsworth‐Emmons [10m,n,p] or Wittig reactions, [10r,t,z] Claisen condensation, [10e] Nozaki‐Kishi‐Hiyama reactions, [10w] Michael addition, [10u] or oxidative furan ring opening [10x] .…”

“…The northern side chain was typically connected by acetylide or vinyllithium addition, [10f,g,l,s,w] Horner‐Wadsworth‐Emmons [10m,n,p] or Wittig reactions, [10r,t,z] Claisen condensation, [10e] Nozaki‐Kishi‐Hiyama reactions, [10w] Michael addition, [10u] or oxidative furan ring opening [10x] . For the attachment of the southern side chain Julia‐Kocienski olefination, [10p,r,s,z] Wittig olefination, [10u] conjugate addition reactions, [10i,o,t,v] cross‐metathesis [10m,n] or Suzuki‐Miyaura coupling reactions [10w,x,y] were most prominently applied. Despite significant effort, these total syntheses thus took 15 to 25 steps and often suffered of low single‐digit overall yields.…”