Total Synthesis of Bafilomycin A1
Total Synthesis of Bafilomycin A1
复制标题
DOI：
10.1002/anie.200804645
复制
发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Carreira, Erick M.
中科院分区：
文献类型：
--
作者：
Kleinbeck, Florian;Carreira, Erick M.
巴菲尔霉素A1(1；方案1)是1983年从灰色链霉菌培养物中首次分离到的。2-4]除了其广泛的抗菌和抗真菌活性外，[1b]巴菲霉素A1选择性抑制V型ATPase[5]的能力最受关注，导致SAR研究和评估其治疗疾病的潜力，如骨质疏松。[6]对这类分子的持续兴趣和对生物活性类似物的需求需要新的合成方法。此外，像巴菲罗霉素A1这样的复合结构提供了一个审查新方法并因此实施新策略的论坛。在这里，我们公开了一种有效的合成方法，它通过锌介导的乙酰基加成反应展示了复杂片段4和5(方案1)的会聚偶联，并通过Ru催化的反氢硅基化和随后的原脱硅反应组成的序列立体选择性地还原了随后的烯炔部分。已经报道了几种巴菲尔霉素A1的全合成，[7-11]以及相关的方法学研究。[12]这些通常展示了已建立的聚酮合成方法的应用。我们的动机是通过实施最近开发的方法来制定一种不同的、补充巴菲罗星A1的策略。这些反应包括非对映选择性的，镁介导的氧化腈与手性烯丙醇的环加成反应，[13]芳基苯基锌的非对映选择性醛加成反应，[14]以及炔的半还原反应(方案1)。[15]我们设想，成功的烯-炔+RCHO加成反应将实现高效的片段偶联步骤。然而，这种方法只有在更大的合成目标的成功时才与更大的合成目标的成功相关，如果密集官能化的产物enyne能够被用来访问在1中发现的反式，反式-1，3-二烯体系。C1-C13片段(4；方案2)的合成开始于6与溴化物7[17]的烯丙基化反应[16]，以87%的产率得到8，辅助的[16d，18]的97：3DR还原裂解提供了中间醇(87%的产率)，经过Dess-Martin氧化以99%的产率得到了9醛。反选择性的Masamune Aldol加成9和10[19]得到了β-羟基酯11作为单一的非对映异构体(产率90%)。在硅烷化(产率98%)和酯还原(产率95%)之后，生成的伯醇被氧化，然后经Wittig烯化得到烯酸酯13(87%，分两步)。酯13到醛14的转化是通过一系列步骤完成的，包括酯基还原得到中间醇(产率98%)，Sonogashira与TMSC CH交叉偶联(产率96%)，[20]和氧化(产率94%)。随后涉及14的Horner-Wadsworth-Emmons缩合得到中间体二烯酸(>；95：5D。R.)，在化学选择性的炔脱硅化(96%的产率，超过2步)后，得到靶向的C1-C13片段4。
Bafilomycin A1 (1; Scheme 1) was first isolated in 1983 from a culture of Streptomyces griseus sp. sulphurus [1] and classified as a member of the plecomacrolide family of natural products.[2–4] In addition to its broad antibacterial and antifungal activity,[1b] the ability of bafilomycin A1 to selectively inhibit V-type ATPases [5] has attracted the most attention, leading to SARstudies and evaluation of its potential for the treatment of diseases, such as osteoporosis.[6] The continued interest in this class of molecules and the need for biologically active analogues demand new synthetic approaches. Moreover, a compex structure such as bafilomycin A1 provides a forum to examine new methods and consequently implement novel tactics. Herein, we disclose an efficient synthesis that showcases the convergent coupling of complex fragments 4 and 5 (Scheme 1) through a zincmediated acetylide addition reaction, and stereoselective reduction of the ensuing enyne moiety by a sequence consisting of a ruthenium-catalyzed trans-hydrosilylation and subsequent protodesilylation. Several total syntheses of bafilomycinA1 have been reported,[7–11] as well as related methodology studies.[12] These generally showcase the application of established methods for polyketide synthesis. We were motivated to craft a different, complementary strategy to bafilomycin A1 through the implementation of recently developed methods. These include diastereoselective, magnesium-mediated nitrile oxide cycloadditions with chiral allylic alcohols,[13] diastereoselective aldehyde addition reactions of zinc-enealkynilides,[14] and alkyne semireduction (Scheme 1).[15] We envisioned that a successful enyne+ RCHO addition reaction would enable a highly efficient fragment–coupling step. However, this approach would only be relevant to the success of the larger synthesis objective if the densely functionalized product enyne could be used to access the trans, trans-1, 3-diene system found in 1.The synthesis of the C1–C13 fragment (4; Scheme 2) commenced with the allylation reaction [16] of 6 with bromide 7 [17] to afford 8 in 87% yield and 97: 3 dr Reductive cleavage of the auxiliary [16d, 18] provided an intermediate alcohol (87% yield), which after Dess–Martin oxidation furnished aldehyde 9 in 99% yield. An anti-selective Masamune aldol addition of 9 with 10 [19] led to β-hydroxy ester 11 as a single diastereoisomer (90% yield). After silylation (98% yield) and ester reduction (95% yield), oxidation of the resulting primary alcohol was followed by Wittig olefination to provide enoate 13 (87%, over 2 steps). Conversion of ester 13 into aldehyde 14 was accomplished by a sequence involving reduction of the ester group to give an intermediate alcohol (98% yield), Sonogashira cross-coupling with TMSC CH (96% yield),[20] and oxidation (94% yield). Subsequent Horner–Wadsworth–Emmons condensation involving 14 gave an intermediate dienoate (> 95: 5d. r.), which after chemoselective alkyne desilylation (96% yield, over 2 steps) afforded the targeted C1–C13 fragment 4.