Total synthesis of rutamycin B and oligomycin C.
Total synthesis of rutamycin B and oligomycin C.
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DOI：
10.1021/jo001767c
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发表时间：
2001-03
期刊：
影响因子：
--
通讯作者：
J. Panek;N. Jain
中科院分区：
文献类型：
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作者：
J. Panek;N. Jain
描述了大环内酯类抗生素(+)-rutamycin B(1)和(+)-oligomycin C(2)的不对称合成。该方法依赖于单个螺旋体片段3a和3b与C1-C17聚本体酸片段4的合成和偶联。螺旋酮片段的制备采用手性(E)-丁基硅烷键构建方法，该方法允许在螺旋酮化之前引入立体中心。本工作详细介绍了C19-C28和C29-C34亚基的合成及其通过锂化N，N-二甲基腙6和8的烷基化反应分别得到单个线性螺旋状中间体5a和5b的聚合组装。经过官能团调整后，这些高级中间体被环化到各自的螺旋轴偶联伙伴40和41上。所需要的聚丙酸片段是用不对称丁基化方法以会聚的方式组装的，以引入九个立体中心中的六个。C3-C12亚基32的构建采用连续三个丁基化反应。用手性α -甲基醛39与mukaiyama型醛醇反应35引入C12-C13立体中心。此抗醛醇完成了C3-C17高级中间体36的构建。双碳同源性完成了聚丙酸片段38的构建。两个大环内酯抗生素的合成是通过两个主要片段的结合完成的，这两个片段是通过分子间钯(0)催化的单个螺旋酮3a和3b的末端乙烯基锡烷与聚丙酸片段4之间的交叉偶联反应完成的。羧酸46和47在山口反应条件下被环化成大环内酯48和49。这些大环内酯的脱保护完成了rutamycin B和oligomycin C的合成。
The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral alpha-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.