Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I.
Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I.
复制标题
( )-Mycottrienol 和 ( )-Mycotrienin I 的全合成。
DOI：
10.1021/jo971793j
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
C. Masse
中科院分区：
文献类型：
--
作者：
J. Panek;C. Masse
1985年，Umezawa及其同事报道了从链霉菌83-16号的培养液中分离出五种新的安莎霉素抗生素，即三烯霉素AE。1这些分子在体外对HeLa S3细胞表现出很强的细胞毒性。2它们的相对和绝对立体化学已由Smith通过仔细的降解和光谱方法确定。3.（+）-mycotrienin I和II，以前已从Streptomyces rishiriensis T-23的发酵液中分离得到，显示出有效的抗真菌活性。4立体化学相关性研究已将三烯霉素的绝对立体化学归属扩展到（+）-真菌三烯苷I和II，并因此扩展到真菌三烯酚（方案1）。[5]到目前为止，Smith及其同事报道了这类化合物的唯一全合成，特别是三烯霉素A和F的合成。6我们用于合成这类抗肿瘤抗生素成员的逆合成计划，如方案1所示，允许高度收敛，并通过串联分子间/分子内Stille偶联来实现大环化。对真菌三烯酚骨架的分析揭示了两种不同的亚基：（i）C9-C16聚丙酸酯亚基3，其立体化学问题通过手性烯丙基硅烷键构建方法容易获得; 7（ii）芳族亚基4，其在C3处的单个立构中心也可以使用手性（E）-巴豆基硅烷试剂来解决。C9-C16亚基的构建通过R-酮基-二苄基缩醛5和硅烷试剂（S）-6之间的不对称巴豆酰化来起始，以建立C12-C13中心（方案2）。第一次加成通过反周面过渡态进行，其中观察到的立体化学与反SE ′相一致。
In 1985, Umezawa and co-workers reported the isolation of five novel ansamycin antibiotics, trienomycins AE, from the culture broth of Streptomyces sp. No. 83-16. 1 These molecules exhibited strong cytotoxicity in vitro against HeLa S3 cells. 2 Their relative and absolute stereochemistry has been determined by Smith through careful degradative and spectroscopic methods. 3 The (+)-mycotrienins I and II, which have previously been isolated from the fermentation broth of Streptomyces rishiriensis T-23, have displayed potent antifungal activity. 4 Stereochemical correlation studies have extended the absolute stereochemical assignments of the trienomycins to the (+)-mycotrienins I and II, and therefore to the mycotrienols (Scheme 1). 5 To date, Smith and coworkers have reported the only total synthesis of members of this class of compounds, specifically the synthesis of trienomycins A and F. 6Our retrosynthetic plan for the synthesis of members of this class of antitumor antibiotics, illustrated in Scheme 1, allows for a high degree of convergency and is highlighted by a tandem inter/intramolecular Stille coupling to effect macrocyclization. Analysis of the mycotrienol skeleton reveals two distinct subunits:(i) the C9-C16 polypropionate subunit 3 whose stereochemical issues are readily accessible through chiral allylsilane bond construction methodology; 7 (ii) the aromatic subunit 4 whose single stereocenter at C3 can also be addressed using a chiral (E)-crotylsilane reagent. The construction of the C9-C16 subunit was initiated by an asymmetric crotylation between the R-keto-dibenzylacetal 5 and silane reagent (S)-6 to establish the C12-C13 centers (Scheme 2). This first addition proceeds through an antiperiplanar transition state where the observed stereochemistry is consistent with an anti-SE′