Chivosazole A -: Elucidation of the absolute and relative configuration
Chivosazole A -: Elucidation of the absolute and relative configuration
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DOI：
10.1002/anie.200605198
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Kalesse, Markus
中科院分区：
文献类型：
--
作者：
Janssen, Dominic;Albert, Dieter;Kalesse, Markus
黏菌是结构多样、具有生物活性的天然产物的宝贵来源。在从纤维素高粱中分离的多种菌株中，Soce12菌株产生几种重要的抗生素或细胞毒性化合物，如soranigicinA、[1]sorangiolides、[2]disorazoles、[3]和chivosazoles。chivosazole（表1）是一个由31个成员组成的大环内酯类化合物家族，于1997年在Helmholtz感染研究中心（HZI，原GBF）从S. cellulosum So ce12中分离出来它们对酵母和丝状真菌有活性，对哺乳动物细胞培养物有很强的细胞毒性（L929和HeLa的IC50为9 ng mLÀ1）。从结构上看，该31元大内酯可分为3个多烯段（C2-C9、C12-C15和C23-C28）、羟基化酮段（C20-C23和C29-C35）和一个恶唑段。除了chivosazole F(7)外，所有的天然变体在C11处都含有6-脱氧葡萄糖吡喃糖（chinovose）。通过质谱和核磁共振研究确定了其结构然而，由于缺乏十个立体中心的立体化学信息，这种非常有效的天然产物的化学合成受到阻碍。然而，其显著的生物活性和效力，结合其复杂的结构，促使我们确定构型的chivosazole A(1)作为其化学合成的先决条件。在这里，我们描述了如何通过化学降解、部分合成、核磁共振波谱和遗传分析的组合来分配齐伏唑的绝对构型和相对构型在调查开始时，我们分析了C32和C34的相对结构。用Rychnovsky和Evans描述的方法在侧链上生成丙酮，并进行了检测；[6]在δ= 24.8, 25.2和101.8 ppm处发现了三个新的13C核磁共振信号，从而表明C32和C34之间存在1,3 -反二醇关系（方案1）。确定邻域的配置
Myxobacteria are a valuable source of structurally diverse biologically active natural products. Among the various strains isolated from Sorangium cellulosum, strain Soce12 produces several important antibiotic or cytotoxic compounds such as soranigicinA,[1] sorangiolides,[2] disorazoles,[3] and chivosazoles. The chivosazoles (Table 1) form a family of 31-membered macrolides which were isolated from S. cellulosum So ce12 at the Helmholtz Centre for Infection Research (HZI, formerly GBF) in 1997.[4] They are active against yeasts and filamentous fungi and they are highly cytotoxic against mammalian cell cultures (IC50 9 ng mLÀ1 for L929 and HeLa). Structurally, the 31-membered macrolactone can be dissected into three polyene segments (C2–C9, C12–C15, and C23–C28), hydroxylated ketide segments (C20–C23 and C29–C35), and an oxazole moiety. Except for chivosazole F (7), all the natural variants possess a 6-desoxyglucopyranose unit (chinovose) at C11.The structure of chivosazole A (1) was established by mass spectrometry and NMR studies.[4] However, chemical synthesis of this very potent natural product was obstructed by the lack of stereochemical information on the ten stereocenters. Nevertheless, its remarkable biological activity and potency combined with its complex structure prompted us to determine the configuration of chivosazole A (1) as a prerequisite for its chemical synthesis. Herein we describe how the absolute and relative configuration of chivosazole has been assigned through a combination of chemical degradation, partial synthesis, NMR spectroscopy, and genetic analysis.[5] At the start of our investigations we analyzed the relative configuration of C32 and C34. An acetonide was generated in the side chain and examined with the aid of the method described by Rychnovsky and Evans;[6] three new 13C NMR signals were found at δ= 24.8, 25.2, and 101.8 ppm, thereby indicating a 1, 3-anti-diol relationship between C32 and C34 (Scheme 1). To determine the configuration of the adjacent