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Total Synthesis of Biologically Active Gamma-Pyrones

生物活性γ-吡喃酮的全合成

基本信息

批准号：
7227164
负责人：
DIRK HARTWIG TRAUNER
金额：
$ 24.84万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-02 至 2008-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Total syntheses of the immunosuppressants SNF4435 C and D as well as the antibiotics spectinabilin and N-acetyl aureothamine are proposed. These highly unsaturated polypropionates were isolated from various strains of Streptomyces sp. Furthermore, synthetic approaches towards the molluscan polypropionates photodeoxytridachione and crispatene as well as the fungal immunosuppressants candelalide A and B are presented. All natural products feature a terminal gamma-pyrone moiety as a common structural motif. Polyenes consisting of an array of conjugated trisubstituted double bonds have been used as synthetic precursors of the complex polypropionates. The stereoselective assembly of these structures will be further investigated. Preliminary studies have shown that the core bicyclo[4.2.0]octadiene core of SNF4435 compounds can be formed using a highly stereoselective tandem Stille cross-coupling / electrocyclization cascade. A novel Lewis-acid catalyzed cyclization leading to the bicyclo[3.1.0]hexane core of photodeoxytridachione and crispatene has also been developed. The proposed total syntheses provide an opportunity to investigate asymmetric electrocyclization reactions. As opposed to cycloadditions and sigmatropic rearrangements, this class of pericyclic reactions has not yet succumbed to asymmetric catalysis. In a further contribution to synthetic methodology, new approaches towards gamma-pyrones are proposed. The significance of the gamma-pyrone moiety for the biological activity of the natural products will be explored. The biological mode of action of SNF4435C and D remains presently unknown. The natural products do not suppress IL-2 production, distinguishing them from FK506 or cyclosporin A. Our synthetic material and derivatives thereof will be used to isolate binding proteins and gain further insight into of the mechanism of these promising new lead compounds for drug development.

描述(由申请人提供)：提出了免疫抑制剂SNF4435C和D以及抗生素壮观比林和N-乙酰金葡胺的全合成方法。这些高度不饱和聚丙酸酯是从链霉菌的不同菌株中分离得到的。此外，还介绍了软体动物聚丙酸酯、光脱氧三达环酮和松香烯的合成方法，以及真菌免疫抑制剂蜡烛内酯A和B的合成方法。所有天然产物都有一个共同的结构基元，即末端的伽马-吡喃酮部分。由一系列共轭三取代双键组成的多烯已被用作复合聚丙酸酯的合成前体。这些结构的立体选择性组装将进一步研究。初步研究表明，SNF4435化合物的核心双环[4.2.0]辛二烯核可以通过高度立体选择性的串联Stille交叉偶联/电环化级联形成。一种新颖的Lewis酸催化的环化反应也被开发出来，该环化反应导致了光脱氧三达环酮和皱纹石烯的双环[3.1.0]正己烷核。所提出的全合成为研究不对称电环反应提供了机会。与环加成反应和顺式重排反应不同，这类周环反应尚未屈服于不对称催化。在对合成方法学的进一步贡献中，提出了伽马-吡喃的新方法。将探讨伽马-吡喃酮部分对天然产物生物活性的意义。 SNF4435C和D的生物学作用机制目前尚不清楚。天然产物不抑制IL-2的产生，区别于FK506或环孢素A，我们的合成材料及其衍生物将用于分离结合蛋白，并进一步深入了解这些有希望的新先导化合物的药物开发机制。