Total Synthesis of Biologically Active Gamma-Pyrones

生物活性γ-吡喃酮的全合成

• 批准号: 6890272
• 负责人: DIRK HARTWIG TRAUNER
• 金额: $ 23.91万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/6890272
• 关键词: Mollusca; Streptomyces; antibiotics; biological products; chemical addition; chemical synthesis; cyclization; drug design /synthesis /production; heterocyclic polycyclic compound; immunosuppressive; ion channel blocker; potassium channel; propionates; pyrones; stereochemistry

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SNF 4435 C和D以及抗生素spectinabilin和N-乙酰金胺的全合成。这些高度不饱和的聚丙酸酯从各种菌株的链霉菌属分离。此外，对软体动物聚丙酸酯光脱氧tridachione和cristapene以及真菌免疫抑制剂candelalide A和B的合成方法。所有天然产物的特征是末端γ-吡喃酮部分作为共同的结构基序。 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，SNF 4435化合物的核心双环[4.2.0]辛环核心可以使用高度立体选择性串联Stille交叉偶联/电环化级联形成。还开发了一种新的路易斯酸催化的环化反应，导致光去氧三达酮和克立巴烯的双环[3.1.0]己烷核。 建议的全合成提供了一个机会，研究不对称电环化反应。与环加成和σ转移重排相反，这类周环反应尚未屈服于不对称催化。在合成方法的进一步贡献，对γ-吡喃酮的新方法提出。γ-吡喃酮部分的天然产物的生物活性的意义将进行探讨。 SNF 4435 C和D的生物学作用模式目前仍不清楚。天然产物不抑制IL-2的产生，与FK 506或环孢菌素A不同。我们的合成材料及其衍生物将用于分离结合蛋白，并进一步了解这些有前途的新先导化合物的药物开发机制。