Total Synthesis of Biologically Active Gamma-Pyrones

生物活性γ-吡喃酮的全合成

• 批准号: 7060127
• 负责人: DIRK HARTWIG TRAUNER
• 金额: $ 2.29万
• 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/7060127
• 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 SNF4435 C 和 D 以及抗生素 spectinabilin 和 N-乙酰基金胺的全合成。这些高度不饱和的聚丙酸酯是从各种链霉菌菌株中分离出来的。此外，还提出了软体动物聚丙酸盐光脱氧三达酮和 Crispatene 以及真菌免疫抑制剂 Candelalide A 和 B 的合成方法。所有天然产品都以末端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得到进一步研究。初步研究表明，SNF4435 化合物的双环[4.2.0]辛二烯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环化反应，形成光脱氧三达酮和 Crispatene 的双环[3.1.0]己烷核心。 所提出的全合成提供了研究不对称电环化反应的机会。与环加成和σ重排相反，这类周环反应尚未屈服于不对称催化。为了对合成方法学做出进一步的贡献，提出了制备γ-吡喃酮的新方法。将探讨γ-吡喃酮部分对于天然产物生物活性的重要性。 SNF4435C 和 D 的生物学作用模式目前仍不清楚。天然产物不会抑制 IL-2 的产生，这与 FK506 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，并进一步深入了解这些有前途的新先导化合物的药物开发机制。