Synthesis of Bioactive Natural Products

生物活性天然产物的合成

• 批准号: 8008963
• 负责人: Amos B Smith
• 金额: $ 9.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-29 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8008963
• 关键词: Anions; Architecture; Area; Biological; Biological Factors; Chemistry; Complex; Cyclization; Development; Frustration; Goals; Indoles; Macrolide Antibiotics; Macrolides; Marines; Methodology; Methods; Modeling; Molecular; Nitrogen; Oxygen; Structure-Activity Relationship; Time; Update; design; discodermolide; experience; flasks; nodulisporic acid A; programs; sorangicin A; spirastrellolide A

The principal goals for the 24-27 years update since July 2005 will now include: (A) development of an enantioselective total synthesis of the potent insecticidal agent (+)-nodulisporic acid A, (B) completion of the total synthesis of the challenging macrolide antibiotic (+)-sorangicin A; and (C) development of a viable enantioselective total synthesis of the architecturally complex marine antitumor macrolide spirastrellolide A. As in the past, each of these targets will require the development of as yet unforeseen new synthetic methodology to overcome unforeseen obstacles. This is indeed the excitement and frustration of target oriented total synthesis. In the area of new synthetic methods, we will: (D) develop the new modular indole synthesis comprising a sequential Stille and Buchwald-Hartwig cross-coupling union/cyclization tactic, devised in conjunction with the nodulisporic acid A synthetic venture; (E) expand and showcase the new concept of Anion Relay Chemistry (ARC), a powerful synthetic tactic introduced at the time of our previous renewal application, albeit without "proof of concept". Towards the latter end,we will explore a wide variety of nucleophiles, silyl linchpins possessing various anion stabilizing groups (ASG), and electrophiles to demonstrate the feasibility and rapid assembly of diverse, stereochemically complex oxygen and nitrogen substituted products in a single flask. Beyond these specific synthetic objectives, a general, long-range goal of this program is the identification of the molecular architecture responsible for biological activity. Thus, as we develop an approach to each target, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships. Our experience with discodermolide gives us great confidence in this area.

自2005年7月以来的24-27年更新的主要目标现在将包括： 有效杀虫剂（+）-节孢酸A的对映选择性全合成，（B）完成 具有挑战性的大环内酯类抗生素（+）-囊兰菌素A的全合成;和（C）开发一种可行的 结构复杂的海洋抗肿瘤大环内酯螺环内酯A的对映选择性全合成。 与过去一样，这些目标中的每一个都需要开发尚未预见的新的合成药物。 克服不可预见的障碍。这的确是塔吉特的兴奋和沮丧 定向全合成 在新的合成方法方面，我们将：（D）开发新的模块化吲哚合成 包括顺序的Stille和Buchwald-Hartwig交叉偶联结合/环化策略， 与nodulisporic酸的合成合资企业;（E）扩大和展示新的概念， 阴离子中继化学（ARC），一个强大的合成策略，在我们以前的更新时间介绍 这是一个“概念证明”，尽管没有“概念证明”。为了达到后者的目的，我们将探讨各种各样的 亲核试剂、具有各种阴离子稳定基团（ASG）的甲硅烷基关键试剂和亲电试剂， 展示了不同的、立体化学复杂的氧和氮的可行性和快速组装 单个烧瓶中的替代产品。 除了这些具体的综合目标之外，该计划的一个总体长期目标是 鉴定负责生物活性的分子结构。因此，当我们开发一个 方法每个目标，我们还将准备模型化合物，旨在允许阐明 构效关系我们在discodermolide方面的经验给了我们在这一领域的巨大信心。