Synthesis of Bioactive Natural Products

生物活性天然产物的合成

• 批准号: 8245370
• 负责人: Amos B Smith
• 金额: $ 30.29万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245370
• 关键词: 3-hydroxybutanal; Accounting; Achievement; Acids; Address; Alkaloids; Alkenes; Anions; Antineoplastic Agents; Bacteria; Biological; Biological Factors; Charge; Chemistry; Clinical; Color; Complex; DNA Sequence Rearrangement; Development; Evaluation; Evolution; FK506; Family member; Generations; Goals; Hematoxylin and Eosin Staining Method; Immigration; Lead; Libraries; Life; Macrolide Antibiotics; Macrolides; Marines; Mediating; Medicine; Methods; Outcome; Phase; Property; Publications; Reaction; Research; Route; Scheme; Sirolimus; Solvents; Spongistatin; Study Section; Terpenes; Time; analog; clinically significant; design; discodermolide; dithiane; innovation; kendomycin; milbemycin; nodulisporic acid A; novel; penitrem D; polymerization; programs; sorangicin A; tedanolide

DESCRIPTION (provided by applicant): This research program (GM-29028), now in the twenty-seventh year, embodies the evolution of our long- standing commitment to: (A) enantioselective total synthesis of architecturally challenging, pharmacologically important natural products, (B) development and application of new, innovative synthetic methods, and (C) delivery of select targets and analogues in sufficient quantities (ca. 1 gram) for detailed biological evaluation. Going forward, the major thrust of 28-31 year program will be to define, at a fundamental level, the exciting potential of Anion Relay Chemistry (ARC). To demonstrate the diverse chemotypes accessible employing the ARC tactic, we will also undertake several target-oriented syntheses. Thus the revised overall Specific Aims for this program now include: (1) Design, synthesize and validate new, structurally novel linchpins to expand the utility of the ARC tactic; (2) Develop a detailed mechanistic understanding of the ARC tactic, with particular focus on the precise timing and stereochemical outcome of [1,n]-Brook rearrangements to maximize ARC efficiency; (3) Devise and explore an alternate route into the ARC reaction manifold; and most significantly, (4) Demonstrate the power of Iterative ARC (I-ARC) tactics (cf. living polymerization) for complex molecule synthesis (vide infra). To showcase the ARC tactic, we will: (5) Complete the total synthesis of (+) spirastrellolide B, an extremely potent marine antitumor macrolide; (6) Construct a small library of curvularin family members; and (7) Achieve effective total syntheses of secu'amamine A and EBC-23, an alkaloid and terpene respectively, representing two additional chemotypes that demonstrate the utility of the step-efficient ARC tactic. PUBLIC HEALTH RELEVANCE: The principal goal of this research program comprises the design and application of new, innovative synthetic methods, in conjunction with the development of effective synthetic strategies to synthesize architecturally complex natural and natural product like compounds possessing significant bio-regulatory properties that serve as lead compounds for the discovery of new medicines.

描述（由申请人提供）：该研究计划（GM-29028）现在在二十七年中，体现了我们长期坚持的承诺的演变：（a）对建筑具有挑战性，药理学上重要的自然产物的结构的启示性完全合成，（b）新的，创新的合成方法和（c）的量子和（c）的量子（c）范围（c）ca and（c）ca and（c）的量详细的生物学评估。 展望未来，28 - 31年计划的主要目的是在基本水平上定义阴离子继电器化学（ARC）的令人兴奋的潜力。为了证明采用ARC策略可访问的不同化学型，我们还将进行几种面向目标的合成。因此，经过修订的该程序的整体特定目标现在包括：（1）设计，合成和验证新的，结构新颖的Linchpins，以扩大ARC策略的实用性； （2）对ARC策略产生详细的机械理解，特别关注[1，n] -brook重排的精确时机和立体化学结果，以最大程度地提高ARC效率； （3）设计并探索进入弧反应歧管的替代路线；最重要的是，（4）证明了迭代弧（I-ARC）策略（参见生活聚合）用于复杂分子合成（INFRA）。为了展示ARC战术，我们将：（5）完成（+）螺旋藻B的总合成，这是一种极有效的海洋抗肿瘤大花环； （6）构建一个小型曲线库林的家族成员； （7）分别获得生物碱和萜烯的Secu'amamine A和EBC-23的有效总合成，代表了另外两种额外的化学型，这些化学型表明了逐步效力的ARC策略的实用性。 公共卫生相关性：该研究计划的主要目标包括新的创新合成方法的设计和应用，结合开发有效的合成策略，以合成建筑具有复杂的自然和天然产品，例如具有重要的生物调控特性，这些化合物具有新药物的发现，可作为新药物的铅化合物。