Synthesis of Bioactive Complex Alkaloids

生物活性复合生物碱的合成

• 批准号: 7278031
• 负责人: David Y Gin
• 金额: $ 25.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-10 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278031
• 关键词: acylation; alkaloids; antineoplastics; benzazepines; biological products; chemical synthesis; cyclization; harringtonines; molecular rearrangement; muscle relaxants; nitrogenous heterocyclic compound; pyrrolidines; stereochemistry; vasodilators; ylide

DESCRIPTION (provided by applicant): This research program focuses on the development of new synthetic strategies for the synthesis of complex biologically active alkaloid natural products. The objective is not only to simply achieve the total syntheses of biologically relevant natural product targets, but also to explore and develop new synthetic approaches and reactions to address specific challenges in synthetic organic chemistry. The antiabortifacient asparagamine A, the anti-leukemic Cephalotaxus esters deoxyharringtonine and drupangtonine, and the potent vaso-dilator kobusine are the targets for chemical synthesis. All of these natural products exhibit potent yet distinct biological activities; however, they are all structurally characterized by a pyrrolidine ring embedded within a complex polycyclic architecture. This research program will investigate new methods and strategies for functionalized nitrogen-heterocycle synthesis, including azomethine ylide generation and cycloaddition via the O-sulfonylation or O-acylation of vinylogous amides for the preparation of complex pyrrolidines, as well as strain-accelerated [3,3]-sigmatropic rearrangement for the synthesis of complex benzazepines. Successful synthesis of these target molecules will not only lay the foundation for efficient and practical strategies for complex alkaloid synthesis, but will also provide access to rare natural products of biological interest and therapeutic potential in a variety of health areas, including: (1) the prevention of health risks associated with pre-term labor; (2) the treatment of leukemia; and (3) the treatment of high blood pressure and congestive heart failure induced by vasoconstriction.

描述（由申请人提供）： 该研究计划的重点是开发新的合成策略，用于合成复杂的生物活性生物碱天然产物。该目标不仅是简单地实现与生物学相关的天然产品目标的总合成，而且还探索和开发新的合成方法和反应，以应对合成有机化学中的特定挑战。抗阳性天冬氨酰胺A，抗白血病的头孢菌素酯脱氧汉丁氏素和drupangtonine以及有效的VASO脱脂剂Kobusine是化学合成的靶标。所有这些天然产品都表现出强大而不同的生物学活动。但是，它们在结构上都是嵌合在复杂的多环体中的吡咯烷环。该研究计划将调查功能化氮突起合成的新方法和策略，包括偶氮胺ylide的产生和通过O-磺酰基化或乙烯基焦点的O-酰化为复杂的吡咯烷的制备的乙烯基副酰胺，以及复杂的pyrrololidines的制备[3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3]苯甲酰苯丙胺。成功合成这些靶分子不仅将为复杂的生物碱合成奠定高效和实用的策略，而且还将在各种健康领域提供罕见的生物学兴趣和治疗潜力的天然产物，包括：（1）预防与预期劳动相关的健康风险； （2）白血病的治疗； （3）血压和血管收缩引起的充血性心力衰竭的治疗。