Asymmetric Synthesis with Strained Molceules

应变分子的不对称合成

• 批准号: 6918070
• 负责人: JOSEPH M FOX
• 金额: $ 26.43万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-05 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918070
• 关键词: alkaloids; aminoacid; chemical addition; chemical models; chemical synthesis; cycloalkene; method development; organometallic compounds; stereochemistry

DESCRIPTION (provided by applicant): The development of new reactions for organic synthesis is at the core of health related fields such as drug discovery, process chemistry, natural products synthesis and biologically inspired molecular design. While the state of the art is such that remarkably complex molecules can be synthesized given ample time and skilled personnel, there persists a need for tandem reactions that couple simple partners to selectively produce complex products. The goal of this research program is to harness the unusual reactivity of high strain molecules to quickly generate molecules that are rich in stereochemical complexity and structural diversity. These 'strain assisted' reactions include directed nucleophilic addition/capture sequences and cycloaddition reactions of cyclopropenes and bicyclobutanes. In order for the methodology to have broad utility, it is explicitly necessary to develop asymmetric and enantioselective syntheses and reactions. While the exploratory stages of any program in synthetic methodology rely on screening, the refinement stage of each method will rely heavily on mechanistic analysis. The applications of this research are threefold: 1) the development of new synthetic methods that will have broad utility because they address fundamental, unsolved problems; 2) the development of unnatural amino acids with applications in environmentally responsive biomaterials; 3) the use of strained molecules in the syntheses of alkaloids with all-carbon quaternary centers and in the synthesis of pycnocomolide - a 12-deoxy-16-hydroxyphorbol natural product that is a potent activator of PKC and a target as a cancer drug. The syntheses of computationally designed pycnocomolide analogs are also proposed.

描述(申请人提供)：有机合成的新反应的开发处于健康相关领域的核心，如药物发现、过程化学、天然产物合成和生物启发的分子设计。虽然目前的技术水平是，只要有充足的时间和熟练的人员，就可以合成非常复杂的分子，但仍然需要串联反应，将简单的伙伴连接起来，选择性地生产复杂的产品。 这项研究计划的目标是利用高应变分子的不同寻常的反应性来快速生成具有丰富的立体化学复杂性和结构多样性的分子。这些“菌株辅助”反应包括定向亲核加成/捕获序列以及环丙烯和双环丁烷的环加成反应。为了使方法学具有广泛的实用性，显然有必要开发不对称和对映体选择性的合成和反应。虽然合成方法论中任何程序的探索阶段都依赖于筛选，但每种方法的精炼阶段将严重依赖于机械分析。这项研究的应用有三个方面：1)开发将具有广泛实用价值的新的合成方法，因为它们解决了根本的、尚未解决的问题；2)开发非天然氨基酸，并将其应用于环境友好型生物材料；3)使用应变分子合成具有全碳四元中心的生物碱，以及合成碧萝蜜--一种12-脱氧-16-羟基佛波醇的天然产物，它是PKC的有效激活剂，也是抗癌药物的靶标。还提出了计算设计的碧萝蜜类似物的合成方法。