Asymmetric Synthesis of Bioactive Chiral Amines

生物活性手性胺的不对称合成

• 批准号: 6744776
• 负责人: GREGORY K FRIESTAD
• 金额: $ 26.51万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744776
• 关键词: amines; antimitotics; biological products; chemical addition; chemical synthesis; cyclization; drug design /synthesis /production; free radicals; glutamate receptor; quinine; silanes; stereochemistry

DESCRIPTION: (provided by applicant) Natural products which contain chiral alpha-branched amine substructures, and their unnatural analogs available only through synthesis, are critically important for medical research. For example, tubulysins are newly discovered anticancer agents with unusual chemical structures and extraordinary potency, and therefore represent a new lead in the search for novel experimental synthetic drugs for chemotherapy. In the specific aims proposed, amine-containing natural products will be synthesized as the first tests of newly developed asymmetric carbon-carbon bond construction methodology in complex molecule synthesis. Novel asymmetric free radical addition, tandem cyclization, hybrid radical-ionic annulation, and allylsilane addition reactions of chiral hydrazones will be used. Synthesis targets include tubulysins (picomolar antimitotic agents), dysiherbaine (non-NMDA glutamate receptor agonist), azasugars (glycosidase inhibitors), quinine (antimalarial agent), and lasubine II (subunit of bioactive quinolizidines). Success in the proposed program has potential to increase overall efficiency in syntheses of medicinally important compounds, a broad and general contribution to the science of organic chemistry which provides critical enabling technology for health sciences research. The projects also provide excellent training to prepare new researchers for productive careers in health-related fields. In the long term, these endeavors will advance the art and science of synthetic organic chemistry toward the ideal of efficiency, a long-term goal which remains mostly inaccessible in syntheses of complex natural products.

性状：（申请人提供）含有手性的天然产物 α-支链胺亚结构及其非天然类似物， 对医学研究至关重要。比如说， 微管溶素是新发现的具有不寻常化学结构的抗癌剂， 结构和非凡的潜力，因此代表了一个新的领导， 寻找新的实验性化学治疗合成药物。在具体 提出的目标，含胺的天然产物将被合成为 新开发的不对称碳-碳键结构的首次测试 复杂分子合成的方法学。新型不对称自由基 加成、串联环化、混合自由基-离子成环和烯丙基硅烷 将使用手性腙的加成反应。综合目标包括 微管溶素（皮摩尔抗有丝分裂剂）、dysiherbaine（非NMDA谷氨酸盐 受体激动剂）、氮杂糖（糖苷酶抑制剂）、奎宁（抗疟药） 活性剂）和lasubine II（生物活性喹嗪啶的亚基）。成功 拟议的计划有可能提高综合的整体效率， 医学上重要的化合物，一个广泛的和一般的贡献， 有机化学的科学，提供关键的使能技术， 健康科学研究。这些项目还为以下人员提供了良好的培训： 为新的研究人员在卫生相关领域的生产性职业生涯做好准备。在 从长远来看，这些努力将促进合成的艺术和科学 有机化学朝着效率的理想，一个长期的目标， 在复杂天然产物的合成中仍然大多难以实现。