Asymmetric Synthesis of Bioactive Chiral Amines

生物活性手性胺的不对称合成

• 批准号: 6890274
• 负责人: GREGORY K FRIESTAD
• 金额: $ 25.81万
• 依托单位: UNIVERSITY OF IOWA
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890274
• 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.

描述：(申请人提供)含有手性成分的天然产品 α-支化胺亚结构及其非天然类似物仅可用 通过合成，对医学研究至关重要。例如, 微管蛋白是新发现的具有特殊化学成分的抗癌药物 结构和非凡的效力，因此代表着在 寻找用于化疗的新的实验性合成药物。在具体的 目标建议，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、杂化自由基离子环化和烯丙基硅烷 将使用手性肼的加成反应。合成目标包括 微管蛋白(微管分子抗分裂药物)、Dysiherbaine(非NMDA谷氨酸 受体激动剂)、氮杂糖(糖苷酶抑制剂)、奎宁(抗疟疾 除草剂)和拉苏宾II(生物活性喹唑类药物的亚单位)。在美国取得的成功 拟议的计划有可能提高合成的整体效率 具有重要药用价值的化合物，对 有机化学提供关键的使能技术 健康科学研究。这些项目还提供出色的培训，以 为新的研究人员在健康相关领域从事富有成效的职业做好准备。在 从长远来看，这些努力将推动人工合成的艺术和科学 有机化学迈向高效的理想，这是一个长期的目标 在复杂的天然产物的合成中，大多数情况下是无法获得的。