Asymmetric Synthesis of Nitrogen Heterocycles

氮杂环的不对称合成

• 批准号: 8332774
• 负责人: Tomislav Rovis
• 金额: $ 27.22万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332774
• 关键词: Agonist; Alkenes; Alkynes; Amides; Amines; Antibiotics; Antidepressive Agents; Complex; Coupling; Cyclopropanes; Goals; Health; Isocyanates; Link; Metals; Methodology; Methods; Names; Nitrogen; Pharmaceutical Preparations; Protocols documentation; Reaction; Research; Science; Structure; System; Therapeutic Agents; Ursidae Family; cycloaddition; cyclopropane; diene; drug discovery; method development; piperidine; programs; propadiene; protein protein interaction; small molecule

DESCRIPTION (provided by applicant): Modern drug discovery mandates the rapid and modular assembly of increasingly complex substances. Medicinally relevant molecules overwhelmingly bear nitrogen functionality with 179 of the top 200 brand name drugs containing at least one N-atom. Increasingly, the nitrogen atom is not merely a functional substituent, such as a pendant amine or linking amide, but is present in the form of a heterocycle, often bearing stereocenters. The development of methods to access these heterocycles from easily accessible precursors is an attractive goal. The resultant heterocycles will facilitate the pace of drug discovery, with the common motifs visible in biologically active agents ranging from antibiotics, antidepressants as well as agonists and antagonists of protein-protein interactions such as Hsp40-Hsp70. The specific goals of this research are as follows: 1) develop temporary tethering strategies for [2+2+2] cycloadditions; 2) Investigate the oxidative coupling of amides and alkene/alkyne ? systems to assemble piperidines by a catalyzed/oxidative protocol; 3) Exploit readily available aza-dienes in metal-catalyzed [4+2] reactions; and 4) Implement isocyanate cycloadditions to involve allenes and vinyl cyclopropanes. The long-term impact of this science is to enable chemists to rapidly assemble complex structures with high efficiency.

描述（由申请人提供）：现代药物发现要求对日益复杂的物质进行快速和模块化组装。医学相关分子绝大多数都带有氮官能团，前 200 种品牌药物中有 179 种至少含有一个氮原子。越来越多地，氮原子不仅仅是功能取代基，例如侧胺或连接酰胺，而且以通常带有立体中心的杂环形式存在。开发从容易获得的前体中获取这些杂环的方法是一个有吸引力的目标。由此产生的杂环将加快药物发现的步伐，其常见的基序在生物活性剂中可见，包括抗生素、抗抑郁药以及蛋白质-蛋白质相互作用的激动剂和拮抗剂，例如Hsp40-Hsp70。本研究的具体目标如下：1）开发[2+2+2]环加成的临时束缚策略； 2) 研究酰胺和烯烃/炔烃的氧化偶联？通过催化/氧化方案组装哌啶的系统； 3) 在金属催化的[4+2]反应中利用容易获得的氮杂二烯； 4)实施异氰酸酯环加成以涉及丙二烯和乙烯基环丙烷。这门科学的长期影响是使化学家能够快速高效地组装复杂的结构。