Asymmetric Synthesis of Nitrogen Heterocycles

描述(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的组装。与医学相关的分子绝大多数带有氮功能，在排名前200位的品牌药物中，有179种至少含有一个N原子。越来越多地，氮原子不仅是功能取代基，如侧胺或连接酰胺，而且以杂环的形式存在，通常带有立体中心。开发从容易获得的前体中获得这些杂环的方法是一个有吸引力的目标。生成的杂环将加快药物发现的步伐，从抗生素、抗抑郁药到蛋白质-蛋白质相互作用的激动剂和拮抗剂，如Hsp40-Hsp70，都有常见的基序可见。本研究的具体目标如下：1)开发[2+2+2]环加成反应的临时系链策略；2)研究酰胺类化合物和烯烃/炔烃？3)在金属催化的[4+2]反应中利用容易获得的氮二烯；以及4)实现异氰酸酯环加成反应，以涉及烯和乙烯基环丙烷。这门科学的长期影响是使化学家能够高效地快速组装复杂的结构。 公共卫生相关性：涉及小分子的健康相关研究的最大障碍之一是治疗剂的快速组装。这项提议寻求开发新的方法，利用易于获得的前体高效地合成复杂的框架。

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. PUBLIC HEALTH RELEVANCE: One of the most significant barriers to health-related research involving small molecules is the rapid assembly of therapeutic agents. This proposal seeks to develop new methods to synthesize complex frameworks using easily accessible precursors with high efficiency.