Development of Efficient Carbon Carbon Bond Formations for Novel Se-, S-, and O-Heterocycle Synthesis

NIH Sure项目-摘要 杂环化合物占所有已知有机化合物的50%以上。他们在中国的丰富活动 生物系统对制药和天然产品很重要。跻身200强品牌 药品名称，75%以上为杂环化合物。在自然界中，杂环是活性成分 防御、交流和繁殖。低区域选择性，低立体/对映体选择性， 在大多数多步合成中，合成序列很长，总收率很低，这使得它非常 为治疗目的提供足够数量的所需生物活性杂环具有挑战性。 NIH SURE计划旨在开发和利用高选择性的金属催化碳碳 键形成反应将导致有效地合成新的硒、硫和氧- 含有具有丰富生物活性的杂环化合物。这项提案还旨在开发 用于在杂环中快速产生官能团和复杂性的多组分耦合方法， 一种新的选择性合并不对称共轭加成反应--酰化反应及合并共轭化合物 加成-氧化策略，将导致合成新类别的生物活性硒、硫- 含有杂环的。提议的新的C-C键形成和多组分反应将 为合成复杂的新型杂环化合物提供了新的机会。金属催化的偶联物 在多烯Michael受体上加成亲核试剂是最有吸引力和最有效的C-C 用于合成相关分子的成键策略，因为它提供了顺序 以直截了当的方式产生两个或多个立体中心。多组分 通过直接捕获金属烯烃而实现的反应可以为 在一个罐中形成多个C-C键和手性中心。合成的多功能杂环 亚基和原位捕获金属烯醇化合物将为新的创新提供极好的机会 新型杂环杂环化合物的合成和药物发现方法。进一步阐述这一点 化学很可能首次实现非常重要的杂环类化合物的对映选择性合成 如双烯黄酮类、二硫代黄酮类和生物活性双黄酮类、潜在小分子 阿尔茨海默病的治疗学。这一SURE项目预计将显著增强和 扩大研究能力，以实现HBCU WSSU的可持续研究卓越。

NIH SuRE Project – Abstract Heterocycles account for more than 50% of all known organic compounds. Their rich activities in biological systems are important for pharmaceuticals and natural products. Among the top 200 brand name drugs, over 75% are heterocyclic compounds. In nature, heterocycles are active components for defense, communication, and reproduction. Low regioselectivities, low stereo-/enantioselectivities, lengthy synthetic sequences, and low overall yields in most multi-step syntheses make it extremely challenging to provide sufficient quantities of desired bioactive heterocycles for therapeutic purposes. This NIH SuRE proposal aims to develop and utilize highly selective metal catalyzed carbon carbon bond formation reactions that will lead to efficient synthesis of novel selenium, sulfur, and oxygen- containing heterocycles with rich biological activities. This proposal also aims to develop multicomponent coupling processes for rapid generation of functionality and complexity in heterocycles, a new selective merged asymmetric conjugate addition-acylation as well as a merged conjugate addition-oxidation strategy that will lead to the synthesis of new classes of bioactive selenium, sulfur- containing heterocycles. The proposed new C-C bond formations and multicomponent reactions will provide new opportunities for complex novel heterocycle synthesis. The metal-catalyzed conjugate addition of nucleophiles onto polyenic Michael acceptors is one of the most attractive and powerful C-C bond forming strategies for synthesis of relevant molecules, as it provides opportunity for sequential generation of two or more stereogenic centers in a straightforward fashion. The multicomponent reactions enabled by direct trapping of metal enolates could provide powerful transformations for the formation of multiple C-C bonds and chiral centers in a single pot. The resultant versatile heterocyclic subunits and trapping of the metal enolates in situ will provide excellent opportunities for new innovative approaches for novel complex heterocyle synthesis and drug discovery. Further elaboration of this chemistry will likely allow the first enantioselective synthesis of very important classes of heterocycles such as biselenoflavonoids, bithioflavonoids and bioactive biflavonoids, potential small molecule therapeutics for Alzheimer’s disease. This SuRE project is expected to significantly enhance and expand the research capacity towards a sustainable research excellence at WSSU, a HBCU.