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。他们丰富的活动， 生物系统对于药物和天然产物是重要的。200强品牌中 在药物名称中，超过75%是杂环化合物。在自然界中，杂环化合物是 防御、交流和繁殖。低区域选择性，低立体/对映选择性， 在大多数多步合成中，冗长的合成序列和低的总产率使得其极其 为治疗目的提供足够量的所需生物活性杂环具有挑战性。 该NIH SuRE提案旨在开发和利用高选择性金属催化碳碳 键形成反应，将导致新的硒，硫，和氧的有效合成， 含有丰富生物活性的杂环化合物。该提案还旨在发展 用于在杂环中快速产生官能度和复杂性的多组分偶联方法， 一种新的选择性合并不对称共轭加成-酰化反应以及合并共轭 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。提出的新的C-C键形成和多组分反应将 为复杂的新型杂环化合物的合成提供了新的机会。金属催化的共轭物 在多烯Michael受体上加成亲核试剂是目前最有吸引力和最有效的C-C 合成相关分子的键形成策略，因为它提供了顺序合成的机会。 以简单的方式产生两个或更多个立体中心。多组分 通过直接捕获金属烯醇化物而实现的反应可以为金属烯醇化物提供强有力的转化。 在一锅中形成多个C-C键和手性中心。得到的多功能杂环 亚基和原位捕获金属烯醇化物将为新的创新提供极好的机会。 新的复杂杂环合成和药物发现的方法。进一步阐述这一点 化学将可能允许第一个非常重要的杂环类的对映选择性合成 例如双硒代黄酮、双硫代黄酮和生物活性双黄酮，潜在小分子 阿尔茨海默病的治疗方法。该SuRE项目预计将显着增强和 扩大研究能力，实现可持续的研究卓越WSSU，HBCU。

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.