Organocatalytic Practical Synthesis of Deuterated Building Blocks and Biologically Important Structures

项目摘要 氢化化学的令人沮丧的复杂性，数量非常有限的氢化积木 制造它们的可获得性和高昂的成本阻碍了获得人们热切寻求的氚生物活性分子。 因此，实用的合成多功能的氢化积木和‘特权’结构将有助于 为了他们的生物学研究和药物发现，构建感兴趣的氚分子。我们希望 发展一种新的胺化活化模式--“铵催化” 综合。我们挑战了加合物中的胺部分的教义，这是由亲核加成得到的。 亚胺离子可以在随后的反应中作为离开基团。推定的胺的原位释放 这些加成产品将为醛的氨基催化直接功能化创造一个新的方案。它 将展示一些前所未有高效催化级联反应将通过以下方式实现 新的有机催化剂和新的反应活性。这些级联过程产生了一系列令人着迷的 具有区域选择性的高价值新型络合物‘特权’苯并吡喃和氢喹啉 在代谢性不稳定的位置掺入氢。此外，第一张二进制照片-和 有机催化甲酰化反应和NHC卡宾促进H/D交换过程 开发低成本的非金刚醛对合成具有重要意义 氢化的醛和烯烃。此外，实用的手性胺催化的对映体选择性H/D 交换-α-官能化级联反应合成手性氚高价化合物 将开发(氨基糖、氨基酸、醇、胺等)块。最后，新的 三甲基亚砜促进CH3/CD3交换反应合成和 具有医疗价值的氢化甲基、环丙烷、环氧化物、氮杂环丙烷和治疗药物 完成了。这些氢化的积木、分子结构和药物用作 生物医学研究人员用于构建生物分子、生物和药物的宝贵工具 发现性研究。

Project Summary The frustrating complexity of deuteration chemistry, a very limited number of deuterated building blocks available and high cost of making them hamper access to highly sought deuterated bioactive molecules. Therefore, practical synthesis of versatile deuterated building blocks and `privileged' structures will facilitate the construction of deuterated molecules of interest for their biological studies and drug discovery. We wish to develop a new aminocatalytic activation mode termed `ammonium catalysis' for deuterated molecule synthesis. We challenge the dogma of amine moieties in adducts resulting from nucleophilic additions to iminum ions can serve as leaving groups in ensuing reactions. In situ release of the presumed amine from the addition products will create a new scenario for aminocatalytic direct functionalization of aldehydes. It will be demonstrate that a number of unprecedented efficient catalytic cascade reactions will be realized by the new organic catalysts and new reactivities. These cascade processes produce a fascinating array of highly valued novel complex `privileged' benzopyrans and hydroquinolines with regioselective incorporation of deuterium at metabolically labile sites. In addition, the first binary photo- and organo-catalytic formylation reaction and NHC carbene promoted H/D exchange process with simple non-deuterated aldehydes will be developed for low cost synthesis of fundamentally important deuterated aldehydes and enals. Furthermore, practical chiral amine-catalyzed enantioselective H/D exchange-α-functionalization cascade reactions for synthesis of chiral deuterated highly valued building blocks such as (amino)sugars, amino acids, alcohols, amines etc. will be developed. Finally, new trimethylsulfoxonium iodide promoted CH3/CD3 exchange reactions for synthesis of synthetically and medicinally valued deuterated methyl, cyclopropanes, epoxides, aziridines and therapeutics will be accomplished. These deuterated building blocks and molecular architectures and drugs serve as valuable tools for biomedical researchers to use for biomolecule constructions and biological and drug discovery studies.