Organocatalytic Practical Synthesis of Deuterated Building Blocks and Biologically Important Structures

项目摘要 令人沮丧的复杂性，氘化学，一个非常有限的数量的氘积木 然而，由于它们的可用性和制造成本高，阻碍了获得高度寻求的氘代生物活性分子。 因此，多功能氘代结构单元和“特权”结构的实际合成将有助于 构建生物学研究和药物发现所感兴趣的氘代分子。我们希望 发展了一种新的氘代分子氨基催化活化模式--“氨催化 合成.我们挑战的教条，胺部分的加合物所产生的亲核加成， 亚胺离子可以在随后的反应中用作离去基团。假定的胺从 加成产物将为醛的氨基催化直接官能化创造新的方案。它 将证明，许多前所未有的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迷人的 具有区域选择性的高价值的新型复合物“特权”苯并吡喃和氢喹啉 氘在代谢不稳定位点的掺入。此外，第一个二元照片-和 有机催化脱氢反应和NHC卡宾促进的H/D交换过程， 非氘代醛将被开发用于低成本合成至关重要的 氘代醛和烯醛。此外，实用的手性胺催化的对映选择性H/D 交换-α-功能化级联反应合成手性氘代高价值建筑物 将开发诸如（氨基）糖、氨基酸、醇、胺等的嵌段。最后，新 三甲基碘化亚砜促进的CH 3/CD 3交换反应用于合成和 具有药用价值的氘代甲基、环丙烷、环氧化物、氮丙啶和治疗剂将是 完成了这些氘化的构建块和分子结构以及药物作为 生物医学研究人员用于生物分子构建以及生物和药物 发现研究

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.