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Organocatalytic Practical Synthesis of Deuterated Building Blocks and Biologically Important Structures

氘代结构单元和生物学重要结构的有机催化实际合成

基本信息

批准号：
9918424
负责人：
WEI WANG
金额：
$ 28.07万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-10 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918424
关键词：
Alcohols Aldehydes Alder plant Amines Amino Acids Amino Sugars Ammonium Architecture Aziridines Benzopyrans Biological Biological Process Biomedical Research Boronic Acids Breslow Thickness CD3 Antigens Carbon Dioxide Catalysis Chemicals Chemistry Complex Coupling Decarboxylation Detection Deuterium Development Dyes Electrons Engineering Epoxy Compounds Esters Hydrogen In Situ Iodides Ions Isotopes Kinetics Lead Metabolic Metals Methods Methylation Molecular Organic Synthesis Pathway interactions Pharmaceutical Preparations Positioning Attribute Preparation Process Property Reaction Reagent Research Research Personnel Safety Series Signal Transduction Site Source Structure System Therapeutic Transition Elements Visible Radiation Water adduct carbene catalyst cost cost effective cyclopropane drug discovery fascinate functional group glyoxylic acid improved innovation interest novel nucleophilic addition operation programs quinone methide small molecule tool wasting ylide

项目摘要

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.

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