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：
9892834
负责人：
WEI WANG
金额：
$ 10万
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/9892834
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.

项目摘要剥离化学的令人沮丧的复杂性，申高的构件数量非常有限可用的和高昂的成本，使它们妨碍了人们获得备受瞩目的属性生物活性分子。因此，多功能授权的构件和“特权”结构的实际综合将有助于为其生物学研究和药物发现的氘化分子的构建。我们希望开发一种新的氨基催化激活模式，称为氘化分子的“铵催化” 合成。我们挑战了胺基部分的教条。米尼克离子可以作为确保反应的群体。原位释放假定的胺从该添加产品将为醛的氨基催化直接功能化创建新的方案。将证明，许多前所未有的有效催化级联反应将由新的有机催化剂和新的反应性。这些级联过程产生了一个引人入胜的阵列具有调节性的高度有价值的新颖的复合物“特权”苯并二氧化碳和氢喹啉在代谢标签位点掺入氘。此外，第一个二进制照片 - 和有机催化的甲基化反应和NHC Carbene促进了H/D交换过程将开发未浇注的醛，以低成本合成根本重要的脱水的醛和烯。此外，实用的手性胺催化对映选择性H/D 交换α功能化级联反应，用于合成手性剥离高价值建筑物将开发（氨基）糖，氨基酸，醇，胺等。最后，新的三甲基硫氧基碘化物促进了CH3/CD3交换反应，以合成合成和具有药物价值的氘代甲基，环丙烷，环氧化物，氮杂胺和治疗将是成就。这些剥离的构件，分子体系结构和药物作为生物医学研究人员可用于生物分子结构以及生物学和药物的有价值的工具发现研究。