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.

项目概要氘化化学的复杂性令人沮丧，氘化结构单元的数量非常有限其可用性和制造成本较高，阻碍了人们获得备受追捧的氘化生物活性分子。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我们希望构建对其生物学研究和药物发现感兴趣的氘化分子。开发一种新的氘代分子氨基催化活化模式，称为“铵催化” 我们挑战了由亲核加成产生的加合物中胺部分的教条。亚胺离子可以在随后的反应中作为离去基团，从其中原位释放假定的胺。该加成产品将为醛的氨基催化直接官能化创造新的场景。将证明，通过以下方法将实现许多前所未有的高效催化级联反应新的有机催化剂和新的反应性这些级联过程产生了一系列令人着迷的反应。具有区域选择性的高价值新型“特权”苯并吡喃和氢喹啉复合物此外，在代谢不稳定位点掺入氘。有机催化甲酰化反应和NHC卡宾促进H/D交换过程，简单将开发非氘代醛用于低成本合成具有根本重要性的化合物此外，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最后，将开发新的嵌段，例如（氨基）糖、氨基酸、醇、胺等。三甲基碘化亚砜促进 CH3/CD3 交换反应，用于合成和合成具有药用价值的氘代甲基、环丙烷、环氧化物、氮丙啶和治疗剂将这些氘代结构单元、分子结构和药物作为。生物医学研究人员用于生物分子构建以及生物和药物的宝贵工具发现研究。