Asymmetric Synthesis with Organofluorines and Terminal Ynamides

有机氟和末端酰胺的不对称合成

基本信息

批准号：
9441070
负责人：
Christian Wolf
金额：
$ 42.61万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-10 至 2020-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9441070
关键词：
Acidity Agrochemicals Alkaloids Alkenes Alkynes Attention Biological Biological Availability Carbon Catalysis Chemicals Chemistry Complement Complex Development Dimerization Educational Status Eflornithine Electrons Exhibits Fluorides Fluorine Future Future Generations Generations Goals Health Sciences Healthcare Industry High School Student Iodides Isatin Laboratories Lead Ligands Metabolic Metals Methodology Methods Motivation Natural Products Outcome Pathway interactions Pattern Pharmaceutical Preparations Pharmacologic Substance Pharmacology Planet Earth Prevalence Process Production Property Protocols documentation Reaction Research Resistance Role Route Scientist Time Ursidae Family Work base c new catalyst chemical synthesis deprotonation dimer drug market enolate functional group graduate student improved infancy insight interest lipophilicity neglect novel nucleophilic addition nucleophilic substitution oxetane scaffold screening stem success tool undergraduate student

项目摘要

The ever-increasing demand for chiral compounds and the impressive prevalence of fluorinated pharmaceuticals on the US drug market generate compelling motivation for the development of synthetic methods that yield practical access to multifunctional organofluorines. The introduction of strategies that provide control over the unique stability and reactivity patterns of fluorinated species offers invaluable opportunities to streamline chemical synthesis of current and future drugs. The versatile chemistry of terminal ynamides which have been barely investigated to date and new C- F functionalization methodology recently discovered in our lab bear similar promise. The goals of the proposed research are to introduce asymmetric methods for catalytic carbon-carbon bond formation with fluorinated nucleophiles generated either by mild deacylative C-C cleavage of readily available precursors or from multifunctional prenucleophiles, to continue our spearheading efforts with asymmetric ynamide addition reactions, and to develop new C-F functionalization chemistry. The general feasibility of the planned activities and the synthetic utility prospects are highlighted with ample proof- of-concept results and mechanistic insights. Considerable emphasis will be placed on the introduction of currently elusive reactions and new methodologies, for example unprecedented asymmetric Michael addition/Nef reactions, C-F activation for selective carbon-carbon and carbon-heteroatom bond formation, and base-free ynamide additions. In addition, the overall usefulness of the proposed multifunctional chiral building blocks for the total synthesis of biologically active compounds will be explored. The reaction development efforts will be guided by detailed mechanistic studies and include screening and systematic optimization of a variety of organocatalysts and chiral ligands, including bisoxazolidines which have been developed previously in our laboratory. Altogether, the anticipated outcomes of this proposal are likely to afford new tools and directions for asymmetric catalysis with organofluorines and terminal ynamides as well as general reaction insights and synthetic opportunities that will be of interest to a wide range of synthetic and medicinal chemists.

对手性化合物的不断增长和令人印象深刻的需求美国药品市场上氟化药物的患病率引起了人们的注意开发合成方法的动机，从而实现实际访问多功能有机氟。引入提供控制权的策略氟化物种的独特稳定性和反应性模式提供了宝贵的宝贵简化当前和未来药物化学合成的机会。多功能迄今为止几乎没有研究的末端YNANIDES的化学性质，新的C- 最近在我们的Lab中发现的F功能化方法论相似。拟议研究的目标是引入不对称方法催化碳 - 碳键形成，由氟接亲核者形成。轻度的脱辅酶C-C裂解，易于使用的前体或多功能核寄移量，以不对称的YNAGIDE添加不对称反应，并开发新的C-F功能化化学。一般的可行性计划的活动和合成效用前景都有充分的证明 - 概念的结果和机械见解。将重点放在引入当前难以捉摸的反应和新方法，例如前所未有的不对称迈克尔添加/NEF反应，C-F激活选择性碳碳和碳杂质键形成以及无基本的Ynamide 加法。另外，提出的多功能性手性的总体有用性将探索生物活性化合物的总合成的基础。反应发展工作将由详细的机械研究和包括筛查和系统优化各种有机催化剂和手性配体，包括以前在我们的实验室。总之，该提案的预期结果可能负担得起新的使用器官氟和终端Ynemides的工具和方向以及一般的反应见解和综合机会广泛的合成和药物化学家。