Use of disilane directing groups to effect catalytic C-H bond functionalization

使用乙硅烷导向基团实现催化 C-H 键官能化

• 批准号: 8981763
• 负责人: Jeffrey Clinton Holder
• 金额: $ 5.24万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-18 至 2017-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8981763
• 关键词: Biological; Biological Factors; Carbon; Chemical Structure; Chemicals; Chemistry; Collection; Complex; Data; Development; Distal; Drug Industry; Drug Kinetics; Electronics; Exhibits; Goals; Human; Hydrogen Bonding; Iridium; Label; Length; Libraries; Ligands; Medical; Methods; Modification; Molecular; Monitor; NMR Spectroscopy; Pharmaceutical Chemistry; Pharmacodynamics; Phenanthrolines; Property; Reaction; Rest; Role; Series; Silicon; Site; Structure; Support Groups; Testing; Therapeutic Agents; Thermodynamics; Transition Elements; catalyst; density; design; functional group; novel; novel therapeutics; public health relevance; screening; small molecule libraries; theories; tool

 DESCRIPTION (provided by applicant): Secondary metabolites often demonstrate potent biological activity, but rarely exhibit the pharmacokinetic or pharmacodynamic properties that are required for safe medical use in humans. Typically, these properties can be imparted by synthetic modification of the molecule's structure. Recently, C-H functionalizaton chemistry has greatly impacted the strategies used to modify chemical structures. However, chemoselective C-H functionalization of complex natural products with transition metal catalysts can be challenging because there are many C-H bonds in each molecule that may react competitively with a given catalyst. A practical strategy for overcoming poor chemoselectivity is to employ a directing group to control the site of reaction at a particular C-H bond. These directed C-H functionalization reactions may then be employed as a tool in the development of new therapeutic agents through selective functionalization of complex natural products. The goal of this proposal is to develop novel disilane directing groups to create a method for the selective silylation and borylation of aliphatic C-H bonds. This objective is achieved by allowing a silicon-containing directing group to react with a transition metal catalyst, consequently tethering the active catalyst adjacent to the C-H bond targeted for functionalization. First, we will examine the effect of tether length on regioselectivity of the reaction. Preliminary calculations indicate that regioselective 1,2-, 1,4- and 1,-6-functionalizations are thermodynamically feasible with the new directing groups proposed herein. Second, to broaden the synthetic value of C-H functionalization products, we wlll expand directed C-H functionalization reactions by achieving borylation of aliphatic C-H bonds. In all cases, bioactive molecules are proposed as substrates to test chemoselectivity on complex structures relevant to the pharmaceutical industry. Next, we will study the electronic factors that govern silyl-directed C-H activation. We propose to use 15N-enriched ligands to study the composition of the catalyst during catalytic reactions by NMR spectroscopy. Lastly, we propose to synthesize and isolate the catalyst resting state and to determine whether there is a correlation between the s- donating ability of the silyl directing group and rate of C-H functionalization. The C-H functionalization platform described herein constitutes a promising strategy for the selective functionalization of C-H bonds in complex molecules. We envision this approach being applied not only to the synthesis and modificaiton of bioactive molecules, but also to the construction of diverse libraries for use in medicinal chemistry.

 DESCRIPTION (provided by applicant): Secondary metabolites often demonstrate potent biological activity, but rarely exhibit the pharmacokinetic or pharmacodynamic properties that are required for safe medical use in humans. Typically, these properties can be imparted by synthetic modification of the molecule's structure. Recently, C-H functionalizaton chemistry has greatly impacted the strategies used to modify chemical structures. However, chemoselective C-H functionalization of complex natural products with transition metal catalysts can be challenging because there are many C-H bonds in each molecule that may react competitively with a given catalyst. A practical strategy for overcoming poor chemoselectivity is to employ a directing group to control the site of reaction at a particular C-H bond. These directed C-H functionalization reactions may then be employed as a tool in the development of new therapeutic agents through selective functionalization of complex natural products. The goal of this proposal is to develop novel disilane directing groups to create a method for the selective silylation and borylation of aliphatic C-H bonds. This objective is achieved by allowing a silicon-containing directing group to react with a transition metal catalyst, consequently tethering the active catalyst adjacent to the C-H bond targeted for functionalization. First, we will examine the effect of tether length on regioselectivity of the reaction. Preliminary calculations indicate that regioselective 1,2-, 1,4- and 1,-6-functionalizations are thermodynamically feasible with the new directing groups proposed herein. Second, to broaden the synthetic value of C-H functionalization products, we wlll expand directed C-H functionalization reactions by achieving borylation of aliphatic C-H bonds. In all cases, bioactive molecules are proposed as substrates to test chemoselectivity on complex structures relevant to the pharmaceutical industry. Next, we will study the electronic factors that govern silyl-directed C-H activation. We propose to use 15N-enriched ligands to study the composition of the catalyst during catalytic reactions by NMR spectroscopy. Lastly, we propose to synthesize and isolate the catalyst resting state and to determine whether there is a correlation between the s- donating ability of the silyl directing group and rate of C-H functionalization. The C-H functionalization platform described herein constitutes a promising strategy for the selective functionalization of C-H bonds in complex molecules. We envision this approach being applied not only to the synthesis and modificaiton of bioactive molecules, but also to the construction of diverse libraries for use in medicinal chemistry.