Formation of C-C Bonds from Unactivated C(sp3)-H Bonds of Hydrosilanes Derived from Common Functional Groups

由常见官能团衍生的氢硅烷的未活化 C(sp3)-H 键形成 C-C 键

• 批准号: 10316163
• 负责人: Masha Elkin
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-16 至 2023-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316163
• 关键词: Acetals; Acylation; Address; Alcohol consumption; Alcohols; Alkenes; Alkylation; Amides; Amines; Biological Testing; Carbon; Carboxylic Acids; Catalysis; Categories; Complex; Coupling; Development; Drug Kinetics; Elements; Ethers; Foundations; GTP-Binding Protein alpha Subunits, Gs; Goals; Hydrogen Bonding; Imines; Industrialization; Iridium; Ketones; Lead; Ligands; Mediating; Methodology; Methods; Modification; Molecular; Natural Products; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Process; Reaction; Reporting; Research; Rhodium; Scheme; Silanes; Structure; Synthesis Chemistry; System; Testing; Therapeutic; Transition Elements; Work; alcohol availability; analog; aryl halide; base; design; drug candidate; experimental study; functional group; method development; novel; novel therapeutics; scaffold; small molecule

PROJECT SUMMARY The process of developing novel therapeutics involves the synthesis of many analogs of bioactive compounds to optimize the efficacy, selectivity, and pharmacokinetic profile of potential drug candidates. The functionalization of C–H bonds can expedite this process by enabling the late-stage introduction of functional groups at the positions of typically inert C–H bonds and by eliminating wasteful functional group manipulations. In addition, new reactions at C–H bonds increase the number of potential retrosynthetic disconnections. Methods to form C–C bonds from unactivated C(sp3)–H bonds have been reported but are limited in the scope of suitable substrates, type of C–C bond formed, and ease of synthetic application. Hydrosilanes are readily available from ubiquitous alcohols, ketones, amines, and olefins and have been demonstrated to convert unactivated C(sp3)– H bonds to C–Si and C–B bonds with iridium and rhodium catalysis. However, hydrosilanes have not mediated the direct formation of C–C bonds from unactivated C–H bonds; the development of such transformations would address many of the limitations of current approaches to the functionalization of C–H bonds. This proposal outlines the development of a catalytic method to convert an unactivated C(sp3)–H bond to various C–C bonds by cross-coupling an organohalide electrophile with a C–H bond proximal to a hydrosilyl group. For example, the cross-coupling of an aryl halide with an unactivated C–H bond of a hydrosilyl ether would generate a γ-aryl alcohol derivative. This approach would combine the dehydrogenative silylation of an alcohol, functionalization of a C–H bond, and deprotection of the alcohol in one reaction vessel to effect γ- arylation of an alcohol. The development of this method with various electrophiles, such as aryl, heteroaryl, vinyl, acyl, allyl, benzyl, and alkyl halides, would lead to many categories of functionalized products. The accomplishment of these goals would expand the scope of substrates suitable for C–H bond functionalization, due to the diversity of functional groups that can be modified as hydrosilanes, including alcohols, ketones, amines, and olefins. In addition, this work would expand underdeveloped transformations, such as the heteroarylation, vinylation, acylation, and alkylation of unactivated C(sp3)–H bonds and achieve unreported transformations, such as the allylation of unactivated C(sp3)–H bonds. The scope of this type of C–H bond functionalization will be established for various silyl-modified functional groups, C–H bonds, and electrophiles, enabling regio- and stereoselective C–H functionalization at positions β, γ, and δ to the directing moiety. The application of this method to the late-stage modification of therapeutically relevant compounds is presented and would demonstrate the potential benefit of the proposed research to synthetic and medicinal chemists. Mechanistic experiments are planned to understand this novel C–H functionalization and to test the hypotheses by which this method is designed. The accomplishment of these goals will result in new methods for C–H bond functionalization and C–C bond formation, and access to products previously unavailable in direct fashion.

项目概要 开发新疗法的过程涉及许多生物活性类似物的合成 化合物来优化潜在候选药物的功效、选择性和药代动力学特征。 C-H键的官能化可以通过后期引入官能团来加速这一过程 基团位于通常惰性的 C-H 键位置，并消除了浪费的官能团操作。 此外，C-H 键上的新反应增加了潜在的逆合成断裂的数量。 由未活化的 C(sp3)-H 键形成 C-C 键的方法已有报道，但仅限于合适的范围 氢硅烷可轻松获得底物、形成的 C-C 键类型以及合成应用的便利性。 普遍存在的醇、酮、胺和烯烃，并已被证明可以转化未活化的 C(sp3)– H 在铱和铑的催化下与 C-Si 和 C-B 键形成键，但氢硅烷没有介导。 从未活化的 C-H 键直接形成 C-C 键； 解决了当前 C-H 键功能化方法的许多局限性。 该提案概述了转化未活化的 C(sp3)–H 键的催化方法的开发 通过将有机卤化物亲电子试剂与靠近氢硅烷基的 C-H 键交叉偶联来形成各种 C-C 键 例如，芳基卤化物与氢硅烷基醚的未活化的C-H键的交叉偶联。 将生成γ-芳基衍生物醇。该方法将结合脱氢甲硅烷基化。 醇、C-H 键的官能化以及在一个反应​​容器中醇的脱保护以产生 γ- 醇的芳基化反应与各种亲电子试剂的开发，例如芳基、杂芳基、乙烯基、 酰基、烯丙基、苄基和烷基卤化物将产生许多类别的功能化产品。 这些目标的实现将扩大适合 C-H 键功能化的底物范围， 由于可改性为氢硅烷的官能团多种多样，包括醇、酮、 此外，这项工作还将扩大尚未开发的转化，例如 未活化的 C(sp3)–H 键的杂芳基化、乙烯基化、酰化和烷基化，并实现了未报道的 转化，例如未活化的 C(sp3)–H 键的烯丙基化 此类 C–H 键的范围。 将为各种甲硅烷基修饰的官能团、C-H键和亲电子试剂建立官能化， 使定向部分的 β、γ 和 δ 位置上的区域选择性和立体选择性 C-H 官能化成为可能。 介绍了该方法在治疗相关化合物的后期修饰中的应用，并 将向合成化学家和药物化学家展示拟议研究的潜在好处。 计划进行机制实验来理解这种新颖的 C-H 功能化并检验假设 该方法的设计目标的实现将产生 C-H 键的新方法。 功能化和 C-C 键形成，以及获得以前无法直接方式获得的产品。