Functionalization of unactivated sp2-hybridized carbon atoms

描述(申请人提供)：自然界已经进化出各种策略来裂解未活化的碳-氢键，以使惰性碳中心功能化。这些反应总是使用金属辅因子来创建强大的氧化剂，这些氧化剂可以从要功能化的碳中心提取氢原子，生成以碳为中心的自由基。在所有已建立的涉及H提取的酶机制中，裂解的C-H键是SP3杂化的，并且相关的均解键解离能(BDEs)小于(或等于)甲烷的104千卡/摩尔特征。最近，越来越多的反应被确定为暗示碳中心的官能化，这些碳中心与BDEs大于105kcal/mol的键的sp2-杂化断裂。本项目旨在表征三种这样的酶反应，包括甲基化、甲硫基化和SP2杂化碳中心的羟基化。前两个反应是由自由基SAM超家族的酶催化的，而第三个反应是由铁(II)和β-酮戊二酸依赖的加氧酶家族的酶催化的。这些研究的结果将大大扩展我们对自然对未活化的sp2杂化碳中心的功能化策略的理解，并揭示可能被证明在设计这些过程的治疗抑制剂方面实际有用的反应机理的细节。)

DESCRIPTION (provided by applicant): Nature has evolved a variety of strategies to cleave unactivated carbon-hydrogen bonds in order to functionalize inert carbon centers. These reactions invariably employ metallocofactors to create powerful oxidants that can abstract hydrogen atoms from the carbon centers to be functionalized, generating carbon-centered radicals. In all well-established enzyme mechanisms involving H abstraction, the cleaved C-H bonds are sp3-hybridized, and the associated homolytic bond-dissociation energies (BDEs) are less than (or equal to) the 104 kcal/mol characteristic of methane. Recently, a growing number of reactions have been identified that imply functionalization of carbon centers that are sp2-hybridized with cleavage of bonds that have BDEs of greater than 105 kcal/mol. This project aims to characterize three such enzymatic reactions involving methylation, methylthiolation, and hydroxylation of sp2-hybridized carbon centers. The first two reactions are catalyzed by enzymes belonging to the radical-SAM superfamily, while the third is catalyzed by an enzyme in the Fe(II)- and ?-ketoglutarate-dependent oxygenase family. The results of these studies should significantly expand our understanding of Nature's strategies for functionalization of unactivated sp2-hybridized carbon centers and reveal details of reaction mechanisms that may prove practically useful in design of therapeutic inhibitors of these processes. )