Enantioselective C-H Oxidation Guided by Rational Catalyst Design

ongoing

Chemo- and enantioselective oxidation of aliphatic C-H bonds is a cornerstone reaction in metabolism. The ubiquitous presence of multiple and diverse C-H bonds in organic molecules is used by oxidative enzymes to deliver functionality and chirality to metabolite precursors, rapidly creating product diversity. Despite its huge potential in organic synthesis, non-enzymatic enantioselective C-H oxidation of aliphatic sites remains inaccessible and has never been incorporated in synthesis. Harnessing the power of this reaction will open straightforward, yet currently inaccessible, paths in synthetic planning. However, realization of this goal requires conceptual breakthroughs in order to chemo-, regio- and stereo-selectively create a C-O bond from a non-activated alkyl C-H bond, even in the presence of a priori more reactive groups. In this project, chemo-, and site-selective asymmetric aliphatic oxidation is targeted by taking advantage of; a) stereoretentive enzyme-like metal-based C-H oxidations performed by small molecule manganese catalysts, devised as minimalistic hydroxylases, and b) polarity reversal exerted by fluorinated alcohol solvents in electron-rich functional groups, which enable chemoselective C-H hydroxylation of densely functionalized molecules. Desymmetrization via enantioselective C-H oxidation is devised as a powerful type of reaction that will create multiple chiral centers in a single step. Building on the rich chemical diversity and modular architecture of aminopyridine manganese complexes, rapid elaboration of libraries of catalysts is targeted. Rational manipulation of steric, electronic, directing effects and supramolecular substrate recognition factors guided by multiple parametrization analyses will be employed for directing evolution in catalyst design. This project will provide the catalysts and their use in paradigmatic reactions in order to establish enantioselective C-H oxidation as a reliable tool in organic synthesis.