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Enantioselective C-H Oxidation Guided by Rational Catalyst Design

Project description

Harnessing enantioselective C-H oxidation in organic synthesis

Organic compounds are characterised by multiple and diverse bonds between carbon (C) and hydrogen (H). In metabolism, these C-H bonds can be converted into functional C-O bonds in a precise manner by oxidative enzymes, producing chiral metabolites of diverse structure and function. The EU-funded ECHO-GRACADE project aims to harness the power of enantioselective C-H oxidation in synthetic chemistry in the absence of real enzymes. For this purpose, scientists will employ small molecule manganese catalysts that will function as minimalistic hydroxylases. The project will focus on the design of these catalysts as tools in organic chemical synthesis for paradigmatic asymmetric reactions that involve C–H oxidation.

Objective

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.

Host institution

UNIVERSITAT DE GIRONA
Net EU contribution
€ 2 499 387,50
Address
PLACA SANT DOMENEC 3
17004 Girona
Spain

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Region
Este Cataluña Girona
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 2 499 387,50

Beneficiaries (1)