Enzymatic and Bio-Inspired Enantioselective Oxidation of Non-Activated C(sp3)–H Bonds

Andrea Palone; Massimo Bietti; Miquel Costas

doi:10.1055/a-2403-0760

Synthesis, Table of Contents

Synthesis 2025; 57(07): 1280-1294
DOI: 10.1055/a-2403-0760

short review

Enzymatic and Bio-Inspired Enantioselective Oxidation of Non-Activated C(sp ³)–H Bonds

Andrea Palone

^aInstitut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Campus Montilivi, Girona 17071, Catalonia, Spain

^bDipartimento di Scienze e Tecnologie Chimiche, Università ‘Tor Vergata’, Via della Ricerca Scientifica, 1 00133 Rome, Italy

,

Massimo Bietti∗

^bDipartimento di Scienze e Tecnologie Chimiche, Università ‘Tor Vergata’, Via della Ricerca Scientifica, 1 00133 Rome, Italy

,

Miquel Costas ∗

^aInstitut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Campus Montilivi, Girona 17071, Catalonia, Spain

› Author Affiliations

Abstract

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Abstract

The enantioselective oxidation of C–H bonds relies on two different approaches: the use of enzymes or bio-inspired transition metal catalysts. Both are powerful tools, as they transform ubiquitous C(sp³)–H bonds into valuable oxygenated building blocks. However, the reaction remains a challenge in synthetic chemistry, continuously demanding efficient catalytic systems to improve substrate scopes. Optimization of site- and enantioselectivities in bio-catalytic systems is underpinned by protein engineering, while ligand design and medium effects play crucial roles in bio-inspired synthetic complexes. In this Short Review, recent advances in the field are described, focusing on reactions that target strong, non-activated C–H bonds.

1 Introduction

1.1 Enantioselective Catalytic C–H Oxidation in Nature and Bio-Inspired Systems

1.2 Biological C–H Oxidation Mechanism and Challenges for the Implementation of Chirality with Synthetic Catalysts

1.3 Bio-Catalytic C–H Oxidation Systems: From Microorganism to Engineered Enzymes

1.4 Mimicking Nature: The Bio-Inspired C–H Oxidation Approach

1.5 Origin of Enantioselectivity

2 Enantioselective C–H Oxidation of Non-Activated C–H Bonds

2.1 Hydroxylation at Non-Activated C–H Bonds by Bio-Catalytic Systems

2.2 Enantioselective C–H Lactonization with Enzymatic Systems

2.3 Oxidation at Non-Activated C–H Bonds by Synthetic Catalysts

2.4 Enantioselective Lactonization with Small-Molecule Catalysts

3 Conclusions

Key words

cytochrome P450 - enantioselectivity - oxidation - bio-inspired catalysts - C–H bond functionalization - hydrogen atom transfer - H₂O₂ - oxygenases - aliphatic C–H hydroxylation

Full Text

References

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Enzymatic and Bio-Inspired Enantioselective Oxidation of Non-Activated C(sp 3)–H Bonds

Enzymatic and Bio-Inspired Enantioselective Oxidation of Non-Activated C(sp ³)–H Bonds