Thioester Synthesis Techniques in Organic Chemistry

Thioesters represent a class of organosulfur compounds characterised by a carbonyl group adjacent to a sulphur atom. Their synthesis has evolved significantly, encompassing classical coupling methods, metal-catalysed carbon–sulphur bond formation, organocatalytic protocols and biomimetic acyl transfer strategies. Traditional approaches often begin with activation of carboxylic acids—for example, conversion to acid chlorides or anhydrides—followed by reaction with thiols under mild conditions. Advances in transition-metal catalysis, notably palladium and nickel systems, have enabled direct transthioesterification of aryl halides and radical-driven cross-couplings under photoredox conditions, improving functional group tolerance and scalability. Meanwhile, organocatalysts such as N-heterocyclic carbenes (NHCs) have been applied to metal-free thioesterification of activated aldehydes, delivering products in high yields with precise chemoselectivity. Chemoenzymatic and biomimetic sequences exploit acyl transfer pathways inspired by natural thioester intermediates, allowing enantioselective and green transformations. Recent trends emphasise sustainability through solvent-free protocols and recyclable catalysts, while applications span chemical biology, materials science and pharmaceutical synthesis. Overall, the field continues to integrate mechanistic insights with innovative catalyst design to widen substrate scope, enhance selectivity and reduce environmental impact.

Research from Nature Portfolio

Recent studies have demonstrated the power of dual photoredox and nickel catalysis to achieve radical cross-thioesterification under mild, visible-light irradiation. In one approach, a sensitized electron transfer mechanism couples alkyl or aryl thiols with activated carbon partners to afford diverse methyl thioesters with exceptional chemoselectivity and broad functional group compatibility. Mechanistic investigations combining transient spectroscopy and computational analysis reveal that the synergy of energy transfer, electron transfer and nickel catalysis facilitates efficient C–S bond formation. This strategy has been applied successfully to the late-stage modification of drug molecules and amino acids, showcasing its potential for rapid diversification of complex scaffolds.

Thioester Synthesis Techniques in Organic Chemistry publication trend

The graph below shows the total number of articles in thioester synthesis techniques in organic chemistry across all publications each year (not limited to Nature Index journals).

Technical terms

Thioester: An organosulfur compound featuring a carbonyl directly bonded to a sulphur atom, analogous to an ester but with improved leaving-group ability and reactivity.

Acyl transfer: A reaction in which an acyl group migrates from one nucleophilic centre to another, a fundamental step in peptide ligation and biomimetic synthesis.

Photoredox catalysis: A mode of catalysis that uses visible light to drive redox reactions via excited-state catalysts, enabling radical pathways under mild conditions.

Nickel catalysis: Use of nickel complexes to facilitate bond-forming reactions, particularly cross-couplings, offering cost-effective alternatives to precious metals.

N-heterocyclic carbene (NHC): A stable, neutral carbon-based ligand with a lone pair that activates substrates through nucleophilic or organocatalytic mechanisms.

References

1. Radical thioesterification via nickel-catalysed sensitized electron transfer. Nature Synthesis (2023).
2. N‑to‑S Acyl Transfer as an Enabling Strategy in Asymmetric and Chemoenzymatic Synthesis. JACS Au (2024).
3. Metal-free thioesterification of α,β-unsaturated aldehydes with thiols. Organic Chemistry Frontiers (2022).
4. Isothiouronium-Mediated Conversion of Carboxylic Acids to Cyanomethyl Thioesters. The Journal of Organic Chemistry (2023).