Asymmetric Synthesis of Sulfoximine-Containing Compounds

Sulfoximines are emerging as versatile chiral scaffolds in pharmaceutical and agrochemical research owing to their unique three-dimensional architecture, tunable electronic properties and potential for hydrogen bonding. The creation of enantiomerically enriched sulfoximines is critical for exploring their bioactive potential, driving demand for efficient asymmetric synthesis strategies. Contemporary approaches encompass metal-catalysed nitrene transfer, organocatalytic desymmetrisation, kinetic resolution and metal-free NH-transfer processes. These methods have unlocked access to a broad spectrum of sulfoximine derivatives, enabling late-stage functionalisation and incorporation into complex molecular frameworks. Key challenges include the control of stereochemistry at the sulfur centre, minimisation of racemisation and expansion of substrate scope to include heteroaryl, alkyl and fluorinated motifs. Advances in reaction design, mechanistic understanding and computational modelling have accelerated the translation of asymmetric sulfoximine synthesis into practical protocols for drug discovery and catalyst development.

Research from Nature Portfolio

Recent studies have demonstrated an organocatalytic pathway for the asymmetric transformation of sulfoximines into S-stereogenic sulfinamides. A peptide-mimic phosphonium salt catalyst mediates a skeletal reorganisation of prochiral or racemic sulfoximines through desymmetrisation or parallel kinetic resolution, delivering a variety of enantiomerically enriched sulfinamides with excellent selectivities. Mechanistic investigations, supported by density functional theory, revealed a stepwise ring-opening and ring-closing sequence, with the ring-opening step identified as pivotal for stereocontrol. This methodology not only broadens the palette of chiral S-centred molecules but also provides insights into catalyst design for asymmetric sulfoximine derivatisation, with potential implications for the synthesis of pharmaceutical intermediates.

Asymmetric Synthesis of Sulfoximine-Containing Compounds publication trend

The graph below shows the total number of articles in asymmetric synthesis of sulfoximine-containing compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Sulfoximine: An organosulfur compound featuring a sulfur–nitrogen bond and a sulfur–oxygen double bond, often possessing a stereogenic sulphur centre.

Enantioselectivity: The degree to which one enantiomer is preferentially formed over the other in a chiral reaction.

Desymmetrisation: A strategy that transforms a symmetrical substrate into a chiral molecule by selective modification of one site.

Nitrene: A highly reactive nitrogen intermediate that can insert into chemical bonds, enabling the formation of nitrogen–sulfur linkages.

Kinetic resolution: A method for enantiomer separation based on differing reaction rates of each enantiomer with a chiral reagent or catalyst.

References

1. Organocatalytic skeletal reorganization for enantioselective synthesis of S-stereogenic sulfinamides. Nature Communications (2024).
2. Transfer of Electrophilic NH Using Convenient Sources of Ammonia: Direct Synthesis of NH Sulfoximines from Sulfoxides. Angewandte Chemie International Edition (2016).
3. Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides. Journal of the American Chemical Society (2020).
4. Synthesis and Transformations of NH‐Sulfoximines. Chemistry - A European Journal (2021).