Access to Four‑membered Cyclic Sulfinamides Through Energy Transfer Catalysis and Photocycloaddition

Authors: Di Zhai, Benedict A. Williams, Loïc R. E. Pantaine, Yiding Chen, Michael C. Willis

Pharmaron is thrilled to share a recent high impact collaborative publication in Science with Professor Michael Willis and his group at the University of Oxford.

Access to Four‑membered Cyclic Sulfinamides via Energy Transfer

The Willis group developed a novel [2+2] photocycloaddition methodology, using sulfinamines as an -as of yet- untapped class of compounds to undergo triplet-triplet energy transfer catalysis to access a wide range of functionalised 4-membered sulfinamide heterocycles.  These small ring sulfinamides allow for rapid and easy access to precursors of β-lactam antibiotic isosteres, a highly sought-after class of chemical compounds which until now were only achievable through challenging and limited synthetic pathways.

The broad series of functionalisation reactions from these 4-membered ring sulfinamides showcased here demonstrates the versatility and wide range of further functionalities accessible through these compounds.

Mechanistic studies, via experimentation and DFT calculations, established the reactive species as a triplet excited state of the sulfinylamine that adds onto the alkene before intersystem crossing and radical recombination close the cycle.

The Pharmaron team in Hoddesdon, UK demonstrated the scalability potential of this novel methodology, and possible future use in the chemical industry, by adapting the light activated [2+2] cycloaddition process from batch to photoflow conditions. This is an essential part of scaling up photoreactions as it avoids commonly encountered issues such as decreasing light efficiency. A rapid reoptimisation of the reaction conditions was performed, in which adjustments were made regarding concentration and catalyst loading. These changes allowed for the synthesis of the chosen model substrate on a gram scale in 60% yield over 1 h, demonstrating the great potential for industry use of this methodology.

Science, 2026 Jan 8;391(6781):202-207.

DOI: 10.1126/science.aec3158

Access the publication at: https://pubmed.ncbi.nlm.nih.gov/41505534/