Researchers Develop New Methods for Chiral Sulfur Compounds with Antiviral Potential
Two research teams have developed catalytic methods for synthesizing chiral sulfur compounds with antiviral potential. One approach uses an organocatalytic strategy to create vinyl sulfinamides that bind to SARS-CoV-2 and HIV-1 proteins, while another employs copper catalysis for high-yield production of chiral sulfilimines. Both methods address critical gaps in accessing valuable chemical space for drug discovery.
Researchers have developed two distinct catalytic methods for synthesizing chiral sulfur-containing compounds, which show promising antiviral activity and potential applications in drug discovery. A team has created an air-stable chiral phosphine-catalyzed enantioselective approach to synthesize enantioenriched S(IV)-stereogenic vinyl sulfinamides—an under-explored class of organosulfur compounds with promising antiviral activity. Separately, another research group has developed a copper-catalyzed enantioselective S-alkylation of sulfenamides enabled by an amino-radical-transfer deboronation pathway.
The importance of chiral-at-sulfur compounds in drug discovery and organic synthesis is indisputable. Over a quarter of top-selling small molecule pharmaceuticals contain sulfur atoms, and chiral sulfinamides bearing S(IV) chirality are key building blocks for medicinal chemistry, asymmetric synthesis auxiliaries, and catalytic ligands. However, current methods to access enantioenriched sulfinamides rely on transition metal catalysis with organometallic nucleophiles, and efficient organocatalytic strategies have long remained unexplored.
The organocatalytic method involves the design and synthesis of a novel C₂-symmetric chiral phosphine catalyst—QianPhos—derived from the SPHENOL chiral skeleton. This custom catalyst exhibits extraordinary air stability and structural rigidity, which enables highly chemo-, enantio-, and diastereoselective C−S bond formation via a [3+2] annulation between Morita–Baylis–Hillman (MBH) esters and sulfinylamines. Unlike conventional transition metal-catalyzed approaches, this organocatalytic method generates in situ phosphorus ylides as vinyl nucleophiles, representing a mechanistically distinct route to chiral cyclic vinyl sulfinamides with excellent enantiopurity.
Notably, these cyclic vinyl sulfinamides bind potently to the mutant SARS-CoV-2 spike protein and HIV-1 ENV protein, highlighting the great antiviral drug development potential of this under-explored chemical space. Through a combination of density functional theory (DFT) calculations and mechanistic experiments (including ³¹P and ¹⁹F NMR spectroscopy), the team uncovered key mechanistic insights: the phosphonium species acts as the catalyst resting state, and sulfinylamines play a dual role as both reaction partners and promoters for the formation of the key catalytic intermediate—an unreported mechanistic feature that underpins the reaction's high selectivity.
The copper-catalyzed method produces chiral sulfilimines in high yields (up to 95%) and enantioselectivities (up to 98% ee) under mild conditions. An isomerizable bis(oxazoline) ligand bearing a bridging CH2 unit is identified as the key factor for both reactivity and stereoselectivity in the copper-catalyzed radical-relay coupling with sulfenamides. The method offers a general platform for accessing enantioenriched S(IV) architectures with aliphatic substituents and demonstrates strong potential for applications in medicinal chemistry.