Oxocarbenium Lewis acid complex: A neutral thiol-specific bioconjugation reagent

Oxocarbenium ions are pivotal intermediates in organic synthesis, driving key transformations like glycosylation, rearrangement and cyclization. However, their generation typically requires Lewis or Brønsted acids, limiting their use with acid-sensitive substrates such as proteins. In this study, we present a neutral oxocarbenium Lewis acid complex that enables thiol-specific bioconjugation of cysteine residues in proteins without compromising their structure. The conjugated products are highly stable across various conditions—unlike maleimide-based conjugates, which often undergo retro-Michael reactions. This complex forms an ionic liquid at room temperature, offering versatility in diverse environments. Our method demonstrates broad substrate scope, efficiently modifying aromatic and aliphatic lactols and thiols, providing a precise and robust platform for applications such as antibody-drug conjugates.