An innovative strategy for radical-mediated, bidirectional controlled disulfide exchange

Metathesis reactions that operate cleanly and reversibly under biocompatible conditions are crucial in diverse fields such as drug development, chemical biology, and dynamic combinatorial chemistry. This paper introduces an innovative strategy using the commercially available and cost-effective hydroxy(tosyloxy)iodobenzene (HTIB) as a radical initiator, enabling clean and bidirectional disulfide metathesis under biocompatible conditions. Our method facilitates efficient forward reactions by utilizing an excess of one disulfide to shift the equilibrium toward unsymmetrical disulfides, while also ensuring clean reverse reactions by the removal of low boiling point dimethyl disulfide. Furthermore, an alternative intramolecular approach using a cyclic five- or eight-membered disulfide avoids the need for an excess of one disulfide, effectively yielding unsymmetrical disulfide molecules. The radical mechanism of this approach, validated through various control experiments and EPR analysis, enables selective and biocompatible modifications of carbohydrates, drugs, native amino acids, and proteins. This study represents a notable advancement in organic chemistry, with significant implications for biomedical sciences, especially in areas that require precise and gentle biomolecular manipulations, such as protein engineering and therapeutic development.