Biomolecule-compatible dehydrogenative Chan-Lam coupling of free sulfilimines Tingting Meng 1 , Lucille A. Wells 2 , Tianxin Wang 1 , Jinyu Wang 1 , Shishuo Zhang 1 , Jie Wang 1 , Marisa C. Kozlowski 2 , Tiezheng Jia 1 1 Southern University of Science and Technology, China, 2 University of Pennsylvania, USA Inspired by the discovery of an S=N bond in the collagen IV network and its essential role in stabilizing basement membranes, sulfilimines have drawn much attention in the fields of chemistry and biology. However, its further uptake is hindered by the lack of mild, efficient and environmentally benign protocols by which sulfilimines can be constructed under biomolecule-compatible conditions. Here, we report a terminal oxidant-free copper-catalyzed dehydrogenative Chan-Lam coupling of free diaryl sulfilimines with arylboronic acids with excellent chemoselectivity and broad substrate compatibility. The mild reaction conditions and biomolecule-compatible nature allow the employment of this protocol in the late-stage functionalization of complex peptides, and more importantly, as an effective bioconjugation method as showcased in a model protein. A combined experimental and computational mechanistic investigation reveals an inner sphere electron transfer process circumvents the sacrificial oxidant employed in traditional Chan-Lam coupling reactions. An energetically viable concerted pathway was located wherein a copper hydride facilitates hydrogen atom abstraction from the isopropanol solvent to produce dihydrogen via a four-membered transition state. Our simple copper catalytic system provides a promising solution toward addressing the challenge associated with construction of sulfilimine covalent crosslink in the context of proteins.
References 1. Meng, T.; Wells, L. A.; Wang, T.; Wang, J.; Zhang, S.; Wang, J.; Kozlowski, M. C.; Jia, T. iomolecule-compatible dehydrogenative Chan-Lam coupling of free sulfilimines. J. Am. Chem. Soc. 2022 , 144 , 12476.
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