Enantioselective sulfonylation reactions mediated by a tetrapeptide catalyst

Nature excels at performing selective modifications of complex polyfunctional molecules by tailoring enzymes, but synthetic chemistry has lagged behind in this regard. In prior work, we have applied a biomimetic approach to this problem, developing small peptides to achieve various group transfer reactions on polyol substrates with high enantio- or regioselectivity. The use of sulfonates as synthetic building blocks and the scarcity of direct, selective methods for their preparation prompted our investigation into this area. In this article we report the development of a π-methyl histidine-based tetrameric peptide that effects the desymmetrization of meso-1,3-diols through enantioselective mono(sulfonylation). The catalyst exhibits structural similarities to another catalyst found to be effective in orthogonal group transfers, but results in modification of the enantiotopic alcohol. The practical and mechanistic implications of this discovery may extend beyond synthetic considerations and provide analogies to the diverse roles of histidine in enzyme active sites. Small peptide-derived catalysts are shown to be effective in the enantioselective sulfonylation of polyols. The observation that, using closely related catalysts, enantiotopic alcohols can be phosphorylated or sulfonylated, raises questions about the details of catalyst–substrate recognition and, from a biomimetic standpoint, the role of histidine residues in enzyme active sites.