Late-stage O-sulfation with a bioinspired sulfuryl donor

O-sulfation is a widespread modification of both endogenous and exogenous biomolecules, where the primary objective is to identify effective sulfuryl donors. In nature, 3′-phosphoadenosine-5′-phosphosulfate (PAPS) and p-nitrophenyl sulfate (PNPS) are efficient sulfuryl donors. However, most chemical sulfuryl donors in O-sulfation, typically require harsh conditions and have not been demonstrated in complex molecules. Here we report a biomimetic O-sulfation method that is compatible with complex natural products and pharmaceutical scaffolds. Key to this approach is the use of tetrabutylammonium (nBu4N+) as a counterion for intrinsically anionic PNPS donor. The role of nBu4N+ goes far beyond simple charge balance; the coordination of nBu4N+ with sulfate in PNPS activates the sulfuryl donor by elongating the S–O bond and enhancing the leaving ability of nitrophenolate group. This unique activation model facilitates the transfer of sulfuryl group to diverse alcohols and phenols under simple and mild reaction conditions, thereby demonstrating its utility for site-selective O-sulfation with multiple hydroxyl groups.