On the Orthogonality of Two Thiol-Based Modular Ligations

The chemoselectivity of two thiol-based modular ligations operating under mild conditions is assessed. For this purpose, a macromolecular scaffold possessing allyl and pentafluorophenyl groups in two distinct parts is employed, which enables facile characterization by NMR spectroscopy (H-1 and F-19) and size-exclusion chromatography. By using appropriate triggers (introduction of a base or light irradiation), it is possible to direct thiols to an arbitrarily chosen part of the scaffold, without any change to the other part and with no involvement of protecting group chemistry. Dual functionalization experiments are achieved by applying these triggers consecutively with no consideration of the reaction sequence order, evidencing full bidirectionality. A set of one-pot, purification-free procedures that enable near-quantitative to full dual functionalization in (very) short reaction times (17-180 min) is also presented.