Z-Selective Alkyne Transfer Semihydrogenation in Drug-Like Molecules via an Organic Photoreductant

The deactivation of transition metal catalysts poses a significant challenge when applying synthetic methods to medicinal chemistry, where Lewis-basic functional groups based on nitrogen and sulfur are prevalent. C–C multiple bond reduction reactions usually depend on Lewis-acidic metal hydrides with open coordination sites that render them incompatible with such functional groups. Reduction mechanisms that replace the Lewis-acidic transition metal with an organic reductant offer a potential solution to this issue. Indeed, reactions via organic hydrides and photoredox catalysts have shown a broad tolerance of Lewis-basic motifs but remain restricted to the reduction of highly electrophilic Michael acceptors. Herein, we report the development of a mechanistically distinct transformation using an organic photoreductant that can be applied to the reduction of unpolarized alkynes. The reaction tolerates most medicinally relevant functional groups including highly Lewis-basic motifs like tetrazoles, guanidines, and triazoles, which have never been tolerated in an alkyne semihydrogenation before. Overreduction is minimized by controlling the redox potential and the high Z-selectivity is ensured by steric matching during association between reduced intermediates and reductant thus mimicking the transition metal mediated mechanism.