Synthesis of Quinine-Inspired Antimalarials by Ni-Catalysed Cross Electrophile Coupling

We describe the efficient synthesis of novel dehydroxyquinines by arylation of quincorine bromide using Ni-catalysed cross electrophile coupling. The method demonstrates robust compatibility with (hetero)aryl bromides bearing diverse functional groups. Oxidation at C-9 of the dehydroxyquinines expediently provided quinine-inspired pseudo-natural products ('quinalogs'). Investigation of the compound collection against Plasmodium falciparum revealed a new insight into the structure activity relationship of quinine. Analogs bearing specifically functionalised pyridines, in place of the 6-methoxyquinoline ring of quinine, retained activity at the same order of magnitude, albeit not exceeding the activity of the natural product. This synthetic strategy conveniently enables iteration of the aromatic component of quinine for the first time, and holds promise for the development of effective new antimalarials. image