Development of an Enantioselective, Kilogram-Scale, Rhodium-Catalysed 1,4-Addition

A rhodium-catalysed 1,4-addition of an arylboron species to an α,β-unsaturated ester was the key chirality-inducing step in the synthesis of an API. We describe herein the development of this chemistry, including optimization of reagent charges, reaction conditions, and metal recovery, in order to allow manufacture at multikilogram scale. A key result was the unexpected discovery that the use of a minimal quantity of an alcohol, rather than water, reduces the extent of rhodium-mediated protodeboronation of the boron species. This allowed the charge of this expensive reagent to be significantly reduced. Furthermore, the use of an alcohol instead of water avoided the agglomeration of the inorganic base present in the reaction, making the process more robust and operationally simpler. To our knowledge this is the first time that this type of C−C bond-forming chemistry has been used in a multikilo manufacture.