Scale-Up of a Rh-Catalyzed Asymmetric sp3-sp2 Suzuki-Miyaura-Type Reaction.

Abstract

Csp2-Csp2 Suzuki-Miyaura couplings (SMCs) are ubiquitous in the synthesis of small molecules, but analogous Csp2-Csp3 bond-forming SMCs are rare, especially asymmetric variants. Recently, we developed a series of Rh-catalyzed couplings between racemic sp3-hybridized allyl chlorides and heteroaryl boronic acids. Here, we demonstrate that these catalytic asymmetric reactions can be scaled-up to give over 100 g of a product. The reaction we chose to test couples a heteroaromatic boronic acid derivative and a racemic bicyclic electrophile to give a product with three contiguous stereogenic centers. The SMC product was obtained as a single diastereomer in 90% yield and 98% ee. Kinetic analysis of the reaction reveals two exothermic steps in the reaction setup and revealed the means by which to prevent the generation of heat spikes detrimental to the stability of the catalyst.