Enantioselective Synthesis of α-Methyl-β-Cyclopropyldihydrocinnamates.

alpha- and beta-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure alpha-methyl-beta-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereo convergent Suzuki-Miyaura cross-coupling conditions affording (Z)-alpha-methyl-beta-cyclopropylcinnamates and subsequent ruthenium catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure alpha-methyl-beta-cyclopropyldihydrocinnamates with high selectivity.