title: Enantioselective Synthesis of α-Methyl-β-cyclopropyldihydrocinnamates.
abstract: α- and β-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-β-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 stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-α-methyl-β-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 α-methyl-β-cyclopropyldihydrocinnamates with high selectivity.
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Melodie
authors.initials: M
authors.lastname: Christensen
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Nolting
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Shevlin
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Weisel
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Maligres
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Orr
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Plummer
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Tudge
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Ruck