title: Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin.
abstract: In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona-based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or α-amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α-amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (-)-(R)-sitagliptin.
authors.affiliation: Department of Chemistry, Sungkyunkwan University, Jangan, Suwon, 440-746, Korea.|Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470, Mülheim an der Ruhr, Germany.
authors.forename: Han Yong
authors.initials: HY
authors.lastname: Bae
authors.affiliation: Department of Chemistry, Sungkyunkwan University, Jangan, Suwon, 440-746, Korea.
authors.forename: Mun Jong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Sungkyunkwan University, Jangan, Suwon, 440-746, Korea.
authors.forename: Jae Hun
authors.initials: JH
authors.lastname: Sim
authors.affiliation: Department of Chemistry, Sungkyunkwan University, Jangan, Suwon, 440-746, Korea. s1673@skku.edu.
authors.forename: Choong Eui
authors.initials: CE
authors.lastname: Song
keywords: Mannich reaction; asymmetric catalysis; dithiomalonates; organocatalysis; β-amino thioesters