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. The third pillar: The intrinsic limitation of asymmetric Mannich reactions—their failure with imine substrates containing a primary alkyl substituent—was solved by employing dithiomalonates as Mannich donors and a chiral squaramide organocatalyst. This protocol was used to develop a concise organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (−)-(R)-sitagliptin (see scheme).

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chiral mannich adducts enantioselectivity up imines malonate cinchonabasedsquaramidecatalyzed enantioselective mannich reactions alkyl amidosulfones asymmetric mannich reactionstheir failure imine substrates study dithiomalonates dtms see scheme organocatalytic couplingreagentfree synthesis antidiabetic drug

Jae Hun Sim, Choong Eui Song, Mun Jong Kim,Han Yong Bae,.Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin. 55 (36),10829-10825.

Jae Hun Sim, et al."Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin" 55

Jae Hun Sim, Choong Eui Song, Mun Jong Kim,Han Yong Bae,"Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin"