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.

Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations

“…Organocatalytic methods that use surrogates of thioester enolates have therefore become popular for the stereoselective incorporation of thioester moieties into organic molecules. [ ][ ][ ]…”

“…For organocatalyzed examples using electron‐poor trifluoroethyl thioesters . For organocatalyzed examples using dithiomalonates …”

Synthesis of (−)‐(R)‐Sitagliptin by RhI‐Catalyzed Asymmetric Hydroamination

“…[3] For this reason the synthesis of (R)-sitagliptin (1) has been established as a benchmark target for chiral amine synthesis and therefore, attracted the attention of many different research groups and pharmaceutical companies reporting of extensive efforts on its asymmetric synthesis. The key methods employed to install the chiral primary amine include auxiliary controlled alkylation of amides followed by Arndt-Eistert homologation, [2,4] intramolecular Pd-catalyzed [2,3]-sigmatropic rearrangement, [5] asymmetric aza-Michael addition, [6] auxiliary controlled amination of enolates, [7] auxiliary controlled reduction or (transfer-)hydrogenation, [8] asymmetric (transfer-) hydrogenation [9] and enantioselective or auxiliary controlled Mannich reaction [10] (Figure 1).…”

Direct asymmetric N-propargylation of indoles and carbazoles catalyzed by lithium SPINOL phosphate

“…Such imines have also proven more difficult to be generated by the traditional methods. Amidosulfones [62][63][64][65][66][67] , which are widely used imine precursors, are not suitable for this purpose. This process must overcome the potential 1,4-addition onto the alkynyl imines 68 .…”