Enantioselective Construction of Amino Carboxylic‐Phosphonic Acid Derivatives Enabled by Chiral Amino Thiourea‐Catalyzed Decarboxylative Mannich Reaction

Abstract

An asymmetric decarboxylative Mannich reaction of phosphonate sultam-ketimines with malonic acid half esters is developed enabled by saccharide-derived bifunctional amino thiourea catalysis. This protocol provides access to a broad range of α-amino-β-carboxylic phosphonates featuring the N,P-containing tetrasubstituted stereocenters with 78-99% ee. Further synthetic derivatizations could allow the introduction of amide, alcohol, and azetidine scaffolds to the core structures.

Synergistic Catalytic Asymmetric Decarboxylative Mannich Reaction of β-Ketoacids with Acyclic α-Arylenamides

“…Over the past decades, catalytic asymmetric transformation has become an important and powerful tool to create a variety of optically active molecules. In this context, the catalytic asymmetric addition of β-ketoacids to cyclic imines has been extensively studied to deliver the desired β-aminoketones and their derivatives in excellent enantioselectivity (Figure a) . The cyclic structure of these cyclic imines, in which the CN bond is constrained in the corresponding geometry, appears to be important for the success of the reactions.…”

Synthesis of Tetrasubstituted Phosphorus Analogs of Aspartic Acid as Antiproliferative Agents

“…While the synthesis of phosphonate analogs of aspartic acid by the isosteric substitution of the β-carboxylic group is well documented [31][32][33], the preparation of the parent α-aminophosphonate analogs III by the substitution of the α-carboxylic moiety has received less attention, and most of the substrates are reported as single examples of general methods leading to α-aminophosphonates or aspartic acid derivatives [32,34,35]. In particular, there are a few examples reported for the synthesis of tetrasubstituted α-aminophosphonates derived from aspartic acid as concrete examples of the scope of reactions that imply C-C or C-P bond formation [36][37][38][39]. It is well known that the development of reactions leading to the formation of tetrasubstituted carbons is a challenging task, due to the lack of reactivity of the substrates, derived from the generation of a highly crowded structure.…”