Abstract
First catalytic and enantioselective conjugate addition of nitromethane to benzylidene-2-benzoyl acetate has been developed using dihydroquinine derived squaramide catalyst with moderate to high selectivities. Asymmetric total synthesis of ABT-627, a potent ETA receptor antagonist is accomplished utilizing the developed method in overall 15.7% yield.
Highlights
The nitro compounds due to their easy transformations into other diverse functional groups, role as valuable reagents as well as their presence in many natural products occupy a distinct position in organic synthesis (Ono, 2001)
From a retrosynthetic view point, 2,4-diaryl pyrrolidine-3-carboxylic acids 1 can be obtained from α-benzoyl-β-aryl-γ-nitro butyric acid derivative 2, which can be synthesized either by Michael addition of 1,3-dicarbonyl compounds to nitrostyrenes or by nitromethane addition to benzylidene-2-benzoyl acetate
Our previous report (Hajra et al, 2013) on enantioselective nitromethane addition to alkylidenemalonates catalyzed by cinchona-alkaloid derived thiourea based organocatalyst offered a simple but efficient route to the non-racemic synthesis of 3-substituted pyrrolidine/pyrrolidone class of compounds
Summary
The nitro compounds due to their easy transformations into other diverse functional groups, role as valuable reagents as well as their presence in many natural products occupy a distinct position in organic synthesis (Ono, 2001). Synthesis of nitrogen containing heterocyclic compounds such as pyrroles, indoles, pyrrolidines, and their derivatives have often been achieved via the intermediacy of suitable nitro compounds. Among the five-membered nitrogen heterocycles, the pyrrolidine-3-carboxylic acid and its aryl substituted analogs are privileged structural motifs present in a wide range of biologically active therapeutic agents (Pandey et al, 2006; Royer, 2009). The important biological profile coupled with the trans-trans stereo disposition of the -CO2H group with adjacent substituents have generated substantial synthetic challenges to organic chemists for the asymmetric synthesis of these 2,4-disubstituted pyrrolidine-3-carboxylic acids. From a retrosynthetic view point, 2,4-diaryl pyrrolidine-3-carboxylic acids 1 can be obtained from α-benzoyl-β-aryl-γ-nitro butyric acid derivative 2, which can be synthesized either by Michael addition of 1,3-dicarbonyl compounds to nitrostyrenes (route A, Scheme 1) or by nitromethane addition to benzylidene-2-benzoyl acetate (route B, Scheme 1).
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