The metabolic cycle of L-proline plays a crucial role in cancer cell survival, proliferation, and metastasis. A key intermediate in the biosynthesis and degradation of proline is 3,4-dihydro-2H-pyrrole-2-carboxylic acid. A direct route for synthesizing substituted derivatives of this acid involves the cyclization of 2-amino-5-oxonitriles. Michael additions of [(diphenylmethylene)amino]acetonitrile to enones in a basic medium—either with aqueous sodium hydroxide or under solid–liquid phase-transfer catalysis conditions using CaO as a base—enable the synthesis of substituted 2-amino-5-oxonitriles as single diastereoisomers or as diastereoisomeric mixtures. Selective removal of the diphenylmethylene-protecting group, followed by in situ cyclization in acidic conditions, yields trans- and cis-3,5-diaryl-3,4-dihydro-2H-pyrrole-2-carbonitriles. The reaction of nitriles with HCl/dioxane/methanol followed by treatment with water produces esters and amides as by-products. In vitro screening of the synthesized compounds against multiple human cancer cell lines revealed that some compounds exhibit a good or high selectivity index. In conclusion, the synthetic schemes presented offer simple and efficient routes for the preparation of the derivatives of substituted 3,4-dihydro-2H-pyrrole-2-carboxylic acids, with some compounds exhibiting promising antiproliferative activity.

The reaction of 2-((diphenylmethylene)amino)acetonitrile with (E)-1-phenyl-3-(thiophen-2-yl)prop-2-en-1-one was performed by using 33% NaOH in CH3CN for 30 min at 0°C. The main product - rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile was isolated and characterized by IR, 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS).

The reaction of 2-((diphenylmethylene)amino)acetonitrile with (E)-1-phenyl-3-(thiophen-2-yl)prop-2-en-1-one was performed by using 33% NaOH in CH₃CN for 30 min at 0 °C. The main product—rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile—was isolated and characterized by IR, ¹H NMR, ¹³C NMR, ¹H-¹H COSY, and high-resolution mass spectrometry (HRMS).