ORGN 348

The 2-pyrrolidinone derivatives have shown activities against a wide range of receptors such as integrin receptors (αvβ3, αvβ5 and αvβ6), the chemokine CCR5 receptor and the CCK receptor. Therefore, developing a solid-phase synthesis around this scaffold allowing library production to be screened against a variety of protein targets was desired. A synthesis of 4-carboxyl-2-pyrrolidinone in solution, which required harsh conditions, has been reported.  Optimization of this reaction has led to the development of a robust solid-phase synthesis of a library of 2-pyrrolidinone derivatives starting from resin-bound primary amines, 1.  These amines were reacted with β–monomethylated itaconate under gentle heat in a mixture of methanol and toluene which led to the formation of 2-pyrrolidinone 4-carboxylate intermediates, 2.  Further derivatization of the carboxylic acid and cleavage led to a series of products 3 of high purity and in good yield.