Solid-phase synthesis of a 4-substituted gamma-lactam library.

Pyrrolidin-2-one (gamma-lactam) derivatives have shown a wide range of activities as ligands to diverse receptors, e.g., integrin, CCR5, and CCK. Therefore, we have prepared a large library of these derivatives for high-throughput screening against various protein targets, after developing a synthesis of pyrrolidin-2-ones on solid phase. Exploration of the ring formation was key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-protected amino acids and subsequent deprotection of the Fmoc group were accomplished readily. The resulting resin-bound primary amines were treated with beta-monomethyl itaconate under gentle heat in a mixture of methanol and toluene to yield the desired intermediates. Finally, saponification, amide formation, and cleavage from the resin led to the production of a library of 12,000 pyrrolidin-2-one derivatives. These products were isolated as diastereomeric mixtures of high purity and were obtained in good yields.