title: Solid-phase synthesis of a 4-substituted gamma-lactam library.
abstract: 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.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C. 8 Clarke Drive, Cranbury, New Jersey 08512, USA.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Vergnon
authors.forename: Richard S
authors.initials: RS
authors.lastname: Pottorf
authors.forename: Michael P
authors.initials: MP
authors.lastname: Winters
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player