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Pure Appl. Chem., 2013, Vol. 85, No. 6, pp. 1079-1087

Published online 2013-02-08

Cycloadditions in heterocycle and alkaloid synthesis

Peter Wipf*, Zhenglai Fang, Laurent Ferrié, Masafumi Ueda, Maciej A. A. Walczak, Yongzhao Yan and Michael Yang

Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA

Abstract: Intramolecular cycloadditions of bicyclo[1.1.0]butylalkyl-amines represent a rich source of novel heterocyclic scaffolds. As a function of the side chain attached to the amine, formal ene- or [2 + 2] cycloaddition products can be obtained in moderate to high yields. By suitable further functionalizations, a library of 3-azatricyclo[,5]-nonanes was prepared and interrogated in 450 biological assays. This discovery collection was found to generate high hit rates and yet the individual samples demonstrated sufficient selectivity to fulfill robust lead criteria. These applications of bicyclo[1.1.0]butanes demonstrate that new synthetic chemistry and novel architectures are promising starting points for the generation of high-value discovery libraries.