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Asymmetric Synthesis of 1,2,3-Trisubstituted Cyclopentanes and Cyclohexanes as Key Components of Substance P Antagonists

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journal contribution
posted on 18.07.2002, 00:00 by Jeffrey T. Kuethe, Audrey Wong, Jimmy Wu, Ian W. Davies, Peter G. Dormer, Christopher J. Welch, Michael C. Hillier, David L. Hughes, Paul J. Reider
An efficient asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes is described. Three methods were developed for the preparation of the 2,3-disubstituted cyclopentenones and cyclohexenones, which are key achiral building blocks. These intermediates are reduced catalytically with (R)-2-methyloxazaborolidine in high yield (82−98%) and excellent ee (89−96%). Directed reduction of the chiral allylic alcohols using Red-Al gives exclusively the 1,2-anti stereochemistry (>99:1). Epimerization of the ester center followed by saponification/crystallization affords the desired hydroxyacids in good yield (65−70%) and in high enantiomeric excess (>99%).