Practical diastereoselective synthesis and scale-up study of (+)-2-((1r,2r,3r,5s)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol: A key intermediate of the novel prostaglandin d2 receptor antagonist s-5751

Abstract

A new synthetic process was developed for (+)-2-((1R,2R,3R,5S)-2-amino-6,6- dimethylbicyclo[3.1.1]hept-3-yl)ethanol, a key intermediate of S-5751. Diastereoselective alkylation of (+)-nopinone with ethyl bromoacetate, formation of O-methyl oxime, and diastereoselective reduction with NaBH4-AlCl3 could be safely carried out. Stereochemistry of the (1R,2R,3R,5S)-6,6- dimethylbicyclo[3.1.1]heptane ring was discussed to achieve high diastereoselectivity on these reactions. For the scale-up, detailed consideration was given to the safety of the NaBH4-AlCl3 reduction. © 2009 American Chemical Society.