Preparation of 9-hydroxy-14-azaprostanoic acids

Abstract

The title compounds 13, 14, 19, and 20 were prepared from 2-(6-carbethoxyhexyl)cyclopent-2-en-l-one (1). Conjugate addition of nitromethane and subsequent stereoselective reduction of the ketone 2 with lithium tri-sec-butyl hydride provided the desired natural prostaglandin stereochemistry on the five-membered ring. Protection of the hydroxyl group and ozonolysis of the nitronate salt gave the aldehyde 7 of the same stereochemistry. Unfortunately, condensation of this aldehyde with n-hexylamine and in situ NaBH4 reduction resulted in epimerization of the lower side chain and loss of stereochemical control. However, the natural prostaglandin stereochemistry could be retained by first reducing the nitro group, before proceeding with condensation (hexanal) and metal hydride reduction. Stereochemical assignments were in part established through intramolecular Condensation of the crude -trans and ß-trans siloxy aldehydes 7 and 8 with n-hexylamine was essentially complete in 4-6 h as judged by TLC. Surprisingly, TLC