Vicinal tricarbonyls and cyano analogs as electrophilic participants in forming pharmacophoric templates for drug discovery

Abstract

During recent years, fresh attention has been given to a functional group aggregate in which three carbonyl groups have been assembled in a 1,2,3-vicinal relationship. This vicinal tricarbonyl system represents a potent electrophilic unit, usually stabilized in the form of a monohydrate, which, in solution, is in equilibrium with the parent tricarbonyl. It reacts with a range of nucleophiles to form products that are not readily accessible via conventional routes. When an ancillary electrophilic functional group is appended to the vicinal tricarbonyl unit the resulting aggregate serves as a novel di- or trielectrophile in reaction with nucleophiles. This behavior is illustrated by the reaction of vicinal tricarbonyls, attached to vinyl and acetylenic groups, with a broad range of donor reagents to form key components of structures having biological relevance. Substitution of a cyano group for one of the terminal carbonyls leads to labile alpha, beta-diketo nitriles, which can be used as intermediates in forming alpha-ketoamide libraries of timely interest as protease inhibitors.