Quaternary Ammonium Salts as Chromophores for Exciton-Coupled Circular Dichroism: Absolute Configuration of Hypocholesterolemic Quinuclidines

Abstract

Exciton-coupled circular dichroism (ECCD), which is based on the spatial interaction of two or more chromophores in a chiral environment, is a nonempirical submicrogram scale method for determining absolute configurations and conformations of organic molecules in solution. The interacting chromophores include those preexisting in the substrate andlor those introduced through 0or N-acylation. The interchromophoric coupling yields a bisignate CD curve, the signs of which establish the absolute sense of twist of the electric transition moments in a nonempirical manner.' Recent studies have focused on extending the applicability of ECCD to unexplored areas by developing (i) chromophores with red-shifted absorption maxima in order to avoid interactions with preexisting chromophores;* (ii) chromophores with intense absorptions, which result in strong interactions over a large distance (e.g., porphyrins with E = 350 000 at 400 nm strongly couple at -50 8, a ~ a r t ) ; ~ and (iii) fluorescent chromophores to scale down the operation to nanogram levelsS4 However, the methods developed so far are not applicable to tertiary amines such as quinuclidine alkaloids. In the following, we describe the extension of ECCD to encompass such compounds through the preparation of quatemary ammonium salts, as shown by application to a class of important hypocholesterolemic quinuclidines, exemplified by 1, and to (R)-( -)-3-quinuclidinol (3) of known absolute configuration. Conversion of farnesyl diphosphate into squalene in the biosynthesis of cholesterol offers an attractive point for therapeutic intervention for the treatment of hypercholesterolemia. This transformation, involving a number of intermediates, is catalyzed by a single enzyme, squalene synthase, which is believed to have a single active sites5 The report by Poulter et aL6 on ammonium ion mimics of proposed carbocation inter-