PREPARATION, STRUCTURE, AND PROPERTIES OF ALL POSSIBLE CYCLIC DIMERS (DIOLIDES) OF 3-HYDROXYBUTANOIC ACID

In connection with the proposed structure of a Irans-membrane cellular ion channel consisting of a complex between poly[(R)-3-hydroxy butano ate] (P(3-HB)) and calcium polyphosphate, CaPPi(ca. 150 units each), w hich is supposed to contain s-cis-bonds or even more highly strained e ster conformations, we have prepared and studied the properties of the cyclic dimer of 3-HB, the diolide 1. All possible forms of 1, the rac -, the meso-, and the enantiomerically pure (R,R)- and (S,S)-compounds were prepared, purified, and characterized. The synthesis (Scheme 1) started from dimethyl succinate with the key step being the Baeyer-Vil liger oxidation of the rac- and meso-2,5-dimethylcyclohexane-1,4-dione s 5. The rac-diolide 1 was resolved by preparative chromatography on a Chiralcel OD column (Fig. 1). The crystal structures of rac-1 (Fig. 3 ) and of meso-1 (Fig. 5) were determined by X-ray diffraction: the dio lides 1 contain s-cis-ester bonds and an ester group with a conformati on half way to the transition state of rotation (Fig.2). Strain energi es for the diolides 1 of up to 17.8 kcal/mol are suggested. Accordingl y, these compounds show reactivities similar to those of carboxylic-ac id anhydrides or even acid chlorides. They cannot be chromatographed o n silica gel, and they react with primary, secondary, and tertiary alc ohols, and with amines to form derivatives of open chain 3-HB 'dimers' , hydroxy acids 6, esters 7, and amides 8 (Scheme 2). The rate of acid -catalyzed ring opening of the diolides 1 with alcohols has been measu red (Figs. 6 and 7). From the results described, we conclude that it i s unlikely for strained and reactive ester conformations to occur as p art of ion channels through phospholipid bilayers of cells.