117. Preparation, Structure, and Properties of All Possible Cyclic Dimers (Diolides) of 3-Hydroxybutanoic Acid

Article abstract of DOI:10.1002/hlca.19950780611

In connection with the proposed structure of a trans-membrane cellular ion channel consisting of a complex poly<(R)-3-hydroxy butanoate> (P(3-HB)) and calcium phosphate, CaPP_i (ca. 150 units each), which is supposed to contain s-cis-bonds or even more highly strained ester 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 enentiomerically 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-Villiger oxidation of the rac- and meso-2,5-dimethylcyclohexane-1,4-diones 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 diolides 1 contain s-cis-ester bonds and an ester group with a conformation half way to the transition state of rotation (Fig. 2).Strain energies for the diolides 1 up to 17.8 kcal/mol are suggested.Accordingly, these compounds show reactivities similar to those of carboxylic-acid anhydrides or even acid chlorides.They cannot be chromatographed on silica gel, and they react with primary, secondary, and tertiary alcohols, and with amines to form derivatives of open chain 3-HB 'dimers', hydroxy acids 6, esters 7, and amines 8 (Scheme 2).The rate of acid-catalyzed ring opening of the diolides 1 with alcohol has been measured (Figs. 6 and 7).From the results described, we conclude that it is unlikely for strained and reactive ester conformations to occur as a part of ion channels through phospholipid bilayers of cells.