Development of a Second Generation Coenzyme A Analogue Synthon

We have previously reported a general synthetic approach to analogues of coenzyme A (CoA) which involves enzymatic synthesis of a general CoA analogue synthon having a thioester linkage in place of the amide bond nearest the thiol group (Martin et al. J. Am. Chem. Soc. 1994, 116, 4660). We report here the synthesis of a second CoA analogue synthon 1c which has the amide bond more distant from the thiol group replaced with a thioester. This analogue was prepared by nonenzymatic synthesis of a racemic phosphopantetheine analogue followed by enzymatic conversion to the corresponding CoA analogue. Stereochemical analysis showed that the natural enantiomer of the phosphopantetheine analogue was selectively converted to product by the enzyme phosphopantetheine adenylyltansferase, yielding a product that possessed the desired stereoconfiguration. Reaction of the new synthon 1c with a primary amine results in amide bond formation to form the CoA analogue of interest. This new methodology provides access to an even broader array of CoA analogues modified in the beta-alanylcysteamine moiety. This has been demonstrated in the synthesis of an analogue having an extra methylene group in the beta-alanine moiety and two analogues in which the amide bond nearest the thiol group is replaced with a pair of methylene groups.