Development of a second generation coenzyme A analogue synthon

We have previously reported a general synthetic approach to analogues of co enzyme 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. Sec. 1994, 116, 4660), We report he re the synthesis of a second CoA analogue synthon 1c which has the amide bo nd more distant from the thiol group replaced with a thioester, This analog ue was prepared by nonenzymatic synthesis of a racemic phosphopantetheine a nalogue followed by enzymatic conversion to the corresponding CoA analogue. Stereochemical analysis showed that the natural enantiomer of the phosphop antetheine analogue was selectively converted to product by the enzyme phos phopantetheine adenylyltansferase, yielding a product that possessed the de sired stereoconfiguration. Reaction of the new synthon 1c with a primary am ine results in amide bond formation to form the CoA analogue of interest. T his new methodology provides access to an even broader array of CoA analogu es modified in the beta-alanylcysteamine moiety, This has been demonstrated in the synthesis of an analogue having an extra methylene group in the bet a-alanine moiety and two analogues in which the amide bond nearest the thio l group is replaced with a pair of methylene groups.