SYNTHESIS OF OPTICALLY PURE CYCLIC LIPOIDAL AMMONIUM-SALTS AND EVALUATION OF INHIBITION OF PROTEIN-KINASE-C

Stereoisomeric cyclic analogues of hexadecylphosphocholine (Miltefosin e) and phosphatidylcholine, (2S,4S)-, (2R,4S)-, (2R,4R)-, and -4-penta decyl-1,3-dioxa-6-aza-2-phosphacyclooctane bromide (2a-d), and the ena ntiomers (S)- and thyl)-N-(2-hydroxyheptadecyl)-N,N-dimethylammonium i odide ((S)-and (R)-11) were prepared in good overall yields using opti cally pure glyceraldehyde surrogates as the starting materials. A four -step synthesis of the key intermediates ((S)- and (R)-1-pentadecyloxi rane ((S)-and (R)-3) gave overall high optical purity and chemical yie lds. Approaches to the synthesis of these key intermediates utilizing asymmetric dihydroxylation on 1-pentadecene gave high chemical yields but only modest optical purity. All ammonium salts inhibited protein k inase C with the following values of IC50 (mu M): 2a (105), 2b (109), 2c (121), 2d (113).