SYNTHESIS AND STRUCTURAL-ANALYSIS OF STEREOSPECIFIC 3,4,5-TRISUBSTITUTED GAMMA-BUTYROLACTONE PHOSPHOLIPIDS

The first synthesis of stereospecific 3,4,5-trisubstituted gamma-butyr olactone phospholipids has been achieved by a ten-step sequence starti ng from N,N-dimethylacetamide (9). Alkylation of 9 with 1-bromohexane gave N,N-dimethyloctanamide (11), which was subjected to aldol condens ation with acrolein and afforded the erythro-N,N-dimethyl-3-hydroxy-2- hexyl-4-pentena (6) and its threo isomer 7, both of which were subsequ ently converted to the corresponding 3-oxy(hexanoyl) esters 15 and 16. Stereospecific cyclization of diastereomeric allylic amides (6,7,15 a nd 16) via iodolactonization gave 3,4,5-trisubstituted gamma-butyrolac tones (19-25) in satisfactory yields (68-89%) and with high stereosele ctivity (at least 6:1), except for the three amide 16 (2:1). Conversio n of the 6-iodo-group of the major iodolactones 23 and 24 to the corre sponding 6-hydroxy lactones 31 and 32 through a wet Prevost reaction a lso resulted in 4-hydroxy droxy lactones 30 and 33, and a mechanism fo r this reaction is proposed. Further phosphorylation of 4- or 6-hydrox y lactones 30, 31 and 32 with diphenyl chlorophosphate gave the corres ponding diphenyl phosphoric acid lactone esters 34, 35 and 36, whereas 33 underwent an elimination reaction under formation of a C(3)-C(4) d ouble bond. Hydrogenolysis of the diphenyl groups of esters 34, 35 and 36 over Adams' catalyst [platinum(IV) oxide] yielded the correspondin g phosphoric acid lactone esters 38, 39 and 40, which were finally tre ated with choline tetraphenylborate to afford the desired lactone phos pholipids 41, 42 and 43 in overall yields of 9, 30 and 18%, respective ly. The structures of all new compounds were unambiguously assigned by analysis of their H-1 and C-13 one dimensional and two-dimensional nu clear magnetic resonance (NMR) spectra obtained on a 300 MHz NMR spect rometer, and the structures were confirmed by low or high resolution m ass spectrometry as well as elemental analysis. The stereoisomeric pur ity of the final products (98.2, 99.0 and 98.5% for 41, 42 and 43, res pectively) was determined by high-performance liquid chromatography.