Stereocontrolled synthesis of plasmalogen-type lipids from glyceryl ester precursors

Article abstract of DOI:10.1021/jo00098a040

Two pathways for the synthesis of naturally occurring Z vinyl ether linkages in plasmalogen lipids (1-O-((Z)-1'-alkenyl)-2-acyl-sn-glycerophosphocholines and ethanolamines) have been investigated: (i) reduction of α-alkoxy enol phosphates and (ii) alkylidenation of diprotectod glyceryl 1-formate esters utilizing 1,1-dibromoalkanes, zinc, TiCl₄, and TMEDA. While both methods reported good chemical yields and high Z selectivity for model substrates, the titanium-mediated coupling sequence failed when the dibromoalkyl chain length exceeded C₃. Treatment of 1-decyl-2-O-benzyl-3-O-(tert-butyldiphenylsilyl)-rac-glycerol with LDA and diethyl chlorophosphate at -78°C followed by reduction of the vinyl phosphate intermediate using Pd(PPh₃)₄ and Et₃Al in DCE at 0°C, however, gave 1-O-(1'-decenyl)-2-O-benzyl-3-O-(tert-butyldiphenylsilyl)-rac-glycerol in 62-65% yield and 2:1 Z:E stereoselectivity; reduction in hexane at 0°C with slow addition of triethylaluminum improved the selectivity to >95% Z. Extension of this method to the preparation of a plasmalogen precursor (1-O-((Z)-1'-hexadecenyl)-2-hexadecanoyl-rac-glycerol) and the first synthesis of a choline derivative of diplasmalogen (1,2-di(O-(Z)-1'-hexadecenyl)-rac-glycerophosphocholine), a major component of rabbit epididymal spermatozoa phospholipid, in moderate chemical yields and excellent Z selectivity is reported.