Synthesis of trideuterated O-alkyl platelet activating factor and lyso derivatives.
Racemic heavy isotope analogs of 1-O-alkyl-sn-glycero-3-phosphocholine (lysoPAF) and 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine (PAF) were prepared for use as internal standards to facilitate quantitative studies based on mass spectrometry. Starting from pentadecane-1,15-diol and rac-glycerol-1,2-acetonide, a convergent synthesis of 1-O-[16'-2H3]hexadecyl and 1-O-[18'-2H3]octadecyl rac-glycero-3-phosphocholine and their acetyl derivatives is described. Three deuterium atoms were introduced at the terminal position of the 1-O-alkyl group by displacement of the p-toluensulfonyl group from 1-O-alkyl-15'-p-toluensulfonate and 1-O-alkyl-17'-p-toluensulfonate with [2H3]-methylmagnesium iodide. The 1-O-alkyl-17'-p-toluensulfonate was obtained by reaction of the 1-O-alkyl-15'-p-toluensulfonate with allylmagnesium bromide, followed by reductive ozonolysis and treatment with p-toluene-sulfonyl chloride. The hydroxyl group at C-2 was protected by a benzyl group and removed at a late stage in the synthesis. This provided the corresponding lyso-derivatives or allowed preparation of racemic PAF by subsequent acetylation of the free hydroxy group. The phosphocholine moiety was introduced at glycerol C-3 by reaction with bromoethyldichlorophosphate and trimethylamine. The synthetic compounds were analyzed by FAB/MS and GC/NICIMS. They were shown to contain less than 0.6% protium impurity.
Prakash
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Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
Saleh
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Taber
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Blair
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D000107:Acetylation; D055598:Chemical Phenomena; D002621:Chemistry; D003903:Deuterium; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D013057:Spectrum Analysis
C029271:O-deacetyl platelet activating factor; D010972:Platelet Activating Factor; D003903:Deuterium