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Lyso platelet activating factor (LysoPAF) and its enantiomer. Total synthesis and carbon‐13 NMR spectroscopy
Author(s) -
Murari M. P.,
Murari R.,
Parthasarathy S.,
Guy C. A.,
Kumar V. V.,
Malewicz B.,
Baumann Wolfgang J.
Publication year - 1990
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/bf02536010
Subject(s) - chemistry , alkyl , enantiomer , acyl group , nuclear magnetic resonance spectroscopy , stereochemistry , alkylation , organic chemistry , phosphocholine , medicinal chemistry , phospholipid , phosphatidylcholine , catalysis , biochemistry , membrane
Described is a reaction sequence for the total synthesis of lyso platelet activating factor (lysoPAF; 1‐ O ‐alkyl‐ sn ‐glycero‐3‐phosphocholine) and its enantiomer. The procedure is versatile and yields optically pure isomers of defined chain length. The synthesis is equally suited for the preparation of lysoPAF analogues and its enantiomers with unsaturation in the long aliphatic chain. First, rac ‐1(3)‐ O ‐alkylglycerol is prepared by alkylation of rac ‐isopropylideneglycerol with alkyl methanesulfonate followed by acid‐catalyzed removal of the ketal group. The primary hydroxy group of alkylglycerol is then protected by tritylation, the secondary hydroxy group is acylated, and the protective trityl group is removed under mild acidic conditions with boric acid on silicic acid, essentially without acyl migration. Condensation of the diradylglycerol with bromoethyl dichlorophosphate in diethyl ether, hydrolysis of the resulting chloride, and nucleophilic displacement of the bromine with trimethylamine gives rac ‐1‐ O ‐alkyl‐2‐acylglycero‐3‐phosphocholine in good overall yield. The racemic alkylacylglycerophosphocholine is finally treated with snake venom phospholipase A 2 ( Ophiophagus hannah ) which affords 1‐ O ‐alkyl‐ sn ‐glycero‐3‐phosphocholine (lysoPAF) of natural configuration in optically pure form. The “unnatural” 3‐ O ‐alkyl‐2‐ O ‐acyl‐ sn ‐glycerol‐1‐phosphocholine enantiomer, which is not susceptible to phospholipase A 2 cleavage, gives 3‐ O ‐alkyl‐ sn ‐glycero‐1‐phosphocholine upon deacylation with methanolic sodium hydroxide. Homogeneity and structure of the intermediates and final products were ascertained by carbon‐13 nuclear magnetic resonance spectroscopy on monomeric solutions.