Syntheses of Enzyme-Inhibitory Phospholipid Analogues. Stereospecific Synthesis of 2-Amidophosphatidylcholines and Related Derivatives

Article abstract of DOI:10.1021/jo00132a031

A novel stereospecific synthesis of the enzyme-inhibitory 2-sn-deoxy-2-amidophosphatidylcholine is reported.The synthesis is based on (1) utilizing the chirality of the α-carbon of the starting amino acid serine, (2) protecting the asymmetric center via formation of an oxazoline ring, and (3) introducing the phosphorylcholine moiety through the 2-chloro-2-oxo-1,3,2-dioxaphospholane-trimethylamine sequence.The compound has been shown to be a specific and potent phospholipase A₂ inhibitor, exhibiting higher affinity to the enzyme under the reaction conditions than the natural substrate.The synthetic method used for the preparation of the inhibitor provides a general route to a wide range of other phospholipid analogues as well.Along these lines 2-deoxy-2-aminolysolecithin has been shown to react with octyl chloroformate and stearoyl isocyanate to form the corresponding 2-sn-carbamoyl and 2-sn-alkylureido derivatives.The scope of the synthesis is being investigated for the preparation of reversible as well as irreversible phospholipase inhibitors.