A New Approach to the Stereospecific Synthesis of Phospholipids. The Use of l-Glyceric Acid for the Preparation of Diacylglycerols, Phosphatidylcholines, and Related Derivatives

• Published in: Journal of organic chemistry Vol. 64; no. 21; pp. 7727 - 7737
• Main Authors: Roodsari, Farzaneh S, Wu, Dongpei, Pum, Gregory S, Hajdu, Joseph
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.10.1999; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; SIGNAL-TRANSDUCTION; P388D MACROPHAGES; PROTEIN-KINASE-C; ANALOGS; ETHER; ENERGY-TRANSFER; MICELLES; PLATELET-ACTIVATING-FACTOR; ARACHIDONIC-ACID; MEMBRANE-LIPIDS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo990414e

A new stereospecific synthesis of phospholipid derivatives of 1,2-diacyl-sn-glycerols is reported. The synthesis is based on (1) the use of l-glyceric acid as the stereocenter for construction of the optically active phospholipid molecule, (2) preparation of 3-triphenylmethyl-sn-glycerol as the key intermediate for sequential introduction of the primary and secondary acyl functions leading to the chiral diglycerides, and (3) elaboration of the sn-3-phosphodiester headgroup via phosphorylation using 2-chloro-2-oxo-1,3,2-dioxaphospholane, followed by ring opening of the five-membered phosphorus heterocycle with trimethylamine, ammonia, as well as oxygen and sulfur nucleophiles. The sequence has been shown to be suitable for the preparation of both symmetric and mixed-chain diacylglycerols with saturated and unsaturated acyl substituents. Phospholipid headgroups including phosphocholine, phosphoethanolamine, phosphoethanol, and phosphoethylthioacetate functions have been prepared. Application of the method to the synthesis of functionalized phosphatidylcholines has also been demonstrated by incorporating spectroscopically active spin-labeled and fluorescent reporter groups via postsynthetic derivatization of chain terminal ω-aminoalkyl functions of the acyl substituents of the compounds. The synthetic methods developed have a great deal of flexibility, providing convenient routes to a wide range of structurally variable phospholipids for physicochemical, enzymological, and cell-biological studies.