2-Hydroxymethyl-2-propyl-1,3-propanediol in the Synthesis of Phospholipids

Abstract

New representatives of nonglycerol polyol phospholipids were synthesized from 2-hydroxymethyl-2-propyl-1,3-propanediol through intermediate phosphoramidites and cyclic phosphites obtained from isopropylidene derivative of the title triol. Treatment of these intermediate products with sulfur or selenium afforded the corresponding thio-and selenophosphates which were converted into lipids by direct acylation with higher carboxylic acid chlorides.* For short communication, see [1]. Phospholipids in which the alcohol fragment is not glycerol but other polyols are very promising for use in biochemical and biophysical studies. Therefore, development of methods for synthesizing such compounds is an important problem [2,3]. Phospholipids modified at the alcoholic fragment were previously synthesized on the basis of 2-hydroxymethyl-2-methyl-1,3-propanediol (metriol) and 1,2,4-butanetriol [4], D-mannite and D-glucite [5], 1,2,5-pentanetriol [6], and isomeric 1,2,3-cyclopentanetriols [7-12]. The products were successfully used in studies on membrane models [13,14] and catalytic activity of some phospholipases [4,8,15]. However, the above syntheses were performed with the use of phosphorus(V) compounds as phosphorylating agents, and the yields of the target products were not high.New methods of synthesis of nonglycerol polyol phospholipids involve phosphorus(III) compounds as phosphorylating agents [16,17], which make it possible to obtain not only phospholipids but also their sulfur-and selenium-containing analogs. The latter attract interest as models for various biophysical studies using NMR spectroscopy. Some advances in the synthesis of lipids by the phosphite technique have been reported [18][19][20][21][22][23][24][25].In continuation of our previous studies in this line, the present communication reports on the synthesis of previously unknown phospholipids on the basis of 2-hydroxymethyl-2-propyl-1,3-propanediol. As initial compound we used readily accessible 5-hydroxymethyl-2,2-dimethyl-5-propyl-1,3-dioxane (I) which was subjected to phosphorylation with hexaethylphosphorous triamide (II) to obtain compound III (Scheme 1). In order to raise the yield of the target product, 3 equiv of triamide II was used, and excess reagent was distilled off when the reaction was complete. The formation of phosphorodiamidite III was monitored by 31 P NMR spectroscopy: a singlet at δ P 134 ppm appeared in the spectrum of the reaction mixture. Scheme 1. O O Pr HO Me Me I + P(NEt 2 ) 3 II O O Pr OP(NEt 2 ) 2 Me Me IIICompound III was converted (without isolation and purification) to the corresponding thio-and selenophosphates IV and V by treatment with sulfur or selenium, respectively (Scheme 2). The transformation of phosphorodiamidite III into phosphorus(V) compounds IV and V was monitored by TLC and 31 P NMR spectroscopy. The 31 P NMR spectra of the reaction mixtures contained singlets at δ P 79 (IV) and 81 ppm (V). In addition, the 31 P NMR spectrum of selenium derivative V contained satellites due to 31 P-77 Se coupling with a con...