Synthesis of first phospholipids from 2,2,6,6-tetrakis(hydroxymethyl)cyclohexanol

Abstract

A procedure has been developed for the synthesis of previously unknown thio phospholipids and cationic ammonium amidophosphorus lipids on the basis of 2,2,6,6-tetrakis(hydroxymethyl)cyclohexanol. Model phospholipids have been prepared using phosphorus-containing cyclic compounds. * For short communication, see [1]. Glycerophospholipids persistently attract attention of researchers [2, 3]. However, phospholipids based on aliphatic polyols have been studied poorly. Up to now, only a few examples of such compounds have been synthesized from aliphatic polyols, in particular from 1,2,4-butanetriol [4], 1,2,5-pentanetriol [5], tris-and tetrakis(hydroxymethyl)alkanes [6, 7], xylitol [8], and ribose [9]. Among the prepared phospholipids there were no compounds having structural fragments of aliphatic carbocyclic polyols. On the other hand, phospholipids whose molecules possess an additional rigidity factor should be characterized by a specific steric structure, and they may be important models for studies in various fields of physical and chemical biology and medicine.The goal of the present work was to synthesize previously unknown thio phospholipids and cationic ammonium phosphoramide lipids having a 2,2,6,6-tetrakis(hydroxymethyl)cyclohexanol moiety as structural fragment. In the first step of our study, 2,2,6,6-tetrakis(hydroxymethyl)cyclohexanol (I) was brought into reaction with acetone to protect four hydroxy groups therein. As a result, two isomeric acetals II and III were obtained (Scheme 1). The reaction was performed in the presence of a catalytic amount of anhydrous p-toluenesulfonic acid with simultaneous removal of the liberated water by azeotropic distillation. Acetals II and III differed in the chromatographic mobility, and we succeeded in separating them by column chromatography on silica gel. Moreover, compound III was less soluble in organic solvents; therefore, products II and III can also be purified by recrystallization. The major product was compound II (yield 65%), while the yield of III was as low as 4.8%.The structure of compounds II and III was confirmed by the 1 H NMR spectra. In the spectrum of bis-acetal II, protons of the geminal methyl groups appeared as singlets at δ 1.35 and 1.45 ppm, methylene protons of the cyclohexane fragment gave a multiplet at δ 1.39 ppm, and the singlet at δ 4.28 ppm was assigned to the 1-H proton. The unsymmetrical structure of compound II follows from the spectral pattern formed by signals from axial and equatorial protons in the 1,3-dioxane rings, which were located at δ 3.12 (d), 4.10 (d) and 3.74 (d), 3.95 ppm (d) with the coupling constants 2 J(ax-eq) = 11.9 and 10.99 Hz, respectively. Scheme 1. OH OH HO OH OH