Tris(hydroxymethyl)nitromethane in phospholipids synthesis

Predvoditelev, D. A.; Malenkovskaya, M. A.; Нифантьев, Э. Е.

doi:10.1007/s11178-005-0079-0

Cited by 3 publications

(3 citation statements)

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“…Like other lipid bromoamidophosphates [12,13], compound XI did not change during isolation by column chromatography on silica gel (yield 55%). It can be stored without appreciable decomposition for several months at room temperature in the dark with protection from air.…”

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confidence: 80%

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

et al. 2004

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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

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

et al. 2004

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“…A sealed ampule with a solution of amidophosphate XV obtained by procedure [21] from 0.5 g (3.12 mmol) of compound I, 0.42 g 2.6 mmol) of N-diethylamino-3-methyl-1,3,2-oxaazaphospholane, and 2.47 g (2.6 mmol) of bromomethane in 20 ml of anhydrous benzene was heated at 60°C for 8 h. The solvent was removed in a vacuum, and phosphonate XVI was isolated on a column packed with silica gel (20 g) and filled with hexane. Compound XVI was eluted with 35 ml of a mixture hexane-dioxane, 1:1.…”

Section: O-[22-(oo-isopropylidenedioxymethyl)-2-nitroethyl]-(n-methmentioning

confidence: 99%

“…2,2-(O,O-Isopropylidenedioxymethyl)-2-nitroethanol (I) was obtained by procedure [21], 2-chloro-1,3,2-dioxaphospholane by method [22], 2-chloro-1,3,2-dioxaphosphorinane as described in [23], and 2-N-diethyl-3-Nmethyl-1,3,2-oxaazaphospholane as in [24]. The compounds used had constants in agreement with the published data.…”

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Cationic Nitrophospoamphiphiles of Phosphonate and Amidophosphonate Types

2005

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Productive synthesis of cationic nitrophosphoamphiphilic lipids was developed basing on available tris(hydroxymethyl)nitromethane and cyclic reagents of trivalent phosphorus.In recent years a promising branch of medicine is successfully developed treating the disturbances of gene functions, genetic therapy [1-3]. One of the key problems of this therapy is delivery into the target cells of the therapeutic gene (transfection) with the use of cationic liposomes [4][5][6][7]. Among the cationic lipids included into these liposomes are widely studied ammonium phosphorus-free lipids [8][9][10][11][12]. At the same time the positively charged ammonium (cationic) phospholipids are far less understood [8,[13][14][15][16], although the pioneering study of cationic phospholipides preparation by an example of glycerophosphonate analogs has been performed more than 25 years ago [17].The present report concerns syntheses of new cationic lipid phosphonoamphiphiles proceeding from the acetone derivative of tris(hydroxymethyl)nitromethane (I). The choice of the trimethylolnitromethane core for the new lipid systems aimed at application in the genetic therapy was determined by the synthetic availability of the initial compound, its polarity, and also by the photosensitivity of its phospholipide derivatives. The latter quality may result in initiation of photochemical degradation reactions in the cell under light. These reactions may decrease the stability of the liposome membranes at fusion with endocytic vesicles and thus facilitate the transfection efficiency. A similar process was already studied in detail for a series of amphiphiles containing nitrobenzyl groups [18].The first line of this investigation consisted in application of O,O-ethylene-(II) and trimethylene-(III) cyclophosphites of the acetone derivative of the nitrooligool to the synthesis of methylphosphonate amphiphiles of ammonium type. To this end Arbuzov alkylation was performed on available alkenylphosphites II and III with bromomethane. P O (CH 2 ) n O RO CH 3 Br P RO O(CH 2 ) n Br CH 3 O IV, V II, III R = N C CH 2 O O _ + C CH 3 CH 2 O CH 3 ; n = 2 (II, IV), 3 (III, V). CH 2 OThe reaction was carried out at 100-120°C. Bromoalkenylphosphonates IV and V, pale yellow oily compounds, were obtained in 40-65% yields. Phosphonates IV and V are stable compounds that can be stored for a long time under inert atmosphere in the dark at room temperature. The alkylation was monitored by 31 P NMR spectroscopy. 31 P NMR spectra of methylphosphonates IV and V consist of singlets at δ 31.47 and 30.82 ppm respectively. In the 1 H NMR spectra of these compounds characteristic groups from all protons were observed. The protons of PCH 3 group appear at δ 1.48 ppm as doublet due to the coupling of methyl group protons with the phosphorus nucleus, methylene protons of CH 2 Βr group give rise to triplets in the region 3.45-3.47 ppm, and the signals from protons of the dioxane fragment are observed as doublets at 3.39 and 4.35 ppm The other signals in the spectra of methylphosphonates...

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