Cationic phospholipids on the basis of higher fatty alcohols

Article abstract of DOI:10.1007/s11176-005-0172-7

A perspective synthetic approach to cationic amidodiester lipid constructions on the basis of cyclic phosphites derived from octadecan-1-ol is presented. The syntheses of phospholipids were carried out by oxidative decyclization of cyclic phosphoramidites

Full text of DOI:10.1007/s11176-005-0172-7

Russian Journal of General Chemistry, Vol. 75, No. 1, 2005, pp. 53 57. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 1, 2005, pp. 61 68.
Original Russian Text Copyright 2005 by Predvoditelev, Malenkovskaya, Nifant’ev.
Cationic Phospholipids on the Basis of Higher Fatty Alcohols
D. A. Predvoditelev, M. A. Malenkovskaya, and E. E. Nifant’ev
Moscow State Pedagogical University, Moscow, Russia
Received April 9, 2003
Abstract A perspective synthetic approach to cationic amidodiester lipid constructions on the basis of
cyclic phosphites derived from octadecan-1-ol is presented. The syntheses of phospholipids were carried out
by oxidative decyclization of cyclic phosphoramidites with bromine.
One of the important priorities of modern lipido-
logy is synthesis of cationic ammonium analogs of
natural phospholipids, as promising starting materials
for genosome design and objects for other biomedical
studies [1 3]. We have previously demonstrated the
promise functionalyzed phosphorus acid halides hold
for synthesis of cationic amidodiester lipids. Such key
has been successfully complemented by modern pre-
parative techniques of organophosphorus chemistry
[7].
The present work continues these studies and deals
with the synthesis of first representatives, with the aid
of phosphoramidobromidates, cationic amidodiester
compounds have been prepared by oxidative decycliza- phospholipids containing an octadecyl radical. The
tion with halogens (Br2, Cl2) of alkylene phosphor-
amidites derived from glycerol [4] or natural menthol
[5]. It has therewith been established that phosphorous
bromides prepared by the above reaction are the most
convenient to use in the phospholipid synthesis [4].
Hence, the classical phosphorylation procedure widely
used in phospholipid chemistry and based on the
employment of traditional phosphorochloridates [6]
synthesis of octadecyl phosphoramidobromidate IV
was carried out in two stages. First we obtained al-
koxyoxazaphospholane III by phosphorylation of
octadecan-1-ol (I) with hexaethylphosphorous tri-
amide followed by reaction of the phosphorodiamidite
II formed with N-methylcolamine (procedure a) or by
phosphorylation of octadecan-1-ol with 2-(diethylami-
no)-3-methyl-1,3,2-oxazaphospholane (procedure b).
P[NEt2]3
C18H37OP[NEt2]2
II
a
CH3
HN(CH3)CH2CH2OH
C18H37OH
N
I
Et2N P
N
O
C18H37OP
b
O
III
Procedures a and b both were accomplished in
dulute solutions in anhydrous dioxane or benzene at
80 85 C for 1 h with simultaneous distillation of the
diethylamine fomed and solvent. The reaction prog-
ress was followed by 31P NMR. Octadecyl phosphoro-
date IV by oxidative decyclization with bromine
under mild conditions (at 0 C).
Br
Br2
III
C18H37P NCH2CH2Br
diamidite (II,
132.98 ppm, s) and cyclic phosphor-
O
amidite III ( P136.70 ppm, s) were used in further
IV
P
syntheses without additional purification.
Acid bromide IV withstands chromatographic puri-
fication on a silica gel column. Its yield per starting
alcohol I achieves 55%. Note that the yields of com-
In the second stage, octadecyl phosphoramidite III
was converted into octadecyl phosphoramidobromi-
1070-3632/05/7501-0053 2005 Pleiades Publishing, Inc.

54
PREDVODITELEV et al.
pound IV from phosphoramidite III prepared by
procedures a and b are approximately the same, but
procedure b is more convenient from the preparative
viewpoint. Note that compound IV can be handled
for several months in the darkness in the absence of
air at room temperature.
The reactions of phosphoramidobromidate IV with
1,2-O-isopropylideneglycerol (V) and cholesterol (VI)
were carried out in anhydrous benzene in the presence
of pyridine for 12 h, and with octadecan-1-ol and 2,6-
di-tert-butyl-4-(3-hydroxypropyl)phenol (VII), heat-
ing at 40 C for 2 h was needed. After purification on
a silica gel column, the yields of phospholipids VIII
IX were 61 62 (from IX and X and 50 51% (from
VIII and XI). Note that octadecyl phosphoramido-
bromidate IV is more reactive than menthyl phos-
phoramidobromidate [5]. The latter reacts with gly-
cerol and cholesterol derivatives under more rigid
conditions (60 80 C, 12 30 h).
The 31P NMR spectrum of phosphoramidobromi-
1
date IV contains a singlet at
5.18 ppm. The H
NMR spectrum of this compoPund displays signals
characteristic of all the proton groups. Hence, protons
of the PNCH3 group appear as a doublet signal at
2.75 ppm (3JPH 8.24 Hz) due to coupling of methyl
protons with phosphorus, and methylene protons of
the PNCH2CH2Br group give a complex multiplet at
3.40 ppm. -Methylene protons of the octadecyl
radical give a doublet of triplets at 4.10 ppm as the
result of coupling with phosphorus and -methylene
protons. -Methylene protons of this radical appear
as a multiplet at 1.71 ppm. The other signals in the
spectrum of compound IV correspond to the presented
structure (see Experimental).
The individuality and structure of octadecyl phos-
phoramidates VIII XI were proved by physicoche-
mical methods. The 31H NMR spectra of com-
pounds VIII and XI contain singlets ( 9.01 and
P
8.99 ppm, respectively) and those of compounds IX
and X, broadened singlets ( 9.62 and 8.51 ppm,
P
respectively), since the latter compounds exist as
mixtures of diastereomers.
1
Octadecyl phosphoramidobromidate IV was used
for phosphorylation of alcohols of the lipid series. Its
reaction with octadecan-1-ol (I) gave symmetrical
phosphoramidate VIII, whereas reactions with gly-
cerol derivative V and natural cholesterol1 (VI) gave
unsymmetrical phosphoramidates IX and X. In addi-
tion, compound IV was used to introduce lipid frag-
ments in ionol derivative VIII, a well known antioxi-
dant widely used in membrane studies [9, 10].
The H NMR spectra of compounds VIII XI con-
1
tain all expected proton signals. Hence, in the H
NMR spectrum of symmetrical amidodiester VIII,
the signals of the C18H37O group doubled integral
intensity compared with the respective signals in the
1
spectrum of acid bromide IV. The H NMR spectrum
of glycerol derivative IX shows singlets at 1.35 and
1.42 ppm due to methyl protons of the acetonyl pro-
tective group. The multiplet of the methine proton on
the -carbon atom of the glycerol residue is observed
at 3.41 ppm. The 1H NMR spectra of cholesterol phos-
pholipid2 X and ionol derivative XI, too, are fully
consistent with the presented structures (see Experi-
mental).
O
N
OR
R OH + IV
I, V VII
C18H37OP
N(CH3)CH2CH2Br
VIII XI
In the final stage of the work, -bromoethylphos-
phoramidates VIII XI were converted into cationic
lipids by treatment with trimethylamine.
CH3
CH3
O
O
R = C18H37 (I, VIII),
(V, IX),
The reactions with trimethylamine were carried out
at 70 80 C for 4 8 h. The yields of ammonium deri-
vatives XII XV were 63 71%. The 31P NMR spectra
of compounds XII XV are quite similar to the spectra
21
22
24
26
20
_
.
.
.
_
.
12
25
.
23
.
17
.
.
11
19
13
27
16
1
4
_
14
_
.
. 9
.
.
.
.
(VI, X),
.
-
-
.
-
-
2
_
-
_
-
1
10
of compounds VIII XI. In H NMR spectra of XII
15
H
H
XV, the multiplet of methylene protons of the
PN(CH3)CH2CH2 group is shifted downfield relative
to the respective signal of VIII XI, and a singlet at
3.55 ppm from methyl protons on the cationic center
N+(CH3)3 appears.
CH3
3
5
7
H3C
6
CH3
OH (VII, XI).
CH2CH2
CH3
CH3
H3C
2
1
Analysis of the H NMR spectra of cholesterol phospholipids
1
The numbering of carbon atoms in the cholesterol radical
corresponds to that accepted in cholesterol chemistry [8].
X and XIV was carried out with account for the detailed
assignment of cholesterol proton signals given in [8, 11, 12].
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CATIONIC PHOSPHOLIPIDS ON THE BASIS OF HIGHER FATTY ALCOHOLS
55
alcohol I and 3.7 g of hexaethylphosphorous triamide
in 3 ml of anhydrous dioxane was heated for 2 h at
80 C with distillation of the evolving diethylamine
and dioxane. The formation of phosphorodiamidite II
was controlled by 31P NMR ( 132.98 ppm, s).
Further compound II was subjectPed to a vacuum (1
mm Hg) at 130 150 C for 2 h, mixed with 0.55 g of
N-methylethanolamine and 5 ml of anhydrous dioxane,
and the mixture was heated at 75 85 C. A solution of
cyclic phosphoramidite III ( 136.70 ppm, s) in 5
ml of anhydrous benzene wasPtreated at 5 C with a
solution of 1.18 g of bromine in 5 ml of the same
solvent, which was added dropwise with vigorous
stirring. After 10 min, the solvent was removed in a
vacuum, and product IV was isolated on a column of
silica gel (10 g), filled with hexane. The product was
eluted with 30 ml of hexane dioxane, 10:1. The sol-
vents were removed in a vacuum, and the residue was
kept for 2 h at 40 C (1 mm Hg), yield 2.2 g (55%),
mp 70 72 C, Rf 0.85 (A) and 0.65 (B). 1H NMR spec-
trum (CDCl3), , ppm: 0.88 t [3H, CH3(CH2)15CH2
O
OR
VIII XI N(CH )
3 2
C H37OP
+
18
N(CH3)CH2CH2N(CH3)3Br
XII XV
CH3
CH3
O
O
(IX, XIII),
R = C18H37 (VIII, XII),
21
22
24
26
20
_
.
.
.
_
.
12
25
.
23
.
17
.
.
11
19
13
27
16
1
4
_
14
_
.
. 9
.
.
.
.
(X, XIV),
.
-
-
.
-
-
2
_
-
_
-
10
15
H
H
3
5
7
6
CH3
H3C
H3C
CH3
OH (XI, XV).
CH2CH2
CH3
CH3
3
CH2O, JHH 6.76 Hz], 1.26 s [30H, CH3(CH2)15CH2
To conclude, oxidative decyclization of cyclic
phosphoramidites with bromine allows synthesis of
phosphorus acid bromides of complex structure under
mild conditions and in high yields. It is significant
that using of such bromides as phosphorylating agents
in the chemistry of natural compounds is a convenient
preparative method for creating a phosphorus entity
and deserves wide synthetic use.
CH2O], 1.71 m [2H, CH3(CH2)15CH2CH2O], 2.75 d
3
(3H, PNCH3, JPH 8.24 Hz), 3.40 m (4H, NCH2
CH2Br), 4.10 d.t [2H, CH3(CH2)15CH2CH2O]. 31P
NMR spectrum (CHCl3), P, ppm: 5.16 s. Found, %:
C 47.32; H 8.30; P 5.97. C21H44Br2NO2P. Calculated,
%: C 47.29; H 8.32; P 5.81.
b. A mixture of 1.7 g of octadecan-1-ol (I) and 1 g
of 2-(diethylamino)-3-methyl-1,3,2-oxazaphospholane
in 3 ml of anhydrous benzene was heatedfor 1.5 h at
80 85 C with distillation of the evolving diethyl-
amine and benzene. The formation of cyclic phos-
phoramidite III was controlled by 31P NMR
EXPERIMENTAL
1
The H NMR spectra were obtained on a Bruker
WM-250 instrument (250 MHz), internal reference
HMDS; signal assignment was performed on the basis
of double resonance spectra. The 31P {1H} NMR
spectra were measured on a Bruker WP-80SY spec-
trometer (32.4 MHz), external reference 85% phos-
phoric acid.
(
P 136.61 ppm, s). Compound III was converted into
acid bromide IV as described above using 0.99 g of
bromine in 3 ml of anhydrous benzene. 31P NMR
spectrum, P, ppm: 5.17 s. Yield 2.17 g (65.5 %). The
1
chromatographic mobility, melting point, and H and
31P NMR spectra of this sample were analogous to
those of the sample obtained by procedure a.
Absorption chromatography was performed on a
column 10 mm in diameter, packed with silica gel L
(100 250 m). Thin-layer chromatography was per-
formed on Silufol UV-254 plates in benzene (A), ben-
zene dioxane, 3:1 (B), hexane dioxane, 3:1 (C), and
chloroform methanol water, 64:25:4 (D). The melt-
ing points were determined in a sealed capillary,
Dioctadecyl N-(2-bromoethyl)-N-methylphos-
phoramidate (VIII). To a solution of 0.86 g of acid
bromide IV in 5 ml of anhydrous benzene, a solution
of 0.45 g of octadecan-1-ol and 0.13 g of freshly
distilled pyridine in 3 ml of anhydrous benzene was
added dropwise with stirring and cooling to 0 C. The
reaction mixture was heated at 40 C for 1.5 h. Pyri-
dine hydrobromide was filtered off, the solvent was
removed in a vacuum, and compound VIII was iso-
lated on a column of silica gel (10 g), filled with
hexane. The product was eluted with 50 ml of hexane.
The solvent was removed in a vacuum, and the re-
sidue the residue was kept for 2 h at 40 C (1 mm Hg),
1
heating rate 1 deg min .
2-(Diethylamino)-3-methyl-1,3,2-oxazaphospho-
lane was prepared according to [13]. The constants of
this compound were coincident with published data.
Octadecyl N-(2-bromoethyl)-N-methylphos-
phoramidobromidate (IV). a. A mixture of 2 g of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 1 2005

56
PREDVODITELEV et al.
yield 0.57 g (50%), mp 45 46 C, Rf 0.85 (A) and 0.60
CH2CH2O], 1.65 m [2H, CH3(CH2)15CH2CH2O],
2.71 d (3H, PNCH3, 3JPH 10.01 Hz), 3.40 3.43 m (4H,
NCH2CH2Br), 3.94 d.t [2H, CH3(CH2)15CH2CH2O,
1
(B). H NMR spectrum (CDCl3), , ppm: 0.88 t [6H,
3
CH3(CH2)15CH2CH2O, JHH 7.01 Hz], 1.25 s [60H,
3
CH3(CH2)16CH2CH2O], 1.65 m [4H, CH3(CH3)15
3JHH 6.58 Hz, JPH 12.01 Hz], 4.15 m (1H, cholesteryl
3
3
CH2CH2O], 2.71 d (3H, PNCH3, JPH 9.50 Hz),
OPC3H), 5.38 d (1H, cholesteryl C6H, JHH 3.20 Hz).
3
3.43 m [2H, N(CH3)CH2], 3.64 t (2H, CH2Br, JHH
31P NMR spectrum (CHCl3), P, ppm: 8.51 br.s.
Found, %: C 68.83; H 10.81; P 3.91. C48H89BrNO3P.
Calculated, %: C 68.70; H 10.89; P 3.69.
3
6.68 Hz), 3.98 d.t [4H, CH3(CH2)15CH2CH2O, JHH
3
6.58 Hz, JPH 11.58 Hz]. 31P NMR spectrum (CDCl3),
P, ppm: 9.01 s. Found, %: C 66.21; H 11.70; P 4.29.
C39H81BrNO3P. Calculated, %: C 66.07; H 11.52;
P 4.37.
3-(2,6-Di-tert-butyl-4-hydroxyphenyl)propyl
octadecyl N-(2-bromoethyl)-N-methylphosphor-
amidate (XI) was prepared analogously to compound
VIII from 0.45 g of acid bromide IV, 0.27 g of 2,6-
di-tert-butyl-4-(3-hydroxypropyl)phenol (VII), and
0.1 g of pyridine in 15 ml of anhydrous benzene at
40 C for 2 h. Compound XI was isolated pure on a
column of silica gel (10 g), filled with hexane. The
product was eluted with 80 ml of hexane dioxane,
3:1. The solvent was removed in a vacuum, and the
residue was kept for 2 h at 40 C (1 mm Hg), yield
0.37 g (51%), n2D0 1.4980, Rf 0.88 (A) and 0.53 (B).
1,2-O-Isopropylideneglycerol octadecyl N-(2-
bromoethyl)-N-methylphosphoramidate (IX) was
obtained analogously to compound VIII from 0.96 g
of acid bromide IV, 0.24 g of 1,2-O-isopropylidene-
glycerol, and 0.15 g of pyridine in 10 ml of anhydrous
benzene at room temperarure for 10 h. Compound IX
was isolated pure on a column of silica gel (10 g),
filled with hexane. The product was eluted with 80
ml of hexane dioxane, 3:1. The solvents were re-
moved in a vacuum, and the residue was kept in a
vacuum for 2 h at 40 C (1 mm), yield 0.51 g (61%),
mp 35 37 C, Rf 0.48 (A) and 0.40 (B). 1H NMR spec-
trum (CDCl3), , ppm: 0.86 t [3H, CH3(CH3)15CH2
1H NMR spectrum (CDCl3), , ppm: 0.88 t [3H, CH3
3
(CH2)15CH2CH2O, JHH 6.58 Hz], 1.26 s [30H,
CH3(CH2)15CH2CH2O], 1.43 s [18H, (CH3)3C],
1.68 m [2H, CH3(CH2)15CH2CH2O], 1.97 m (2H,
3
3
CH2O, JHH 6.39 Hz], 1.24 s [30 H, CH3(CH2)15
OCH2CH2CH2), 2.62 t (2H, CH2C7H5, JHH 8 Hz),
3
CH2CH2O], 1.35 s (3H), 1.42 s (3H) [C(CH3)2],
2.72 d (3H, PNCH3, JPH 9.34 Hz), 3.42 3.54 m (4H,
1.66 m [2H, CH3(CH2)15CH2CH2O], 2.72 d (3H,
NCH2CH2Br), 3.90 4.10 m [4H, OCH2CH2CH3,
3
PNCH3, JPH 9.77 Hz), 3.38 3.48 m (4H, NCH2
CH3(CH2)15CH2CH2O), 5.10 s (1H, OH), 6.97 s (2H,
CH2Br), 3.82 m (2H, CH2CHCH2OP), 3.96 m (2H,
CH2CHCH2OP), 4.07 d.t [2H, CH3(CH2)15CH2CH2O,
C6H2). 31P NMR spectrum (CHCl3), P, ppm: 8.99 s.
Found, %: C 63.72; H 9.59; P 4.41. C38H68BrNO4P.
Calculated, %: C 63.84; H 9.73; P 4.33.
3
3JHH 6.51 Hz, JPH 11.15 Hz], 4.31(1H, CH2CH
3
CH2OP, JHH 5.50 Hz). 31P NMR spectrum (CHCl3),
P, ppm: 9.62 br.s. Found, %: C 58.43; H 9.96; P 5.52.
C27H55NO3P. Calculated, %: C 58.68; H 10.03; P
5.61.
Dioctadecyl N-(2-bromoethyl)-N-methylphos-
phoramidate bromomethylate (XII).
A sealed
ampule with a solution of 0.4 g phosphoramidate VIII
and 0.5 g of trimethylamine in 4 ml of anhydrous
benzene was heated for 5 h at 60 C. The precipitate
that formed was filtered off, washed in succession
with benzene (2 5 ml), acetone (2 5 ml), and di-
ethyl ether (2 5 ml), and dried for 2 h at 40 C (1 mm
Hg). Yield 0.31 g (70%), mp 192 193 C (gets wet at
Cholesteryl octadecyl N-(2-bromoethyl)-N-
methylphosphoramidate (X) was prepared analo-
gously to compound VIII from 0.65 g of acid bro-
mide IV, 0.47 g of cholesterol (VI), and 0.1 g of
pyridine in 10 ml of anhydrous benzene at room
temperature for 12 h. Compound X was isolated pure
on a column of silica gel (15 g), filled with hexane.
The product was eluted with 100 ml of hexane di-
oxane, 1:1. The solvent was removed in a vacuum,
and the residue was kept for 2 h at 40 C (1 mm Hg),
yield 0.63 g (62%), mp 32 33 C, Rf 0.75 (A) and
1
110 C), Rf 0.66 g (B). H NMR spectrum (CDCl3), ,
ppm: 0.87 t [6H, CH3(CH2)15CH2CH2O], 1.24 s
[60 H, CH3(CH2)15CH2CH2O], 2.71 d (3H, PNCH3,
3JPH 9.87 Hz), 3.47 m [2H, NCH2CH2N+], 3.51 s [9H,
N+(CH3)3], 3.71 m (2H, NCH2CH2N+), 3.93 m (4H,
CH3(CH2)15CH2CH2O]. 31P NMR spectrum (CHCl3),
P, ppm: 9.15 s. Found, %: C 64.63; H 10.44; P 4.01.
C42H90BrN2O3P. Calculated, %: C 64.50; H 10.31;
P 3.96.
1
0.55 (B). H NMR spectrum (CDCl3), , ppm: 0.68
2.42 ppm (cholesteryl H),3 0.85 t [3H, CH3(CH2)15
3
CH2CH2O, JHH 6.62 Hz], 1.26 s [30H, CH3(CH2)15
1,2-O-Isopropylideneglycerol octadecyl N-(2-
bromoethyl)-N-methylphosphoramidate bromo-
methylate (XIII) was obtained analogously to bro-
momethylate XII from 0.5 g of phosphoramidate IX
3
Here and hereinafter, the range
tic of the protons on the C , C C , and C
phosphocholesterol moiety [8] is labeled cholesteryl H.
0.68 2.42 ppm characteris-
P
1,2 4,
5
7 27
atoms of the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 1 2005

CATIONIC PHOSPHOLIPIDS ON THE BASIS OF HIGHER FATTY ALCOHOLS
57
3
and 0.65 g of trimethylamine in 3 ml of anhydrous
benzene for 5 h at 80 C. The solvent was removed in
a vacuum, and the residue was washed with an-
hydrous benzene (2 2 ml). Additional purification of
bromomethylate XIII was carried out by crystalliza-
tion from anhydrous acetone at 5 C (acetone-insoluble
admixtures were preliminarily removed by centrifuga-
tion at 50 C). The product was kept for 3 h at 40 C
(1 mm Hg), yield XIII 0.42 g (71%), mp 183 185 C
2.77 d (3H, PNCH3, JPH 10.07 Hz), 3.44 s [9H,
N+(CH3)3], 3.48 m (2H, NCH2CH3N+), 3.65 m (2H,
NCH2CH2N+), 3.83 4.00 m [4H, OCH2CH2CH2,
CH3(CH2)15CH2CH2O), 5.54 s (1H, OH), 6.95 s (2H,
C6H2). 31P NMR spectrum (CHCl3), P, ppm: 9.01 s.
Found, %: C 63.54; H 9.93; P 4.28. C41H78BrN2O4P.
Calculated, %: C 63.62; H 10.16; P 4.00.
ACKNOWLEDGMENTS
1
(gets wet at 85 C), Rf 0.61 (B). H NMR spectrum
(CDCl3), , ppm: 0.87 t [3H, CH3(CH2)15CH2CH2O,
3JHH 6.59 Hz], 1.25 s [30H, CH3(CH2)15CH2CH2O],
1.35 s and 1.42 s {2x3H, [C(CH3)]3}, 1.65 m [2H,
The work was financially supported by the Russian
Foundation for Basic Research (project no. 01-03-
32459).
3
CH3(CH2)15CH2CH2O], 2.62 d (3H, PNCH3, JPH
9.90 Hz), 3.46 m (2H, NCH2CH2N+), 3.55 s [9H,
N+(CH3)3], 3.68 m (2H, NCH2CH2N+), 3.79 m (2H,
CH2CHCH2OP), 3.96 m [2H, CH3(CH2)15CH2CH2O],
4.06 m (2H, CH3CHCH2OP), 4.29 m (1H, CH2CH
CH2OP). 31P NMR spectrum (CHCl3), P, ppm:
9.53 br.s. Found, %: C 55.81; H 9.89; P 4.69.
C30H64BrN2O5P. Calculated, %: C 55.97; H 10.02;
P 4.81.
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Cholesteryl octadecyl N-(2-bromoethyl)-N-
methylphosphoramidate bromomethylate XIV was
prepared analogously to bromomethylate XII from
0.45 g of compound X and 0.55 g of trimethylamine
in 3 ml of anhydrous benzene for 4 h at 60 C, yield
0.34 g (69%), mp 230 232 C (gets wet at 180 C), Rf
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1
0.65 (B). H NMR spectrum (CDCl3), , ppm: 0.66
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2.45 ppm (cholesteryl H), 0.86 t [3H, CH3(CH2)15
CH2CH2O, JHH 6.60 Hz], 1.23 s [30H, CH3(CH2)15
3
CH2CH2O], 1.62 m [2H, CH3(CH2)15CH2CH2O],
3
7. Predvoditelev, D.A. and Nifant’ev, E.E., Zh. Org.
Khim., 1995, vol. 31, no. 12, p. 1761.
2.74 d (3H, PNCH3, JPH 9.76 Hz), 3.46 m (2H,
NCH2CH2N+), 3.51 s [9H, N+(CH3)3], 3.91 m [3H,
CH3(CH2)15CH2CH2O, cholesteryl OPC3H], 4.03 m
(2H, NCH2CH2N+), 5.36 d (1H, cholesteryl C6H, 3JHH
8. Facke, T. and Boger, S., Tetrahedron, 1995, vol. 51,
no. 12, p. 3521.
4.40 Hz). 31P NMR spectrum (CHCl3), P, ppm: 9.15
br.s. Found, %: C 66.53; H 10.69; P 3.45. C51H98Br
N2O3P. Calculated, %: C 66.71; H 10.76; P 3.37.
9. Nifant’ev, E.E., Predvoditelev, D.A., and Zolo-
tov, M.A., Bioorg. Khim., 1981, vol. 7, no. 7, p. 1100
10. Akhrem, A.A., Dolgopalets, M.A., Kisel’, M.A.,
Mezep, H.I., Timoshchuk, V.A., Fedulov, A.S., and
Shadyro, O.I., Bioorg, Khim., 1995, vol. 21, no. 5,
p. 391.
3-(2,6-Di-tert-butyl-4-hydroxyphenyl)propyl
octadecyl N-(2-bromoethyl)-N-methylphosphor-
amidate bromomethylate (XV) was obtained analo-
gously to bromomethylate XII from 0.37 g of com-
pound XI and 0.48 g of trimethylamine in 3 ml of
anhydrous benzene for 8 h at 80 C, yield 0.25 g
(63%), mp 140 142 C (gets wet at 98 C), Rf 0.59 (B).
1H NMR spectrum (CDCl3), , ppm: 0.87 t [3H, CH3
11. Malenkovskaya, M.A., Predvoditelev, D.A., Bel’-
skii, V.K., and Nifant’ev, E.E., Zh. Obshch. Khim.,
2003, vol. 73, no. 12, p. 1976.
12. Predvoditelev, D.A., Malenkovskaya, M.A., Vasyani-
na, L.K., and Nifant’ev, E.E., Zh. Obshch. Khim.,
2004, vol. 74, no. 8, p 1257.
3
(CH2)15CH2CH2O, JHH 6.65 Hz], 1.24 s [30H,
CH3(CH2)15CH2CH2O], 1.42 s [18H, (CH3)3C],
1.60 m [2H, CH3(CH2)15CH2CH2O], 1.96 m (2H,
13. Mukaiyama, T. and Kodaira, Y., Bull Chem. Soc. Jpn.,
3
OCH2CH2CH2), 2.67 t (2H, CH2C6H5, JHH 7.95 Hz),
1966, vol. 39, no. 6, p. 1297.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 1 2005