Synthesis of 1-β-D-arabinofuranosyl-cytosine 5'-phosphate-L-1,2-diacylglycerols

Article abstract of DOI:10.1016/S0009-3084(97)00056-X

5'-O-MMTr-cytosine arabinoside was prepared on a large scale from 5'-O-MMTr-cytidine with diphenyl carbonate via 5'-protected cytidine-2',3'-carbonate-ara-cytidine-2',2-anhydro derivative at a 67% yield. 1,2-Dipalmitoyl-sn-glycerol,1,2-distearoyl-sn-glycerol and 1,2-dioleoyl-sn-glycerol were phosphorylated first with 2-chlorphenyl-phosphorobis-triazolide quantitatively. This method was used in order to avoid acyl migration, then the glycerophosphate intermediates were condensed with 2',3',N⁴-trileulinyl-1-β-D-arabinofuranosylcytosine in the presence of 2-mesytilensulphonyl chloride (MSCl) and 1-methylimidazole (MeIm) - which was used in the coupling of nucleotides - in an 85-88% yield compared with the low yielding diester method of Ryu et al. Deblocking was carried out in two steps with tetrabutylammonium fluoride (TBAF) and hydrazine hydrate, producing target compounds (9a, 9b, 9c) at a 50% yield.

Full text of DOI:10.1016/S0009-3084(97)00056-X

Chemistry and Physics of Lipids
89 (1997) 75–81
Short communication
Synthesis of 1-i-
D
-arabinofuranosyl-cytosine
5%-phosphate-
L-1,2-diacylglycerols
´
Agnes Nyilas *
Uni6ersity of Uppsala, Department of Bioorganic Chemistry, Biomedical Center, S-751 23 Uppsala ,Sweden
Received 28 April 1997; received in revised form 7 July 1997; accepted 10 July 1997
Abstract
5%-O-MMTr-cytosine arabinoside was prepared on a large scale from 5%-O-MMTr-cytidine with diphenyl carbonate
via 5%-protected cytidine-2%,3%-carbonate-ara-cytidine-2%,2-anhydro derivative at a 67% yield. 1,2-Dipalmitoyl-sn-glyc-
erol, 1,2-distearoyl-sn-glycerol and 1,2-dioleoyl-sn-glycerol were phosphorylated first with 2-chlorphenyl-phosphoro-
bis-triazolide quantitatively (Welch and Chattopadhyaya, 1985. Acta Chem. Scand. B39, 47–57). This method was
used in order to avoid acyl migration, then the glycerophosphate intermediates were condensed with 2%,3%,N4-
trileulinyl-1-i-D-arabinofuranosylcytosine in the presence of 2-mesytilensulphonyl chloride (MSCl) and 1-methylimi-
dazole (MeIm)—which was used in the coupling of nucleotides (Nyilas et al., 1986. Acta Chem. Scand. B40,
678–684)—in an 85–88% yield compared with the low yielding diester method of Ryu et al., 1982. J. Med. Chem.
25, 1322–1329. Deblocking was carried out in two steps with tetrabutylammonium fluoride (TBAF) and hydrazine
hydrate, producing target compounds (9a, 9b, 9c) at a 50% yield. © 1997 Elsevier Science Ireland Ltd.
Keywords: Leukemia; Ara-CMP-dipalmitin; Ara-CMP-distearin; Ara-CMP-diolein; MMTr-ara-C; Diphenyl carbon-
ate
1. Intoduction
prepared from 2%-O-methanesulphonyl derivative
of cytidine (Fromageot and Reese, 1966). Con-
densation of the appropriate sugar and base pro-
duced ara-C also (Shimidzu and Shimidzu, 1970).
Cytidine 2%,3%-cyclic phosphate was converted to
aracytidine 3%-phosphate (Nagyva´ry and Tapiero,
1969; Nagyva´ry, 1969). These procedures need
several steps with a relatively low yield. Ogilvie
Cytosine arabinoside (ara-C) is an important
drug used against leukemia (Alberto, 1978). A
survey of the literature shows, that ara-C has been
* Present address: Tisza L. krt. 18/D, 6720. Szeged, Hun-
gary. Tel.: +36 62 487310.
0009-3084/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved.
PII S0009-3084(97)00056-X

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A. Nyilas / Chemistry and Physics of Lipids 89 (1997) 75–81
76
(1972) introduced a one step process from cy-
tidine using diphenyl carbonate. Beranek et al.
(1974) improved the reproducibility with several
additions of diphenyl carbonate and purification
of the reaction mixture with Zerolite FF and
Dowex 50WX2 (H+). However the purification
was tedious and time consuming and gave ara-C
in only a 32% yield overall. These two papers
did not give NMR data of the product.
The clinical effectiveness of ara-C may be im-
proved with granulocite colony-stimulating factor
(G-CSF) (Waga et al., 1992) and interleukin-3
(IL-3) (Brach et al., 1991). Furthermore the use
of hydrocortisone will protect cells from the
toxic effect of ara-C (Yang et al., 1991). Another
way to improve the effectiveness of ara-C and
overcome the problems associated with its use as
a chemotherapeutic agent is to synthesize ara-C-
phospholipid. Ryu et al. (1982) and Hong et al.
(1995) have prepared several conjugates. Their in
vivo and in vitro studies concentrated mostly on
the ara-C diphosphate analogue. Ryu et al.
(1982) have synthesized one ara-C monophos-
phate analogue by the diester method, thus the
was used as an internal standard in CDCl3–
CD3OD=9:1 solutions (l scale). 31P NMR spec-
tra were recorded at 36 MHz in the same solvent
mixture as in 1H NMR using 85% phosphoric
acid as an external standard on the l scale.
UV absorption spectra were recorded with a
Varian-Cary 2200 spectrometer in ethanol.
Short column chromatographic separations
were carried out using Merck G60 silica gel
eluted with a linear gradient of mixtures of n-
hexane–CH2Cl2 and MeOH–CH2Cl2.
Elemental analyses were performed in Upp-
sala. Results were within 90.4% of the theoreti-
cal values.
2.1. 5%-O-MMTr-cytidine (2)
The 5%-OH function of cytidine (2.43 g, 10
mmol) was protected with monomethoxyrtityl
chloride (MMTrCl) (3.71 g, 12 mmol) in dry
pyridine overnight in the dark. The reaction mix-
ture was partitioned between chloroform (500
ml) and saturated sodium bicarbonate (500 ml),
followed by evaporation of the organic phase
and coevaporation with toluene in vacuo. One
aliquot (about 20 mg) was purified on a silica gel
column with dichloromethane followed by 10%
methanol–dichloromethane in order to record
the 1H NMR spectrum of 5%-O-MMTr-cytidine
(2). 1H NMR (CDCl3, CD3OD) l: 8.1 (d, 1H,
yield of condensation of protected ara-C and
L-
h-diacylglycero-phosphoric acid did not exceed
22%. It should be worth preparing monophos-
phate analogue with different lengths of fatty
acids also, because the 1-i-D-arabinofuranosyl-
cytosine 5%-phosphate-1,2-dipalmitoyl-sn-glycerol
showed antiproliferative activity (Ryu et al.,
1982).
The synthesis of ara-C-phospholipid needs a
careful choice of protecting groups for the differ-
ent functionalities and a mild deprotection condi-
tion in order to avoid acyl migration. Since the
activation method of coupling could cause iso-
merisation, the glycerol part should be phospho-
rylated first (Welch and Chattopadhyaya, 1985).
J
H-5, H-6=9.0 Hz) H-6, 7.3 (m, 12H) aromatic,
6.9 (d, 2H) aromatic, 5.8 (d, 1H, JH-1%,H-2%=2.0
Hz) H-1%, 5.4 (d, 1H) H-5, 4.2 (m, 3H) H-2%, H-3%
and H-4%, 3.8 (s, 3H) OCH3, 3.5 (m, 2H) H-5%
and H-5%%. UV (pH 2): umax 285 nm; (pH 7) 276
nm; (pH 12) 274 nm.
2.2. 5%-O-MMTr-ara-cytidine (3)
The major part of the reaction mixture was
treated with diphenyl carbonate (9.0 g, 42 mmol)
and sodium bicarbonate (6.7 g, 80 mmol) in
dimethylformamide (24 ml) for 3 h at 80°C. Af-
ter evaporation in vacuo the residue was dis-
solved in chloroform (about 20 ml) and purified
by silica gel chromatography with chloroform
then 10% methanol–dichloromethane as eluents.
2. Experimental procedures
Diphenyl carbonate and TBAF were pur-
chased from Sigma.
A Jeol FX90 spectrometer was used at 89.5
MHz to measure 1H NMR; tetramethylsilane

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A. Nyilas / Chemistry and Physics of Lipids 89 (1997) 75–81
77
phoro-bis-triazolide solution (0.768 mmol, in
acetonitrile) was added. The reaction mixture
was stirred at room temperature for 20 min,
then quenched with 0.5 M triethylammonium bi-
carbonate solution (10 ml) and partitioned be-
tween 50 ml CH2Cl2 and 50 ml saturated
sodium bicarbonate. The organic layer was ex-
tracted with water (2×100 ml) then evaporated
and coevaporated several times to remove any
traces of pyridine. The resulting gum was 0.324
g, 100%. 31P NMR (CDCl3, CD3OD) l:−7.4.
Evaporation of the appropriate fractions gave
compound 3 (3.3 g, 67% for two reaction steps)
1H NMR (CDCl3, CD3OD) l: 7.9 (d, 1H, J5,6
=
9.0 Hz) H-6, 7.3 (m, 12H) aromatic, 6.8 (d, 2H)
aromatic, 6.2 (d, 1H, J1%,2%=5.1 Hz) H-1%, 5.5(d,
1H) H-5, 4.1 (m, 3H) H-2%, H-3% and H-4%, 3.8
(s, 3H) OCH3, 3.4 (m, 2H) H-5%, H-5%%. UV (pH
2): umax 285 nm; (pH 7) 276 nm; (pH 12) 274
nm.
2.3. 5%-O-MMTr-2%,3%,N4-trile6ulinyl-1-i-
arabinofuranosylcytosine (4)
D-
2.6. 1,2-Distearoyl-sn-glycero-3-(2-chlorophenyl)-
phosphate triethylammonium salt (6b)
5%-O-MMTr-ara-C was levulinated as in the
literature (Ryu et al., 1982) with a 96% yield. H
1
NMR (CDCl3) l: 7.0 (d, 1H, J5,6=7.6 Hz) h-6,
7.3 (m, 14H) aromatic of MMTr, 6.8 (d, 1H,
Distearoyl-sn-glycerol was phosphorylated
analogously to the preparation of 6a to give 6b
(0.32 g, 100%). 31P NMR (CDCl3, CD3OD)
l:−7.1
J5,6=7.6 Hz) H-5, 6.2 (d, 1H, J1%,2%=4.2 Hz)
H-1%, 5.2 (m, 1H) H-2%, 5.1 (m, 1H) H-3%, 4.2 (m,
1H) H-4%, 3.7 (s, 3H) OCH3, 3.4 (m, 2H) H-5%,
H-5%%, 2.7–2.4 (m, 12H) CH2 of Lev, 2.1–2.0 (m,
9H) CH3 of Lev.
2.7. 1,2-Dioleoyl-sn-glycero-3-(2-chlorophenyl)-
phosphate triethylammonium salt (6c)
2.4. 2%,3%,N4-trile6ulinyl-1-i-
sylcytosine (5)
D-arabinofurano-
Dioleoyl-sn-glycerol
was
phosphorylated
analogously to the preparation of 6a. The yield
was 0.41 g, 93.5%. 31P NMR (CDCl3, CD3OD)
l:−6.5.
Compound 4 (0.802, 1.07 mmol) was dissolved
in 10 ml 80% aqueous acetic acid. The reaction
mixture was stirred at room temperature for 3 h
then evaporated and coevaporated with water
several times. The resulting foam was dissolved
in CH2Cl2 and loaded onto silica gel. The target
compound was eluted with CH2Cl2. The yield
was 0.34 g, 67%. 1H NMR (CDCl3) l: 8.2 (d,
1H, J5,6=7.8 Hz) H-6, 7.4 (d, 1H, J5,6=7.8 Hz)
H-5, 6.2 (d, 1H, J1,2=4.2 Hz) H-1%. 5.5 (m, 1H)
H-2%, 5.2 (m, 1H) H-3%, 4.1 (m, 1H) H-4%, 3.9 (m,
2H) H-5%, H-5%%, 2.7–2.4 (m, 12H) CH2 of Lev,
2.1–2.0 (m, 9H) CH3 of Lev.
2.8. 2%,3%,N4-trile6ulinyl-1-i-arabinofurano-
sylcytosine-5%-(2-chlorophenyl)-phosphate-
1,2-dipalmitoyl-sn-glycerol (7a)
Compound 6a (0.1 g, 0.12 mmol) and com-
pound 5 (0.047 g, 0.098 mmol) were dissolved in
1 ml dry pyridine. MsCl (0.077 g, 0.35 mmol)
and MeIm (0.058g, 0.71 mmol) were added to
the reaction mixture. After 20 min stirring the
reaction mixture was partitioned between 10 ml
CH2Cl2 and 10 ml citric acid solution. The or-
ganic phase was evaporated and dissolved in 2
ml CH2Cl2 and loaded onto silica gel. 50%
CH2Cl2–n-hexane and CH2Cl2 eluted the target
compound. The proper fractions were evapo-
rated and gave a foam, 0.123 g, 86%. 31P NMR
(CDCl3, CD3OD) l:−6.6, −6.8.
2.5. 1,2-Dipalmitoyl-sn-glycero-3-(2-chloro-
phenyl)-phosphate triethylammonium salt (6a)
1,2-Dipalmitoyl-sn-glycerol
mmol) was dissolved in 2 ml dry CH2Cl2 and 2
ml dry pyridine. 3 ml 2-Chlorophenyl-phos-
(0.219,
0.384

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A. Nyilas / Chemistry and Physics of Lipids 89 (1997) 75–81
78
2.9. 2%,3%,N4-trile6ulinyl-1-i-arabinofurano-
sylcytosine-5%-(2-chlorophenyl)-phosphate-1,2-
distearoyl-sn-glycerol (7b)
g, 100%. 31P NMR (CDCl3, CD3OD) l:−1.0.
2.14. 1-i-arabinofuranosylcytosine-5%-mono-
phosphate-1,2-dipalmitoyl-sn-glycerol tributyl-
ammonium salt (ara-CMP-dipalmitin) (9a)
Compound 6b and
5
were condensed
analogously to 6a. The yield was 0.335 g, 95%. 31
NMR (CDCl3, CD3OD) l:−6.6, −6.8.
P
Compound 8a was delevulinated with hydrazine
hydrate as described in the literature (Ryu et al.,
1982). The yield was 0.076 g, 50%. 1H NMR
2.10. 2%,3%,N4-trile6ulinyl-1-i-arabinofurano-
sylcytosine-5%-(2-chlorophenyl)-phosphate-
1,2-dioleoyl-sn-glycerol (7c)
(CDCl3-CD3OD-D2O, 2:3:1) l: 7.8 (d, 1H, J5,6
=
7.8 Hz) H-6, 6.1 (d, J1%,2%=4.4 Hz) H-1%, 6.0 (d,
1H, J5,6=7.8 Hz) H-5, 5.2 (m, 1H) 2-CH of
glycerol, 4.3–3.9 (m, 15H) H-2%, H-3%, H-4%, H-5%,
H-5%%+glycerol CH2%s+tributylamine CH2%s, 2.3
(m, 2H) CH2CO, 1.6–1.3 (m, 26H) CH2 of palmi-
toyl, 0.9 (t, 9H) palmitoyl+tributylamine CH3.
31P NMR (CDCl3, CD3OD) l:−2.3. UV (pH 2)
umax 285 nm; (pH 7) 276 nm; (pH 12) 274 nm.
Compound 6c and
5
were condensated
analogously to 6a. The yield was 0.38 g, 85%. 31P
NMR (CDCl3, CD3OD) l:−6.7, −6.9.
2.11. 2%,3%,N4-trile6ulinyl-1-i-arabinofurano-
sylcytosine-5%-monophosphate-1,2-dipalmitoyl-sn-
glycerol tributylammonium salt (8a)
2.15. 1-i-arabinofuranosylcytosine-5%-mono-
phosphate-1,2-distearoyl-sn-glycerol tributyl-
ammonium salt (ara-CMP-dipalmitin) (9b)
Compound 7a (0.129 g, 0.115 mmol) was dis-
solved in 31 ml pyridine–H2O–THF(tetrahydro-
furan)=1:1:8 and 1 M TBAF solution in THF
(1.55 ml) was added. After 4.5 h stirring at room
temperature the reaction mixture was evaporated
and the residue was dissolved in 2 ml CH2Cl2 and
loaded onto silica gel. Compound 8a was eluted
with 10% MeOH–CH2Cl2. The proper fractions
were combined and evaporated. The yield was
0.185 g, 88%. 31P NMR (CDCl3, CD3OD) l:−
2.3.
Compound 8b was treated with hydrazine hy-
drate analogously to compound 8a. The yield was
1
0.073 g, 52%. H NMR (CDCl3–CD3OD–D2O,
2:3:1) l: 7.8 (d, 1H, J5,6=7.6 Hz) H-6, 6.1 (d, 1H,
J1%,2%=4.4 Hz) H-1%, 5.9 (d, 1H, J5,6=7.6 Hz) H-5,
5.2 (m, 1H) CH of glycerol. 4.7–3.8 (m, 15H)
H-2%, H-3%, H-4%, H-5%, H-5%%+glycerol CH%2s+
tributylamine CH2%s, 2.3 (m, 4H) CH2CO, 1.6–1.0
(m, 30H) CH2 of stearoyl, 0.9 (t, 9H) CH3 of
stearoyl and tributylamine. 31P NMR (CDCl3,
CD3OD) l:−0.9. UV (pH 2) umax 285 nm; (pH 7)
276 nm; (pH 12) 274 nm.
2.12. 2%,3%,N4-trile6ulinyl-1-i-arabinofurano-
sylcytosine-5%-monophosphate-1,2-distearoyl-sn-
glycerol tributylammonium salt (8b)
Compound 7b was treated with TBAF and
worked up analogously to compound 7a. The
yield was 0.188 g, 80%.31P NMR (CDCl3,
CD3OD) l:−1.9.
2.16. 1-i-arabinofuranosylcytosine-5%-mono-
phosphate-1,2-dioleoyl-sn-glycerol tributyl-
ammonium salt (ara-CMP-dipalmitin) (9c)
2.13. 2%,3%,N4-trile6ulinyl-1-i-arabinofurano-
sylcytosine-5%-monophosphate-1,2-dioleoyl-sn-
glycerol tributylammonium salt (8c)
Compound 8c was deblocked analogously to
compound 8a. The yield was 0.067 g, 53%. H
NMR (CDCl3–CD3OD–D2O, 2:3:1) l: 7.9 (d,
1H, J5,6=7.6 Hz) H-6, 6.1 (d, 1H, J1%,2%=4.4 Hz)
H-1%, 5.9 (d, 1H, J5,6=7.6 Hz) H-5, 5.3 (m, 5H)
CH of glycerol+(CH=CH)2, 4.7–3.7 (m, 15H)
1
Compound 7c was partially deblocked
analogously to compound 7a. The yield was 0.352

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A. Nyilas / Chemistry and Physics of Lipids 89 (1997) 75–81
79
Fig. 1. Synthesis of the protected ara-C.
anomeric proton becomes more shielded (Bazin et
al., 1986) compared to compound 2. This relative
shielding of H-1% may be due to a lone pair effect
of the C-2% substituent. The H-1% chemical shift of
compound 3 (6.2 ppm) is 0.4 ppm more shielded
than that of compound 2 (5.8 ppm). JH,H of 2% or
3% increases as the configuration of the sub-
stituent—which is directly attached to it—
changes (Bazin et al., 1986). We have noticed the
same tendency because in the 5%-O-MMTr-cytidin
2 JH-1%,H-2%=2.0 Hz and in the 5%-O-MMTr-ara-cy-
tidine 3 it has a higher value (5.1 Hz).
The synthesis of phospholipid was carried out
as previously described (Nyilas, 1997) employing
the Eibl, 1981 method for the preparation of
isopropilidene glycerol. The 3 position of glycerol
was protected by FMOC in an 80% yield and the
isopropilidene group was removed with formic
acid treatment. The fatty acids were introduced
quantitative, then the FMOC group was removed
by dry triethylamine (Nyilas, 1997).
H-2%, H-3%, H-4%, H-5%, H-5%%+glycerol CH%2s+
tributylamine CH2%s, 2.3 (m, 4H) CH2CO, 1.6–1.3
(m, 26H) CH2 of oleoyl, 0.9 (m, 9H) CH3 of
oleoyl and tributylamine. 31P NMR (CDCl3,
CD3OD) l:−0.6. UV (pH 2) umax 285 nm; (pH 7)
276 nm; (pH 12) 274 nm.
3. Results and discussions
In the synthesis of 5%-O-MMTr-ara-C (Fig. 1)
we showed that increasing the liphophility of the
starting material (cytidine) by protecting the 5%-
OH of cytidin with monomethoxytrityl chloride
we could prepare 5%-O-MMTr-ara-C 3 with the
Ogilvie, 1972 procedure then purify from the re-
maining few percent of starting material with fast
short silica gel chromatography instead of with
Zerolite FF and Dowex 50WX2 (H+) by Beranek
et al. (1974). Compound 3 could be used directly
with the temporary 5%-O-MMTr protection of
ara-C for the synthesis of ara-C phospholipid.
The UV spectra of 5%-O-MMTr-cytidine 2 and
5%-O-MMTr-ara-cytidine 3 are the same and the
1H NMR spectra corroborate the structure of
compound 3. In the 5%-O-MMTr-ara-C 3 the
The levulination of 5%-O-MMTr-ara-C was car-
ried out as in the literature (Ryu et al., 1982) and
the MMTr group was removed with aqueous
acetic acid treatment at room temperature for 3 h,
giving compound 5 (67%) (Fig. 1). The phospho-

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A. Nyilas / Chemistry and Physics of Lipids 89 (1997) 75–81
Fig. 2. Synthesis of ara-C-phospholipid conjugates.
were similar to the dinucleotides (Nyilas et al.,
1986).
rylation of diacyl-sn-glycerols was performed with
2-chlorophenyl-phosphoro-bis-triazolide (Welch
and Chattopadhyaya, 1985) giving the phospho-
glycerols (6a, 6b, 6c) quantitative. Condensation
of phosphoglycerols with 2%,3%,N4-trilevulinyl-ara-
C 5 (Fig. 2) was performed also with a high yield
in the presence of MsCl and MeIm (Nyilas et al.,
1986). The TBAF treatment and delevulination
with hydrazine hydrate gave the target com-
pounds (9a, 9b, 9c) at a 50% yield, which were
characterized by UV, 1H NMR and 31P NMR
spectroscopy. The umax at different pH was the
4. Summary
We have improved the yield of the synthesis of
ara-C from 32 to 67% with MMTr protection of
5%-OH of cytidine and shortened the time of
purification with silica gel of the reaction mixture.
We have characterized the 5%-O-MMTr-ara-C
by 1H NMR spectroscopy compared with the
spectrum of 5%-O-MMTr-C.
1
same as that of cytidine. H NMR spectrum of
We showed here that the 1,2-diacylglycerols
synthesized by FMOC protection on the sn-3
position could be phosphorylated with 2-
compound 9a is similar to the literature (Ryu et
al., 1982). Chemical shifts of 31P NMR spectra of
the triesters (6a, 6b, 6c) and diesters (9a, 9b, 9c)

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A. Nyilas / Chemistry and Physics of Lipids 89 (1997) 75–81
81
Fromageot, H.P., Reese, C.B., 1966. N4,O3%,O5%-Triacetyl-2,2%-
chlorophenyl-phosphoro-bis-triazolide and could
be used for the preparation of ara-C-phospholipid
conjugates without acyl migration, within the
anhydrocytidine 3%-phosphate, a precursor of 1-i-D-ara-
binocytosine. Tetrahedron Lett. 29, 2499–3505.
Hong, C.I., Nechaev, A., Kirisits, A.J., Vig, R., Hui, S.W.,
West, C.R., 1995. Nucleoside conjugates. 14. Synthesis and
antitumor activity of 1-i-arabinofuranosylcytosine conju-
gates of ether lipids with improved water solubility. J.
Med. Chem. 38, 1629.
1
limit of the sensitivity of H NMR.
Employing the phosphotriester methodology of
Welch and Chattopadhyaya (1985) instead of the
diester method of Ryu et al. (1982) the yield of
condensation of phosphoglycerols and 2%,3%N4-
trilevulinyl-ara-C could be improved from 22 to
85–95%.
Nagyva´ry, J., 1969. Arabinonucleosides. II. The synthesis of
O2-anhydrocytidin3%-phosphate, a precursor of 1-i-
D-ara-
binocytosine. J. Am. Chem. Soc. 91, 5409–5410.
Nagyva´ry, J., Tapiero, C.M., 1969. Arabinonucleosides III.
The conversion of cytidylic acid into aracytidine-3%-phos-
phate at low temperature. Tetrahedron Lett. 40, 3481–
3484.
´
Nyilas, A., 1997.
A new protecting group: 9-Fluorenyl-
Acknowledgements
methoxycarbonyl (FMOC) in the synthesis of 1,2-diacyl-
glycerols. Chem. Phys. Lipids (submitted).
´
The autor gratefully acknowledge financial sup-
port from the Swedish Board of Technical Devel-
opment and the Swedish Natural Science
Research Council. I thank Professor Dr Jyoti
Chattopadyaya for valuable discussions.
8
Nyilas, A., Vrang, L., Drake, A., Oberg, B., Chattopadhyaya,
J., 1986. The cordycepin analogue of 2,5 A and its threo
isomer. Chemical synthsis, conformation and biological
activity. Acta Chem. Scand. B40, 678–684.
Ogilvie, K.K., 1972. Conversion of cytidine into 1-i-
D-ara-
binocytosine. Carbohydr. Res. 24, 210–211.
Ryu, E.K., Ross, R.J., Matsusita, T., Mac Coss, M., Hong,
C.I., West, C.R., 1982. Phospholipid-nucleoside conju-
gates. 3. Synthesis and preliminary biological evaluation of
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