New and one pot chemoselective synthesis of nucleoside 5′-H- phosphonate diesters

Article abstract of DOI:10.1080/15257770500230467

Arbuzov reaction of phenyl phosphorodichloridite with two equiv of alcohol, or mixture of one equiv of alcohol and one equiv of tert-butyl alcohol, led to the corresponding aryl H-phosphonate diesters. Following displacement of the H-phosphonate diesters

Full text of DOI:10.1080/15257770500230467

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New and One Pot Chemoselective Synthesis of
Nucleoside 5′-H-Phosphonate Diesters
Xin Guo a , Peng Jiang a , Hua Fu a , Yuyang Jiang a b & Yufen Zhao a
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of
Education, Department of Chemistry , Tsinghua University , Beijing, P.R. China
b Key Laboratory of Chemical Biology, Guangdong Province, Graduate School of Shenzhen ,
Tsinghua University , Shenzhen, P.R. China
Published online: 31 Aug 2006.
To cite this article: Xin Guo , Peng Jiang , Hua Fu , Yuyang Jiang & Yufen Zhao (2005) New and One Pot Chemoselective
Synthesis of Nucleoside 5′-H-Phosphonate Diesters, Nucleosides, Nucleotides and Nucleic Acids, 24:9, 1325-1331, DOI:
10.1080/15257770500230467
To link to this article: http://dx.doi.org/10.1080/15257770500230467
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (9):1325–1331, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1080/15257770500230467
NEW AND ONE POT CHEMOSELECTIVE SYNTHESIS OF NUCLEOSIDE
5’-H-PHOSPHONATE DIESTERS
5
Xin Guo, Peng Jiang, and Hua Fu
Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua
University, Beijing, P.R. China
5
Yuyang Jiang
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology, Ministry of Education, Department of Chemistry, Tsinghua University, Beijing, P.R.
China and Key Laboratory of Chemical Biology, Guangdong Province, Graduate School of
Shenzhen, Tsinghua University, Shenzhen, P.R. China
5
Yufen Zhao
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology,
Ministry of Education, Department of Chemistry, Tsinghua University, Beijing, P.R. China
5
Arbuzov reaction of phenyl phosphorodichloridite with two equiv of alcohol, or mixture of one equiv of
alcohol and one equiv of tert-butyl alcohol, led to the corresponding aryl H-phosphonate diesters.
Following displacement of the H-phosphonate diesters with unprotected nucleosides chemoselectively
produced nucleoside 5’-H-phosphonate diesters in good yields, respectively.
Keywords H-Phosphonate Diester, Nucleoside, Chemoselective, Arbuzov Reaction
INTRODUCTION
H-Phosphonates are useful intermediates in chemistry, and finding new
synthetic routes to these compounds constitutes a valuable target. In the past two
Received 16 February 2005, accepted 2 May 2005.
The program is supported from the Excellent Dissertation Foundations by the Chinese Ministry of Education
(No. 200222), the Excellent Young Teacher Program of MOE, P.R. China, and the National Natural Science
Foundation of China (Grand No. 20472042).
Address correspondence to Hua Fu, Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057,
P.R. China; Fax: 86-10-62781695; E-mail: fuhua@mail.tsinghua.edu.cn
1325
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1326
X. Guo et al.
decades, studies on H-phosphonate derivatives have greatly progressed;[1–4] a more
complete picture of synthetic potential of these compounds unfolded.[5,6] H-
phosphonates were widely used as synthetic intermediates in nucleotide,[1–6]
carbohydrate,[7,8] peptide,[9,10] lipid,[11,12] and general phosphorus chemistry.[13,14]
Advances on the development of a comprehensive H-phosphonate methodology
and the underlying chemistry for the preparation of biologically important
phosphate esters and their analogues have been discussed by Stawinski and
Kraszewski.[15] Preparation of H-phosphonate monoesters mainly comes from the
following systems: PCl3/imidazole,[16] salicylchlorophosphite,[17] H-pyrophospho-
nate,[18] and diphenyl H-phosphonate.[19] Synthesis of H-phosphonate diesters
includes transesterification of easily available members of the family,[20] acidolysis
or hydrolysis of phosphorochloridites or mixed anhydrides,[21–23] addition of
phosphonic acid to oxiranes,[24] alcoholysis of bis(N,N-dimethylamino)phospho-
nate,[25] or condensation of alcohols with phosphonic acid by dicyclohexylcarbo-
diimide (DCC).[26] However, most of the methods require protection of amino and
hydroxyl groups in the starting materials.
Since chemistry on uncharged and stable H-phosphonates appears to combine
the advantages of two other phosphorus chemistries, that of P(V) phosphoryl
compounds and that of tervalent P(III) derivatives, their synthetic potential certainly
is worth further exploration.[15] In this article, we would like to report a simple,
general, and efficient method for preparation of nucleoside H-phosphonate diesters,
preferably based on inexpensive, commercial reagents.
RESULTS AND DISCUSSION
There are two routes to nucleoside H-phosphonate diesters, as shown in
Scheme 1. In route 1, two equiv of alcohol was added to phenyl phosphorodi-
chloridite in CH2Cl2 at 0°C under nitrogen atmosphere, the corresponding phenyl
dialkyl phosphite triester (2) intermediate was obtained. The following Arbuzov
rearrangement reaction of the phosphite triester with HCl produced phenyl alkyl H-
phosphonate diester (4) with minor dialkyl H-phosphonate diester appearing. The
displacement reaction of 4 with adenosine or uridine in dry pyridine at room
temperature led to 5 or 6 in 58–67% (see Table 1). Route 2 is similar to route 1;
however, mixture of one equiv of alcohol and one equiv of tert-butyl alcohol
replaced two equiv of alcohol in the Arbuzov reaction, and the reaction yields are
61–70%. For example, in route 1, two equiv of isopropyl alcohol in CH2Cl2 was
added dropwise to phenyl phosphorodichloridite at 0°C under nitrogen
atmosphere. Thirty minutes later, the 31P NMR showed that phenyl phosphorodi-
chloridite at 177.58 ppm transferred into phenyl isopropyl H-phosphonate diester at
3.24 ppm with a minor peak at 4.96 ppm, corresponding to diisopropyl H-
phosphonate diester (12% relative to phenyl isopropyl H-phosphonate diester). The
solvent and HCl in the reaction solution were removed by distillation, the residue
was dissolved in dry pyridine, and adenosine in pyridine was added dropwise to the

Chemoselective Synthesis of Nucleoside 5’-H-Phosphonate Diesters
1327
SCHEME 1 Synthetic routes of nucleoside H-phosphonate diesters.
solution at 20°C under nitrogen atmosphere. Six hours later, phenyl isopropyl H-
phosphonate diester almost quantitatively transferred into a pair of diastereomers
adenosine isopropyl H-phosphonate diester at 31P NMR 8.92, 8.58 ppm (peak area
ratio 1:1). After evaporation of pyridine, the crude product was purified by column
chromatography using CHCl3 and CH3OH (8:1 to 6:1) as eluent, and adenosine
isopropyl H-phosphonate diester was obtained in 67% yield, its structure was
determined by 31P, 1H, 13C NMR, and ESI-MS. The regioselectivity was proved by
TABLE 1 Yields and 31P NMR of the Synthesized Compounds
Entry
Nucleoside
Alcohol
Product
Yield %
31P NMR (ppm)
10.05, 9.62
1
2
3
4
5
6
7
8
A
A
A
A
A
A
A
A
U
U
U
U
U
U
U
U
C16H33OH
5a
5a
5b
5b
5c
5c
5d
5d
6a
6a
6b
6b
6c
6c
6d
6d
59
62
67
70
58
61
60
68
58
64
64
68
61
63
65
70
C16H33OH:tert-butyl alcohol
Isopropyl alcohol
Isopropyl alcohol:tert-butyl alcohol
Allyl alcohol
Allyl alcohol:tert-butyl alcohol
Cyclohexanol
Cyclohexanol:tert-butyl alcohol
C16H33OH
C16H33OH:tert-butyl alcohol
Isopropyl alcohol
Isopropyl alcohol:tert-butyl alcohol
Allyl alcohol
Allyl alcohol:tert-butyl alcohol
Cyclohexanol
Cyclohexanol:tert-butyl alcohol
8.92, 8.57
10.21, 9.94
8.77, 8.22
10.13, 9.70
8.83, 7.77
10.37, 10.02
8.46, 7.82
9
10
11
12
13
14
15
16

1328
X. Guo et al.
1H NMR spectra during phosphonylation of nucleosides. 1H NMR spectrum of 5’-
CH2 for a free nucleoside should show a pair of doublet peaks and two pair of
doublet peaks for 2’ or 3’-monophosphonylated nucleoside because of existence of
a pair of diastereomers. However, we found multiplet peaks of 5’-CH2 in 1H NMR
spectra of nucleoside alkyl 5’-H-phosphonates, which showed the coupling (3JP-H
between P and 5’-CH2.
)
In route 2, mixture of one equiv of alcohol and one equiv of tert-butyl alcohol
was added dropwise to phenyl phosphorodichloridite at 0°C under nitrogen
atmosphere, and the 31P NMR showed alkyl phenyl H-phosphonate diester with
minor dialkyl H-phosphonate diester appearing (8–12% relative to alkyl phenyl H-
phosphonate diester). The following reaction and work-up is similar to the
procedure in route 1. The advantage of route 2 is to reduce use of one equiv of
alcohol, which is important for expensive alcohols such as preparation of
dinucleotides, and the study on this project is in progress.
Displacement reaction of 4 with free nucleosides chemoselectively produced
nucleoside 5’-phosphonate diesters. This is due to the difference in reactivity among
amino of base, 5’, 2’ and 3’-OH, and 5’-OH is of high reactivity and small steric
hindrance compared with other active groups. In addition, we believe that the
similar regioselectivity can also be observed for other nucleosides and the
corresponding deoxyribonucleosides with good solubility in pyridine.
EXPERIMENTAL
General procedure for preparation of nucleoside 5’-H-phos-
phonate diesters. 2 mmol of alcohol (primary or secondary alcohol) or
mixture of 1 mmol of alcohol (primary or secondary alcohol) and 1 mmol of tert-
butyl alcohol (74 mg) in 5 mL of CHCl3 was added dropwise to phenyl
phosphorodichloridite in 5 mL of dichloromethane at 0°C under nitrogen
atmosphere, and the solution was stirred for 30 min at this temperature. The
solvent was removed under reduced pressure, and the residue was dissolved in 5
mL of dry pyridine. One mmol of adenosine or uridine in 5 mL of dry pyridine was
added dropwise to the above solution at room temperature. Six hours later, the
reaction solution was evaporated by rotary evaporation, and the residue was
purified by silica gel column chromatography using CHCl3:MeOH (8:1 to 6:1) as
1
eluent to give the target products. The target products were identified by 31P, H,
13C NMR, and HRESI-MS.
Adenosine hexadecyl 5’-H-phosphonate (5a). 31P NMR (122
MHz, DMSO-d6, ppm): d 10.05, 9.62 (a pair of diastereomers, peak area ratio 1:1);
1H NMR (300 MHz, DMSO-d6, ppm): d 8.30 (1H, s, H-2), 8.13 (1H, d, H-8,
3JH-H = 1.38 Hz), 7.30 (2H, s, NH2), 6.81 (0.5 H, d, P-H, 1JP-H = 701 Hz), 6.75 (0.5H,
1
3
d, P-H, JP-H = 702 Hz), 5.93 (1H, q, H-1’, JH-H = 4.80 Hz), 5.59 (1H, br, 3’-OH),
5.39 (1H, br, 2’-OH), 4.65 (1H, m, H-2’), 4.25–4.22 (1H, m, H-3’), 4.08 (1H, m, H-4’),

Chemoselective Synthesis of Nucleoside 5’-H-Phosphonate Diesters
1329
3.92–3.89 (2H, m, H-5’), 3.44–3.37 (2H, m, –CH2OP), 1.52 (2H, m, –CH2CH2OP),
3
1.30–1.19 (26H, m, –CH2–), 0.83 (3H, t, CH3, JH-H = 6.18 Hz); 13C NMR (75
MHz, DMSO-d6, ppm): d 156.05 (C-6), 152.59 (C-2), 149.33 (C-4), 139.62 (C-8),
119.17 (C-5), 87.63 (C-1’), 82.41 (C-4’), 72.97 (C-2’), 69.89 (C-3’), 65.04 (–CH2–OP),
56.03 (C-5’), 31.31 (CH3CH2CH2–), 29.78 (–CH2CH2OP), 29.07–28.91 (–CH2–),
24.91 (–CH2CH2CH2OP), 22.11 (CH3CH2–), 13.94 (CH3–); HRESI-MS: Calcd for
C26H47N5O6P [M + H]+ (m/z) 556.3264, Found 556.3252.
Uridine hexadecyl 5’-H-phosphonate (6a). 31P NMR (122 MHz,
CDCl3, ppm): d 10.13, 9.70 (a pair of diastereomers, peak area ratio 1:1); 1H NMR
3
(300 MHz, CDCl3, ppm): d10.48 (1H, br, H-3), 7.62 (1H, d, H-6, JH-H = 7.89 Hz),
1
1
6.92 (0.5H, d, P-H, JP-H = 705 Hz), 6.90 (0.5H, d, P-H, JP-H = 708 Hz), 5.86 (1H,
3
d, H-1’), 5.74 (1H, d, H-5, JH-H = 9.27 Hz), 4.40–4.36 (1H, m, H-2’), 4.22–4.26
(2H, m, H-3’, 4’), 4.13–4.07 (2H, m, H-5’), 3.77 (2H, m, –CH2OP), 1.68 (2H, m,
3
–CH2CH2OP), 1.30–1.21 (26H, m, –CH2–), 0.88 (3H, t, CH3–, JH-H = 6.51 Hz);
13C NMR (75 MHz, CDCl3, ppm): d 166.88 (C-4), 153.87 (C-2), 143.34 (C-6),
105.34 (C-5), 92.85 (C-1’), 85.02 (C-4’), 77.00 (C-2’), 72.39 (C-3’), 69.37 (–CH2OP),
67.55 (C-5’), 34.67 CH3CH2CH2–), 33.13 (–CH2CH2OP), 32.70–31.92 (–CH2–),
28.22 (–CH2CH2CH2OP), 25.43 (CH3CH2–), 16.86 (CH3–); HRESI-MS: Calcd
for C25H46N2O8P [M + H]+ (m/z) 533.2992, Found m/z 533.2973.
Adenosine isopropyl 5’-H-phosphonate (5b). 31P NMR (122
MHz, CD3OD, ppm): d 8.92, 8.57 (a pair of diastereomers, peak area ratio 1:1);
3
1H NMR (300 MHz, CD3OD, ppm): d 8.27 (1H, d, H-2), 8.20 (1H, d, H-8, JH-
1
= 1.74 Hz), 7.24–7.21 (2H, m, NH2), 6.83 (0.5H, d, P-H, JP-H = 714 Hz), 6.77
H
1
3
(0.5H, d, P-H, JP-H = 714 Hz), 6.03 (1H, q, H-1’, JH-H = 4.47 Hz), 4.76–4.71 (1H,
m, H-2’), 4.47–4.42 (1H, m, H-3’), 4.38–4.30 (2H, m, H-5’), 4.28–4.22 (1H, m, H-
4’), 3.30 (1H, m, >CH-O-P), 1.28 (6H, m, CH3); 13C NMR (75 MHz, DMSO-d6,
ppm): d 156.07 (C-6), 152.66 (C-2), 149.37 (C-4), 139.70 (C-8), 119.18 (C-5), 87.72
(C-1’), 82.46 (C-4’), 79.19 (C-2’), 70.51 (>CHOP), 69.98 (C-3’), 64.95 (C-5’), 23.55
(CH3–); HRESI-MS: Calcd. for C13H21N5O6P [M + H]+ (m/z) 374.1229, Found
374.1236.
Uridine isopropyl 5’-H-phosphonate (6b). 31P NMR (122 MHz,
1
CDCl3, ppm): d 8.83, 7.77 (a pair of diastereomers, peak area ratio 1:1); H NMR
(300 MHz, CDCl3, ppm): d 10.43 (1H, br, H-3), 7.62 (1H, q, H-6, 3JH-H = 4.47 Hz),
6.93 (0.5H, d, P-H, 1JP-H = 702 Hz), 6.92 (0.5H, d, P-H, 1JP-H = 705 Hz), 5.87 (1H, d,
H-1’), 5.74 (1H, d, H-5, 3JH-H = 8.58 Hz), 4.77 (1H, m, H-2’), 4.34–4.31 (2H, m, H-3’,
3
4’), 4.26–4.20 (2H, m, H-5’), 3.76 (1H, m, >CH-OP), 1.36 (6H, d, CH3–, JH-
= 1.71 Hz); 13C NMR (75 MHz, CDCl3, ppm): d 164.21 (C-4), 151.04 (C-2),
H
136.18 (C-6), 102.52 (C-5), 89.95 (C-1’), 82.22 (C-4’), 74.16 (C-2’), 72.17 (>CH-OP),
69.62 (C-3’), 64.61 (C-5’), 23.86 (CH3–); HRESI-MS: Calcd for C12H20N2O8P
[M + H]+ (m/z) 351.0957, Found 351.0946.

1330
X. Guo et al.
Adenosine allyl 5’-H-phosphonate (5c). 31P NMR (122 MHz,
1
DMSO-d6, ppm): d 10.21, 9.94 (a pair of diastereomers, peak area ratio 1:1); H
3
NMR (300 MHz, DMSO-d6, ppm): d 8.31 (1H, d, H-2, JH-H = 1.38 Hz), 8.13 (1H,
3
1
d, H-8, JH-H = 4.41 Hz), 7.33–7.30 (2H, s, NH2), 6.88 (0.5H, d, P-H, JP-H = 702
1
Hz), 6.81 (0.5H, d, P-H, JP-H = 708 Hz), 5.91–5.82 (2H, m, H-1’, CH2 = CH–),
5.58 (1H, d, 3’-OH), 5.41 (1H, d, 2’-OH), 5.30–5.20 (2H, m, CH2 = CH-), 4.68–
4.60 (1H, m, H-2’), 4.48–4.46 (1H, m, H-3’), 4.25–4.15 (4H, m, H-5’,–CH2–OP),
4.08 (m, 1H, H-4’); 13C NMR (75 MHz, DMSO-d6, ppm): d 156.06 (C-6), 152.49
(C-2), 149.34 (C-4), 139.73 (C-8), 133.01 (CH2 = CH–), 118.56 (C-5), 115.20
(CH2 = CH–), 87.57 (C-1’), 82.33 (C-4’), 72.79 (C-2’), 69.91 (C-3’), 65.41
(–CH2–OP), 64.88 (C-5’); HRESI-MS: Calcd. for C13H19N5O6P [M + H]+ (m/z)
372.1073, Found 372.1081.
Uridine allyl 5’-H-phosphonate (6c). 31P NMR (122 MHz, DMSO-
d6, ppm): d 10.37, 10.02 (a pair of diastereomers, peak area ratio 1:1); 1H NMR (300
MHz, DMSO-d6, ppm): d 11.37 (1H, s, H-3), 7.63 (1H, q, H-6, 3JH-H = 7.62 Hz), 6.94
(0.5H, d, P-H, 1JP-H = 705 Hz), 6.92 (0.5H, d, P-H, 1JP-H = 708 Hz), 6.00–5.90 (1H,
m, H-1’), 5.77–5.74 (2H, m, H-5, CH2 = CH–), 5.65–5.61 (1H, d, 3’-OH), 5.51–5.48
(1H, d, 2’-OH), 5.37–5.29 (2H, m, CH2 = CH–), 4.53 (1H, m, H-2’), 4.22–4.17 (3H,
m, H-3’, –CH2–OP), 4.07 (1H, m, H-4’), 3.97 (2H, m, H-5’); 13C NMR (75 MHz,
DMSO-d6, ppm): d 163.07 (C-4), 150.71 (C-2), 140.58 (C-6), 133.08 (CH2 = CH–),
117.91 (CH2 = CH–), 102.07(C-5), 88.48 (C-1’), 81.96 (C-4’), 72.50 (C-2’), 69.48 (C-
3’), 65.58 (–CH2–OP), 64.79 (C-5’); HRESI-MS: Calcd. for C12H18N2O8P [M + H]+
(m/z) 349.0801, Found 349.0812.
Adenosine cyclohexyl 5’-H-phosphonate (5d). 31P NMR (122
MHz, DMSO-d6, ppm): d 8.77, 8.22 (a pair of diastereomers, peak area ratio 1:1);
3
1H NMR (300 MHz, DMSO-d6, ppm): d 8.30 (1H, d, H-2, JH-H = 1.71 Hz), 8.14
(1H, d, H-8, 3JH-H = 1.38 Hz), 7.29 (2H, s, NH2), 6.84 (0.5H, d, P-H, 1JP-H = 702 Hz),
6.78 (0.5H, d, P-H, 1JP-H = 699 Hz), 5.91 (1H, d, H-1’, 3JH-H = 5.16 Hz), 5.57 (1H, d,
3’-OH), 5.38 (1H, d, 2’-OH), 4.66 (1H, m, H-2’), 4.29–4.18 (3H, m, H-3’, H-5’), 4.07
(1H, m, H-4’), 3.57–3.55 (1H, m, H-5’), 1.76 (2H, br, cyclohexyl), 1.57 (2H, br,
cyclohexyl), 1.40 (3H, m, cyclohexyl), 1.17 (3H, m, cyclohexyl); 13C NMR (75
MHz, DMSO-d6, ppm): d 156.08 (C-6), 152.64 (C-2), 149.35 (C-4), 139.65 (C-8),
119.13 (C-5), 87.64 (C-1’), 82.45 (C-4’), 79.17 (C-2’), 74.85 (C-3’), 72.86 (>CH-OP),
69.85 (C-5’), 38.67 (cyclohexyl), 24.52 (cyclohexyl), 22.86 (cyclohexyl); HRESI-MS:
Calcd. for C16H27N5O6P [M + H]+ (m/z) 414.1542, Found 414.1560.
Uridine cyclohexyl 5’-H-phosphonate (6d). 31P NMR (122 MHz,
1
CDCl3, ppm): d 8.46, 7.82 (a pair of diastereomers, peak area ratio 1:1); H NMR
(300 MHz, CDCl3, ppm): d 10.40 (1H, br, H-3), 7.63 (1H, q, H-6, 3JH-H = 7.92 Hz),
6.94 (0.5H, d, P-H, 1JP-H = 708 Hz), 6.93 (0.5H, d, P-H, 1JP-H = 711 Hz), 5.87 (1H, d,
H-1’), 5.76 (1H, d, H-5, 3JH-H = 6.87 Hz), 4.52–4.48 (1H, m, H-2’), 4.35–4.30 (2H, m,

Chemoselective Synthesis of Nucleoside 5’-H-Phosphonate Diesters
1331
H-3’, H-4’), 4.26–4.23 (3H, m, H-5’, >CH-OP), 1.91 (2H, br, cyclohexyl), 1.72 (2H,
br, cyclohexyl), 1.57–1.50 (3H, m, cyclohexyl), 1.35–1.29 (3H, m, cyclohexyl); 13C
NMR (75 MHz, CDCl3, ppm): d 164.12 (C-4), 150.24 (C-2), 136.19 (C-6), 102.49 (C-
5), 89.90 (C-1’), 82.22 (C-4’), 76.83 (C-2’), 74.18 (>CH-OP), 69.54 (C-3’), 64.44 (C-5’),
33.50 (cyclohexyl), 24.83 (cyclohexyl), 23.38 (cyclohexyl); HRESI-MS: Calcd. for
C15H24N2O8P [M + H]+ (m/z) 391.1270, Found 391.1258.
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