Synthesis of 3'-O-phosphonoethyl nucleosides with an adenine and a thymine base moiety

Article abstract of DOI:10.1080/15257770903044184

The synthesis and antiviral evaluation of new 3'-O-phosphonoethyl modified phosphonate nucleosides related to PMDTA and PMDTT is described. The reaction scheme starts from protected L-threose and the phosphonate group is introduced by the Arbuzov reaction. The 2'-OH as well as the 2'-deoxygenated nucleosides have been obtained. Unfortunately, none of these synthesized compounds shows activity against HIV and HCV.

Full text of DOI:10.1080/15257770903044184

Nucleosides, Nucleotides and Nucleic Acids, 28:337–351, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903044184
SYNTHESIS OF 3ꢀ-O-PHOSPHONOETHYL NUCLEOSIDES WITH AN
ADENINE AND A THYMINE BASE MOIETY
Qiuya Huang and Piet Herdewijn
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, K.U. Leuven,
Leuven, Belgium
The synthesis and antiviral evaluation of new 3ꢁ-O-phosphonoethyl modified phosphonate
2
nucleosides related to PMDTA and PMDTT is described. The reaction scheme starts from protected
L-threose and the phosphonate group is introduced by the Arbuzov reaction. The 2ꢁ-OH as well
as the 2ꢁ-deoxygenated nucleosides have been obtained. Unfortunately, none of these synthesized
compounds shows activity against HIV and HCV.
Keywords Phosphonate nucleosides; PMDTA; PMDTT; Arbuzov reaction
INTRODUCTION
Nucleotide phosphonates are widely used therapeutic agents known to
have a broad spectrum of antiviral activity.[1] Upon intracellular conversion
to the active mono- and diphosphates by cellular kinases, they are incor-
porated into viral DNA, eventually leading to termination of DNA chain
elongation.[2] Unlike nucleoside agents, a phosphonate nucleoside has the
advantage of skipping the requisite first phosphorylation step, which is an in-
efficient and often rate-limiting step, to reach its active metabolic form. Like-
wise, a nucleoside phosphonate has the advantage over its phosphate coun-
terpart of being metabolically stable, as its phosphorus-carbon bond is not
susceptible to phosphatase hydrolysis.[3] Since the acyclic nucleoside phos-
phonates (ANPs) were first discovered in 1986 by Holy and De Clercq,[4]
Received 16 January 2009; accepted 4 March 2009.
This article is dedicated to Dr. Robins on his 70th birthday.
The authors are indebted to Dr. R. L. Mackman (Gilead Sciences) for helpful discussions and for
providing the antiviral data and to Gilead Sciences for the financial support.
Address correspondence to Piet Herdewijn, Laboratory of Medicinal Chemistry, Rega Insti-
tute for Medical Research, K.U. Leuven, Minderbroedersstraat 10B-3000, Leuven, Belgium. E-mail:
piet.herdewijn@rega.kuleuven.be
337

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Q. Huang and P. Herdewijn
FIGURE 1 Structure of representative phosphonate nucleosides.
three ANPs have been licensed for antiviral therapy: cidofovir ((S)-1-
[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (S)-HPMPC), which has
been approved for treatment of CMV retinitis in AIDS patients; adefovir
(a prodrug of 9-[2-(phosphonomethoxy)ethyl]adenine PMEA), which has
been approved for treatment of chronic HBV infection; and tenofovir (a
prodrug of (R)-9-[2-(phosphonomethoxy)propyl]adenine PMPA), which
has been approved for treatment of HIV infections (Figure 1).[5] Some
limitations of these currently used phosphonate nucleoside drugs (cido-
fovir, adefovir, and tenofovir), that need to be surpassed are their long-
term side effects, the emergency of resistance, and the presence of drug-
drug interactions.[6] Recently, a novel phosphonate nucleoside, 9-[(1-
phosphonomethoxycylcopropyl)methyl]-guanine (PMCG) was reported
with highly potent and selective anti-HBV activity (EC50 = 0.5 µM), while
exhibiting no significant cytotoxicity in several human cell lines (up to
1.0 mM). By contrast to the classic PMEA analogs, the introduction of a
cyclopropyl moiety at the 2ꢁ-position restricts conformational mobility of
the acyclic phosphonate chain and a highly potent, specific, and selective
anti-HBV activity is obtained.[7] Until now, there are no phosphonate nucle-
osides with a cyclic sugar moiety available for antiviral therapy. A few cyclic
phosphonate nucleosides have been described with potent antiviral activity.
The D-d4AP nucleoside was described by Kim et al. in 1991, which shows
potent anti-HIV activity (EC50) of 0.6–2 µM with an excellent resistance
profile, unfortunately, commensurate with mitochondrial toxicity.[8–10] D-
2ꢁFd4AP (Figure 1) is a somewhat less active compound (EC50: 12 µM)
but with an excellent resistance profile.[10,11] PMDTA and PMDTT (Figure
1) were described as selective anti-HIV-1/HIV-2 phosphonate nucleosides

Synthesis of 3-O-Phosphonoethyl Nucleosides
339
FIGURE 2 Structure of target nucleoside phosphonates.
with an activity of 2.5 µM and 6.6 µM respectively (EC50 values),[12] while
no cytotoxicity was observed at the highest concentration tested. PMDTA
has a phosphonomethyl moiety at the 3ꢁ-position of the furanose ring and
no substituent at the 4ꢁ-position. The absence of a 4ꢁ-hydroxymethyl group
avoids problems of steric hindrance during phosphorylation reaction by
kinases. In order to investigate the importance of the stereochemistry in the
1ꢁ- and 3ꢁ-position of PMDTA, compound IVa and IVb, the isomeric analogs
of PMDTA, were synthesized and evaluated (Figure 1). However, none
of these compounds showed activity in an HIV-assay.[13] In this study, we
would like to keep the L-threosyl nucleoside scaffold intact and pay specific
attention to the 3ꢁ-phosphonate linkage. Therefore, we have synthesized
a series of 3ꢁ-O-phosphonoethyl modified analogs (1a-1d) of PMDTA and
PMDTT (Figure 2).
RESULT AND DISCUSSION
As shown in Scheme 1, diethylphosphonoethanol 5 was synthesized
starting from ethylene glycol. Unfortunately, by reaction of diethylphos-
phonoethanol 5 with trifluoromethanesulfonyl chloride using NaH as base,
the formation of triflate 6 could not be observed. Therefore, the more
stable tosylate 7 and mesylate 8 were synthesized by sulfonylation of the free
hydroxyl group of 5. However, reaction of the tosylate 7 or the mesylate 8
with 9 did not lead to the expected alkylation of the 3ꢁ-hydroxyl group of
9. Likewise, using the less reactive bromide 10, we were unable to observe
the formation of compound 14. The reason of the unsuccessful attempts
could be the β-elimination reaction of 7, 8 and 10 under basic condition
to give rise to the α, β-unsaturated phosphonate. As shown in Scheme 2,
an alternative strategy was used by first introducing the mono-protected
ethylene glycol chain to the 3ꢁ-oxygen position of L-threosyl sugar moiety,
followed by introducing the phosphonate function. The nucleosides 1a-d
were synthesized starting from 1,2-di-O-tert-butyldimethylsilyl-L-threose (9)
(Scheme 2).[12] Reaction of 3ꢁ-hydroxyl group of compound 9 with the
triflate of monobenzylglycol using NaH in THF gave compound 11. Removal

340
Q. Huang and P. Herdewijn
SCHEME 1 (a) NaH, BnBr, DMF-THF; (b) NBS, PPh3, DCM; (c) Triethylphosphite, 165–170◦C; (d) H2,
Pd-C (10%), EtOH; (e) trifluoromethanesulfonylchloride, NaH, diethyl ether; (f) TsCl or MsCl, TEA,
t
t
DMAP, DCM; (g) NaH, THF; (h) BuLi, THF; (i) BuOK, THF; (j) Ag2CO3, Celite, DCM; (k) Ag2O,
DCM.
of the benzyl group of 11 by hydrogenation with 10% Pd-C afforded
compound 12. The free hydroxyl group of 12 was converted into bromine
with NBS and PPh3 to give compound 13. The phosphonate function was
introduced by the Arbuzov reaction of 13 with triethylphosphite to give
14. The two silyl protecting groups of 14 were removed and replaced
with two benzoyl protecting groups. The presence of a 2ꢁ-O-benzoyl group
allows selective introduction of the base moiety in the α-configuration. The
nucleobase adenine and thymine were introduced after silylation and using
SnCl4 as Lewis catalyst (giving 16 and 17). Deprotection of 16 and 17 was
done in two steps, firstly, removal of the benzoyl protecting groups with
ammonia in methanol (yielding 18 and 19) and, secondly, hydrolysis of the
diethyl protecting groups with TMSI at 0◦C (giving 1a and 1b). To obtain
the 2ꢁ-deoxygenated ananlogues, the 2ꢁ-hydroxyl group of 18 and 19 was
removed by Barton deoxygenation,[14] giving 20 and 21. Hydrolysis of the
phosphonate ester function of 20 and 21 was carried out with TMSI at 0◦C.
After purification by silica gel chromatography, reverse phase C18 HPLC
and Dowex-sodium ion-exchange resin, nucleoside phosphonates 1c and 1d
were obtained.
BIOLOGICAL RESULTS
Phosphonate nucleosides 1a, 1b, 1c, and 1d, in their sodium form, were
evaluated in vitro for their cytotoxicity in MT4 cell-line and for their activity

Synthesis of 3-O-Phosphonoethyl Nucleosides
341
SCHEME 2 (a) triflate of monobenzylglycol, NaH, THF; (b) Pd/C (10%), H2, ethanol; (c)
N-bromosuccinimide, PPh3, CH2Cl2; (d) triethylphosphite, refluxed; (e) (1) TFA/H2O; (2)
BzCl, pyridine; (f) SnCl4, ABz or T(Si), MeCN; (g) saturated NH3 in MeOH; (h) (1)
phenyl(chloro)thionocarbonate, DMAP, MeCN; (2) Bu3SnH, AIBN, toluene; (i) (1) TMSI, CH2Cl2; (2)
reverse phase C18 HPLC, Dowex-Na+.
against HIV and HCV. PMDTT was used as a reference compound for anti-
HIV activity,[12] and 2ꢁ-C-Me-A was used as a reference compound for anti-
HCV activity.[15] None of the compounds shows activity against HIV and
HCV as well as cytotoxicity at the highest concentration tested (250 µM; see
Table 1).
CONCLUSION
A synthetic scheme has been developed for the synthesis of 3ꢁ-O-
phosphonoethyl-L-threosyl nucleosides (1a and 1b) as well as their 2ꢁ-
deoxy analogs (1c, 1d). Replacement of the methyl group in the 3ꢁ-O-
phosphonomethyl group of PMDTA with an ethyl congener results in loss
of biological activity. The reason for the loss of activity may be that these

342
Q. Huang and P. Herdewijn
TABLE 1 Summary of biological activities tested for compounds 1a, 1b, 1c, 1d
Compound
HCV
HIV
MT-4
a
a
b
EC50 (µM)
EC50 (µM)
CC50 (µM)
1a
1b
1c
1d
>250
>250
>250
>250
—
>250
>250
>250
140
6.59
—
>250
>250
>250
>250
>343
—
PMDTT
2ꢁ-C-Me-A
0.256
aEC50 = 50% effective concentration, or concentration required to protect 50% of
the cells against viral cytopathicity.
bCC50 = 50% cytotoxic concentration, or concentration reducing the number of
viable cells by 50%.
compounds are poor substrates for kinases, and therefore fail to be further
converted into their metabolic diphosphate form.
EXPERIMENTAL SECTION
For all reactions, analytical grade solvents were used. All moisture-
sensitive reactions were carried out in oven-dried glassware (135◦C)
under a nitrogen atmosphere. Anhydrous THF was refluxed over
sodium/benzophenone and distilled. A Varian Unity 500 MHz spectrometer
1
and a 300 MHz Varian Gemini apparatus were used for H, 13C, and
1
31P NMR; TMS was used as internal reference for all H NMR. Exact
mass measurements were performed on a guadrupole time-of-flight mass
spectrometer (Q-Tof -2, Micromass, Manchester, UK) equipped with a
standard electrospray-ionization (EI) interface; samples were infused in
CH3CN/H2O (1:1) at 3 µL/min. Precoated aluminum sheets (Fluka Silica
gel/TLC-cards, 254 nm) were used for TLC; the spots were examined with
UV light and visualized with ceric ammonium molybdate (CAM) stain.
˚
Column chromatography was performed on ICN silica gel 63–200, 60 A. For
the sake of clarity, NMR signals of sugar protons and carbons are indicated
with a prime, and signals of base protons and carbons are given without a
prime.
1,2-Di-O-tert-butyldimethylsilyl-3-O-(2-benzyloxyethyl)-L- threose
(11)
To a suspension of NaH (60% dispersion in mineral oil, 228 mg,
5.7 mmol) in 5 mL of dried THF was added dropwise 1,2-Di-O-tert-
butyldimethylsilyl-L-threose (9) (414 mg, 1.19 mmol) in 5 mL of dried THF
at −20◦C under nitrogen. The stirred solution was slowly warmed to room
temperature and maintained for 10 minutes, then cooled to −78◦C and the

Synthesis of 3-O-Phosphonoethyl Nucleosides
343
solution of the triflate of 2-benzylglycol (0.94 g, 3.31 mmol) generated in
situ in 5 mL of dried THF was added dropwise. The reaction mixture was
slowly warmed to room temperature and continuously stirred overnight.
The reaction was quenched with saturated NaHCO3 and concentrated.
The residue was partitioned between H2O and EtOAc. The organic layer
was washed with water and brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by chromatography on a silica gel
column (n-Hexane:EtOAc = 19:1) to afford 11 (462 mg, 0.952 mmol,
1
80%) as a light yellow oil. Data for 11: H NMR (300 MHz, CDCl3) δH
0.07–0.09 (m, 24H, SiCH3), 0.89–0,90 (m, 36H, CH3), 3.53–3.76 (m, 10H,
(OCH2, 8H), (C(3ꢁ)H, 2H)), 3.82–3.93 (m, 2H, C(4ꢁ)Ha), 4.02–4.19 (m, 4H,
(C(4ꢁ)Hb, 2H), (C(2ꢁ)H, 2H)), 4.56 (s, 4H, BnCH2O), 5.11 (s, 1H, C(1ꢁ)H),
5.12 (d, J = 3.1 Hz, 1H, C(1ꢁ)H), 7.27–7.35 (m, 10H, Ar H); 13C NMR
(75 MHz, CDCl3) δC -5.17 (SiCH3), -5.01 (SiCH3), -4.88 (SiCH3), −4.75
(SiCH3), −4.60 (SiCH3), −4.45 (SiCH3), −4.26 (SiCH3), 17.88 (C(CH3)3),
18.00 (C(CH3)3), 18.11 (C(CH3)3), 25.71 (C(CH3)3), 25.74 (C(CH3)3),
25.76 (C(CH3)3), 25.82 (C(CH3)3), 69.09 (OCH2), 69.47 (OCH2), 69.54
(OCH2), 69.61 (OCH2), 69.92 (C-4ꢁ), 70.51 (C-4ꢁ), 73.27 (BnCH2O), 73.31
(BnCH2O), 78.93 (C-2ꢁ), 82.84 (C-2ꢁ), 83.79 (C-3ꢁ), 86.06 (C-3ꢁ), 97.30 (C-
1ꢁ), 104.09 (C-1ꢁ), 127.59 (aroma-C), 127.67 (aroma-C), 127.71 (aroma-C),
128.31 (aroma-C), 128.35 (aroma-C), 138.25 (aroma-C); exact mass calcd.
for C25H47O5Si2 [M+H]+ 483.296, found 483.297.
1,2-Di-O-tert-butyldimethylsilyl-3-O-(2-hydroxyethyl)-L- threose
(12)
Compound 11 (462 mg, 0.957 mmol) and palladium-carbon (10%, 102
mg, 0.0957 mmol) in 4 mL of degassed dry ethanol was hydrogenated for 2.5
hours. The palladium-carbon was filtered through a celite pad, the volatiles
were evaporated and the residue was purified by chromatography on a silica
gel column (n-Hexane:EtOAc = 6:1) to afford 12 (315 mg, 0.803 mmol,
84%) as a colorless oil. It was not identified at this stage which compound
represents which isomer (α or β). The mixture of 12a and 12b was used
1
in the next step reaction). Data for 12a: H NMR (300 MHz, CDCl3) δH
0.04–0.10 (m, 12H, SiCH3), 0.87 (s, 9H, CH3), 0.88 (s, 9H, CH3), 2.55 (br,
1H, OH), 3.56–3.80 (m, 5H, (OCH2, 2H), (CH2OH, 2H), (C(3ꢁ)H, 1H)),
3.92 (dd, J1 = 9.4 Hz, J2 = 3.4 Hz, 1H, C(4ꢁ)Ha), 4.07–4.16 (m, 2H, C(4ꢁ)Hb,
C(2ꢁ)H), 5.13 (s, 1H, C(1ꢁ)H); 13C NMR (75 MHz, CDCl3) δC −5.11
(SiCH3), −4.76 (SiCH3), −4.64 (SiCH3), −4.50 (SiCH3), 17.97 (C(CH3)3),
25.71 (C(CH3)3), 61.77 (CH2OH), 70.53 (OCH2), 71.66 (C-4ꢁ), 81.07 (C-2ꢁ),
85.27 (C-3ꢁ), 104.12 (C-1ꢁ); exact mass calcd. for C18H40O5Si2Na1 [M+Na]+
1
415.231, found 415.229. Data for 12b: H NMR (300 MHz, CDCl3) δH
0.05–0.08 (m, 12H, SiCH3), 0.88 (s, 18H, CH3), 2.25 (br, 1H, OH), 3.50–3.69
(m, 5H, (CH2OH, 2H), (OCH2, 2H), (C(3ꢁ)H, 1H)), 3.99–4.07 (m, 2H,

344
Q. Huang and P. Herdewijn
C(4ꢁ)H), 4.12–4.18 (m, 1H, C(2ꢁ)H), 5.11 (d, J = 11.5 Hz, 1H, C(1ꢁ)H); 13
C
NMR (75 MHz, CDCl3) δC −5.05 (SiCH3), −4.93 (SiCH3), −4.48 (SiCH3),
−4.43 (SiCH3), 17.97 (C(CH3)3), 18.06 (C(CH3)3), 25.70 (C(CH3)3), 25.77
(C(CH3)3), 62.00 (CH2OH), 68.85 (OCH2), 71.54 (C-4ꢁ), 78.90 (C-2ꢁ),
83.67 (C-3ꢁ), 97.22 (C-1ꢁ); exact mass calcd. for C18H40O5Si2Na1 [M+Na]+
415.231, found 415.233.
1,2-Di-O-tert-butyldimethylsilyl-3-O-(2-bromoethyl)-L-threose (13)
A solution of PPh3 (0.393 g, 1.5 mmol) in dried CH2Cl2 (3 mL)
was added dropwise to a suspension of N-bromosuccinimide (0.267 g, 1.5
mmol) in dried CH2Cl2 (4 mL) at −78◦C under nitrogen in the dark-
ness. Stirring was continued until the suspension was completely dissolved
(approx. 10min). A solution of compound 12 (0.491 g, 1.25 mmol) in
dried CH2Cl2 (3 mL) was dropwise added, the cooling bath was removed
and stirring was continued for 1 hour. The reaction solution was poured
into aqueous NH4Cl solution; the organic layer was washed with water and
brine, dried over Na2SO4, and the volatiles were evaporated in vacuo. The
residue was purified by chromatography on a silica gel column (CH2Cl2:
n-Hexane = 1:2 and 1:1) to afford 13 (358 mg, 0.787 mmol, 63%) as a
colorless oil. 1H NMR (300 MHz, CDCl3) δH 0.08–0.10 (m, 12H, SiCH3),
0.89 (s, 18H, CH3), 3.40 (t, J = 6.3 Hz, 2H, BrCH2), 3.72–3.91 (m, 4H,
(OCH2, 2H), (C(3ꢁ)H, 1H), (C(4ꢁ)Ha, 1H)), 4.04–4.14 (m, 2H, C(4ꢁ)Hb,
C(2ꢁ)H), 5.10–5.13(m, 1H, C(1ꢁ)H); 13C NMR (75 MHz, CDCl3) δC -5.18
(SiCH3), −5.04 (SiCH3), −4.89 (SiCH3), −4.77 (SiCH3), −4.59 (SiCH3),
−4.46 (SiCH3), −4.41 (SiCH3), −4.28 (SiCH3), 17.86 (C(CH3)3), 17.99
(C(CH3)3), 18.07 (C(CH3)3), 25.65 (C(CH3)3), 25.69 (C(CH3)3), 25.72
(C(CH3)3), 25.80 (C(CH3)3), 30.01 (BrCH2), 30.21 (BrCH2), 68.74 (C-
4ꢁ), 69.95 (C-4ꢁ), 70.29 (OCH2), 70.32 (OCH2), 78.92 (C-2ꢁ), 82.84 (C-2ꢁ),
83.72 (C-3ꢁ), 85.98 (C-3ꢁ), 97.23 (C-1ꢁ), 103.96 (C-1ꢁ); exact mass calcd. for
C18H39BrO4Si2Na1 [M+Na]+ 477.147, found 477.148.
1,2-Di-O-tert-butyldimethylsilyl-3-O-(diethylphosphonoethyl)-
L-threose (14)
A mixture of 13 (0.358 g, 0.786 mmol) and triethylphosphite (0.384
g, 2.31 mmol) was heated to 160◦C under nitrogen and refluxed for 8
hours. The unreacted triethylphosphite was removed by vacuum distillation.
The residue was purified by chromatography on a silica gel column (n-
Hexane:EtOAc = 2:1 and 1:1) to afford 14 (352 mg, 0.686 mmol, 87%) as
1
a colorless oil. H NMR (300 MHz, CDCl3) δH 0.06–0.09 (m, 12H, SiCH3),
0.88–0.89 (m, 18H, CH3), 1.29 (t, J = 6.9 Hz, 6H, OCH2CH3), 2.03–2.14 (m,
2H, PCH2), 3.64–3.85 (m, 3H, (OCH2, 2H), (C(3ꢁ)H, 1H)), 3.99–4.11 (m,
7H, (OCH2CH3, 4H), (C(4ꢁ)H, 2H), (C(2ꢁ)H, 1H)), 5.09 (m, 1H, C(1ꢁ)H);

Synthesis of 3-O-Phosphonoethyl Nucleosides
345
13C NMR (75 MHz, CDCl3) δC −5.21 (SiCH3), −5.06 (SiCH3), −4.94
(SiCH3), −4.81(SiCH3), −4.72 (SiCH3), −4.64 (SiCH3), −4.48 (SiCH3),
−4.32 (SiCH3), 16.36 (OCH2CH3), 16.44 (OCH2CH3), 17.84 (C(CH3)3),
17.97 (C(CH3)3), 18.05 (C(CH3)3), 25.66 (C(CH3)3), 25.70 (C(CH3)3),
25.77 (C(CH3)3), 26.30 (C(CH3)3), 26.44 (C(CH3)3), 28.15 (d, JP,C = 138.7
Hz, PCH2), 28.29 (d, JP,C = 138.6 Hz, PCH2), 61.53 (OCH2), 61.61 (OCH2),
61.69 (OCH2), 61.78 (OCH2), 63.90 (OCH2CH3), 64.29 (OCH2CH3), 68.81
(C-4ꢁ), 70.31 (C-4ꢁ), 78.86 (C-2ꢁ), 82.77 (C-3ꢁ), 83.44 (C-2ꢁ), 85.78 (C-3ꢁ),
97.21 (C-1ꢁ), 104.02 (C-1ꢁ); 31P NMR (121.5 MHz, CDCl3) δP 28.19; exact
mass calcd. for C22H49O7P1Si2Na1 [M+Na]+ 535.265, found 535.265.
1,2-Di-O-benzoyl-3-O-(diethylphosphonoethyl)-L-threose (15)
Compound 14 (0.89 g, 1.735 mmol) was dissolved in a solution of
trifluoroacetic acid/H2O (2.8 mL, V/V = 3:1) at 0◦C. The reaction mixture
was allowed to stand for 3 hours at room temperature. Saturated NaHCO3
(5 mL) was added at 0◦C, followed by adding solid NaHCO3 to neutralize
the TFA. The reaction mixture was extracted with CHCl3 (15 mL × 5), the
organic layer was dried over Na2SO4, and the volatile was evaporated in
vacuo. The residue was purified by chromatography on a silica gel column
(CH2Cl2: MeOH = 19:1 and 9:1) to give 3-O-diethylphosphonoethyl-L-
threose (0.43 g, 1.51 mmol, 87%) as a colorless oil. To the solution of
3-O-diethylphosphonoethyl-L-threose (0.43 g, 1.51 mmol) in dry pyridine
(6 mL) was added dropwise BzCl (527 µL, 4.54 mmol) at 0◦C. The reaction
mixture was slowly warmed to room temperature and stirred overnight. The
reaction mixture was concentrated and co-evaporated with 10 mL of toluene
two times in vacuo. The residue was partitioned between water (10 mL)
and EtOAc (50 mL). The organic layer was washed with water and brine,
dried over Na2SO4, and concentrated in vacuo. The residue was purified
by chromatography on a silica gel column (n-Hexane:EtOAc = 3:1) to give
1
15 (0.56 g, 1.14 mmol, 76%) as a yellow oil. H NMR (300 MHz, CDCl3)
δH 1.24–1.31 (m, 12H, CH3), 2.07–2.23 (m, 4H, PCH2), 3.75–3.90 (m, 3H,
OCH2), 3.92–4.16 (m, 11H, (OCH2, 1H), (OCH2CH3, 8H), (C(3ꢁ)H, 2H)),
4.22–4.25 (m, 1H, C(4ꢁ)H), 4.36–4.53 (m, 3H, C(4ꢁ)H), 5.50 (t, J = 4.4 Hz,
1H, C(2ꢁ)H), 5.55 (s, 1H, C(2ꢁ)H), 6.54 (s, 1H, C(1ꢁ)H), 6.73 (d, J = 4.5
Hz, 1H, C(1ꢁ)H), 7.30–7.62 (m, 12H, Bz Ar-H), 7.88–8.08 (m, 8H, Bz Ar-H);
13C NMR (75 MHz, CDCl3) δC 16.36 (CH3), 16.44 (CH3), 26.15 (d, JP,C
=
139.6 Hz, PCH2), 26.21 (d, JP,C = 139.5 Hz, PCH2), 61.69 (d, JP,C = 11.5
Hz, OCH2), 61.77 (OCH2), 64.18 (OCH2CH3), 64.48 (OCH2CH3), 70.82
(C-4ꢁ), 73.48 (C-4ꢁ), 77.75 (C-2ꢁ), 80.29 (C-2ꢁ), 80.90 (C-3ꢁ), 82.19 (C-3ꢁ),
95.63 (C-1ꢁ), 100.18 (C-1ꢁ), 128.34 (aroma-C), 128.37 (aroma-C), 128.45
(aroma-C), 128.50 (aroma-C), 128.56 (aroma-C), 128.95 (aroma-C), 129.48
(aroma-C), 129.57 (aroma-C), 129.70 (aroma-C), 129.73 (aroma-C), 129.85
(aroma-C), 129.97 (aroma-C), 133.33 (aroma-C). 133.47 (aroma-C). 133.51

346
Q. Huang and P. Herdewijn
(aroma-C). 133.69 (aroma-C). 164.96 (OBz, CO), 165.09 (OBz, CO), 165.29
(OBz, CO), 165.34 (OBz, CO); 31P NMR (121.5 MHz, CDCl3) δP 27.95,
27.97; exact mass calcd. for C24H30O9P1 [M+H]+ 493.163, found 493.163.
1-(Adenin-9-yl)-2-O-benzoyl-3-O-(diethylphosphonoethyl)-
L-threose (16)
SnCl4 (95 µL, 0.812 mmol) was added dropwise to a solution of 15 (100
mg, 0.203 mmol) and N6-benzoyladenine (97 mg, 0.406 mmol) in 4 mL
of dry CH3CN at room temperature under N2. The reaction mixture was
allowed to stir for 3 hours. Then the reaction was quenched with aqueous
NH4Cl and concentrated. The residue was partitioned between H2O (10
mL) and CHCl3 (50 mL × 3). The organic layer was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by chromatography on a silica gel column (CH2Cl2:MeOH =
29:1, 19:1 and 9:1) to give 16 (86 mg, 0.168 mmol, 83%) as an amorphous
solid. 1H NMR (300 MHz, MeOH-d4) δH 1.28–1.32 (m, 6H, CH3), 2.11–2.19
(m, 2H, PCH2), 3.88–3.94 (m, 2H, OCH2), 4.04–4.12 (m, 4H, OCH2CH3),
4.45–4.46 (m, 3H, (C(4ꢁ)H, 2H), (C(3ꢁ)H, 1H)), 5.82 (s, 1H, C(2ꢁ)H),
6.44(s, 1H, C(1ꢁ)H), 7.52–7.67 (m, 3H, Ar H), 8.06–8.08 (m, 2H, Ar H), 8.37
(s, 1H, A C(2)H), 8.53 (s, 1H, A C(8)H); 13C NMR (75 MHz, MeOH-d4)
δC 15.27 (CH3), 15.35 (CH3), 24.87 (d, JP,C = 140.0 Hz, PCH2), 61.99
(OCH2CH3), 62.08 (OCH2CH3), 63.73 (d, JP,C = 3.3 Hz, OCH2), 73.53
(C-4ꢁ), 80.48 (C-2ꢁ), 81.63 (C-3ꢁ), 88.62 (C-1ꢁ), 118.69 (A C(5)), 128.44
(aroma-C), 128.73 (aroma-C), 129.47 (aroma-C), 133.66 (aroma-C), 142.10
(A C(8)), 145.84 (A C(4)), 148.43 (A C(2)), 151.48 (A C(6)), 165.25
(OBz, CO); 31P NMR (121.5 MHz, CDCl3) δP 27.47; exact mass calcd. for
C22H29N5O7P1 [M+H]+ 506.180, found 506.180.
1-(Thymin-1-yl)-2-O-benzoyl-3-O-(diethylphosphonoethyl)-
L-threose (17)
Thymine (192 mg, 1.523 mmol), ammonium sulfate (4.8 mg, 0.036
mmol) and 3 mL of HMDS were added to a dried flask. The mixture was
refluxed overnight under N2. HMDS was removed in vacuo. To the flask
with the residue was added a solution of compound 15 (300 mg, 0.609
mmol) in 10 mL of dried CH3CN, followed by dropwise adding SnCl4 (214
µL, 1.827 mmol) at room temperature under N2. The reaction mixture was
allowed to stir for 4 hours. The reaction was quenched with saturated NH4Cl
and concentrated to a small volume. The residue was partitioned between
H2O (10 mL) and EtOAc (50 mL). The organic layer was washed with water
and brine, dried over Na2SO4 and concentrated in vacuo. The residue was
purified by chromatography on a silica gel column (n-Hexane:EtOAc = 1:3
and CH2Cl2: MeOH = 29:1) to afford 17 (286 mg, 0.576 mmol) as a colorless

Synthesis of 3-O-Phosphonoethyl Nucleosides
347
amorphous solid in 94% yield. 1H NMR (300 MHz, CDCl3) δH 1.30 (t, J = 6.9
Hz, 6H, CH3), 1.94 (s, 3H, T CH3), 2.05–2.16 (m, 2H, PCH2), 3.85–3.98 (m,
2H, OCH2), 4.07–4.17 (m, 6H, (OCH2CH3, 4H), (C(4ꢁ)Ha, 1H), (C(3ꢁ)H,
1H)), 4.33–4.36 (d, J = 10.7 Hz, 1H, C(4ꢁ)Hb), 5.35 (s, 1H, C(2ꢁ)H), 6.23
(s, 1H, C(1ꢁ)H), 7.43–7.62 (m, 4H, (Ar H, 3H), (T C(6)H, 1H)), 8.01 (d, J
= 7.6 Hz, 2H, Ar H), 9.32 (br, 1H, T NH); 13C NMR (75 MHz, CDCl3) δC
12.50 (T CH3), 16.38 (CH3), 16.46 (CH3), 26.03 (d, JP,C = 140.1 Hz, PCH2),
61.80 (d, JP,C = 4.8 Hz, OCH2), 61.95 (OCH2), 63.81 (OCH2), 73.08 (C-4ꢁ),
80.19 (C-2ꢁ), 81.43 (C-3ꢁ), 89.08 (C-1ꢁ), 110.84 (T C(5)), 128.56 (aroma-C),
128.67 (aroma-C), 129.87 (aroma-C), 133.79 (T C(6)), 136.16 (aroma-C),
150.37 (T C(2)), 163.89 (T C(4)), 165.19 (BzO, CO); 31P NMR (121.5 MHz,
CDCl3) δP 27.35; exact mass calcd. for C22H30N2O9P1 [M+H]+ 497.169,
found 497.169.
1-(Adenin-9-yl)-3-O-(diethylphosphonoethyl)-L-threose (18)
A solution of 16 (142 mg, 0.281 mmol) in methanol saturated with
ammonia (3 mL) was stirred at room temperature overnight. The mixture
was concentrated, and the residue was purified by chromatography on a
silica gel column (CH2Cl2: MeOH = 19:1 and 9:1) to afford 18 (97 mg,
1
0.241 mmol) as a white powder in 86% yield: H NMR (300 MHz, CDCl3)
δH 1.24–1.30 (m, 6H, CH3), 1.95–2.08 (m, 2H, PCH2), 3.65–3.81 (m, 2H,
OCH2), 4.00–4.15 (m, 5H, (OCH2, 4H), (C(3ꢁ)H, 1H)), 4.24 (dd, J1 =
9.7 Hz, J2 = 3.1 Hz, 1H, C(4ꢁ)Ha), 4.30 (dd, J1 = 9.7 Hz, J2 = 4.9 Hz,
1H,C(4ꢁ)Hb), 4.64 (s, 1H, C(2ꢁ)H), 6.01 (d, J = 2.7 Hz, 1H, C(1ꢁ)H), 6.20
(br s, 2H, NH2), 8.06 (s, 1H, A C(2)H), 8.27 (s, 1H, A C(8)H); 13C NMR
(75 MHz, CDCl3) δC 16.34 (OCH2CH3), 16.41 (OCH2CH3), 25.98 (d, JP,C
=
139.6 Hz, PCH2), 61.76 (d, JP,C = 13.1 Hz, OCH2), 61.85 (OCH2), 63.84
(OCH2), 72.78 (C-4ꢁ), 77.44 (C-2ꢁ), 83.50 (C-3ꢁ), 91.12 (C-1ꢁ), 119.61 (A
C(5)), 139.12 (A C(8)), 149.09 (A C(4)), 152.64 (A C(2)), 155.51 (A C(6));
31P NMR (121.5 MHz, CDCl3) δP 28.23; exact mass calcd. for C15H25N5O6P1
[M+H]+ 402.154, found 402.153.
1-(Thymin-1-yl)-3-O-(diethylphosphonoethyl)-L-threose (19)
A solution of 17 (153 mg, 0.309 mmol) in methanol saturated with
ammonia (3 mL) was stirred at room temperature overnight. The mixture
was concentrated, and the residue was purified by chromatography on a
silica gel column (CH2Cl2: MeOH = 29:1 and 9:1) to afford 19 (107 mg,
1
0.272 mmol) as a white powder in 88% yield: H NMR (300 MHz, CDCl3)
δH 1.29 (t, J = 7.0 Hz, 6H, CH3), 1.91 (s, 3H, T CH3), 1.96–2.02 (m, 2H,
PCH2), 3.65–3.76 (m, 2H, OCH2), 4.01–4.13 (m, 5H, (OCH2CH3, 4H),
(C(4ꢁ)Ha, 1H)), 4.28–4.34 (m, 3H, (C(4ꢁ)Hb, 1H), (C(3ꢁ)H, 1H), (C(2ꢁ)H,
1H)), 5.42 (br s, 1H, OH), 5.80 (s, 1H, C(1ꢁ)H), 7.37 (s, 1H, T(C6)H), 10.36

348
Q. Huang and P. Herdewijn
(br s, 1H, NH); 13C NMR (75 MHz, CDCl3) δC 12.43 (T CH3), 16.39 (CH3),
16.47 (CH3), 26.03 (d, JP,C = 139.7 Hz, PCH2), 61.80 (OCH2CH3), 61.88
(OCH2CH3), 63.29 (OCH2), 74.11 (C-4ꢁ), 78.57 (C-2ꢁ), 82.74 (C-3ꢁ), 93.16
(C-1ꢁ), 109.50 (C(5)), 136.48 (C(6)), 150.99 (C(2)), 164.52 (C(4)); 31P
NMR (121.5 MHz, CDCl3) δP 27.60; exact mass calcd. for C15H25N2O8P1Na1
[M+Na]+ 415.125, found 415.124.
1-(Adenin-9-yl)-2-deoxy-3-O-(diethylphosphonoethyl)-L-threose
(20)
To a solution of PhOC(S)Cl (70 µL, 0.506 mmol) and DMAP (185 mg,
1.516 mmol) in dried MeCN (8 mL) was added compound 18 (135 mg,
0.337 mmol) at room temperature under N2. The reaction mixture was
stirred for 3 hours. The mixture was concentrated at room temperature, and
the residue was purified by chromatography on a silica gel column (CH2Cl2:
MeOH = 29:1 and 19:1) to give 1-(adenin-9-yl)-2-O-phenoxythionocarbonyl-
3-O-(diethylphosphonoethyl)-L-threose as a white amorphous foam in
63% yield. To a solution of 1-(adenin-9-yl)-2-O-phenoxythionocarbonyl-3-O-
(diethylphosphonoethyl)-L-threose in dry and degassed toluene (10 mL)
was added AIBN (18 mg, 0.106 mmol) and tributyltin hydride (115 µL,
0.428 mmol) under N2. The reaction mixture was refluxed for 8 hours and
concentrated in vacuo. The residue was purified by chromatography on a
silica gel column (CH2Cl2: MeOH = 19:1 and 9:1) to give compound 20
1
(75 mg, 0.194 mmol) as a colorless oil in 57% yield: H NMR (300 MHz,
CDCl3) δH 1.24–1.30 (m, 6H, CH3), 1.95–2.08 (m, 2H, PCH2), 2.51–2.67
(m, 2H, C(2ꢁ)H), 3.57–3.76 (m, 2H, OCH2), 4.00–4.11 (m, 5H, (OCH2,
4H), (C(3ꢁ)H, 1H)), 4.25–4.28 (m, 2H, C(4ꢁ)H), 6.06 (br s, 2H, A NH2),
6.42 (dd, J1 = 7.3 Hz, J2 = 2.1 Hz, 1H, C(1ꢁ)H), 8.26 (s, 1H, A C(2)H),
8.32 (s, 1H, A C(8)H); 13C NMR (75 MHz, CDCl3) δC 16.36 (OCH2CH3),
16.44 (OCH2CH3), 26.02 (d, JP,C = 139.8 Hz, PCH2), 38.45 (C-2ꢁ), 61.72
(OCH2), 61.81 (OCH2), 63.49 (OCH2), 73.94 (C-4ꢁ), 78.39 (C-3ꢁ), 83.57
(C-1ꢁ), 119.51 (A C(5)), 139.58 (A C(8)), 149.63 (A C(4)), 152.96 (A C(2)),
155.49 (A C(6)); 31P NMR (121.5 MHz, CDCl3) δP 27.84; exact mass calcd.
for C15H25N5O5P1 [M+H]+ 386.159, found 386.158.
1-(Thymin-1-yl)-2-deoxy-3-O-(diethylphosphonoethyl)-L-threose
(21)
This compound was prepared as described for 20, using 19 (131 mg,
0.334 mmol) as starting material. Column chromatographic purification
(CH2Cl2: MeOH = 29:1) gave compound 21 (100 mg, 0.265 mmol) as a
colorless oil in 79% yield. 1H NMR (300 MHz, CDCl3) δH 1.30 (dd, J1 = 7.0
Hz, J2 = 1.6 Hz, 3H, CH3), 1.32 (dd, J1 = 7.0 Hz, J2 = 1.6 Hz, 3H, CH3),
1.92 (d, J = 0.9 Hz, 3H, T CH3), 2.01–2.16 (m, 3H, (PCH2, 2H), (C(2ꢁ)Ha,

Synthesis of 3-O-Phosphonoethyl Nucleosides
349
1H)), 2.44–2.54 (m, 1H, C(2ꢁ)Hb), 3.62–3.74 (m, 2H, OCH2), 3.82 (dd, J1
= 10.2 Hz, J2 = 3.5 Hz, 1H, C(4ꢁ)Ha), 4.06–4.18 (m, 5H, (C(4ꢁ)Hb, 1H),
(OCH2CH3, 4H)), 4.27 (d, J = 9.3 Hz, 1H, C(3ꢁ)H), 6.20 (dd, J1 = 7.8 Hz, J2
= 2.4 Hz, 1H, C(1ꢁ)H), 7.50 (d, J = 1.1 Hz, 1H, T C(6)H), 9.4 (s, 1H, NH);
13C NMR (75 MHz, CDCl3) δC 12.54 (T CH3), 16,38 (CH3), 16.45 (CH3),
26.08 (d, JP,C = 139.9 Hz, PCH2), 38.18 (C-2ꢁ), 61.75 (OCH2CH3), 61.83
(OCH2CH3), 63.04 (OCH2CH2P), 73.80 (C-4ꢁ), 77.91 (C-3ꢁ), 85.02 (C-1ꢁ),
110.12 (T C(5)), 136.51 (T C(6)), 150.69 (T C(2)), 164.11 (T C(4)); 31P
NMR (121.5 MHz, CDCl3) δP 27.69; exact mass calcd. for C15H25N2O7P1Na1
[M+Na]+ 399.129, found 399.127.
1-(Adenin-9-yl)-3-O-(phosphonoethyl)-L-threose Sodium Salt (1a)
To a solution of compound 18 (190 mg, 0.473 mmol) and Et3N (665
µL, 4.73 mmol) in 20 mL of dry CH2Cl2 was added iodotrimethylsilane
(515 µL, 3.787 mmol) at 0◦C under nitrogen. The reaction mixture was
continuously stirred for 4 hours at 0◦C. The reaction was quenched with 0.5
M TEAB solution. The mixture was concentrated in vacuo, and the residue
was purified by chromatography on a silica gel column (CH2Cl2: MeOH =
2:1 and CHCl3: MeOH: H2O = 5:4:1) to give crude 1a. Purification by HPLC
using reverse phase C18 column (isocratic mobile phase: 1% MeCN and 99%
H2O) and ion exchange with Dowex-Na+ resin offered 1a (140 mg, 0.359
1
mmol) as a colorless solid after lyophilization in 76% yield. H NMR (500
MHz, D2O) δH 1.67–1.90 (m, 2H, PCH2), 3.67–3.78 (m, 2H, OCH2), 4.22
(s, 1H, C(3ꢁ)H), 4.36 (d, J = 3.1 Hz, 2H, C(4ꢁ)H), 4.71 (s, 1H, C(2ꢁ)H), 6.03
(s, 1H, C(1ꢁ)H), 8.13 (s, 1H, C(2)H), 8.20 (s, 1H, C(8)H); 13C NMR (125
MHz, D2O) δC 28.40 (d, JP,C = 128 Hz, PCH2), 65.25 (OCH2), 72.79 (C-4ꢁ),
77.17 (C-2ꢁ), 82.38 (C-3ꢁ), 89.57 (C-1ꢁ), 118.08 (A C(5)), 139.84 (A C(8)),
148.83 (A, C(4)), 152.16 (A, C(2)), 154.93 (A, C(6)); 31P NMR (202.5 MHz,
D2O) δP 19.04; exact mass calcd. for C11H15N5O6P1 [M-H]− 344.076, found
344.075.
1-(Thymin-1-yl)-3-O-(phosphonoethyl)-L-threose Sodium Salt (1b)
This compound was prepared as described for 1a, using 19 (234 mg,
0.596 mmol) as starting material and iodotrimethylsilane (649 µL, 4.77
mmol). Compound 1b (158 mg, 0.415 mmol) was obtained as a colorless
solid after lyophilization in 69% yield: 1H NMR (500 MHz, D2O) δH
1.72–1.88 (m, 2H, PCH2), 1.90 (d, J = 1.0 Hz, 3H, T-CH3), 3.58–3.70 (m, 2H,
OCH2), 4.13 (d, J = 4.0 Hz, 1H, C(3ꢁ)H), 4.25 (dd, J1 = 10.8 Hz, J2 = 4.0 Hz,
1H, C(4ꢁ)Ha), 4.40 (d, J = 10.8 Hz, 1H, C(4ꢁ)Hb), 4.41 (s, 1H, C(2ꢁ)H), 5.81
(s, 1H, C(1ꢁ)H), 7.56 (d, J = 1.0 Hz, 1H, T C(6)H); 13C NMR (125 MHz,
D2O) δC 11.19 (T CH3), 28.68 (d, JP,C = 128 Hz, PCH2), 65.21 (OCH2),
73.09 (C-4ꢁ), 77.15 (C-2ꢁ), 81.85 (C-3ꢁ), 91.31 (C-1ꢁ), 109,66 (T C(5)), 137.53

350
Q. Huang and P. Herdewijn
(T C(6)), 151.15 (T, C(2)), 166.37 (T C(4)); 31P NMR (202.5 MHz, D2O) δP
18.37; exact mass calcd. for C11H16N2O8P1 [M-H]− 335.064, found 335.062.
1-(Adenin-9-yl)-2-deoxy-3-O-(phosphonoethyl)-L-threose Sodium
Salt (1c)
This compound was prepared as described for 1a, using 20 (55 mg, 0.142
mmol) as starting material and iodotrimethylsilane (155 µL, 1.138 mmol).
Compound 1c (40 mg, 0.107 mmol) was obtained as a colorless solid after
lyophilization in 75% yield: 1H NMR (500 MHz, D2O) δH 1.75–1.92 (m, 2H,
PCH2), 2.62 (d, J = 15.2 Hz, 1H, C(2ꢁ)Ha), 2.70 (ddd, J1 = 15.2 Hz, J2 = 7.4
Hz, J3 = 5.6 Hz, 1H, C(2ꢁ)Hb), 3.62–3.74 (m, 2H, OCH2), 4.11 (dd, J1 = 10.5
Hz, J2 = 4.1 Hz, 1H, C(4ꢁ)Ha), 4.33 (d, J = 10.5 Hz, 1H, C(4ꢁ)Hb), 4.46 (t, J
= 4.7 Hz, 1H, C(3ꢁ)H), 6.37 (dd, J1 = 5.4 Hz, J2 = 1.7 Hz, 1H, C(1ꢁ)H), 8.19
(s, 1H, C(2)H), 8.33 (s, 1H, C(8)H); 13C NMR (125 MHz, D2O) δC 28.24 (d,
JP,C = 128 Hz, PCH2), 36.81 (C-2ꢁ), 64.43 (OCH2), 73.69 (C-4ꢁ), 77.32 (C-3ꢁ),
83.96 (C-1ꢁ), 118.24 (A C(5)), 140.14 (A C(8)), 147.94 (A, C(4)), 152.10 (A,
C(2)), 155,08 (A, C(6)); 31P NMR (202.5 MHz, D2O) δP 19.70; exact mass
calcd. for C11H15N5O5P1 [M-H]− 328.081, found 328.082.
1-(Thymin-1-yl)-2-deoxy-3-O-(phosphonoethyl)-L-threose Sodium
Salt (1d)
This compound was prepared as described for 1a, using 21 (127 mg,
0.337 mmol) as starting material and iodotrimethylsilane (367 µL, 2.698
mmol). Compound 1d (50 mg, 0.137 mmol) was obtained as a colorless solid
1
after lyophilization in 41% yield: H NMR (500 MHz, D2O) δH 1.80–1.89
(m, 2H, PCH2), 1.90 (d, J = 1.0 Hz, 3H, T-CH3), 2.25 (d, J = 15.2 Hz, 1H,
C(2ꢁ)Ha), 2.53 (ddd, J1 = 15.1 Hz, J2 = 7.6 Hz, J3 = 5.5 Hz, 1H, C(2ꢁ)Hb),
3.63–3.75 (m, 2H, OCH2), 3.97 (dd, J1 = 10.5 Hz, J2 = 3.6 Hz, 1H, C(4ꢁ)Ha),
4.36 (t, J = 8.8 Hz, 1H, C(3ꢁ)H), 4.40 (d, J = 10.5 Hz, 1H, C(4ꢁ)Hb), 6.12
(dd, J1 = 7.6 Hz, J2 = 1.9 Hz, 1H, C(1ꢁ)H), 7.68 (d, J = 1.1 Hz, T C(6)H); 13
C
NMR (125 MHz, D2O) δC 11.26 (T CH3), 28.57 (d, JP,C = 128 Hz, PCH2),
36.82 (C-2ꢁ), 64.41 (OCH2), 73.81 (C-4ꢁ), 77.02 (C-3ꢁ), 85.69 (C-1ꢁ), 109.85
(T C(5)), 137.89 (T C(6)), 151.24 (T C(2)), 166.36 (T C(4)); 31P NMR
(202.5 MHz, D2O) δP 19.00; exact mass calcd. for C11H16N2O7P1 [M-H]−
319.069, found 319.067.
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