One-pot synthesis of 5'-diaryl esters and diamidates of phosphate, phosphorothioate, and phosphoroselenoate derivatives of AZT and d4T

Article abstract of DOI:10.1080/00397910802527706

Modified nucleosides such as 3'-azido-2',3'-dideoxythymide (AZT) and 2',3'-dideoxy-2',3'-didehydrothymide (d4T) are of importance as antiviral agents and in other medicinal applications. Consequently, there is interest in new analogs of these compounds an

Full text of DOI:10.1080/00397910802527706

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One-Pot Synthesis of 5′-Diaryl
Esters and Diamidates of
Phosphate, Phosphorothioate,
and Phosphoroselenoate
Derivatives of AZT and d4T
An-Fu Hu a , Peng-Xiang Xu a , Mei-Xiang Zhu a , Tao
Ji a , Guo Tang a & Yu-Fen Zhao a b
a Department of Chemistry and the Key Laboratory
for Chemical Biology of Fujian Province , College
of Chemistry and Chemical Engineering, Xiamen
University , Xiamen, China
b Key Laboratory of Bioorganic Phosphorous
Chemistry and Chemical Biology (Ministry of
Education), Department of Chemistry , Tsinghua
University , Beijing, China
Published online: 19 Mar 2009.
To cite this article: An-Fu Hu , Peng-Xiang Xu , Mei-Xiang Zhu , Tao Ji , Guo Tang
& Yu-Fen Zhao (2009) One-Pot Synthesis of 5′-Diaryl Esters and Diamidates of
Phosphate, Phosphorothioate, and Phosphoroselenoate Derivatives of AZT and d4T,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:8, 1342-1354, DOI: 10.1080/00397910802527706
To link to this article: http://dx.doi.org/10.1080/00397910802527706

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Synthetic Communications1, 39: 1342–1354, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802527706
One-Pot Synthesis of 50-Diaryl Esters and
Diamidates of Phosphate, Phosphorothioate, and
Phosphoroselenoate Derivatives of AZT and d4T
An-Fu Hu,1 Peng-Xiang Xu,1 Mei-Xiang Zhu,1 Tao Ji,1 Guo Tang,1
and Yu-Fen Zhao1,2
1Department of Chemistry and the Key Laboratory for Chemical Biology
of Fujian Province, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, China
2Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing, China
Abstract: Modified nucleosides such as 30-azido-20,30-dideoxythymide (AZT) and
20,30-dideoxy-20,30-didehydrothymide (d4T) are of importance as antiviral agents
and in other medicinal applications. Consequently, there is interest in new analogs
of these compounds and in new methods for preparing them. In this article, a
simple but efficient, one-pot synthesis of 50-diaryl esters and diamidates of phos-
phate, phosphorothioate, and phosphoroselenoate derivatives of AZT and d4T is
described. The reaction of AZT=d4T with phosphorus trichloride, followed with
phenols, aniline, or amino acid methyl esters in the presence of a base, led to the
corresponding tricoordinated phosphite compounds of AZT=d4T, which were
then oxidized with 3-chloroperoxybenzoic acid (m-CPBA), sulfur, or selenium
powder to finally afford the corresponding target compounds in good yield.
Keywords: AZT=d4T pro-drug, diamidate of phosphate, 50-diaryl esters,
phosphoroselenoate derivatives, phosphorothioate
Received May 12, 2008.
Address correspondence to Peng-Xiang Xu, Department of Chemistry and
the Key Laboratory for Chemical Biology of Fujian Province, College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005,
China. E-mail: xpengxiang@xmu.edu.cn
1342

Derivatives of AZT and d4T
INTRODUCTION
1343
Some dideoxynucleosides (ddNs) including 30-azido-20,30-dideoxythymi-
dine (AZT, zidovudine)[1] and 20,30-dideoxy-20,30-didehydrothymidine
(d4T, stavudine)[2] have emerged as efficient drugs against human
immunodeficiency virus (HIV).[3–5] However, ddNs such as AZT=d4T
are associated with myelosuppressive side effects, such as anemia and
neutropenia.[6] Certain other ddNs such as 20,30-dideoxyuridine (ddU)
are poor substrates for thymidine kinase or other cellular kinases and
are, therefore, not converted into the corresponding triphosphates.[7,8]
In an attempt to overcome these problems, there is interest in new
analogs of these compounds and in new methods for preparing them.
Numerous chemical strategies have been developed by medicinal chemists
for designing AZT=d4T prodrugs. In general, the goals of these
approaches have been to achieve stability in the extracellular medium,
rapid intracellular hydrolysis to release the phosphate monoester, and
with low side effects. The expected advantages of 50-substituted prodrugs
can be multiple improved in anti-HIV activity, synergistic drug interac-
tion, enhancement of intracellular uptake, and decrease of toxicity.[9]
Among the 50-substituted prodrugs, phosphate triester and phosphoro-
diamidates have been proposed as potential pronucleotides because they
are neutral compounds capable of entering cells by passive diffusion and
with lower toxicity.[10] On the other hand, usually various phosphates
modified by sulfur or selenium atoms replacing the nonbridging oxygen
atom, show similar function and certain specificity such as resistance to
nuclease[11] and also play an important role in biological processes.[12,13]
In this article, a simple but efficient one-pot approach to synthesize new
kinds of 50-diaryl esters and diamidates of phosphate, phosphorothioate,
and phosphoroselenoate derivatives of AZT and d4T to search for
more efficient compounds with low toxicity and high anti-HIV activity
was reported.
RESULTS AND DISCUSSION
Phosphate triester and phosphorodiamidates are usually synthesized
through phosphorochloridate chemistry.[14,15] However, the phosphoro-
chloridate is of lower reactivity than phosphorus trichloride. The reaction
with nucleosides usually needs long reaction time, and yields are often very
low.[16] In addition, there is a lack of sufficiently effective techniques for
purification.[17] In contrast, phosphorus trichloride, an electrophile reagent
of high reactivity, reacts easily with nucleosides to yield dichloro(O-nucleo-
side)phosphine. Furthermore, the biologically significant pV derivatives

1344
A.-F. Hu et al.
(phosphate, phosphorothioate and phosphoroselenoate) also can easily be
obtained from the tricoordinated phosphite by oxidation with commer-
cially available and inexpensive peroxides, sulfur, or selenium powder.
Thus, a threefold choice of molecular diversity can be achieved. Optimum
experimental conditions have been developed (Scheme 1).
For initial investigations of this approach, it was decided to
synthesize diaryl phosphate, phosphorothioate, and phosphoroselenoate
derivatives of AZT=d4T. 31P NMR spectroscopy was used to record the
overall progress of the reactions. The three-step, one-pot reactions were
completed smoothly. We attempted the following procedure. For exam-
ple, a two-component reaction of d4T (1) with 10 equivalents phosphorus
trichloride gave d4T phosphorodichloride (3) almost quantitatively
(31P NMR: ꢀ ¼ 178.55 ppm). Then the solvent and excess PCl3 were
removed under reduced pressure. Et3N was added to the solution after
stirring for 10 min; p-chlorophenol was then added and stirred again
for 30 min, which then afforded the d4T diaryl phosphite (5) in ca. 93%
yield (31P NMR: ꢀ ¼ 125.87 ppm). Without isolation, the diaryl phosphite
was oxidized directly with m-chloroperbenzoic acid (m-CPBA), sulfur
(S8), or selenium (Se) respectively. After purification, the targets (7) were
obtained in reasonable yield (Table 1). Encouraged by these good results,
other AZT=d4T derivatives were synthesized using the same method. In
particular, at low temperature (0 ꢀC) and with short reaction time (0.5 h),
the phosphorus intermediates of these syntheses did not react intramole-
cularly with the azido function of AZT in a Staudinger reduction-like
conversion. This reaction could happened at ambient temperature when
stirring for 16 h (or 24 h).[18] It is noteworthy that 77Se coupling was
Scheme 1. Synthetic route of diaryl phosphate, phosphorothioate, and phospho-
roselenoate derivatives of AZT or d4T. (a) (1) CH2Cl2, ꢁ5 ꢀC, 30 min; (2) rt 3 h;
(b) ROH, CH2Cl2, Et3N, 0 ꢀC, 30 min; (c) m-CPBA 15 min or S, Se powder 4 h.

Derivatives of AZT and d4T
1345
Table 1. 31P NMR (1Jp-Se) data and yield of the synthesized compounds
31P NMR
Compound NuOH
X
R
ꢀ (ppm)
1JP-Se Yielda (%)
7ad
7bd
7be
7cd
d4T
d4T
d4T
d4T
O
S
p-Cl-Ph
p-Cl-Ph
p-CH3O-Ph
ꢁ8.79
=
=
=
87
88
74
85
59.09
60.64
S
Se p-Cl-Ph
71.69, 68.56 1014.12
65.43
7cf
d4T
Se p-CH3S-Ph
68.42, 65.31 1030.32
62.19
77
8ag
8ah
8bi
8cj
AZT
AZT
AZT
AZT
O
O
S
Ph
p-I-Ph
p-NO2-Ph
ꢁ12.87
=
=
=
90
80
72
82
ꢁ12.30
55.30
66.79
63.64
60.49
3.14
Se Naphthyl
1020.60
12k
11l
AZT
d4T
d4T
O
S
N-phenyl
Gly-OMe
=
=
72
68
63
73.86
76.54
73.89
71.23
11m
Se Val-OMe
861.84
aIsolated yield of the three steps.
observed in 31P NMR spectra with typical coupling constants that show a
direct connection between the phosphorus and selenium atoms. Mass
spectral (MS) detection also showed selenium isotope clusters.
To further confirm the scope of this methodology, aniline, glycine, and
L-valine methyl esters were chosen to synthesize phosphorodiamidate ana-
logs (Scheme 2). The corresponding target diamidates of phosphate (12k),
phosphorothioate (11l), and phosphoroselenoate (11m) were obtained in
60–72% yield (Table 1) with DIPEA as a base. The chemical shift of
31P NMR for d4T diamidates phosphite (pIII) was 121.65 ppm. However,
we found that DIPEA was better than Et3N as a base in this reaction.
For this kind of derivatives, McGuigan et al. have proved that phosphoro-
diamidates are potent inhibitors of viral proliferation, active against
urethane leukemia virus (ULV) and a murine leukemia virus (MuLV).[14d]
In conclusion, through tricoordinated phosphorus chemistry, various
diaryl ester and diamidates of phosphate, phosphorothioate, and phos-
phoroselenoate derivatives of AZT=d4T have been prepared under mild
reaction conditions. Their structures were confirmed by 31P, 1H, and
13C NMR and high-resolution mass spectrometry (HRMS, ESI). Anti-
HIV activity of these compounds is being evaluated. Details of the

1346
A.-F. Hu et al.
Scheme 2. Synthetic route of diamidates phosphate, phosphorothioate, and phos-
phoroselenoate derivatives of AZT or d4T. (d) Aniline or amino acid esters,
DIPEA, CH2Cl2, 0 ꢀC, 30 min; (e) m-CPBA, 15 min or S, Se powder 4 h.
pharmacological properties will appear in a forthcoming report. The
reported method should easily be extended to other nucleoside analogs.
EXPERIMENTAL
NMR spectroscopy was performed on a Bruker 400 (1H: 400 MHz;
13C: 100 MHz; 31P: 162 MHz) spectrometer, using CDCl3 as solvent and
tetramethylsilane (TMS) as internal standard. Mass spectra were recorded
on a Bruker mass spectrometer applying the ESI method. HRMS were
obtained using a Shimadzu Fourier transform ion cyclotron resonance
mass spectrometer with an ESI source. Column chromatography was per-
formed on silica gel (300–400 mesh). Unless otherwise noted, all reagents
were obtained commercially and used without further purification.
General Procedure for Preparation of Diaryl Phosphate,
Phosphorothioate, and Phosphoroselenoate Derivatives
AZT=d4T (1.0 mmol) was added in portions at ꢁ5 ꢀC, to a solution of
PCl3 (10 mmol) in 10 mL dry dichloromethane, and the solution was

Derivatives of AZT and d4T
1347
stirred for 0.5 h at this temperature and at rt for 3 h. The solvent and
excess PCl3 were removed under reduced pressure. The residue was dis-
solved in 10 mL dry dichloromethane and cooled to 0 ꢀC, Et3N (2.5
mmol, 0.35 mL, dry) was added to the solution after stirring for
10 min, and then phenol (2 mmol) was added and stirred again for
30 min. Without isolation, it was oxidized directly with 2.5 mmol m-
CPBA, sulfur (S8), or selenium (Se) respectively, and the solution was
stirred for the corresponding time. The solvent was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel with CH2Cl2–MeOH (40:1) or EtOAc–PE (1:1) as eluent.
The solvent was evaporated by rotary distillation, and the target product
was obtained as white=pale yellow foam or clear oil.
General Procedure for Preparation of Diamidates Phosphate,
Phosphorothioate, and Phosphoroslenoate Derivatives
To a solution of PCl3 (10 mmol) in 10 mL dry dichloromethane, AZT=d4T
(1.0 mmol) was added in portions at ꢁ5 ꢀC, and the solution was stirred for
0.5 h at this temperature, and at rt for 3 h. The solvent and excess PCl3 were
removed under reduced pressure. The residue was dissolved in 10 mL dry
dichloromethane and cooled to 0 ꢀC, DIPEA (2.5 mmol, 0.41 mL, dry)
was added to the solution after stirring for 10 min, and then aniline,
glycine, or L-valine methyl esters (2 mmol) was then added and stirred
again for 30 min. Without isolation, it was oxidized directly with
(2.5 mmol) m-CPBA, sulfur (S8), or selenium (Se) respectively, and the
solution was stirred for corresponding time. The residue was purified by
column chromatography on silica gel with EtOAc–PE (1:1) as eluent.
The solvent was evaporated by rotary distillation, and the target product
was obtained as pale yellow foam or colorless oil.
Data
20,30-Dideoxy-20,30-didehydrothymidine 50-(bis-4-chlorophenyl)
Phosphate Triester (7ad)
White foam. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ ꢁ8.79. 1H NMR (CDCl3,
400 MHz): ꢀ ¼ 9.41 (s, 1H, NH-3), 7.34–7.29 (m. 4H, ortho-Ar), 7.27
(m, 1H, H-6), 7.21–7.05 (m, 5H, meta-Ar and H-10), 6.32–6.30 (m, 1H,
H-20), 5.94–5.92 (m, 1H, H-30), 5.06 (br, 1H, H-40), 4.54–4.44 (m, 2H,
H-50), 1.78 (s, 3H, 5-Me). 13C NMR (CDCl3, 100MHz): ꢀ ¼ 163.7 (C-4),
150.9 (C-2), 148.4 (Ar-ispo), 135.5 (C-6), 132.5 (C-30), 131.3 (Ar-para),

1348
A.-F. Hu et al.
130.0 (Ar-meta), 128.0 (C-20), 121.4, 121.3, (Ar-ortho), 111.4 (C-5), 89.5
(C-10), 84.1 (C-40), 68.8 (C-50), 12.2 (5-Me); ESI-MS (þ): m=z ¼ 547
(M þ Na)þ.
20,30-Dideoxy-20,30-didehydrothymidine 50-(bis-4-chlorophenyl)
Phosphorothioate Triester (7bd)
1
White foam. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ 59.09. H NMR (CDCl3,
400 MHz): ꢀ ¼ 9.46 (s, 1H, NH-3), 7.38–7.27 (m. 5H, H-6 and ortho-Ar),
7.11–7.07 (m, 5H, meta-Ar and H-10), 6.35–6.33 (m, 1H, H-20), 5.98–5.95
(m, 1H, H-30), 5.09 (m, 1H, H-40), 4.50–4.47 (m, 2H, H-50), 1.78 (s, 3H,
5-Me). 13C NMR (CDCl3, 100 MHz): ꢀ ¼ 163.9 (C-4), 151.0 (C-2),
148.7 (Ar-ispo), 135.6 (C-6), 132.7 (C-30), 131.5 (Ar-para), 129.9 (Ar-
meta), 128.0 (C-20), 122.4, 122.3, (Ar-ortho), 111.5 (C-5), 89.7 (C-10),
84.2 (C-40), 69.3, 69.2 (C-50), 12.4 (5-Me). HRMS (ESI): m=z calcd. for
[M þ Na]þ (562.9976); found: 562.9972 (M þ Na)þ.
20,30-Dideoxy-20,30-didehydrothymidine 50-(bis-4-methoxyphenyl)
Phosphorothioate Triester (7be)
1
White foam. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ 60.64. H NMR (CDCl3,
400 MHz): ꢀ ¼ 9.74 (s, 1H, NH-3), 7.35 (s, 1H, H-6), 7.09–7.05 (m, 5H,
meta-Ar and H-10), 6.86–6.83 (m, 4H, ortho-Ar), 6.35–6.34 (m, 1H,
H-20), 5.95–5.94 (m, 1H, H-30), 5.07 (br, 1H, H-40), 4.49–4.44 (m, 2H,
H-50), 3.78 (s, 6H, OCH3), 1.76 (s, 3H, 5-Me). 13C NMR (CDCl3,
100 MHz): ꢀ ¼ 164.0 (C-4), 157.0 (Ar-para), 151.0 (C-2), 143.6 (Ar-ispo),
135.8 (C-6), 132.9 (C-30), 127.6 (C-20), 121.7 (Ar-ortho), 114.5 (Ar-meta),
111.3 (C-5), 89.4 (C-10), 84.3 (C-40), 68.7 (C-50), 55.5 (OCH3), 12.2
(5-Me). HRMS (ESI): m=z calcd. for [M þ Na]þ. (555.0961); found:
555.0947 (M þ Na)þ.
20,30-Dideoxy-20,30-didehydrothymidine 50-(bis-4-chlorophenyl) Phospho-
roselenoate Triester (7cd)
White foam. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ 71.69, 68.56, 65.43,
1
1JP-Se ¼ 1014.12. H NMR (CDCl3, 400 MHz): ꢀ ¼ 9.31 (s, 1H, NH-3),
7.37–7.27 (m, 5H, H-6 and ortho-Ar), 7.16–7.08 (m, 5H, meta-Ar and
H-10), 6.37–6.36 (m, 1H, H-20), 5.99–5.94 (m, 1H, H-30), 5.11 (m, 1H,
H-40), 4.55–4.44 (m, 2H, H-50), 1.79 (s, 3H, 5-Me). 13C NMR (CDCl3,
100 MHz): ꢀ ¼ 163.7 (C-4), 150.9 (C-2), 148.5 (Ar-ispo), 135.6 (C-6),
132.7 (C-30), 131.6 (Ar-para), 129.8 (Ar-meta), 127.9 (C-20), 122.5

Derivatives of AZT and d4T
1349
(Ar-ortho), 111.4 (C-5), 89.6 (C-10), 84.0 (C-40), 69.7 (C-50), 12.4 (5-Me).
HRMS (ESI): m=z calcd. for [M þ Na]þ. (610.9415); found: 610.9411
(M þ Na)þ.
20,30-Dideoxy-20,30-didehydrothymidine 50-(bis-4-methylthiophenyl)
Phosphoro- Selenoate Triester (7cf)
Pale yellow foam. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ 68.42, 65.31, 62.19,
1
1JP-Se ¼ 1030.32. H NMR (CDCl3, 400 MHz): ꢀ ¼ 9.30 (s, 1H, NH-3),
7.34 (s, 1H, H-6), 7.28–7.21 (m, 4H, ortho-Ar), 7.11–7.07 (m, 5H, meta-
Ar and H-10), 6.38–6.37 (m, 1H, H-20), 5.98–5.96 (m, 1H, H-30), 5.11
(m, 1H, H-40), 4.57–4.44 (m, 2H, H-50), 2.48 (s, 6H, SCH3), 1.78 (s, 3H,
5-Me). 13C NMR (CDCl3, 100 MHz): ꢀ ¼ 163.7 (C-4), 150.9 (C-2), 147.6
(Ar-ispo), 136.2 (Ar-para), 135.7 (C-6), 132.8 (C-30), 127.7 (Ar-meta
and C-20), 121.6 (Ar-ortho), 111.4 (C-5), 89.5 (C-10), 84.1 (C-40), 69þ.4
(C-50), 16.04 (SCH3), 12.3 (5-Me). HRMS (ESI): m=z calcd. for [M þ Na] .
(634.9949); found: 634.9958 (M þ Na)þ.
30-Azido-20,30-dideoxythymidine 50-(bis-phenyl) Phosphate
Triester (8ag)
1
Pale yellow foam. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ ꢁ12.87. H NMR
(CDCl3, 400 MHz): ꢀ ¼ 9.99 (s, 1H , NH-3), 7.36–7.17 (m, 11H, H-
6 and phenyl), 6.24–6.20 (m, 1H, H-10), 4.57–4.44 (m, 2H, H-50), 4.44–
4.29 (m, 1H, H-30), 4.06–4.04 (m, 1H, H-40), 2.43–2.36 (m, 1H, H-20),
2.26–2.21 (m, 1H, H-20), 1.26 (s, 3H, 5-Me). 13C NMR (CDCl3,
100 MHz): ꢀ ¼ 163.9 (C-4), 150.3, 150.0 (ph-ispo), 149.9 (C-2), 135.0
(C-6), 129.8, 129.8 (ph-meta), 125.7 (ph-para), 119.8, 119.7 (ph-ortho),
111.4 (C-5), 84.6 (C-10), 81.8, 81.8 (C-40), 67.4, 67.3 (C-50),þ59.8 (C-30),
37.1 (C-20), 12.2 (5-Me). ESI-MS ( þ ): m=z ¼ 522 (M þ Na) .
30-Azido-20,30-dideoxythymidine 50-(bis-4-iodophenyl) Phosphate
Triester (8ah)
1
Pale yellow foam. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ ꢁ12.30. H NMR
(CDCl3, 400 MHz): ꢀ ¼ 9.32 (s, 1H, NH-3), 7.69–7.64 (m, 4H, metra-
Ar), 7.28 (s, 1H, H-6), 6.98–6.96 (m, 4H, ortho-Ar), 6.19–6.16 (m, 1H,
H-10), 4.58–4.45 (m, 2H, H-50), 4.34–4.30 (m, 1H, H-30), 4.06–4.04
(m, 1H, H-40), 2.50–2.33 (m, 2H, H-20), 1.84 (s, 3H, 5-Me). 13C NMR
(CDCl3, 100 MHz): ꢀ ¼ 163.5 (C-4), 150.1, 149.9 (Ar-ispo), 149.8 (C-2),
139.0, 138.9 (Ar-meta), 135.3 (C-6), 122.1, 122.0 (Ar-ortho), 111.6

1350
A.-F. Hu et al.
(C-5), 89.7 (Ar-para), 85.3 (C-10), 81.9, 81.8 (C-40), 67.7 (C-50), 59.8 (C-
30), 37.2 (C-20), 12.4 (5-Me). HRMS (ESI): m=z calcd. for [M þ Na]þ.
(773.8718); found: 773.8735 (M þ Na)þ.
30Azido-20,30-dideoxythymidine 50-(bis-4-nitrophenyl) Phosphorothioate
Triester (8bi)
1
Pale yellow foam. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ 55.30. H NMR
(CDCl3, 400 MHz): ꢀ ¼ 9.68 (s, 1H, NH-3), 8.31–8.27 (m, 4H, metra-
Ar), 7.39–7.37 (m, 4H, ortho-Ar), 7.21 (s, 1H, H-6), 6.13–6.10 (m, 1H,
H-10), 4.65–4.54 (m, 2H, H-50), 4.44–4.12 (m, 1H, H-30), 4.14 (m, 1H,
H-40), 2.59–2.51 (m, 2H, H-20), 1.91 (s, 3H, 5-Me). 13C NMR (CDCl3,
100 MHz): ꢀ ¼ 163.5 (C-4), 154.5, 154.4 (Ar-ispo), 150.1 (C-2), 145.6
(C-6), 136.0 (Ar-para), 125.8, 125.7 (Ar-meta), 121.8, 121.8 (Ar-ortho),
111.6 (C-5), 86.6 (C-10), 82.0, 81.9 (C-40), 68.5 (C-50), 60.4, 60.1 (C-3þ0),
37.1 (C-20), 12.4 (5-Me). HRMS (ESI): m=z calcd. for [M þ Na] .
(628.0258); found: 628.0262 (M þ Na)þ.
30-Azido-20,30-dideoxythymidine 50-(bis-naphthyl) Phosphoroselenoate
Triester (8cj)
Colorless oil. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ 66.79, 63.64, 60.49,
1JP-Se ¼ 1020.60. 1H NMR (CDCl3, 400 MHz): ꢀ ¼ 9.23 (s, 1H, NH-
3), 8.12–8.07 (m, 2H, H-ꢁ-Nap), 7.90–7.87 (m, 2H, H-ꢁ-Nap),
7.77–7.74 (m, 2H, H-ꢁ-Nap), 7.55–7.38 (m, 8H, H-ꢁ-Nap), 7.25 (s,
1H, H-6), 6.18–6.15 (m, 1H, H-10), 4.63–4.53 (m, 2H, H-50), 4.07–
4.04 (m, 2H, H-30 and H-40), 2.28–2.21 (m, 1H, H-20), 1.90–1.86
(m, 1H, H-20), 1.63 (S, 3H, 5-Me). 13C NMR (CDCl3, 100 MHz):
ꢀ ¼ 163.5 (C-4), 150.2 (C-2), 146.6, 146.3 (Nap-ispo), 134.8 (C-6),
127.9, 126.6, 126.0, 125.2, 121.6, 116.5 (c-Nap), 111.6 (C-5), 84.6
(C-10), 81.7 (C-40), 68.7 (C-50), 60.3 (C-30), 37.0 (C-20), 12.2 (5-Me).
HRMS (ESI): m=z calcd for [M þ Na]þ. (686.0314); found: 686.0323
(M þ Na)þ.
30-Azido-20,30-dideoxythymidine 50-(N,N-diphenyl)
Phosphorodiamidate (12k)
Pale yellow foam. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ 3.14. 1H NMR
(CDCl3, 400 MHz): ꢀ ¼ 9.70 (s, 1H, NH-3), 7.21–6.93 (m, 11H, H-6
and phenyl), 6.39–6.30 (m, 2H, phenyl-NH), 6.05–6.02 (m, 1H, H-10),
4.34–4.29 (m, 3H, H-30 and H-50), 4.00–3.99 (m, 1H, H-40), 2.39–2.34

Derivatives of AZT and d4T
1351
(m, 2H, H-20), 1.79 (S, 3H, 5-Me). 13C NMR (CDCl3, 100 MHz):
ꢀ ¼ 164.1 (C-4), 150.4 (C-2), 139.2, 139.1 (ph-ispo), 136.1 (C-6), 129.3
(ph-meta), 122.3 (ph-para), 118.2, 118.1, 118.1, 118.0 (ph-ortho), 111.4
(C-5), 85.9 (C-10), 82.3, 82.3 (C-40), 64.6 (C-50), 60.3 (C-30), 36.7 (C-20),
12.3 (5-Me). ESI-MS (þ): m=z ¼ 520 (M þ Na)þ.
20,30-Dideoxy-20,30-didehydrothymidine 50-(N,N-di-glycine Methyl Ester)
Phosphorothiodiamidate (11l)
Colorless oil. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ 73.86. 1H NMR
(CDCl3, 400 MHz): ꢀ ¼ 9.16 (s, 1H, NH-3), 7.28 (s, 1H, H-6), 7.02–7.00
(m, 1H, H-10), 6.34–6.33 (m, 1H, H-20), 5.90–5.89 (m, 1H, H-30), 5.02
(br, 1H, H-40), 4.29–4.25 (m, 1H, H-50), 4.21–4.12 (m, 1H, H-50), 3.82–
3.50 (m, 12H, Gly-OMe, Gly-NH and Gly-ꢁ-CH), 1.91 (s, 3H, 5-Me).
13C NMR (CDCl3, 100 MHz): ꢀ ¼ 171.8, 171.5 (Gly-CO), 163.9 (C-4),
150.9 (C-2), 135.8 (C-6), 133.4 (C-30), 127.2 (C-20), 111.4 (C-5), 89.7
(C-10), 84.8 (C-40), 68.3 (C-50), 52.5 (Gly-OCH3), 42.9 (Gly-ꢁ-CH), 12.4
(5-Me). HRMS (ESI): m=z calcd. for [M þ Na]þ. (485.0872); found:
485.0797 (M þ Na)þ.
20,30-Dideoxy-20,30-didehydrothymidine 50-(N,N-di-L-valine Methyl
Ester) Phosphoroselenodiamidate (11m)
1
Colorless oil. 31P NMR (CDCl3, 162 MHz): ꢀ ¼ 76.54, 73.89, 71.23, Jp-
¼ 861.84. 1H NMR (CDCl3, 400 MHz): ꢀ ¼ 9.32 (s, 1H, NH), 7.23
se
(m, 1H, H-6), 7.04–7.02 (m, 1H, H-10), 6.34–6.32 (m, 1H, H-20), 5.91–
5.88 (m, 1H, H-30), 5.03 (br, 1H, H-40), 4.20–4.16 (m, 2H, H-50), 3.89–
3.85 (m, 2H, NH of Val), 3.75–3.73 (d, 6H, OCH3), 3.64–3.54 (m, 2H,
ꢁ-CH of Val), 2.11–2.05 (m, 2H ꢂ-CH of Val), 1.95 (s, 3H, 5-Me),
0.95–0.85 (m, 12H, CH3 of Val). 13C NMR (CDCl3, 100 MHz):
ꢀ ¼ 173.6, 173.5 (Val-CO), 163.8 (C-4), 150.8 (C-2), 135.4 (C-6), 133.3
(C-3), 127.1 (C-20), 111.5 (C-5), 89.9 (C-10), 84.6 (C-40), 67.8 (C-50),
60.3 (ꢁ-CH of Val), 53.4, 52.2 (OCH3), 31.7 (ꢂ-CH of Val), 18.9, 18.7
(CH3 of Val), 17.7, 17.5 (CH3 of Val), 12.6 (5-Me). HRMS (ESI): m=z
calcd for [M þ H]þ(617.0886); found: 617.0897 (M þ Na)þ.
ACKNOWLEDGMENT
The authors thank the National Natural Science Foundation of China
(No. 20572061) and the Major Program of National Natural Science
Foundation of China (No. 20732004) for financial support.

1352
A.-F. Hu et al.
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