Synthesis of dinucleotide thiophosphoramidates as anti-HIV new prodrugs

Article abstract of DOI:10.1055/s-2003-41039

Sequential transesterification of diphenyl phosphite with 5′-O-(4,4′-dimethoxytrityl)thymidine (1) and hydrogen sulfide gave O-[5′-O-(4,4′-dimethoxytrityl)thymidine-3′-yl] H-thiophosphonate (2), and subsequent condensation of 2 with AZT or d4T in the presence of diphenyl chlorophosphoate provided the dinucleotide H-thiophosphonates 3 or 3′. The Antherton-Todd reaction of 3 or 3′ with L-amino acid methyl ester in a solution of CCl₄-Et ₃N-H₂O-MeCN gave the dinuleotide thiophosphoramidates 4 or 4′, and removal of the dimethoxytrityl protecting group in formic acid yielded the target products AZT/d4T thiophosphoramidates 5 and 5′.

Full text of DOI:10.1055/s-2003-41039

PAPER
1989
Synthesis of Dinucleotide Thiophosphoramidates as Anti-HIV New Prodrugs
Dinucleotide
Thi
h
m
a
idates as
A
n
nti-HIV
N
ew
g
Prodrugs xue Lin,a Hua Fu,*a Guangzhong Tu,b Yufen Zhao*a
a
The Key Laboratory of Bioorganic Phosphorus Chemistry, Ministry of Education, Department of Chemistry,
School of Life Sciences and Engineering, Tsinghua University, Beijing 100084, P. R. China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
b
Beijing Institute of Microchemistry, Beijing 100091, P. R. China
Received 6 May 2003; revised 16 June 2003
poration and subsequent chain termination of growing vi-
ral DNA strands.5 The major limitations of AZT/d4T are
due to clinical toxicity6 and to the development of AZT/
d4T resistance by HIV.7 In an attempt to overcome these
Abstract: Sequential transesterification of diphenyl phosphite with
5¢-O-(4,4¢-dimethoxytrityl)thymidine (1) and hydrogen sulfide
gave O-[5¢-O-(4,4¢-dimethoxytrityl)thymidine-3¢-yl] H-thiophos-
phonate (2), and subsequent condensation of 2 with AZT or d4T in
the presence of diphenyl chlorophosphoate provided the dinucle- problems, numerous chemical strategies have been devel-
otide H-thiophosphonates 3 or 3¢. The Antherton–Todd reaction of
3 or 3¢ with L-amino acid methyl ester in a solution of CCl4–Et3N–
H2O–MeCN gave the dinuleotide thiophosphoramidates 4 or 4¢,
and removal of the dimethoxytrityl protecting group in formic
acid yielded the target products AZT/d4T thiophosphoramidates 5
and 5¢.
oped by medicinal chemists for designing AZT/d4T pro-
drugs, which mainly included 5¢-O-carboxylic ester
derivatives and 5¢-O-masked phosphonates.8 The expect-
ed advantages of these 5¢-substituted prodrugs can be
multiple improvement in anti-HIV activity, synergistic
drug interaction, enhancement of intracellular uptake and
decrease of toxicity.
Key words: nucleotides, phosphorus, antiviral agents, esterifica-
tion, drugs
Among the prodrugs, dinucleotide phosphate derivatives
have attracted great attention. Various homo- and hetero-
dinucleotides, such as AZT-P-ddI, AZT-P-ddZ, AZT-P-
AZT, have been synthesized and tested for HIV-infected
MT-2 cells9. It was found that dinucletide analogues
showed enhanced anti-HIV potency relative to mono-
mers. In addition, AZT-P-ddI was 10 times less toxic than
AZT to human granulocyte macrophage progenitor
cells.10 Almost all the dinucleotide prodrugs contain two
unnatural nucleosides, namely 2¢,3¢-dideoxynucleside
(ddNs). Because the cellular kinases involved in activat-
ing the nucleoside prodrugs are usually specific,11 it is
thought that the replacement of ddNs with natural nucleo-
sides, such as thymidine, could improve the rate of phos-
phorylation and inhibit the HIV-RT. On the other hand,
the substitution of a single non-bridging oxygen atom
with a sulfur atom renders the internucleotide linkage nu-
clease resistant and ensures that thymidine is not hydro-
lyzed.12 Therefore, the dinucleotide analogues could be
phosphorylated at the 5¢-position of thymidine and direct-
ly linked to the DNA chains. In order to improve the lipo-
philicity and member-penetration, we introduced amino
acid methyl esters in the molecules. McGuigan et al.13
suggested that HIV-aspartate proteinase could recognize
phosphonoamidate derivatives of certain nucleosides and
thus specifically hydrolyze these membrane-soluble pro-
drugs. The resultant bioactive nucleotides would then be
trapped inside the infected cells and act as potent inhibi-
tors of viral proliferation. Taking into account these find-
ings, we synthesized dinucleotide thiophosphoramidates
containing AZT or d4T as new anti-HIV prodrugs, as de-
scribed in this paper.
In combating acquired immunodeficiency syndrome
(AIDS) and its related complex, the search for therapeutic
agents possessing activity against human immunodefi-
ciency virus (HIV) has yielded a number of compounds
demonstrating potent and selective antiviral activity. De-
spite the recent introduction of HIV protease1 and inte-
grase,2 reverse transcriptase is an attractive target for the
chemotherapy of human immunodeficiency virus (HIV).3
Among the current diversity of compounds against HIV,
the 2¢,3¢-dideoxynucleosides (ddNs) remain by far the
most potent,4 and 3¢-azido-2¢,3¢-dideoxythymidine (AZT,
zidovudine) and 2¢,3¢-dideoxythymidine (d4T, stavudine)
are prime (Figure 1).
O
O
NH
NH
N
O
N
O
HO
O
HO
O
N3
AZT
d4T
Figure 1
It has been proven that ddNs must be converted into their
5¢-O-triphosphate analogues (ddNs-TP) by a cellular en-
zyme to inhibit HIV reverse transcriptase, by competitive
inhibition of the viral reverse transcriptase and/or incor-
Dinucleotide thiophosphoramidates were prepared as
shown in Scheme 1. Diphenyl phosphite reacted with 5¢-
O-dimethoxytritylthymidine (1) in anhyd pyridine for 20
Synthesis 2003, No. 13, Print: 18 09 2003. Web: 28 08 2003.
Art Id.1437-210X,E;2003,0,13,1989,1994,ftx,en;F04103SS.pdf.
DOI: 10.1055/s-2003-41039
© Georg Thieme Verlag Stuttgart · New York

1990
C. Lin et al.
PAPER
Column chromatography was performed using silica gel 300–400
mesh. Pyridine was dried over CaH2 by refluxing for 4–5 hours. 1H
and 13C NMR spectra were recorded (tetramethylsilane as internal
standard) on a Bruker AM 500 spectrometer using CD3OD as the
solvent. 31P NMR spectra were taken on a Bruker AC 200 spectrom-
eter at 81 MHz under 1H decoupled conditions. 31P NMR chemical
shifts were reported in ppm downfield (+) or upfield (–) from exter-
nal 85% H3PO4 as reference. Mass spectra were obtained using a
Bruker Esquire ion-trap mass spectrometer in positive ion mode.
minutes, and then mixtures of H2S and triethylamine in di-
oxane were added to the resulting solution at room tem-
perature under a nitrogen atmosphere to give the product
2. The coupling of 2 with AZT or d4T by diphenyl chlo-
rophosphoate led to dinucleotide H-thiophosphate 3.
Atherton–Todd reaction14 of 3 with L-amino acid methyl
ester in CCl4–Et3N–H2O–MeCN solution at room temper-
ature gave product 4 or 4¢. Product 5 or 5¢ was obtained as
a white foam after 5¢-deprotection of 4 or 4¢ in formic acid
and purification on silica gel column chromatography.
5¢-O-Dimethoxytritylthymidine (1)
The starting material 5¢-dimethoxytritylthymidine was prepared ac-
cording to the published procedure.15
In conclusion, dinucleotide thiophosphoramidates
[(2R,4S,5R)-1-(4-Azidotetrahydro -5-{[(3¢-O-thymidin-
yl)(methoxy-L-alaninyl)phosphoryl]methyl-2-furyl}thy-
Yield: 95%; mp 126–129 ºC
mine (diastereoisomeric mixture) (5) and (2R,4S,5R)-1- O-[5¢-O-(4,4¢-Dimethoxytrityl)thymidine-3¢-yl] H-Thiophos-
phonate (2)
(2,5-dihydro-5-{[(3¢-O-thymidinyl) (methoxy-L-alani-
According to the literature,16 5¢-dimethoxytritylthymidine in anhyd
nyl)phosphoryl]methyl-2-furyl}thymine (diastereoiso-
pyridine was added to diphenyl phosphite in pyridine solution at
room temperature, and the reaction lasted for 20 min. Et3N and H2S
(1:1) dioxane solution (10 mL) was added to the reaction solution,
and the reaction continued for a further 20 minutes. After evapora-
meric mixture) (5¢)] were synthesized through Atherton–
Todd reaction of dinucleotide H-thiophosphonates with
amino acid methyl esters. Compounds 5 and 5¢ were ob-
tained as mixtures of diastereoisomers due to the chirality
of phosphorus. The ratio of the two isomers was almost
tion of the solvent, 2 was obtained after column chromatography.
Yield: 84%; brittle yellow foam.
1
1:1, as judged from 31P and H NMR. Their structures
1H NMR (CDCl3): d = 9.23 (d, J = 581 Hz, 1 H, PH), 6.96–7.86 (m,
14 H, H-6), 6.10–6.20 (m, 1 H, H-1¢), 4.82 (m, 1 H, H-3¢), 3.71–3.74
(m, 3 H, H4¢, 2 × H-5¢), 3.68 (d, 6 H, J = 1.2 Hz, OCH3), 2.78–2.82
(m, 2 H, H-2¢), 1.68 (d, 3 H, J = 8.06 Hz, C5-CH3).
were confirmed by 31P, 1H, 13C NMR and ESI-MS. Anti-
HIV activity of these compounds is in progress. The de-
tails of the pharmacological properties will be described
elsewhere.
T
T
DMTrO
DMTrO
T
O
DMTrO
O
T
O
DMTrO
O
O
P
H
O
O
or
i,ii
iii
OPh
PhO
+
O
P
S
P
H
S
P
H
T
T
O
O
S
H
OH
O
O
O-N+HEt3
1
2
N3
3
3'
T
DMTrO
T
DMTrO
O
O
(i)
Py ;
O
O
NEt /
(ii)
H2S ;
R
3
R
iv
S
P
NH CH
COOCH3
or
S
P
NH CH
(iii)
AZT or d4T/DPCP;
COOCH3
T
O
T
O
(iv) CCl4/NEt3/H2O/CH3CN
AAOCH3
O
O
(v) HCOOH/CH2Cl2
N3
4
4'
O
NH
T =
T
HO
O
N
O
T
HO
O
O
R
a
b
c
d
e
f
R=H
R=CH3
R=CH2Ph
R=CH(CH3)2
R=CH2CH(CH3)2
R=CH(CH3)CH2CH3
v
NH CH
S
P
or
COOCH3
O
R
T
O
NH CH
S
P
COOCH3
O
T
O
O
N3
5
5'
Scheme 1
Synthesis 2003, No. 13, 1989–1994 © Thieme Stuttgart · New York

PAPER
Dinucleotide Thiophosphoramidates as Anti-HIV New Prodrugs
1991
13C NMR (CDCl3): d = 165.0, 159.4 (C-4), 151.9 (C-2), 135.7 (C-
6), 130.9–114.1 (Ph), 111.4–111.3 (C-5), 85.5 (C-4¢), 85.1(C-1¢),
76.2(C-3¢), 64.8 (C-5¢), 55.2 (OCH3), 40.2 (C-2¢), 12.3 (CH3).
31P NMR (CDCl3): d = 55.8, 55.2.
ESI-MS: m/z = 726 [M + H]+.
and MeCN (5mL)] and stirred at r.t. until the H-thiophosphonate
disappeared (31P NMR determination). The crude product 4 or 4¢
was obtained after the solvents were removed by rotary evapora-
tion, and then treated with HCO2H and CH2Cl2 until complete
deprotection (TLC determination). The solution was neutralized
with a few drops of sat. aq. NaHCO3, and then concentrated under
reduced pressure. The product 5 or 5¢ was purified by column chro-
matography (CH2Cl2–MeOH, from 30:1 to 15:1).
Dinucleotide H-Thiophosphonate; General Procedure
5¢-O-Dimethoxytritylthymidine 3¢-phosphonothioate (2) (0.8g,
1.1mmol) and AZT/d4T (1 mmol) were dissolved in anhyd pyridine
and co-evaporated twice. The residue was then dissolved in anhyd
pyridine (10 mL), diphenyl chlorophosphoate (684 L, 3.3 mmol)
was added dropwise and the reaction mixture was stirred at r.t. for
10 min. After addition of a few drops of H2O, and the solvent was
removed under reduced pressure. The residue was dissolved in
EtOAc (25 mL) and washed with sat. aq NaCl. The organic phase
was dried (Na2SO4). The crude product was purified with column
chromatography. After concentration the product was obtained as
white foam.
(2R,4S,5R)-1-{4-Azidotetrahydro-5-[(3¢-O-thymidinyl)(meth-
oxy-L-glycinyl)phosphoryl]methyl-2-furyl}thymine (Diastereo-
isomeric Mixture) (5a)
Yield: 76.7%; Rf = 0.4 (CH2Cl2–MeOH, 30:1).
1H NMR (CD3OD, 500 MHz): d = 7.83, 7.82 (s, 1 H, T-H-6), 7.60,
7.58 (s, 1 H, AZT-H-6), 6.31–6.27 (m, 1 H, T-H-1¢), 6.18–6.15 (m,
1 H, AZT-H-1¢), 5.19–5.16 (m, 1 H, T-H-3¢), 4.48–4.45 (m, 1 H,
AZT-H-3¢), 4.28–4.22 (m, 4 H, 2 × H-4¢, 2 × AZT-H-5¢), 3.86–3.78
(m, 4 H, 2 × T-H-5¢, CH2), 3.71, 3.70 (s, 3 H, OCH3), 2.53–2.30 (m,
4 H, 2 × H-2¢), 1.93–1.87 (m, 6 H, 2 × C5-CH3).
O-(5¢-Dimethoxytrityl-2¢-deoxythymidin-3¢-yl)-O-(3¢-azido-2¢-
deoxythymidin-5¢-yl) H-Thiophosphonate (3)
13C NMR (CD3OD, 125 MHz): d = 175.32, 173.22 (COO), 166.33
(2 × C-4), 152.38, 152.22 (2 × C-2), 137.88, 137.82, 137.72 (2 × C-
6), 111.96–111.85 (2 × C-5), 87.54–86.04 (T-C-4¢, 2 × C-1¢),
83.92, 83.79 (AZT-C-4¢), 79.83, 79.36 (T-C-3¢), 67.06, 66.75
(AZT-C-5¢), 62.87, 62.75 (T-C-5¢), 62.17, 61.94 (AZT-C-3¢), 52.65
(OCH3), 44.45, 44.15 (CH2), 39.84, 39.65 (T-C-2¢), 37.95 (AZT-C-
2¢), 12.67, 2.49 (2 × C5-CH3).
Yield: 0.635g (72.7%); Rf 0.4 (CHCl3–MeOH, 40:1).
1H NMR (CD3COCD3): d = 10.27–10.26 (m, 2 H, 3NH), 7.63 (d, 1
H, PH, JPH = 673 Hz), 7.58–6.79 (m, 15 H, H-6, Ph), 6.42–6.35 (m,
1 H, H-1¢), 6.19–6.17 (m, 1 H, H-1¢), 5.23–5.19 (m, 1 H, H-3¢),
4.52–4.49 (m, 1 H, H-3¢), 4.42–4.32 (m, 4 H, 2 × H-4¢, H-5¢), 3.76–
3.72 (m, 2 H, H-5¢), 2.54–2.36 (m, 4 H, 2 × H-2¢), 1.49–1.46 (m, 6
H, 2 × C5-CH3).
31P NMR (CD3OD, 81 MHz): d = 76.19, 75.21.
ESI-MS: m/z = 659 [M + H]+, 681 [M + Na]+.
13C NMR (CD3COCD3): d = 166.53 (2 × C-4), 152.48, 152.37
(2 × C-2), 137.96, 137.89, 137.81 (2 × C-6), 130.6–114.9 (Ph),
111.88–111.83 (2 × C-5), 87.52–86.08 (T-C-4¢, 2 × C-1¢), 83.86,
83.78 (AZT-C-4¢), 79.85, 79.42 (T-C-3¢), 67.06, 66.79 (AZT-C-5¢),
62.93, 62.85 (T-C-5¢), 62.18, 61.98 (AZT-C-3¢) 55.8 (OCH3),
39.85, 39.66 (T-C-2¢), 37.91 (AZT-C-2¢), 12.66, 2.47 (2 × C5-CH3).
31P NMR (CD3COCD3): d = 72.17, 71.01 (JPH = 671 Hz) (mixture
of diastereoisomers).
ESI-MS: m/z =874 [M + H]+, 896 [M + Na]+.
(2R,4S,5R)-1-{4-Azidotetrahydro-5-[(3¢-O-thymidinyl)(meth-
oxy-L-alaninyl)phosphoryl]methyl-2-furyl}thymine (Diastereo-
isomeric Mixture) (5b)
Yield: 62.8%; Rf 0.4 (CH2Cl2–MeOH, 30:1).
1H NMR (CD3OD, 500 MHz): d = 7.83, 7.82 (s, 1 H, T-H-6), 7.60,
7.58 (s, 1 H, AZT-H-6), 6.31–6.27 (m, 1 H, T-H-1¢), 6.18–6.15 (m,
1 H, AZT-H-1¢), 5.19–5.16 (m, 1 H, T-H-3¢), 4.48–4.45 (m, 1 H,
AZT-H-3¢), 4.28–4.02 (m, 5 H, 2 × H-4¢, 2 × AZT-H-5¢, CH), 3.80–
3.78 (m, 2 H, 2 × T-H-5¢), 3.71, 3.70 (s, 3 H, OCH3), 2.56–2.27 (m,
4 H, 2 × H-2¢), 1.92–1.87 (m, 6 H, 2 × C5-CH3), 0.92–0.88 (m, 3 H,
CH3).
13C NMR (CD3OD, 125 MHz): d = 175.82 (COO), 166.33 (2 × C-
4), 152.39, 150.18 (2 × C-2), 137.89, 137.78, 137.67 (2 × C-6),
112.00–111.86 (2 × C-5), 87.47–86.02 (T-C-4¢, 2 × C-1¢), 83.83,
83.75 (AZT-C-4¢), 79.94, 79.24 (T-C-3¢), 67.03, 66.55 (AZT-C-5¢),
62.88, 62.72 (T-C-5¢), 62.13, 61.80 (AZT-C-3¢) 52.78 (OCH3),
52.40, 51.99 (CH), 39.71 (T-C-2¢), 37.87, 37.81 (AZT-C-2¢), 20.35,
20.29 (CH3), 12.68, 12.64, 12.48 (2 × C5-CH3).
O-(5¢-Dimethoxytrityl-2¢-deoxythymidin-3¢-yl)-O-(2¢,3¢-dideox-
ythymidin-5¢-yl) H-Thiophosphonate (3¢)
Yield: 0.575g (69.3%); Rf = 0.4 (CHCl3–MeOH, 30:1).
1H NMR (CD3COCD3): d = 10.26–10.24 (m, 2 H, 3NH), 7.65 (d, 1
H, PH, JPH = 682 Hz), 7.82 (s, 1 H, H-6), 7.59–6.82 (m, 15 H, H-6,
d4T-H-1¢, Ph), 6.43–6.41 (m, 1 H, d4T-H-2¢), 6.30–6.28 (m, 1 H, H-
1¢), 5.98, 5.97 (s, 1 H, d4T-H-3¢), 5.19–5.16 (m, 1 H, T-H-3¢), 5.03
(s, 1 H, d4T-H-4¢), 4.28–4.19 (m, 3 H, 2 × d4T-H-5¢, T-H-4¢), 3.80–
3.73 (m, 2 H, T-H-5¢), 2.52–2.28 (m, 2 H, T-H-2¢), 1.93–1.87 (m, 6
H, 2 × 5-CH3).
13C NMR (CD3COCD3): d = 166.45, 166.37 (2 × C-4), 152.84,
152.37, 152.34 (2 × C-2), 138.02, 137.92, 137.88 (2 × C-6), 134.77
(d4T-C-2¢), 130.6–114.2 (Ph, d4T-C-3¢, 2 × C-5), 91.34, 91.11
(d4T-C-1¢), 87.54, 87.29 (T-C-4¢), 86.36–86.06 (T-C-1¢, d4T-C-4¢),
79.78, 79.12 (T-C-3¢), 68.48, 68.17 (d4T-C-5¢), 62.89, 62.75 (T-C-
5¢), 55.9 (OCH3), 39.87, 39.67 (T-C-2¢), 12.74, 12.67, 12.45 (5-
CH3).
31P NMR (CD3OD, 81 MHz): d = 74.29, 73.24.
ESI-MS: m/z = 673 [M + H]+, 695 [M + Na]+.
(2R,4S,5R)-1-{4-Azidotetrahydro-5-[(3¢-O-thymidinyl)(meth-
oxy-L-phenylalaninyl)phosphoryl]methyl-2-furyl}thymine
(Diastereoisomeric Mixture) (5c)
Yield: 63.9%; Rf 0.4 (CH2Cl2–MeOH, 30:1).
1H NMR (CD3OD, 500 MHz): d = 7.83 (s, 1 H, T-H-6), 7.58, 7.53
(s, 1 H, AZT-H-6), 6.31–6.29 (m, 1 H, T-H-1¢), 6.15–6.12 (m, 1 H,
AZT-H-1¢), 5.15–5.10 (m, 1 H, T-H-3¢), 4.48–4.42 (m, 1 H, AZT-
H-3¢), 4.27–4.07 (m, 4 H, 2 × H-4¢, 2 × AZT-H-5¢), 3.92–3.79 (m, 3
H, 2 × T-H-5¢, NHCH), 3.72, 3.71 (s, 3 H, OCH3), 2.56–2.28 (m, 4
H, 2 × H-2¢), 2.09–2.01 [m, CH(CH3)2], 1.98, 1.87 (s, 6 H, 2 × C5-
CH3), 0.98–0.92 (m, 6 H, 2 × CH3).
31P NMR (CD3COCD3): d = 73.29, 72.13 (JPH = 682 Hz, mixture of
diastereoisomers).
ESI-MS: m/z = 831 [M + H]+, 853 [M + Na]+.
Thiophosphoramidates 5 and 5¢; General Procedure
Dinucleotide H-thiophosphonate (0.2 mmol) in MeCN (2 mL) was
added dropwise to L-amino acid methyl ester hydrochloride
(0.22mmol) in solution [H2O (100 mL), Et3N (70 mL), CCl4 (100 mL)
13C NMR (CD3OD, 125 MHz): d = 175.10, 175.05 (COO), 166.33
(2 × C-4), 152.39, 150.17 (2 × C-2), 137.88, 137.78, 137.71 (2 × C-
Synthesis 2003, No. 13, 1989–1994 © Thieme Stuttgart · New York

1992
C. Lin et al.
PAPER
6), 112.02–111.92, 111.72 (2 × C-5), 87.50–86.05 (T-C-4¢, 2 × C-
1¢), 83.77, 83.67 (AZT-C-4¢), 80.25, 79.33 (T-C-3¢), 67.33, 66.67
(AZT-C-5¢), 62.91, 62.75 (T-C-5¢), 62.16, 62.10 (AZT-C-3¢), 61.79
(NHCH), 52.53, 52.51 (OCH3), 39.78 (T-C-2¢), 37.78 (AZT-C-2¢),
33.04, 32.98 [CH(CH3)2], 19.70, 18.63 (CH3), 12.69, 12.51 (2 × C5-
CH3).
31P NMR (CD3OD, 81 MHz): d = 74.47, 72.71.
ESI-MS: m/z = 749 [M + H]+, 771 [M + Na]+.
H-3¢), 4.28–4.08 (m, 4 H, 2 × H-4¢, 2 × AZT-H-5¢), 3.98–3.84 (m, 1
H, NHCH), 3.79 (s, 2 H, 2 × T-H-5¢), 3.71, 3.70 (s, 3 H, OCH3),
2.55–2.28 (m, 4 H, 2 × H-2¢), 1.92, 1.88 (s, 6 H, 2 × C5-CH3), 1.83–
1.80 [m, 1 H, CH(CH3)CH2CH3], 1.53–1.15 (m, 2 H, CH2), 0.96–
0.93 (m, 6 H, 2 × CH3).
13C NMR (CD3OD, 125 MHz): d = 175.06 (COO), 166.34 (2 × C-
4), 152.39, 152.17 (2 × C-2), 137.89, 137.82, 137.71 (2 × C-6),
112.03–111.92, 111.83 (2 × C-5), 87.48–86.06 (T-C-4¢, 2 × C-1¢),
83.70 (AZT-C-4¢), 80.25, 79.34 (T-C-3¢), 67.33, 66.76 (AZT-C-5¢),
62.91, 62.75 (T-C-5¢), 62.10, 61.84 (AZT-C-3¢), 61.66, 61.22
(NHCH), 52.52, 52.48 (OCH3), 48.51 [CH(CH3)CH2CH3], 39.84
(T-C-2¢), 37.84, 37.80 (AZT-C-2¢), 26.29, 26.26 (CH2), 16.13,
16.06 [CH(CH3)CH2CH3], 12.71, 12.52 (5-CH3), 11.79, 11.76
[CH(CH3)CH2CH3].
(2R,4S,5R)-L-{4-Azidotetrahydro-5-[(3¢-O-thymidinyl)(meth-
oxy-L-valinyl)phosphoryl]methyl-2-furyl}thymine (Diastereo-
isomeric Mixture) (5d)
Yield: 65.1%; Rf 0.4 (CH2Cl2–MeOH, 30:1).
1H NMR (CD3OD, 500 MHz): d = 7.78 (s, 1 H, T-H-6), 7.47, 7.43
(s, 1 H, AZT-H-6), 7.28–7.17 (m, 5 H, Ph), 6.24–6.20 (m, 1 H, T-
H-1¢), 6.13–6.07 (m, 1 H, AZT-H-1¢), 5.03–4.96 (m, 1 H, T-H-3¢),
4.29–4.27 (m, 1 H, AZT-H-3¢), 4.22–3.87 (m, 4 H, 2 × H-4¢,
2 × AZT-H-5¢), 3.76–3.74 (m, 3 H, 2 × T-H-5¢, NHCH), 3.70, 3.69
(s, 3 H, OCH3), 3.18–2.81 (m, 2 H, CH2), 2.46–2.14 (m, 4 H, 2 × H-
2¢), 1.89–1.85 (m, 6 H, 2 × C5-CH3).
13C NMR (CD3OD, 125 MHz): d = 175.07, 174.96 (COO), 166.32
(2 × C-4), 152.35, 152.16 (2 × C-2), 138.60–127.96 (2 × C-6, Ph),
112.05–111.99, 111.87 (2 × C-5), 87.40–85.97 (T-C-4¢, 2 × C-1¢),
83.69, 83.63 (AZT-C-4¢), 80.37, 79.34 (T-C-3¢), 66.85, 66.48
(AZT-C-5¢), 62.93, 62.68 (T-C-5¢), 62.23, 61.82 (AZT-C-3¢), 58.82,
58.25 (CH) 52.91 (OCH3), 40.77, 40.65 (CH2), 39.83, 39.66 (T-C-
2¢), 38.03, 37.96 (AZT-C-2¢), 12.87, 12.60 (2 × C5-CH3).
31P NMR (CD3OD, 81 MHz): d = 75.66, 74.61.
ESI-MS: m/z = 715 [M + H]+, 737 [M + Na]+.
(2R,4S,5R)-1-{2,5-Dihydro-5-[(3¢-O-thymidinyl)(methoxy-L-
glycinyl)phosphoryl]methyl-2-furyl}thymine (Diastereoisomer-
ic Mixture) (5¢a)
Yield: 71.8%; Rf 0.4 (CH2Cl2–MeOH, 20:1).
1H NMR (CD3OD, 500 MHz): d = 7.82 (s, 1 H, T-H-6), 7.47, 7.41
(s, 1 H, d4T-H-6), 6.93 (s, 1 H, d4T-H-1¢), 6.43–6.41 (m, 1 H, d4T-
H-2¢), 6.30–6.26 (m, 1 H, T-H-1¢), 5.98, 5.97 (d, 1 H, d4T-H-3¢),
5.19–5.16 (m, 1 H, T-H-3¢), 5.03 (s, 1 H, d4T-H-4¢), 4.28–4.19 (m,
3 H, 2 × d4T-H-5¢, T-H-4¢), 3.80–3.73 (m, 4 H, T-H-5¢, CH2), 3.70
(s, 3 H, OCH3), 2.52–2.28 (m, 2 H, T-H-2¢), 1.93–1.87 (m, 6 H,
2 × 5-CH3).
13C NMR (CD3OD, 125 MHz): d = 173.19 (COO), 166.47, 166.35
(2 × C-4), 152.80, 152.38, 152.34 (2 × C-2), 138.02, 137.92, 137.88
(2 × C-6), 134.77 (d4T-C-2¢), 128.05, 127.90 (d4T-C-3¢), 111.98,
111.92, 111.80 (2 × C-5), 91.30, 91.11 (d4T-C-1¢), 87.54, 87.29 (T-
C-4¢), 86.36–86.06 (T-C-1¢,d4T-C-4¢), 79.78, 79.12 (T-C-3¢),
68.48, 68.17 (d4T-C-5¢), 62.89, 62.75 (T-C-5¢), 52.61 (OCH3),
44.32, 43.90 (CH2), 39.87, 39.67 (T-C-2¢), 12.74, 12.68, 12.47 (5-
CH3).
31P NMR (CD3OD, 81 MHz): d = 75.79, 74.68.
ESI-MS: m/z = 701 [M + H]+, 723 [M + Na]+.
(2R,4S,5R)-1-{4-Azidotetrahydro-5-[(3¢-O-thymidinyl)(meth-
oxy-L-leucinyl)phosphoryl]methyl-2-furyl}thymine (Diastereo-
isomeric Mixture) (5e)
Yield: 61.5%; Rf 0.4 (CH2Cl2–MeOH, 30:1).
1H NMR (CD3OD, 500 MHz): d = 7.83, 7.82 (s, 1 H, T-H-6), 7.59,
7.54 (s, 1 H, AZT-H-6), 6.31–6.29 (m, 1 H, T-H-1¢), 6.17–6.13 (m,
1 H, AZT-H-1¢), 5.17–5.11 (m, 1 H, T-H-3¢), 4.48–4.43 (m, 1 H,
AZT-H-3¢), 4.32–4.08 (m, 5 H, 2 × H-4¢, 2 × AZT-H-5¢ , NHCH),
3.80–3.71 (m, 2 H, 2 × T-H-5¢), 3.71, 3.70 (s, 3 H, OCH3), 2.56–
2.26 (m, 4 H, 2 × H-2¢), 1.92, 1.86 (s, 6 H, 2 × C5-CH3), 1.79–1.72
[m, 1 H, CH(CH3)2], 1.57–1.53 (m, 2 H, CH2), 0.95–0.92 (m, 6 H,
2 × CH3).
13C NMR (CD3OD, 125 MHz): d = 176.03 (COO), 166.35, 166.32
(2 × C-4), 152.36, 152.17 (2 × C-2), 137.89, 137.78, 137.69 (2 × C-
6), 112.01–111.98, 111.81 (2 × C-5), 87.48–86.05 (T-C-4¢, 2 × C-
1¢), 83.79, 83.72 (AZT-C-4¢), 80.16, 80.13 (T-C-3¢), 67.24, 66.9
(AZT-C-5¢), 62.91, 62.75 (T-C-5¢), 62.16, 62.10 (AZT-C-3¢), 55.47,
55.09 (NHCH), 52.69, 52.66 (OCH3), 43.83, 43.70 (CH2), 39.78,
39.74 (T-C-2¢), 37.94, 37.84 (AZT-C-2¢), 25.72, 25.67 [CH(CH3)2],
23.20, 21.99(CH3), 12.70, 12.50 (2 × C5-CH3).
31P NMR (CD3OD, 81 MHz): d = 76.13, 75.28.
ESI-MS: m/z = 644 [M + H]+, 666 [M + Na]+.
(2R,4S,5R)-1-{2,5-Dihydro-5-[(3¢-O-thymidinyl)(methoxy-L-
alaninyl)phosphorylmethyl-2-furyl}thymine (Diastereoisomer-
ic Mixture) (5¢b)
Yield: 72.3%; Rf 0.4 (CH2Cl2–MeOH, 20:1).
1H NMR (CD3OD, 500 MHz): d = 7.84, 7.82 (s, 1 H, T-H-6), 7.47,
7.39 (s, 1 H, d4T-H-6), 6.92 (s, 1 H, d4T-H-1¢), 6.44–6.41 (s, 1 H,
d4T-H-2¢), 6.30–6.27 (m, 1 H, T-H-1¢), 6.00–5.97 (m, 1 H, d4T-H-
3¢), 5.18–5.15 (m, 1 H, T-H-3¢), 5.05–5.02 (s, 1 H, d4T-H-4¢), 4.30–
4.17 (m, 3 H, 2 × d4T-H-5¢, T-H-4¢), 4.07–3.95 (m, 1 H, NHCH),
3.80–3.77 (m, 2 H, T-H-5¢), 3.70 (s, 3 H, OCH3), 2.54–2.25 (m, 2
H, T-H-2¢), 1.92, 1.90 (s, 6 H, 2 × 5-CH3), 1.35–1.28 (m, 3 H, CH3).
31P NMR (CD3OD, 81 MHz): d = 75.08, 74.16.
ESI-MS: m/z = 715 [M + H]+, 737 [M + Na]+.
13C NMR (CD3OD, 125 MHz): d = 175.87, 175.71 (COO), 166.47,
166.35 (2 × C-4), 152.79, 152.39, 152.32 (2 × C-2), 137.91, 137.85
(2 × C-6), 134.77, 134.72 (d4T-C-2¢), 128.04, 127.93 (d4T-C-3¢),
112.04, 111.97, 111.79 (2 × C-5), 91.37, 91.28 (d4T-C-1¢), 87.48,
87.27 (T-C-4¢), 86.40-86.04 (T-C-1¢,d4T-C-4¢), 79.91, 79.15 (T-C-
3¢), 68.88, 68.54, 68.15 (d4T-C-5¢), 62.91, 62.73 (T-C-5¢), 52.79–
51.73 (NHCH, OCH3), 39.84, 39.69 (T-C-2¢), 20.36, 20.29, 20.21
(CH3), 12.78, 12.74, 12.47 (5-CH3).
(2R,4S,5R)-1-{4-Azidotetrahydro-5-[(3¢-O-thymidinyl)(meth-
oxy-L-isoleucinyl)phosphoryl]methyl-2-furyl}thymine (Dia-
stereoisomeric Mixture) (5f)
Yield: 62.3%; Rf 0.4 (CH2Cl2–MeOH, 30:1).
1H NMR (CD3OD, 500 MHz): d = 7.82 (s, 1 H, T-H-6), 7.58, 7.53
(s, 1 H, AZT-H-6), 6.31–6.29 (m, 1 H, T-H-1¢), 6.16–6.13 (m, 1 H,
AZT-H-1¢), 5.15–5.12 (m, 1 H, T-H-3¢), 4.48–4.40 (m, 1 H, AZT-
31P NMR (CD3OD, 81 MHz): d = 74.54, 73.36.
ESI-MS: m/z = 658 [M + H]+, 680 [M + Na]+.
Synthesis 2003, No. 13, 1989–1994 © Thieme Stuttgart · New York

PAPER
Dinucleotide Thiophosphoramidates as Anti-HIV New Prodrugs
1993
(2R,4S,5R)-1-{2,5-Dihydro-5-[(3¢-O-thymidinyl)(methoxy-L-
phenylalaninyl)phosphoryl]methyl-2-furyl}thymine (Dia-
stereoisomeric Mixture) (5¢c)
52.65, 52.62 (OCH3), 43.82 (CH2), 39.88, 39.75 (T-C-2¢), 25.65
[CH(CH3)2], 23.25, 22.03 (2 × CH3), 12.82, 12.77, 12.48 (5-CH3).
31P NMR (CD3OD, 81 MHz): d = 75.01, 74.12.
Yield: 76.2%; Rf 0.4 (CH2Cl2–MeOH, 15:1).
ESI-MS: m/z = 672 [M + H]+, 694 [M + Na]+.
1H NMR (CD3OD, 500 MHz): d = 7.80 (s, 1 H, T-H-6), 7.39–7.17
(m, 6 H, d4T-H-6, Ph), 6.91, 6.88 (s, 1 H, d4T-H-1¢), 6.31–6.28 (s,
1 H, d4T-H-2¢), 6.24–6.20 (m, 1 H, T-H-1¢), 5.96–5.93 (m, 1 H,
d4T-H-3¢), 5.05–5.00 (m, 2 H, T-H-3¢, d4T-H-4¢), 4.27–4.04 (m, 3
H, 2 × d4T-H-5¢, T-H-4¢), 4.00–3.83 (m, 1 H, NHCH), 3.77–3.75 (s,
2 H, T-H-5¢), 3.70–3.67 (m, 3 H, OCH3), 3.16–3.03 (m, 2 H, CH2),
2.42–2.30 (m, 2 H, T-H-2¢), 1.90, 1.86 (s, 6 H, 2 × 5-CH3).
13C NMR (CD3OD, 125 MHz): d = 174.98, 174.77 (COO), 166.45,
166.35 (2 × C-4), 152.75, 152.35, 152.29 (2 × C-2), 138.52,
137.81(2 × C-6), 134.66, 134.53 (d4T-C-2¢), 130.63–127.89 (m,
d4T-C-3¢, Ph), 111.99, 111.76(2 × C-5), 91.26, 91.19 (d4T-C-1¢),
87.43, 87.20 (T-C-4¢), 86.28–85.96 (T-C-1¢,d4T-C-4¢), 80.15, 78.96
(T-C-3¢), 68.13, 68.06 (d4T-C-5¢), 62.90, 62.65 (T-C-5¢), 58.73,
58.06 (NHCH), 53.17, 52.71 (OCH3), 40.82, 40.76 (CH), 39.79,
39.62 (T-C-2¢), 12.86, 12.77, 12.48 (5-CH3).
(2R,4S,5R)-1-{2,5-Dihydro-5-[(3¢-O-thymidinyl)(methoxy-L-
isoleucinyl)phosphoryl]methyl-2-furyl]thymine (Diastereoiso-
meric Mixture) (5¢f)
Yield: 74.2%; Rf 0.4 (CH2Cl2–MeOH, 15:1).
1H NMR (CD3OD, 500 MHz): d = 7.83 (s, 1 H, T-H-6), 7.46, 7.37
(s, 1 H, d4T-H-6), 6.92–6.91 (m, 1 H, d4T-H-1¢), 6.43, 6.41 (s, 1 H,
d4T-H-2¢), 6.30–6.26 (m, 1 H, T-H-1¢), 6.00–5.98 (m, 1 H, d4T-H-
3¢), 5.12–5.09 (m, 1 H, T-H-3¢), 5.04 (s, 1 H, d4T-H-4¢), 4.29–4.10
(m, 3 H, 2 × d4T-H-5¢, T-H-4¢), 3.91–3.88 (m, 1 H, NHCH), 3.79–
3.77 (m, 2 H, T-H-5¢), 3.74, 3.72 (s, 3 H, OCH3), 2.52–2.26 (m, 2
H, T-H-2¢), 1.92–1.87 (m, 6 H, 2 × 5-CH3), 1.77–1.73 [m, 1 H,
CH(CH3)CH2CH3], 1.51–1.14 (m, 2 H, CH2), 0.91–0.87 (m, 6 H,
2 × CH3).
13C NMR (CD3OD, 125 MHz): d = 175.02 (COO), 166.47, 166.35
(2 × C-4), 152.77, 152.37, 152.31 (2 × C-2), 137.92, 137.85 (2 × C-
6), 134.74, 134.63 (d4T-C-2¢), 128.20, 127.94 (d4T-C-3¢), 112.06,
111.98, 111.79 (2 × C-5), 91.43, 91.32 (d4T-C-1¢), 87.49, 87.25 (T-
C-4¢), 86.41–86.07 (T-C-1¢,d4T-C-4¢), 80.20, 79.29 (T-C-3¢),
68.92, 68.39 (d4T-C-5¢), 62.92, 62.76 (T-C-5¢), 61.45, 60.92
(NHCH), 52.44 (OCH3), 48.51 [CH(CH3)CH2CH3], 39.88, 39.83
(T-C-2¢), 26.28 (CH2), 16.03, 15.93 [CH(CH3)CH2CH3], 12.85,
12.77 (5-CH3), 11.73, 11.67 [CH(CH3)CH2CH3].
31P NMR (CD3OD, 81 MHz): d = 74.60, 73.04.
ESI-MS: m/z = 706 [M + H]+, 728 [M + Na]+.
(2R,4S,5R)-1-{2,5-Dihydro-5-[(3¢-O-thymidinyl)(methoxy-L-
valinyl)phosphoryl]methyl-2-furyl}thymine (Diastereoisomeric
Mixture) (5¢d)
Yield: 68.4%; Rf 0.4 (CH2Cl2–MeOH, 15:1).
1H NMR (CD3OD, 500MHz): d = 7.83 (s, 1 H, T-H-6), 7.46, 7.37
(s, 1 H, d4T-H-6), 6.93–6.91 (m, 1 H, d4T-H-1¢), 6.44–6.41 (s, 1 H,
d4T-H-2¢), 6.30–6.26 (m, 1 H, T-H-1¢), 6.00–5.97 (m, 1 H, d4T-H-
3¢), 5.12–5.10 (m, 1 H, T-H-3¢), 5.04–5.03 (m, 1 H, d4T-H-4¢),
4.29–4.11 (m, 3 H, 2 × d4T-H-5¢, T-H-4¢), 3.85–3.80 (m, 1 H,
NHCH), 3.80–3.77 (s, 2 H, T-H-5¢), 3.71, 3.68 (s, 3 H, OCH3),
2.53–2.26 (m, 2 H, T-H-2¢), 2.05–1.92 (m, 1 H, CH), 1.92, 1.88 (s,
6 H, 2 × 5-CH3), 0.92, 0.90 (s, 6 H, 2 × CH3).
13C NMR (CD3OD, 125 MHz): d = 175.03 (COO), 166.48, 166.35
(2 × C-4), 152.79, 152.37, 152.30 (2 × C-2), 137.91, 137.81 (2 × C-
6), 134.76, 134.65 (d4T-C-2¢), 128.15, 127.89 (d4T-C-3¢), 112.06,
111.98, 111.78 (2 × C-5), 91.44, 91.34 (d4T-C-1¢), 87.50, 87.31(T-
C-4¢), 86.40–86.05 (T-C-1¢,d4T-C-4¢), 80.16, 79.27 (T-C-3¢),
68.88, 68.38 (d4T-C-5¢), 62.91, 62.75 (T-C-5¢), 62.59, 62.04
(NHCH), 52.50, 52.46 (OCH3), 39.81, 39.71 (T-C-2¢), 33.07, 33.01
(CH), 19.63, 19.59, 18.66 (2 × CH3), 12.82, 12.75, 12.47 (5-CH3).
31P NMR (CD3OD, 81 MHz): d = 75.47, 74.50.
ESI-MS: m/z = 672 [M + H]+, 694 [M + Na]+.
Acknowledgments
The authors would like to thank the financial supports from the Na-
tional Natural Science Foundation of China (No. 29902003,
20132020 and 20175026), the Ministry of Science and Technology,
the Chinese Ministry of Education and Tsinghua University.
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