Synthesis and antiviral evaluation of carbocyclic 3′-azidothymidine (AZT) analogues and their cycloSal-phosphate triesters

Article abstract of DOI:10.1002/ejoc.200500719

Carbocyclic analogues of the anti-HIV dideoxynucleoside 3′-azido-3′-deoxythymidine AZT (1) were synthesized. Starting from the enantiomerically pure carbocyclic 2′-deoxythymidine 2, four different carbocyclic AZT analogues 2,4-6 were prepared. Moreover, t

Full text of DOI:10.1002/ejoc.200500719

FULL PAPER
DOI: 10.1002/ejoc.200500719
Synthesis and Antiviral Evaluation of Carbocyclic 3Ј-Azidothymidine (AZT)
Analogues and Their cycloSal-Phosphate Triesters
Olaf R. Ludek,[a] Jan Balzarini,[b] and Chris Meier*[a]
Keywords: Carbocyclic nucleosides / Prodrugs / cycloSal-pronucleotide / Antiviral agents
Carbocyclic analogues of the anti-HIV dideoxynucleoside 3Ј-
verted into their membrane-permeable cycloSal-phosphate
azido-3Ј-deoxythymidine AZT (1) were synthesized. Starting triesters. All compounds were tested in vitro for their anti-
from the enantiomerically pure carbocyclic 2Ј-deoxythymi-
dine 2, four different carbocyclic AZT analogues 2,4–6 were
HIV activity in human T-lymphocytes (CEM/0).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
prepared. Moreover, the nucleoside analogues were con- Germany, 2006)
replaced by a cyclopentane system are stable towards hy-
Introduction
drolysis by phosphorylases. Therefore they display an en-
Nucleoside analogues have attracted considerable inter-
est due to their wide range of biological activity.[1] Several
structural modifications were applied to both the heterocy-
clic base and the sugar moiety.[2] Due to this modified struc-
ture, these compounds are widely used as antiviral or anti-
tumor drugs in chemotherapy.[3] Since the discovery of AZT
1 as the first nucleoside drug for the treatment of AIDS,[4]
considerable efforts have been made to develop new nucleo-
side analogues that would be more active but less toxic in-
hibitors of the HIV reverse transcriptase (RT).[5] In order
to act as polymerase inhibitors or DNA chain termination
agents the nucleoside analogues need to be activated to
their 5Ј-triphosphates by a specific intracellular phosphory-
lation cascade.[6] However, due to the structural differences
compared to natural nucleosides, this metabolisation is
often inefficient and therefore only a reduced biological ac-
tivity is observed.[7]
hanced biostability.[12]
Here we report the synthesis of 3Ј-modified carbocyclic
nucleosides 3–7 that are structurally related to AZT 1 and
their antiviral activity against HIV (Figure 1).
Furthermore, nucleoside analogues 2,3,5–7 were trans-
ferred into their cycloSal phosphates 8–12 to bypass the first
intracellular phosphorylation step.
Results and Discussion
Recently we reported on a new convergent strategy for
the synthesis of carbocyclic nucleosides which allows the
preparation of the nucleoside analogues in gram quanti-
ties.[13] Thus, as starting material enantiomerically pure
carba-dT 2 was used for the synthesis of the carbocyclic
nucleoside analogues 3–7.
The intracellular fate of the majority of nucleoside ana-
logues has not been studied in detail. Often these com-
pounds are tested exclusively as nucleosides and if found
inactive, they are discarded. For many nucleoside analogues
the rate-limiting step of activation is the first phosphoryla-
tion to the corresponding 5Ј-monophosphate due to the
high substrate specificity of the nucleoside kinases.[8,9] Con-
sequently, the biological activity of nucleoside analogues
may be increased in these cases by applying a nucleotide
delivery system (pronucleotide), e.g. the cycloSal-ap-
proach.[10,11] Carbocyclic nucleosides like carbocyclic 2Ј-de-
oxythymidine 2 (carba-dT) in that the -ribose moiety is
For the synthesis of carba-AZT 3 the enantiomerically
pure starting material carba-dT 2 was selectively protected
at the 5Ј-position with the trityl group to give 13 in 92%
yield (Scheme 1). Then a cyclisation under Mitsunobu con-
dition[14] led to the 2,3Ј-anhydro derivative 14 (90%), which
is a useful intermediate for substitutions at the 3Ј-position.
Opening of the aza-enol-ether in 14 with sodium azide in
DMF gave the protected carba-AZT 15 in 87% yield which
was subsequently detritylated with trifluoroacetic acid[15] in
CH2Cl2/MeOH (7:3) leading to carba-AZT 3 in 66% overall
yield.[16]
Recently, Décout and co-workers have shown, that 2-(tri-
methylsilyl)ethanethiol is an interesting reagent for intro-
ducing sulfur into nucleosides by formation of stable 2-(tri-
methylsilyl)ethyl sulfides.[17] These alkyl sulfides undergo
cleavage with cyanogen bromide in a modified von Braun
reaction[18] to selectively form thiocyanates.[17] The thio-
ether 16 was formed by treatment of the anhydro derivative
[a] Institut für Organische Chemie, Universität Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax: +49-40-42838-2495
E-mail: chris.meier@chemie.uni-hamburg.de
[b] Rega Institute for Medical Research, Katholieke Universiteit
Leuven,
3000 Leuven, Belgium
932
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 932–940

Carbocyclic 3Ј-Azidothymidine Analogues
FULL PAPER
Figure 1. Carbocyclic nucleoside analogues and their corresponding cycloSal-phosphates.
Scheme 1. (a) TrtCl, pyridine, 90 °C, 3 h (b) P(Ph)3, DIAD, MeCN, 0 °C, 12 h (c) NaN3, DMF, 140 °C, 12 h, (d) TFA, CH2Cl2/MeOH,
room temp., 10 h, (e) 2-(trimethylsilyl)ethanethiol, NaH, DMF, 90 °C, 2 h (f) HCOOH, Et2O, room temp. 12 h (g) BrCN, MeOH, room
temp. 18 h.
14 with sodium 2-(trimethylsilyl)ethanethiolate, which was position has been achieved by using an organotin-mediated
prepared in situ by reaction of the corresponding thiol with diastereoselective free-radical coupling reaction.[21]
sodium hydride in DMF (Scheme 1). After heating the mix-
The synthesis of the carbocyclic nucleosides 5 and 6
ture for 2 h at 90 °C, the mixed sulfide 16 was isolated in started with the activation of the 3Ј-hydroxy group in the
80% yield. After detritylation with formic acid in diethyl protected carba-dT derivative 13 by reaction with phenoxy-
ether[19] (59%), the sulfide 17 was subjected to cyanogen thiocarbonyl chloride (PTC-Cl).[22] The resulting thiocar-
bromide cleavage in methanol at room temperature. Selec- bonate 18 was isolated in 95% yield (Scheme 2). For the
tively one nucleoside was formed, which was characterized coupling reaction, the thiocarbonate 18 and azobis(isobu-
as the thiocyanate 4 (74% yield).
tyronitrile) (AIBN) was heated with excess allyltributylstan-
The reaction sequence for the synthesis of the carbocyclic nane in oxygen-free toluene. After heating for 24 h at 80 °C
3Ј-allyl and 3Ј-propargyl derivatives 5 and 6 was based a considerable amount of starting material 18 was still ob-
upon the published work on the natural 2Ј-deoxyribose sys- served by TLC analysis. Therefore, a second portion of
tem by Chu and co-workers[20a] as well as Fiandor and AIBN was added and the mixture was stirred for further
Tam.[20b] The formation of the new C–C bond at the 3Ј- 24 h. After work-up, carba-3Ј-allyl-5Ј-trityl-dT 19 was iso-
Eur. J. Org. Chem. 2006, 932–940
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
933

O. R. Ludek, J. Balzarini, C. Meier
FULL PAPER
Scheme 2. (a) PTC-Cl, pyridine, CH2Cl2, room temp. 12 h (b) nBu3Sn-allyl, AIBN, toluene, 80 °C, 48 h (c) TFA, CH2Cl2/MeOH, room
temp., 12 h, (d) Br2, CCl4, –10 °C, 1 h (e) TFA, CH2Cl2/MeOH, room temp., 12 h (f) KOH, EtOH/H2O, reflux, 20 h.
lated in 64% yield as one single diastereoisomer. Obviously,
The described synthetic approaches towards carbocyclic
the different preferred conformations of carbocyclic nucleo- analogues of AZT open the possibility to study the bioac-
sides and their natural counterparts did not effect the selec- tivity of these compounds as well as the corresponding nu-
tivity of the free-radical reaction. The stereochemistry at C- cleotides after conversion into the cycloSal-phosphate tri-
3Ј was confirmed by NOE experiments. As a by-product,
the protected carba-2Ј,3Ј-dideoxythymidine 20 was isolated
in 19% yield. Both carbocyclic nucleosides were detritylated
(TFA in CH2Cl2/MeOH) to give carba-3Ј-allyl-dT 5 and
carba-ddT 7[23] with 50% and 15% over all yield, respec-
tively.
The synthesis of carba-3Ј-propargyl-dT 6 started with the
[24]
reaction of the allyl compound 19 with bromine in CCl4
leading to a mixture of the two diastereomers of dibromide
21 (Scheme 2). Interestingly, the trityl protection group was
not stable under the reaction conditions and as a by-prod-
uct the detritylated dibromide 22 was isolated in 22% yield.
After deprotection of the tritylated compound 21 with TFA
in CH2Cl2/MeOH (87%), the combined brominated deriva-
tives 22 were heated under reflux with excess potassium hy-
droxide[20b,24] in H2O/EtOH for 20 h, leading to the target
Scheme 3. (a) 3-methyl-cyclosaligenylphosphorchloridate, pyri-
compound carba-3Ј-propargyl-dT 6 in 62% yield.
dine, –40 °C, 2 h.
934
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 932–940

Carbocyclic 3Ј-Azidothymidine Analogues
FULL PAPER
esters.[11] It has been shown before, that cycloSal-phosphate More interestingly, cycloSal-triester 10 derived from 3Ј-al-
triesters release the nucleotides and the masking group se- lyl-carba-dT 5 retained all antiviral activity observed in the
lectively by a controlled, chemically induced tandem reac- wild-type CEM cells in thymidine-kinase (TK) deficient
tion.[25] Often an improvement in the biological activity has CEM cells while nucleoside 5 was entirely inactive (EC50
Ͼ
been observed.[26] Finally, the phosphate triesters 8–12 were 250). Thus, the antiviral activity is clearly independent on
easily obtained by reaction of 3-methyl-cyclosaligenylphos- the presence of the enzyme and on the other hand this sug-
phorchloridate[27] with the appropriate carbocyclic nucleo- gests that thymidine-kinase is responsible for the activation
side analogue in dry pyridine at –40 °C in good yields of nucleoside analogue 5. Although the antiviral potency
(Scheme 3).
found is not spectacular, this clearly shows that thymidine-
kinase is also able to metabolise certain carbocyclic nucleo-
side analogues.
Biological Activity
Nucleosides 2–7 and triesters 8–12 were evaluated for
their antiviral potential against HIV replication (Table 1;
AZT and d4T are given for comparison). In agreement to
a report by Béres et al.,[16] carba-AZT 3 and carba-ddT 7
showed no protection against HIV-1 in the CEM/0 system
(183 µ and Ͼ250 µ, respectively). Nevertheless, by apply-
ing the cycloSal-pronucleotide concept, cycloSal-carba-
AZTMP 9 proved to be sixfold more active compared to
the nucleoside analogue 3 (30 µ). However and in contrast
to the reported data from Béres,[16] carba-dT 2 was found
to be equipotent (EC50 0.5 µ) as the approved thymidine
analogue 2Ј,3Ј-dideoxy-2Ј,3Ј-didehydrothymidine (d4T)
against HIV without increasing cytotoxicity. However, both
compounds were inactive in the thymidine-kinase deficient
cell line (CEM/TK–). Surprisingly, the attachment of the
cycloSal moiety (8) to carba-dT 2 did not improve the anti-
viral activity in these cells. This result points to a different
mechanism of activation for this nucleoside analogue. The
3Ј-thiocyanato derivative 4 proved to be inactive against
both HIV strains (Ͼ250 µ) and showed no cytotoxicity
(Ͼ250 µ). Except for carba-dT 2, aliphatic substitutions
in 5 and 6 led to weak anti-HIV activity (48.3 µ and Ͼ10
µ, respectively). Unfortunately, the 3Ј-propargyl com-
pound 6 was also the most cytotoxic with a CC50 value
of 17.4 µ for some unknown reasons. Again, the cycloSal
modification (10, Table 1) in the allyl-substituted com-
Conclusion
In summary, the synthesis of 3Ј-modified carbocyclic an-
alogues of AZT 1 was achieved. Moreover, the conversion
of the nucleoside analogues 2, 3 and 5–7 into their cycloSal-
phosphate triesters is reported. All new compounds were
tested in vitro for their biological activity in HIV-1- and
HIV-2-infected wild-type human T-lymphocyte (CEM/0)
cells. Most of the nucleoside analogues were entirely inac-
tive against HIV. However, the cycloSal derivatives showed
better antiviral potency particularly in the case of triester
10. Interestingly, the activity of triester 10 was entirely re-
tained in the TK-deficient cell line.
Experimental Section
General Remarks: All experiments involving water-sensitive com-
pounds were conducted under totally dry conditions (nitrogen at-
mosphere) using standard syringe, cannula and septa apparatus.
Solvents: benzene, Et2O and THF were distilled from sodium or
potassium benzophenone and stored over molecular sieves.
CH2Cl2, pyridine and CH3CN were distilled from CaH2 and stored
over molecular sieves. Ethyl acetate, CH2Cl2, and MeOH employed
in chromatography were distilled before used. Chromatography:
Chromatotron (Harrison Research 7924), silica gel 60Pf (Merck,
“gipshaltig” = containing CaSO4). UV detection at 254 nm. TLC:
pound 5 led to a fivefold improvement in antiviral activity. analytical thin-layer chromatography was performed on Merck pre-
Table 1. Antiviral evaluation of the inhibitory effect on HIV-1 and HIV-2-replication of carbocyclic nucleosides 2–6 and cycloSal-com-
pounds 8–11 in CEM/0 cells and in thymidine kinase-deficient CEM/TK– cells.
Compound (R)
EC50 [µM][a]
CEM/0
HIV-1
CC50 [µM][b]
CEM/TK–
HIV-2
HIV-2
2 (OH)
3 (N3)
4 (SCN)
5 (allyl)
6 (propargyl)
7 (H)
8 (OH)
9 (N3)
10 (allyl)
11 (propargyl)
12 (H)
0.5 0.14
183 115
Ͼ 250
48 20
Ͼ 10
Ͼ 250
0.65 0.07
30 20
11.7 7.6
Ͼ 10
Ͼ 50
0.4 0.0
107 125
Ͼ 250
75 66
Ͼ 10
Ͼ 250
0.7 0.14
32 25
16.7 12.6
Ͼ 10
Ͼ 50
Ͼ 250
Ͼ 250
Ͼ 250
Ͼ 250
Ͼ 10
Ͼ 250
Ͼ 250
Ͼ 50
10 0.0
Ͼ 10
Ͼ 50
25 2.5
Ͼ100
63 5.5
Ͼ 250
Ͼ 250
138 12
17 3.5
Ͼ 250
77 22
135 40
61 1.1
21 0.9
Ͼ 250
d4T
AZT, 1
0.37 0.24
0.006 0.002
0.35 0.09
0.005 0.003
Ն 250
Ͼ100
[a] 50% Effective concentration. [b] 50% Cytotoxic concentration.
Eur. J. Org. Chem. 2006, 932–940
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
935

O. R. Ludek, J. Balzarini, C. Meier
FULL PAPER
coated aluminium plates 60 F254 with a 0.2-mm layer of silica gel
containing a fluorescence indicator; sugar-containing compounds
were visualized with the sugar spray reagent (0.5 mL of 4-methoxy-
benzaldehyde, 9 mL of ethanol, 0.5 mL of concentrated sulfuric
acid, and 0.1 mL of glacial acectic acid) by heating with a fan.
NMR spectra were recorded using (1H NMR) Bruker AC 250 at
250 MHz, Bruker WM 400 at 400 MHz, Bruker AMX 400 at
4.39–4.35 (m, 1 H, H-1Ј), 3.18 (dd, 1 H, J = 9.3 Hz, 9.0 Hz, H-
5Јa), 2.98 (dd, 1 H, J = 9.3 Hz, 6.5 Hz, H-5Јb), 2.59–2.51 (m, 1 H,
H-4Ј), 2.26–2.21 (m, 1 H, H-2Јa), 2.16–2.06 (m, 2 H, H-2Јb, H-
6Јa), 1.74 (d, 3 H, J = 1.0 Hz, H-7), 1.50 (ddd, 1 H, J = 14.0 Hz,
4.9 Hz, 2.5 Hz, H-6Јb) ppm. 13C NMR (101 MHz, [D6]DMSO): δ
= 171.3 (C-4), 153.9 (C-2), 144.0 (Cq arom.), 137.9 (C-6), 128.6,
128.2, 127.3 (CH arom.), 116.8 (C-5), 86.5 (Cq Trt.), 80.7 (C-3Ј),
400 MHz or Bruker DMX 500 at 500 MHz; (13C NMR) Bruker 62.5 (C-5Ј), 60.5 (C-1Ј), 43.5 (C-4Ј), 35.5 (C-2Ј), 33.3 (C-6Ј), 13.5
WM 400 at 101 MHz, Bruker AMX 400 at 101 MHz or Bruker
DMX 500 at 123 MHz (calibration was done in both cases with
the solvent); (31P NMR) Bruker AMX 400 at 162 MHz or Bruker
(C-7) ppm. IR (KBr): ν = 3430, 3060, 2920, 1660, 1630, 1510, 1480,
˜
1450, 1310, 1270, 1210, 1140, 1070, 1030, 970, 870, 770, 700,
630 cm–1. HRMS-FAB: m/z calcd. for C30H28N2O3 [M + H]:
465.2178; found: 465.2157.
1
DMX 500 at 202 MHz (H3PO4 as external standard). All H and
13C NMR chemical shifts (δ) are quoted in parts per million (ppm)
downfield from tetramethylsilane, (CD3)(CD2H)SO being set at δH
2.49 as a reference. 31P NMR chemical shifts are quoted in ppm
using H3PO4 as external reference. The spectra were recorded at
room temperature, and all 13C and 31P NMR were recorded in
proton-decoupled mode. Mass spectra were obtained with a VG
Analytical VG/70–250 F spectrometer (FAB, matrix was m-ni-
trobenzyl alcohol). Analytical HPLC was performed on a Merck–
Hitachi system with LiChroCART 250-3 containing LiChrospher
100-3 RP-18 (5 µm). Standard gradient: 5–100% CH3CN in water
in 20 min, then 10 min. 5% CH3CN in water, flow: 0.5 mL/min.
Optical rotations were measured on a Perkin–Elmer Polarimeter
241 and a Jasco DIP-370 digital polarimeter at 589 nm. IR spectra
were recorded using a ThermoNicolet Avatar 370 FT-IR.
3Ј-Azido-6Ј-carba-2Ј,3Ј-dideoxy-5Ј-O-tritylthymidine (15): Com-
pound 14 (300 mg, 0.646 mmol) was dissolved in dry DMF
(3.0 mL) under a nitrogen atmosphere and sodium azide (420 mg,
6.46 mmol) was added. The mixture was stirred for 12 h at 140 °C.
After removal of the solvent the residue was treated with CH2Cl2
(50 mL) and the organic layer was washed with water (3×20 mL),
dried with Na2SO4 and concentrated. The crude was purified on
silica gel (hexanes/EtOAc, 2:1) to yield 15 (260 mg, 79%) as a
colourless foam. [α]2D0 = +2.3 (c = 0.58, CHCl3); Rf (TLC) = 0.43
1
(CH2Cl2/MeOH, 30:1). H NMR (400 MHz, C6D6): δ = 9.80–9.40
(br. m, 1 H, NH), 7.55–7.48 (m, 6 H, CH arom.), 7.20–7.12 (m, 6
H, CH arom.), 7.09–7.02 (m, 3 H, CH arom.), 6.02 (s, 1 H, H-6),
4.42–4.33 (m, 1 H, H-1Ј), 3.61 (dd, 1 H, J = 13.4 Hz, 6.7 Hz, H-
3Ј), 3.14 (dd, 1 H, J = 9.4 Hz, 5.3 Hz, H-5Јa), 3.07 (dd, 1 H, J =
9.4 Hz, 5.3 Hz, H-5Јb), 1.83–1.76 (m, 1 H, H-4Ј), 1.69 (s, 3 H, H-
7), 1.68–1.65 (m, 1 H, H-6Јa), 1.58–1.50 (m, 2 H, 2×H-2Ј), 1.33
(ddd, 1 H, J = 12.7 Hz, 10.3 Hz, 10.3 Hz, H-6Јb) ppm. 13C NMR
(101 MHz, C6D6): δ = 162.2 (C-4), 149.4 (C-2), 143.0 (Cq arom.),
135.6 (C-6), 127.6, 126.9, 126.8 (CH arom.), 109.2 (C-5), 85.8 (Cq
Trt.), 62.5 (C-5Ј), 60.9 (C-3Ј), 53.9 (C-1Ј), 43.9 (C-4Ј), 34.3 (C-2Ј),
6Ј-Carba-2Ј-deoxy-5Ј-O-tritylthymidine (13): To a stirred solution
of carba-dT 2 (1.10 g, 4.58 mmol) in dry pyridine (30 mL) was
slowly added triphenylmethyl chloride (1.81 g, 6.49 mmol) at room
temperature. The mixture was stirred for 3 h at 90 °C. After evapo-
ration of the solvent, the residue was partitioned between water
(100 mL) and CH2Cl2 (100 mL). The aqueous layer was extracted
again with CH2Cl2 (2×50 mL) and the combined organic phases
were dried with Na2SO4. The crude product was purified on silica
gel (CH2Cl2/MeOH, 20:1) to yield 13 (1.87 g, 85%) as a colourless
foam. [α]2D0 = –4.8 (c = 0.62, CH3CN); Rf (TLC) = 0.65 (CH2Cl2/
31.3 (C-6Ј), 12.8 (C-7) ppm. IR (KBr): ν = 3180, 3060, 2920, 2100
˜
(-N3), 1690, 1470, 1450, 1370, 1265, 1070, 1030, 898, 760, 700,
630 cm–1. HRMS-FAB: m/z calcd. for C30H29N5O3 [M + H]:
508.2349; found: 508.2361.
1
MeOH, 9:1). H NMR (400 MHz, [D6]DMSO): δ = 11.20 (br. s, 1
3Ј-Azido-6Ј-carba-2Ј,3Ј-dideoxythymidine (carba-AZT) (3): A solu-
tion of compound 15 (250 mg, 0.49 mmol) in CH2Cl2/MeOH (7:3
v/v, 10 mL) was treated slowly with TFA (100 µL) and stirred at
room temperature for 10 h, until complete conversion by TLC was
observed. The solvent was evaporated off and the residue was puri-
fied on a Chromatotron (CH2Cl2/MeOH gradient 0–10%) to yield
3 (105 mg, 81%) as a colourless foam. After lyophilization
(CH3CN/H2O, 1:1) compound 3 was obtained as a colourless cot-
ton. [α]2D0 = +10.0 (c = 0.61, CH3CN) ref.[16] [α]2D0 = +16.0 (c = 0.98,
acetone); Rf (TLC) = 0.39 (CH2Cl2/MeOH, 9:1). 1H NMR
(400 MHz, CDCl3): δ = 8.98 (br. s, 1 H, NH), 7.10 (q, 1 H, J =
1.2 Hz, H-6), 4.90–4.80 (m, 1 H, H-1Ј), 3.84 (dd, 1 H, J = 10.5 Hz,
4.5 Hz, H-5Јa), 3.75 (dd, 1 H, J = 10.5 Hz, 4.8 Hz, H-5Јb), 2.33–
2.22 (m, 2 H, H-2Јa, H-6Јa), 2.21–2.08 (m, 2 H, H-2Јb, H-4Ј), 1.93
(d, 3 H, J = 1.2 Hz, H-7), 1.88–1.80 (m, 1 H, H-6Јb) ppm. 13C
NMR (101 MHz, CDCl3): δ = 164.1 (C-4), 151.3 (C-2), 138.4 (C-
6), 111.7 (C-5), 63.5 (C-5Ј), 62.7 (C-3Ј), 56.7 (C-1Ј), 46.8 (C-4Ј),
H, NH), 7.46 (d, 1 H, J = 1.0 Hz, H-6), 7.40–7.25 (m, 15 H, CH
arom.), 4.98–4.90 (m, 1 H, H-1Ј), 4.81 (d, 1 H, J = 5.0 Hz, 3Ј-OH),
3.98–3.92 (m, 1 H, H-3Ј), 3.17 (dd, 1 H, J = 9.0 Hz, 5.6 Hz, H-
5Јa), 2.96 (dd, 1 H, J = 9.0 Hz, 7.4 Hz, H-5Јb), 2.21–2.16 (m, 1 H,
H-6Јa), 2.12–2.16 (m, 1 H, H-4Ј), 1.93 (ddd, 1 H, J = 13.4 Hz,
9.0 Hz, 7.4 Hz, H-2Јb), 1.73 (d, 3 H, J = 1.0 Hz, H-7), 1.44–1.36
(m, 1 H, H-6Јb) ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 164.1
(C-4), 151.3 (C-2), 144.3 (Cq arom.), 138.2 (C-6), 128.9, 128.3,
127.3 (CH arom.), 109.5 (C-5), 86.2 (Cq Trt.), 71.9 (C-3Ј), 65.5 (C-
5Ј), 53.4 (C-1Ј), 47.4 (C-4Ј), 39.2 (C-2Ј), 33.7 (C-6Ј), 12.4 (C-
7) ppm. IR (KBr): ν = 3435, 3955, 2925, 1685, 1475, 1450, 1275,
˜
1070, 750, 705, 630 cm–1. HRMS-FAB: m/z calcd. for C30H30N2O4
[M + H]: 483.2283; found: 483.2268.
2,3Ј-Anhydro-6Ј-carba-2Ј-deoxy-5Ј-O-tritylthymine (14): To
a
stirred suspension of triphenylphosphane (980 mg, 3.73 mmol) in
dry CH3CN (15 mL) was slowly added DIAD (730 µL, 3.73 mmol)
at 0 °C under a nitrogen atmosphere. The yellow solution was
stirred for 0.5 h at 0 °C and then added to a solution of the trityl-
ated nucleoside 13 (900 mg, 1.87 mmol) in dry CH3CN (10 mL) at
0 °C in a nitrogen atmosphere. The mixture was warmed to room
temperature and stirred overnight at that temperature. The solvent
was evaporated off and the crude was purified on silica gel
(CH2Cl2/MeOH, 9:1) to yield the title compound 14 (770 mg, 87%)
36.8 (C-2Ј), 32.0 (C-6Ј), 13.0 (C-7) ppm. IR (KBr): ν = 3430, 3040,
˜
2100 (-N3), 1690, 1470, 1370, 1270, 1130, 1050, 780, 570, 420 cm–1.
HRMS-FAB: m/z calcd. for C11H15N5O3 [M + H]: 266.1253;
found: 266.1275.
6Ј-Carba-2Ј,3Ј-dideoxy-3Ј-[2-(trimethylsilyl)ethyl]thio-5Ј-O-trityl-
thymidine (16): To a stirred suspension of sodium hydride (37.0 mg,
0.77 mmol, 50% in oil) in dry DMF (2.0 mL) was slowly added a
as a colourless foam. [α]2D0 = +26.6 (c = 0.21, CH3CN) Rf (TLC) =
1
0.31 (CH2Cl2/MeOH, 9:1). H NMR (400 MHz, [D6]DMSO): δ = solution of 2-(trimethylsilyl)ethanethiol (112 µL, 0.70 mmol) in dry
7.40–7.25 (m, 16 H, CH arom., H-6), 5.17–5.14 (m, 1 H, H-3Ј),
936
DMF (2.0 mL). The clear solution was stirred for 15 min under a
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 932–940

Carbocyclic 3Ј-Azidothymidine Analogues
FULL PAPER
nitrogen atmosphere, and then the 2,3Ј-anhydronucleoside 14
(300 mg, 0.65 mmol) was added in one portion. After being heated
at 90 °C for 2 h the DMF was evaporated off. The residue was
dissolved in CH2Cl2 (50 mL), washed with aqueous NaH2PO4
6.6 Hz, H-2Јa), 2.32 (ddd, 1 H, J = 14.5 Hz, 9.3 Hz, 7.3 Hz, H-
2Јb), 2.28–2.17 (m, 2 H, H-4Ј, H-6Јa), 2.07 (ddd, 1 H, J = 11.7 Hz,
9.3 Hz, 9.3 Hz, H-6Јb), 1.87 (d, 3 H, J = 1.2 Hz, H-7) ppm. 13C
NMR (101 MHz, CDCl3): δ = 164.2 (C-4), 151.1 (C-2), 139.0 (C-
(10%, 20 mL), water (2×20 mL), dried with Na2SO4 and concen- 6), 111.8 (C-5), 111.4 (S–CN), 61.8 (C-5Ј), 57.7 (C-1Ј), 47.8 (C-4Ј),
trated. The crude was purified by chromatography on silica gel
(hexanes/EtOAc, 1:2) to yield the title compound 16 (310 mg, 80%)
as a colourless foam. [α]2D0 = +13.4 (c = 0.59, CH3CN); Rf (TLC)
= 0.61 (hexanes/EtOAc, 1:2). 1H NMR (500 MHz, [D6]benzene): δ
= 9.19 (s, 1 H, NH), 7.59 (d, 6 H, J = 7.2 Hz, CH arom.), 7.22–
7.17 (m, 6 H, CH arom.), 7.10–7.06 (m, 3 H, CH arom.), 6.25 (q,
1 H, J = 1.0 Hz, H-6), 4.80–4.70 (m, 1 H, H-1Ј), 3.40 (dd, 1 H, J
= 9.1 Hz, 4.8 Hz, H-5Јa), 3.28 (dd, 1 H, J = 9.1 Hz, 6.3 Hz, H-
5Јb), 3.10 (ddd, 1 H, J = 7.8 Hz, 7.8 Hz, 5.9 Hz, H-3Ј), 2.54–2.50
(m, 1 H, S–CH2-), 2.09–2.03 (m, 1 H, H-4Ј), 2.02–1.97 (m, 1 H, H-
6Јa), 1.94–1.88 (m, 2 H, H-2Јa, H-2Јb), 1.73 (d, 3 H, J = 1.0 Hz,
H-7), 1.53 (ddd, 1 H, J = 12.8 Hz, 10.2 Hz, 10.2 Hz, H-6Јb), 0.90–
0.85 (m, 2 H, -CH2–Si), 0.00 [s, 9 H, Si(CH3)3] ppm. 13C NMR
(101 MHz, [D6]benzene): δ = 164.5 (C-4), 152.5 (C-2), 146.3 (Cq
arom.), 138.6 (C-6), 130.8, 129.9, 129.3 (CH arom.), 112.1 (C-5),
84.6 (Cq Trt.), 66.9 (C-5Ј), 57.8 (C-1Ј), 47.4 (C-4Ј), 45.8 (C-3Ј), 40.0
(C-2Ј), 36.2 (C-6Ј), 29.2 (S–CH2–), 19.2 (CH2–Si), 14.3 (C-7), 0.0
46.4 (C-3Ј), 38.8 (C-2Ј), 32.7 (C-6Ј), 12.9 (C-7) ppm. IR (KBr): ν
˜
= 3430, 3050, 2930, 2150, 1690, 1470, 1380, 1270, 1220, 1130, 1050,
780, 590 cm–1. HRMS-FAB: m/z calcd. for C12H15N3O3S [M + H]:
282.0912; found: 282.0890.
6Ј-Carba-2Ј-deoxy-3Ј-O-phenoxythiocarbonyl-5Ј-O-tritylthymidine
(18): Compound 13 (1.80 g, 3.73 mmol) was dissolved in CH2Cl2
(10 mL) at 0 °C under a nitrogen atmosphere, then pyridine
(1.5 mL) was added. This solution was treated slowly with phen-
oxythiocarbonyl chloride (PTC-Cl, 1.30 g, 1.00 mL, 7.40 mmol) at
0 °C, then the mixture was warmed to room temperature and
stirred at this temperature for 12 h. The solvents were evaporated
off and the residue was dissolved in EtOAc (50 mL). The organic
phase was washed with water (3×50 mL), dried with Na2SO4 and
concentrated. The crude material was purified by chromatography
on silica gel (hexanes/EtOAc, 1:2) to yield compound 18 (2.17 g,
95%) as a colourless foam. [α]2D0 = +2.5 (c = 0.57, CHCl3); Rf (TLC)
= 0.36 (hexanes/EtOAc, 1:2). 1H NMR (400 MHz, C6D6): δ = 9.42–
9.30 (br. s, 1 H, NH), 7.55–7.50 (m, 6 H, CH arom.), 7.18–7.10 (m,
6 H, CH arom.), 7.08–7.00 (m, 8 H, CH arom.), 6.19 (q, 1 H, J =
1.0 Hz, H-6), 5.68 (ddd, 1 H, J = 6.5 Hz, 4.3 Hz, 3.9 Hz, H-3Ј),
4.86–4.76 (m, 1 H, H-1Ј), 3.32 (dd, 1 H, J = 9.1 Hz, 5.3 Hz, H-
5Јa), 3.15 (dd, 1 H, J = 9.1 Hz, 5.8 Hz, H-5Јb), 2.37–2.29 (m, 1 H,
H-4Ј), 2.00–1.90 (m, 2 H, 2×H-2Ј), 1.78–1.70 (m, 1 H, H-6Ј), 1.66
(d, 3 H, J = 1.0 Hz, H-7), 1.29–1.25 (m, 1 H, H-6Јb) ppm. 13C
NMR (101 MHz, C6D6): δ = 195.3 (C=S), 164.2 (C-4), 157.3 (Cq
phenol) 151.2 (C-2), 144.7 (Cq arom.), 136.4 (C-6), 130.1, 129.4,
128.1, 127.89, 127.7, 122.6 (CH arom.), 109.4 (C-5), 86.1 (C-3Ј),
84.9 (Cq Trt.), 64.8 (C-5Ј), 55.1 (C-1Ј), 44.5 (C-4Ј), 36.7 (C-2Ј), 32.5
[Si(CH ) ] ppm. IR (neat): ν = 3175, 3060, 2950, 1685, 1470, 1450,
˜
3 3
1270, 1070, 860, 740, 700 cm–1. HRMS-FAB: m/z calcd. for
C35H42N2O3SSi [M + H]: 599.2764; found: 599.2758.
6Ј-Carba-2Ј,3Ј-dideoxy-3Ј-[2-(trimethylsilyl)ethyl]thiothymidine
(17): A solution of compound 16 (200 mg, 0.33 mmol) in Et2O
(2 mL) was treated with formic acid (1.0 mL) and stirred at room
temperature for 12 h, until complete conversion by TLC was ob-
served. The solvent was evaporated off and the residue was purified
on a Chromatotron (CH2Cl2/MeOH gradient 0–10%) to yield 17
(68.9 mg, 59%) as a colourless foam. [α]2D0 = +41 (c = 0.18,
CH3CN); Rf (TLC) = 0.17 (hexanes/EtOAc, 1:2). 1H NMR
(500 MHz, CDCl3): δ = 8.18 (br. s, 1 H, NH), 7.09 (q, 1 H, J = (C-6Ј), 12.9 (C-7) ppm. IR (KBr): ν = 3435, 3060, 2930, 1690, 1490,
˜
1.2 Hz, H-6), 5.00–4.91 (m, 1 H, H-1Ј), 3.80 (dd, 1 H, J = 10.0 Hz,
4.2 Hz, H-5Јa), 3.75 (dd, 1 H, J = 10.0 Hz, 5.0 Hz, H-5Јb), 3.20
(ddd, 1 H, J = 8.1 Hz, 8.1 Hz, 5.8 Hz, H-3Ј), 2.59–2.55 (m, 2 H,
S–CH2), 2.29–2.21 (m, 2 H, H-2Јa, H-6Јa), 2.10–2.14 (m, 1 H, H-
2Јb), 2.10–2.02 (m, 1 H, H-4Ј), 1.91 (d, 3 H, J = 1.2 Hz, H-7), 1.75
(ddd, 1 H, J = 12.6 Hz, 10.0 Hz, 10.0 Hz, H-6Јb), 0.89–0.78 (m, 2
H, CH2–Si), 0.00 [s, 9 H, Si(CH3)3] ppm. 13C NMR (101 MHz,
CDCl3): δ = 164.3 (C-4), 152.0 (C-2), 139.3 (C-6), 65.9 (C-5Ј), 57.7
(C-1Ј), 48.2 (C-4Ј), 45.6 (C-3Ј), 40.6 (C-2Ј), 34.9 (C-6Ј), 29.2 (S–
1450, 1370, 1280, 1200, 1070, 1000, 900, 770, 705, 630 cm–1
.
HRMS-FAB: m/z calcd. for C37H34N2O5S [M + H]: 619.2267;
found: 619.2299.
3Ј-Allyl-6Ј-carba-2Ј,3Ј-dideoxy-5Ј-O-tritylthymidine (19): A mixture
of 18 (2.10 g, 3.39 mmol) allyltributyltin (5.60 g, 17.0 mmol) and
AIBN (180 mg, 1.10 mmol) in dry and degassed toluene (15 mL)
was heated to 80 °C for 24 h. A second portion of AIBN was added
(180 mg, 1.10 mmol) and the mixture was stirred at 80 °C for fur-
ther 24 h. The solvent was evaporated in vacuo, and the residue
was purified on silica gel (hexanes/EtOAc, 2:3) to yield compound
19 (1.10 g, 64%) as the major fraction as a colourless foam. [α]2D0
= +2.2 (c = 0.97, CH3CN); Rf (TLC) = 0.45 (hexanes/EtOAc, 1:2).
CH ), 19.1 (CH –Si), 14.3 (C-7), 0.0 [Si(CH ) ] ppm. IR (neat): ν
˜
2
2
3 3
= 3440, 1650, 1470, 1420, 1250, 1050, 590 cm–1. HRMS-FAB:
m/z calcd. for C16H28N2O3SSi [M + H]: 357.1668; found: 357.1667.
6Ј-Carba-2Ј,3Ј-dideoxy-3Ј-thiocyanatothymidine (4): To a solution 1H NMR (400 MHz, C6D6): δ = 9.90 (br. s, 1 H, NH), 7.65–7.60
of compound 17 (60.0 mg, 0.17 mmol) in methanol (1.5 mL) was (m, 6 H, CH arom.), 7.25–7.15 (m, 9 H, CH arom.), 6.45 (q, 1 H,
added BrCN (178 mg, 1.70 mmol) in one portion. After being
stirred for 18 h at room temperature, the mixture was treated with
aqueous phosphate buffer (0.5 , pH 7.0, 4 mL) and stirred for
further 30 min at room temperature, then water (10 mL) was added.
The aqueous phase was extracted with CH2Cl2 (3×15 mL). The
combined organic fractions were dried with Na2SO4, concentrated
and the crude material was purified by chromatography on a chro-
matotron (CH2Cl2/MeOH gradient 0–10 %) to yield 4 (36.2 mg,
75%) as a colourless foam. After lyophilization (CH3CN/H2O, 1:1)
compound 4 was obtained as a colourless cotton. [α]2D0 = +25.0 (c
= 0.52, CH3CN); Rf (TLC) = 0.43 (CH2Cl2/MeOH, 9:1). 1H NMR
J = 1.0 Hz, H-6), 5.69–5.59 (m, 1 H, CH=CH2), 5.05–5.00 (m, 2
H, CH=CH2), 4.99–4.90 (m, 1 H, H-1Ј), 3.28 (dd, 1 H, J = 9.0 Hz,
5.0 Hz, H-5Јa), 3.08 (dd, 1 H, J = 9.0 Hz, 6.6 Hz, H-5Јb), 2.14–
2.02 (m, 2 H, CH2–CH=), 1.82 (d, 3 H, J = 1.0 Hz, H-7), 1.78–
1.70 (m, 2 H, H-4Ј, H-6Јa), 1.69–1.62 (m, 2 H, H-3Ј, H-2Јa), 1.45–
1.32 (m, 2 H, H-2Јb, H-6Јb) ppm. 13CNMR (101 MHz, C6D6): δ
= 164.3 (C-4), 151.9 (C-2), 145.0 (Cq arom.), 137.3 (C-6), 136.2
(CH=CH2), 128.0, 127.6, 127.5 (CH arom.), 116.5 (CH=CH2),
111.0 (C-5), 84.8 (Cq Trt.), 66.1 (C-5Ј), 54.4 (C-1Ј), 44.4 (C-4Ј),
39.9 (CH2–CH=), 39.7 (C-3Ј), 36.5 (C-2Ј), 36.1 (C-6Ј), 13.0 (C-
7) ppm. IR (KBr): ν = 3430, 3180, 3060, 2920, 1685, 1490, 1470,
˜
(400 MHz, CDCl3): δ = 8.90 (br. s, 1 H, NH), 7.03 (q, 1 H, J = 1450, 1270, 1070, 760, 750, 700, 630 cm–1. HRMS-FAB: m/z calcd.
1.2 Hz, H-6), 4.78–4.69 (m, 1 H, H-1Ј), 3.86 (dd, 1 H, J = 11.0 Hz,
4.0 Hz, H-5Јa), 3.81 (d, 1 H, J = 7.5 Hz, H-3Ј), 3.76 (dd, 1 H, J =
11.0 Hz, 3.6 Hz, H-5Јb), 2.52 (ddd, 1 H, J = 14.5 Hz, 8.1 Hz,
for C33H34N2O3 [M + H]: 507.2648; found: 507.2650. As a side
product, the deoxygenated compound 20 (294 mg, 19%) was iso-
lated as a colourless foam. [α]2D0 = –130.1 (c = 0.95, CHCl3); Rf
Eur. J. Org. Chem. 2006, 932–940
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
937

O. R. Ludek, J. Balzarini, C. Meier
FULL PAPER
(TLC) = 0.36 (hexanes/EtOAc, 1:2). H NMR (400 MHz, C6D6): δ
1
compound 21 (310 mg, 59%) as a mixture of two inseparable iso-
= 9.95–9.85 (m, 1 H, NH), 7.55–7.50 (m, 6 H, CH arom.), 7.20– mers as a colourless foam. Rf (TLC) = 0.43 (hexanes/EtOAc, 1:2).
7.10 (m, 6 H, CH arom.), 7.06–7.00 (m, 3 H, CH arom.), 6.26 (q,
1H NMR (500 MHz, CDCl3): δ = 8.25 (br. s, 2 H, 2×NH), 7.45–
1 H, J = 1.0 Hz, H-6), 4.80–4.70 (m, 1 H, H-1Ј), 3.03 (dd, 1 H, J 7.40 (m, 12 H, CH arom.), 7.35–7.28 (m, 12 H, CH arom.), 7.25–
= 8.8 Hz, 6.0 Hz, H-5Јa), 2.97 (dd, 1 H, J = 8.8 Hz, 6.6 Hz, H- 20 (m, 6 H, CH arom.), 7.06 (q, 1 H, J = 1.2 Hz, H-6), 7.01 (q, 1
5Јb), 1.94–1.80 (m, 2 H, H-4Ј, H-6Јa), 1.68 (d, 3 H, J = 1.0 Hz, H-
H, J = 1.2 Hz, H-6), 5.06–4.94 (m, 2 H, 2×H-1Ј), 4.05 (dddd, 1 H,
7), 1.60–1.52 (m, 1 H, H-2Јa), 1.44–1.35 (m, 1 H, H-3Јa), 1.33–1.20 J = 10.7 Hz, 9.9 Hz, 4.0 Hz, 3.0 Hz, CHBr), 4.98 (dddd, 1 H, J =
(m, 2 H, H-2Јb, H-3Јb), 1.00–0.90 (m, 1 H, H-6Јb) ppm. 13C NMR 9.5 Hz, 9.5 Hz, 4.0 Hz, 3.3 Hz, CHBr), 3.85 (dd, 1 H, J = 10.2 Hz,
(101 MHz, C6D6): δ = 164.3 (C-4), 152.0 (C-2), 145.0 (Cq arom.),
136.1 (C-6), 128.1, 127.9, 127.6 (CH arom.), 111.0 (C-5), 84.5 (Cq
Trt.), 67.6 (C-5Ј), 56.0 (C-1Ј), 38.3 (C-4Ј), 35.4 (C-2Ј), 29.9 (C-6Ј),
4.0 Hz, CHHBr), 3.75 (dd, 1 H, J = 10.2 Hz, 4.0 Hz, CHHBr), 3.54
(dd, 1 H, J = 12.8 Hz, 9.6 Hz, CHHBr), 3.52 (d, 1 H, J = 12.8 Hz,
9.6 Hz, CHHBr), 3.23 (dd, 1 H, J = 9.6 Hz, 5.0 Hz, H-5Јa), 3.21–
3.16 (m, 3 H, H-5Јb, 5Ј-CH2), 2.50–2.40 (m, 1 H, H-3Ј), 2.37–2.28
(m, 5 H, H-3Ј, 2 × CH2–CHBr–), 2.05–1.95 (m, 4 H, 2 × H-2Јa,
2×H-6Јa), 1.91 (d, 3 H, J = 1.2 Hz, H-7), 1.88 (d, 3 H, J = 1.2 Hz,
H-7), 1.87–1.84 (m, 2 H, 2×H-4Ј), 1.80–1.70 (m, 2 H, 2×H-2Јb),
1.65–1.58 (m, 2 H, 2×H-6Јb) ppm. 13C NMR (101 MHz, CDCl3):
δ = 164.7 (C-6), 151.2 (C-2), 144.3 (Cq arom.), 144.3 (Cq arom.),
136.8 (C-6), 136.7 (C-6), 129.1, 129.1, 128.3, 128.3, 127.6, 127.5
(CH arom.), 84.3 (Cq Trt.), 65.9 (C-5Ј), 64.5 (C-5Ј), 54.7 (C-1Ј),
54.3 (C-1Ј), 52.3 (CHBr), 51.7 (CHBr), 45.2 (C-4Ј), 44.9 (C-4Ј),
43.1 (CH2–CHBr), 38.4 (C-3Ј), 38.0 (CH2Br), 37.0 (CH2Br), 37.0
(C-2Ј) 36.3 (C-2Ј), 36.2 (C-6Ј), 36.1 (C-6Ј), 13.1 (C-7), 13.1 (C-
7) ppm.
27.4 (C-3Ј), 13.0 (C-7) ppm. IR (KBr): ν = 3440, 3060, 2950, 2920,
˜
1685, 1470, 1450, 138, 1270, 1070, 760, 700 cm–1. HRMS-FAB:
m/z calcd. for C30H30N2O3 [M + H]: 467.2335; found: 467.2333.
3Ј-Allyl-6Ј-carba-2Ј,3Ј-dideoxythymidine (carba-3Ј-allyl-dT) (5): A
solution of compound 19 (180 mg, 0.35 mmol) in CH2Cl2/MeOH
(7:3 v/v, 10 mL) was treated slowly with TFA (100 µL) and stirred
at room temperature for 12 h, until complete conversion by TLC
was observed. The solvent was evaporated off and the residue was
purified on a Chromatotron (CH2Cl2/MeOH gradient 0–10%) to
yield 5 (65.0 mg, 69%) as a colourless foam. After lyophilization
(CH3CN/H2O, 1:1) compound 5 was obtained as a colourless cot-
ton. [α]2D0 = +14.4 (c = 0.42, CH3CN); Rf (TLC) = 0.41 (CH2Cl2/
MeOH, 9:1). 1H NMR (400 MHz, CDCl3): δ = 8.85 (br. s, 1 H,
NH), 7.15 (q, 1 H, J = 1.0 Hz, H-6), 5.81–5.70 (m, 1 H, CH=CH2),
5.09–5.00 (m, 2 H, CH=CH2), 4.95–4.88 (m, 1 H, H-1Ј), 3.78–3.63
(m, 2 H, 5Ј-CH2), 2.33–2.20 (m, 2 H, CH2–CH, H-6Јa), 2.09–1.99
(m, 2 H, H-3Ј, H-2Јa), 1.92 (d, 3 H, J = 1.0 Hz, H-7), 1.88–1.80
(m, 2 H, H-4Ј, H-2Јb), 1.70–1.60 (m, 1 H, H-6Јb) ppm; –13C NMR
(101 MHz, CDCl3): δ = 164.0 (C-4), 152.3 (C-2), 137.5 (C-6), 136.9
(CH=CH2), 117.0 (CH=CH2), 111.1 (C-5), 64.9 (C-5Ј), 55.1 (C-1Ј),
46.0 (C-4Ј), 39.7 (C-2Ј), 39.1 (C-3Ј), 36.7 (CH2–CH=), 35.2 (C-6Ј),
6Ј-Carba-3Ј-(2,3-dibrompropyl)-2Ј,3Ј-dideoxythymidine (22): A solu-
tion of compound 21 (300 mg, 0.450 mmol) in CH2Cl2/MeOH (7:3
v/v, 10 mL) was treated slowly with TFA (200 µL) and stirred at
room temperature for 12 h, until complete conversion by TLC was
observed. The solvent was evaporated off and the residue was puri-
fied on a Chromatotron (CH2Cl2/MeOH gradient 0–15%) to yield
22 (170 mg, 89%) as an inseparable mixture of two isomers as a
1
colourless foam. Rf (TLC) = 0.33 (CH2Cl2/MeOH, 9:1). H NMR
(400 MHz, CDCl3): δ = 9.45 (br. s, 2 H, 2×NH), 7.17–7.14 (m, 2
H, 2×H-6), 5.05–4.88 (m, 2 H, 2×H-1Ј), 4.23 (dddd, 1 H, J =
9.3 Hz, 9.3 Hz, 4.0 Hz, 4.0 Hz, CHBr), 4.06 (dddd, 1 H, J =
10.5 Hz, 9.7 Hz, 4.1 Hz, 2.8 Hz, CHBr), 3.86 (dd, 1 H, J = 10.3 Hz,
4.1 Hz, CHHBr), 3.85 (dd, 1 H, J = 10.4 Hz, 4.3 Hz, CHHBr),
3.77–3.67 (m, 4 H, 2×5Ј-CH2), 3.61 (dd, 1 H, J = 10.3 Hz, 3.2 Hz,
CHHBr), 3.59 (dd, 1 H, J = 10.3 Hz, 4.0 Hz, CHHBr), 2.40–2.30
(m, 3 H, CH2–CHBr, H-3Ј), 2.28–2.15 (m, 4 H, H-3Ј, CH2–CHBr,
H-2Јa), 2.12–2.00 (m, 3 H, H-2Јa, 2×H-6Јa), 1.91 (d, 3 H, J =
1.0 Hz, H-7), 1.90 (d, 3 H, J = 1.0 Hz, H-7), 1.88–1.75 (m, 4 H,
2×H-4Ј, 2×H-2Јb), 1.73–1.60 (m, 2 H, 2×H6Јb) ppm. 13C NMR
(101 MHz, CDCl3): δ = 164.3 (C-4), 164.3 (C-4), 151.6 (C-2), 137.5
(C-6), 137.3 (C-6), 111.7 (C-5), 111.5 (C-5), 64.0 (C-5Ј), 62.1 (C-
5Ј), 55.4 (C-1Ј), 54.9 (C-1Ј), 52.3 (CHBr), 51.9 (CHBr), 46.7 (C-
4Ј), 46.2 (C-4Ј), 43.1 (CH2–CHBr), 42.0 (CH2–CHBr), 38.4 (C-3Ј),
38.0 (CH2Br), 37.6 (C-3Ј), 37.0 (CH2Br), 36.3 (C-2Ј), 35.3 (C-2Ј),
34.8 (C-6Ј), 33.6 (C-6Ј), 13.1 (C-7), 13.0 (C-7) ppm.
13.0 (C-7) ppm. IR (KBr): ν = 3430, 3060, 2920, 1680, 1470, 1695,
˜
1270, 1220, 1045, 910, 590, 490 cm–1. HRMS-FAB: m/z calcd. for
C14H20N2O3 [M + H]: 265.1552; found: 265.1548.
6Ј-Carba-2Ј,3Ј-dideoxythymidine (carba-ddT) (7): A solution of
compound 20 (300 mg, 0.643 mmol) in CH2Cl2/MeOH (7:3 v/v,
10 mL) was treated slowly with TFA (200 µL) and stirred at room
temperature for 10 h, until complete conversion by TLC was ob-
served. The solvent was evaporated off and the residue was purified
on a Chromatotron (CH2Cl2/MeOH gradient 0–10%) to yield 7
(132 mg, 92%) as a colourless foam. After lyophilization (CH3CN/
H2O, 1:1) compound 7 was obtained as a colourless cotton. [α]2D0
= –9.5 (c = 0.72, CH3CN) ref.[23] 13 (c = 1.0, EtOH); Rf (TLC) =
1
0.29 (CH2Cl2/MeOH, 9:1). H NMR (400 MHz, CDCl3): δ = 8.75
(br. s, 1 H, NH), 7.11 (q, 1 H, J = 1.0 Hz, H-6), 4.95–4.85 (m, 1
H, H-1Ј), 3.67 (d, 2 H, J = 5.0 Hz, 5Ј-CH2), 2.31–2.16 (m, 2 H, H-
4Ј, H-6Јa), 2.14–2.05 (m, 1 H, H-2Јa), 1.93 (d, 3 H, J = 1.0 Hz, H-
7), 1.89–1.81 (m, 1 H, H-3Јa), 1.77–1.61 (m, 2 H, H-2Јb, H-3Јb),
1.55–1.45 (m, 1 H, H-6Јb) ppm. 13C NMR (101 MHz, CDCl3): δ
= 164.3 (C-4), 152.2 (C-2), 137.3 (C-6), 111.4 (C-5), 66.6 (C-5Ј),
56.8 (C-1Ј), 39.9 (C-4Ј), 34.5 (C-2Ј), 30.6 (C-2Ј), 26.9 (C-3Ј), 13.0
6Ј-Carba-2Ј,3Ј-dideoxy-3Ј-propargylthymidine (carba-3Ј-propargyl-
dT) (6): Compound 22 (165 mg, 0.39 mmol) was dissolved in etha-
nol (5.0 mL) and treated with aqueous KOH solution (435 mg,
7.75 mmol, in 10 mL). The mixture was refluxed for 20 h, cooled
to room temperature and concentrated in vacuo to half of the vol-
ume. After neutralization with aqueous HCl (2 ) a colourless pre-
cipitate was formed. The aqueous phase was extracted with CH2Cl2
(3×10 mL) and the combined organic fractions were dried with
(C-7) ppm. IR (KBr): ν = 3470, 3160, 3030, 2950, 1680, 1470, 1420,
˜
1400, 1375, 1270, 1125, 1055, 1015, 590, 425 cm–1. HRMS-FAB:
m/z calcd. for C11H16N2O3 [M + H]: 225.1239; found: 225.1239.
6Ј-Carba-3Ј-(2,3-dibrompropyl)-2Ј,3Ј-dideoxy-5Ј-O-tritylthymidine Na2SO4 and concentrated. The crude material was purified by
(21): A solution of compound 19 (400 mg, 0.790 mmol) in CCl4 chromatography on a chromatotron (CH2Cl2/MeOH gradient 0–
(5.0 mL) was treated with bromine (126 mg, 0.788 mmol, dissolved 10%) to yield compound 6 (63.0 mg, 62%) as a colourless foam.
in 1.0 mL CCl4) at –10 °C over a period of 45 min. The solution
was stirred for further 30 min at that temperature, then the solvent
was evaporated in vacuo. The residue was purified by chromatog-
raphy on a chromatotron (CH2Cl2/MeOH gradient 0–10%) to yield
After lyophyllization (CH3CN/H2O, 1:1) the nucleoside 6 was ob-
tained as a colourless cotton. [α]2D0 = +4.7 (c = 0.45, CH3CN); Rf
1
(TLC) = 0.27 (CH2Cl2/MeOH, 9:1). H NMR (400 MHz, CDCl3):
δ = 8.35 (br. s, 1 H, NH), 7.12 (q, 1 H, J = 1.2 Hz, H-6), 5.03–4.94
938
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 932–940

Carbocyclic 3Ј-Azidothymidine Analogues
FULL PAPER
(m, 1 H, H-1Ј), 3.76 (d, 1 H, J = 5.0 Hz, H-5Јa), 3.74 (d, 1 H, J =
5.0 Hz, H-5Јb), 2.37 (ddd, 1 H, J = 16.6 Hz, 6.0 Hz, 2.5 Hz, CHH–
C), 2.30 (ddd, 1 H, J = 16.6 Hz, 6.0 Hz, 2.5 Hz, CHH–C), 2.26–
6.94–6.90 (m, 2 H, 2 × H-5 arom.), 5.77–5.62 (m, 2 H,
2×CH=CH2), 5.42–5.25 (m, 4 H, 2×CH2 benzyl), 5.07–4.99 (m, 4
H, 2×CH=CH2), 4.96–4.87 (m, 2 H, 2×H-1Ј), 4.31–4.21 (m, 2 H,
2.20 (m, 2 H, H-3Ј, H-6Јa), 2.10–2.00 (m, 2 H, H-4Ј, H-2Јa), 1.99 2×H-5Јa), 4.20–4.11 (m, 2 H, 2×H-5Јb), 2.28 (s, 3 H, 3-CH3), 2.27
(dd, 1 H, J = 2.5 Hz, 2.5 Hz, CH alkyne), 1.98–1.93 (m, 1 H, H-
2Јb), 1.93 (d, 3 H, J = 1.2 Hz, H-7), 1.73–1.63 (m, 1 H, H-6Јb)
ppm. 13C NMR (101 MHz, CDCl3): δ = 164.3 (C-4), 151.3 (C-2),
137.3 (C-6), 111.4 (C-5), 82.7 (Cq alkyne), 70.2 (CH alkyne), 64.5
(C-5Ј), 55.1 (C-1Ј), 45.4 (C-4Ј), 38.7 (C-3Ј), 36.7 (C-2Ј), 35.2 (C-
(s, 3 H, 3-CH3), 2.26–2.20 (m, 4 H, 2×H-6Јa, 2×CH2–CH=), 2.10–
1.98 (m, 4 H, 2×H-4Ј, 2×H-3Ј), 1.91 (d, 3 H, J = 1.0 Hz, H-7),
1.91 (d, 3 H, J = 1.0 Hz, H-7), 1.88–1.81 (m, 4 H, 2×2Ј-CH2),
1,65–1.55 (m, 2 H, 2×H-6Јb) ppm. 13C NMR (101 MHz, CDCl3):
δ = 163.7 (C-4), 151.2 (C-2), 146.8 (C-2 arom), 136.8 (C-6), 136.2
(CH=CH2), 136.1 (CH=CH2), 131.7 (C-6 arom.), 128.6 (C-1
arom.), 124.4 (C-4 arom.), 123.3 (C-5 arom.), 122.7 (C-3 arom.),
117.5 (CH=CH2), 117.5 (CH=CH2), 111.6 (C-5), 70.7 (d, J =
6.0 Hz, 5Ј-CH2), 70.6 (d, J = 5.5 Hz, 5Ј-CH2), 69.0 (d, J = 6.6 Hz,
CH2 benzyl), 54.6 (C-1Ј), 54.6 (C-1Ј), 44.1 (d, J = 2.5 Hz, H-4Ј),
44.0 (d, J = 2.5 Hz, H-4Ј), 39.5 (CH2–CH=), 39.5 (CH2–CH=),
39.0 (C-3Ј), 36.2 (C-2Ј), 36.2 (C-2Ј), 35.4 (C-6Ј), 35.3 (C-6Ј), 15.8
(3-CH3), 15.8 (3-CH3), 13.0 (C-7) ppm. 31P NMR (162 MHz,
CDCl3): δ = –8.3, –8.4 ppm; UV: λmax = 263.9 nm (MeCN). IR
6Ј), 23.7 (CH –C), 13.0 (C-7) ppm. IR (KBr): ν = 3430, 3300, 3040,
˜
2
2925, 1685, 1470, 1430, 1395, 1370, 1270, 1130, 1040, 630, 590,
490, 420 cm–1. HRMS-FAB: m/z calcd. for C14H18N2O3 [M + H]:
263.1396; found: 263.1408.
Synthesis of the cycloSal-phosphate triesters: General Procedure
The nucleoside is dissolved in dry pyridine and 5 pieces of activated
molecular sieves (3 Å) are added. The mixture is cooled to –40 °C
under a nitrogen atmosphere and the 3-methyl-cycloSal-phosphor-
chloridate (1.23  in toluene) is added dropwise over a period of
2 hrs. Stirring is continued for an additional 0.5 hrs at –40 °C. The
reaction is warmed to room temperature and the pyridine is evapo-
rated off. The crude is purified by chromatography on a chromato-
tron (CH2Cl2/MeOH gradient 0–10%) to yield the cycloSal-phos-
phate triesters as colourless foams. After lyophilization (CH3CN/
H2O, 1:1) the products are obtained as colourless cottons.
(KBr): ν = 3440, 3180, 3060, 2950, 1685, 1470, 1395, 1300, 1190,
˜
1020, 940, 780 cm–1. HRMS-FAB: m/z calcd. for C22H27N2O6P [M
+ H]: 447.1685; found: 447.1691. HPLC: tR = 13.96, 14.17 min.
3-Methyl-cyclosSaligenyl-(6Ј-carba-2Ј,3Ј-dideoxy-3Ј-propargyl-
thymidinyl)monophosphate (3-Me-cycloSal-carba-3Ј-propargyl-
dTMP) (11): The reaction has been carried out according to the
described general procedure with nucleoside 6 (40.0 mg,
0.152 mmol), pyridine (400 µL) and 3-methyl-cycloSal-phosphor-
chloridate (260 µL). Yield: 46.0 mg, (69%) as a mixture of two dia-
stereomers. Rf (TLC) = 0.56 (CH2Cl2/MeOH, 9:1). 1H NMR
(500 MHz, CDCl3): δ = 8.31 (m, 2 H, 2×NH), 7.20–7.15 (m, 2 H,
2×H-6 arom.), 7.05–7.00 (m, 2 H, 2×H-4 arom.), 7.00 (q, 1 H, J
= 1.0 Hz, H-6), 6.99 (q, 1 H, J = 1.0 Hz, H-6), 6.94–6.90 (m, 2 H,
2×H-5 arom.), 5.43–5.25 (m, 4 H, 2×CH2 benzyl), 4.99–4.90 (m,
2 H, 2×H-1Ј), 4.34–4.19 (m, 4 H, 2×5Ј-CH2), 2.40–2.30 (m, 4 H,
2×CH2–C), 2.28 (s, 6 H, 2×3-CH3), 2.26–2.15 (m, 6 H, 2×H-3Ј,
2×H-4Ј, 2×H-6Јa), 2.09–2.00 (m, 2 H, 2×H-2Јa), 1.96 (dd, 1 H,
J = 2.5 Hz, 2.5 Hz, CH alkyne), 1.95 (dd, 1 H, J = 2.5 Hz, 2.5 Hz,
CH alkyne), 1.95–1.92 (m, 2 H, 2×H-2Јb), 1.92 (d, 6 H, J = 1.0 Hz,
2×H-7), 1.70–1.60 (m, 2 H, 2×H-6Јb) ppm. 13C NMR (101 MHz,
CDCl3): δ = 164.7 (C-4), 151.0 (C-2), 145.4 (C-2 arom.), 136.9 (C-
6), 131.7 (C-6 arom.), 129.1 (C-1 arom.), 124.4 (C-4 arom.), 123.3
(C-5 arom.), 121.0 (d, J = 2.0 Hz, C-3 arom.), 120.9 (d, J = 2.4 Hz,
C-3 arom.), 111.7 (C-5), 81.8 (Cq alkyne), 81.8 (Cq alkyne), 70.7
(CH alkyne), 70.7 (CH alkyne), 70.3 (d, J = 6.0 Hz, C-5Ј), 70.1 (d,
J = 6.0 Hz, C-5Ј), 69.1 (d, J = 6.8 Hz, CH2 benzyl), 54.8 (C-1Ј),
43.44 (C-4Ј), 43.4 (C-4Ј), 38.3 (C-3Ј), 38.2 (C-3Ј), 36.0 (C-2Ј) 36.0
(C-2Ј), 35.0 (C-6Ј), 35.2 (C-6Ј), 23.5 (CH2–C), 23.4 (CH2–C), 15.8
(3-CH3), 13.0 (C-7) ppm. 31PNMR (162 MHz, CDCl3): δ = –8.3,
3-Methyl-cycloSaligenyl-(3Ј-azido-6Ј-carba-2Ј,3Ј-dideoxythymidin-
yl)monophosphate (3-Me-cycloSal-carba-AZTMP) (9): The reac-
tion has been carried out according to the described general pro-
cedure with nucleoside 3 (50.0 mg, 0.19 mmol), pyridine (500 µL)
and 3-methyl-cycloSal-phosphorchloridate (330 µL). Yield:
72.0 mg, (85%) as a mixture of two diastereomers. Rf (TLC) = 0.62
(CH2Cl2/MeOH, 9:1) 1H NMR (500 MHz, CDCl3): δ = 8.70 (br.
s, 2 H, 2 ×NH), 7.19–7.16 (m, 2 H, 2×H-6 arom.), 7.05–7.01 (m,
2 H, 2×H-4 arom.), 6.97 (q, 1 H, J = 1.0 Hz, H-6), 6.95 (q, 1 H,
J = 1.0 Hz, H-6), 6.94–6.90 (m, 2 H, 2×H-5 arom.), 5.42–5.30 (m,
4 H, 2×CH2 benzyl), 4.85–4.77 (m, 2 H, 2×H-1Ј), 4.26 (ddd, 1 H,
J = 10.8 Hz, 6.8 Hz, 4.6 Hz, H-5Јa), 4.22–4.19 (m, 2 H, 5Ј-CH2),
4.17 (ddd, 1 H, J = 10.8 Hz, 7.7 Hz, 5.2 Hz, H-5Јb), 4.12–4.09 (m,
2 H 2×H-3Ј), 2.23 (s, 6 H, 2×3-CH3), 2.22–2.11 (m, 6 H, 2×H-
4Ј; 2×H-6Јa, 2×H-2Јa), 2.10–2.04 (m, 2 H, 2×H-2Јb), 1.85 (d, 6
H, J = 1.0 Hz, 2×H-7), 1.74–1.68 (m, 2 H, 2×H-6Јb) ppm. 13C
NMR (101 MHz, CDCl3): δ = 163.9 (C-4), 151.0 (C-2), 150.9 (C-
2), 148.9 (C-2 arom.), 137.9 (C-6), 137.9 (C-6), 131.8 (C-6 arom.),
128.4 (C-1 arom.), 128.3 (C-1 arom.), 124.5 (C-4 arom.), 124.5 (C-
4 arom.), 123.3 (C-5 arom.), 122.4 (C-3 arom.), 69.2 (d, J = 6.5 Hz,
CH2 benzyl), 69.2 (d, J = 6.5 Hz, CH2 benzyl), 68.8 (d, J = 6.0 Hz,
C-5Ј), 68.7 (d, J = 5.6 Hz, C-5Ј), 62.0 (C-3Ј), 62.0 (C-3Ј), 56.0 (C-
1Ј), 56.0 (C-1Ј), 36.5 (C-2Ј), 36.4 (C-2Ј), 32.1 (C-6Ј), 32.0 (C-6Ј),
15.8 (3-CH3), 12.9 (C-7) ppm. 31P NMR (162 MHz, CDCl3): δ = –
–8.4 ppm; UV: λmax = 264.5 nm (MeCN). IR (KBr): ν = 3440,
˜
3245, 3050, 2950, 1685, 1470, 1370, 1300, 1190, 1020, 940, 870,
820, 780, 650, 590, 480, 420 cm–1. HRMS-FAB: m/z calcd. for
8.7, –8.8 ppm; UV: λmax = 262.8 nm (CH CN); IR (KBr): ν = 3440,
˜
3
3180, 3050, 2950, 2105, 1690, 1470, 1270, 1295, 1190, 1020, 940,
C22H25N2O6P [M + H]: 445.1529; found: 445.1523. HPLC: tR
13.21, 13.35 min.
=
870, 820, 770, 650, 495, 415 cm–1. HRMS-FAB: m/z calcd. for
C19H22N5O6P [M + H]: 448.1386; found: 448.1397. HPLC: tR
13.05, 13.20 min.
=
3-Methyl-cycloSaligenyl-(6Ј-carba-2Ј,3Ј-dideoxythymidinyl)mono-
phosphate (3-Me-cycloSal-carba-ddTMP) (12): The reaction has
been carried out according to the described general procedure with
nucleoside 7 (45.0 mg, 0.20 mmol), pyridine (500 µL) and 3-methyl-
cycloSal-phosphorchloridate (350 µL). Yield: 63.0 mg, (78%) as a
mixture of two diastereomers. Rf (TLC) = 0.54 (CH2Cl2/MeOH,
9:1) 1H NMR (400 MHz, CDCl3): δ = 8.44 (br. s, 2 H, 2×NH),
7.19–7.15 (m, 2 H, 2 × H-6 arom.), 7.05–7.00 (m, 4 H, 2 × H-6,
3-Methyl-cycloSaligenyl-(3Ј-allyl-6Ј-carba-2Ј,3Ј-dideoxythymidin-
yl)monophosphate (3-Me-cycloSal-carba-3Ј-allyl-dTMP) (10): The
reaction has been carried out according to the described general
procedure with nucleoside 5 (50.0 mg, 0.19 mmol), pyridine
(500 µL) and 3-methyl-cycloSal-phosphorchloridate (330 µL).
Yield: 55.0 mg, (65%) as a mixture of two diastereomers. Rf (TLC)
= 0.57 (CH2Cl2/MeOH, 9:1). 1H NMR (400 MHz, CDCl3): δ = 2×H-4 arom.), 6.94–6.98 (m, 2 H, 2×H-5 arom.), 5.41–5.25 (m, 4
8.36 (br. s, 2 H, 2×NH), 7.20–7.15 (m, 2 H, 2×H-6 arom.), 7.05– H, 2×CH2 benzyl), 4.93–4.84 (m, 2 H, 2×H-1Ј), 4.25–4.12 (m, 4
7.00 (m, 3 H, 2×H-4 arom., H-6), 6.99 (q, 1 H, J = 1.0 Hz, H-6), H, 2×5Ј-CH2), 2.46–2.35 (m, 2 H, 2×H-4Ј), 2.29 (s, 3 H, 3-CH3),
Eur. J. Org. Chem. 2006, 932–940
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
939

O. R. Ludek, J. Balzarini, C. Meier
FULL PAPER
wijn, E. De Clercq, S. Broder, D. G. Johns, Mol. Pharmacol.
1987, 32, 162–167.
[9] Z. Hao, D. A. Cooney, D. Farquhar, C.-F. Perno, K. Zhang,
R. Masood, Y. Wilson, N. R. Hartman, J. Balzarini, D. G.
Johns, Mol. Pharmacol. 1990, 37, 157–163.
[10] a) C. Meier, Synlett 1998, 233–242; b) C. R. Wagner, V. V. Iyer,
E. J. McIntee, J. Med. Res. Rev. 2000, 20, 417–451.
[11] a) C. Meier, Mini Rev. Med. Chem. 2002, 2, 219–234; b) C.
Meier, Advances in Antiviral Drug Design, Elsevier, 2004, vol.
4, 147–213.
[12] For reviews see a) A. D. Borthwick, K. Biggadike, Tetrahedron
1992, 48, 571–623; b) L. Agrofoglio, E. Suhas, A. Farese, R.
Condom, S. R. Challand, R. A. Earl, R. Guedj, Tetrahedron
1994, 50, 10611–10670; c) V. E. Marquez, in: Advances in anti-
viral drug design (Ed.: E. De Clercq), JAI Press, Greenwich
1996, 2, 89–146; d) M. T. Crimmins, Tetrahedron 1998, 54,
9229–9272.
2.27 (s, 3 H, 3-CH3), 2.26–2.17 (m, 2 H, 2×H-6Јa), 2.13–2.04 (m,
2 H, 2×H-2Јa), 1.92 (d, 3 H, J = 1.2 Hz, H-7), 1.91 (d, 3 H, J =
1.2 Hz, H-7), 1.90–1.81 (m, 2 H, 2×H-3Јa), 1.75–1.60 (m, 4 H,
2×H-2Јb, 2 ×H-3Јb), 1.50–1.40 (m, 2 H, 2×H-6Јb) ppm. 13C NMR
(101 MHz, CDCl3): δ = 163.7 (C-4), 151.3 (C-2), 146.6 (C-2 arom.),
136.8 (C-6), 136.8 (C-6), 131.7 (C-6 arom.), 128.3 (d, J = 8.0 Hz,
C-1 arom.), 124.3 (C-4 arom.), 123.3 (C-5 arom.), 120.9 (C-3
arom.), 111.6 (C-5), 71.9 (d, J = 6.0 Hz, CH2 benzyl), 71.8 (d, J =
6.0 Hz, CH2 benzyl), 69.0 (d, J = 6.7 Hz, C-5Ј), 56.3 (C-1Ј), 38.1
(d, J = 6.6 Hz, C-4Ј), 38.0 (d, J = 8.1 Hz, C-4Ј), 34.5 (C-2Ј), 34.4
(C-2Ј), 30.2 (C-6Ј), 30.1 (C-6Ј), 26.6 (C-3Ј), 26.5 (C-3Ј), 15.8 (3-
CH3), 13.0 (C-7) ppm. 31P NMR (162 MHz, CDCl3): δ = –8.2,
–8.3 ppm; UV: λmax = 263.1 nm (CH CN). IR (KBr): ν = 3440,
˜
3
3180, 3050, 2955, 1685, 1470, 1370, 1300, 1190, 1020, 940, 870,
820, 780, 490 cm–1. HRMS-FAB: m/z calcd. for C19H23N2O6P [M
+ H]: 407.1372; found: 407.1371. HPLC: tR = 11.25, 12.48 min.
[13] O. R. Ludek, C. Meier, Synthesis 2003, 13, 2101–2109.
[14] a) R. P. Glinski, M. S. Khan, R. L. Kalamas, C. L. Stevens,
M. B. Sporn, J. Chem. Soc., Chem. Commun. 1970, 915–916;
b) J. Hiebl, E. Zbiral, J. Balzarini, E. De Clercq, J. Med. Chem.
1990, 33, 845–848.
[1] For selected reviews, see a) E. De Clercq, Ann. New York Acad.
Sci. 1994, 438–456; b) V. Nair, T. S. Jahnke, Antimicrob. Agents
Chemother. 1995, 39, 1017–1029; c) L. J. Wilson, M. W. Hager,
[15] E. Krainer, F. Naider, J. Becker, Tetrahedron Lett. 1993, 34,
1713–1716.
Y. A. El-Kattan, D. Liotta, Synthesis 1995, 1465–1479; d) S. [16] carba-AZT has been synthesized before by nucleophilic substi-
Pan, N. M. Amankulor, K. Zhao, Tetrahedron 1998, 54, 6587–
6604; e) C. K. Chu, Nucleic Acids Symp. Ser. 1996, 35, 1–22.
[2] a) L. Agrofoglio, E. Suhas, A. Farese, R. Condom, S. R. Chal-
land, R. A. Earl, R. Guedj, Tetrahedron 1994, 50, 10611–10670;
b) E. De Clercq, J. Med. Chem. 1995, 38, 2491–2517; c) E.
De Clercq, Nucleosides Nucleotides 1994, 13, 1271–1295; d) L.
Naesens, R. Snoeck, G. Andrei, J. Balzarini, J. Neyts, E.
De Clercq, Antiviral Chem. Chemother. 1997, 8, 1–23; e) M.
Nomura, S. Shuto, M. Tanaka, T. Sasaki, S. Mori, S. Shigeta,
tution of a mesylate: J. Béres, G. Sági, I. Tömösközi, L. Gruber,
E. Baitz-Gács, L. Ötvos, E. De Clercq, J. Med. Chem. 1990,
33, 1353–1360.
[17] a) S. Chambert, I. Gautier-Luneau, M. Fontecave, J.-L.
Décout, J. Org. Chem. 2000, 65, 249–253; b) S. Chambert, F.
Thomasson, J.-L. Décout, J. Org. Chem. 2002, 67, 1898–1904;
c) P. Herdewijn, J. Balzarini, E. De Clercq, R. Pauwels, M.
Baba, S. Broder, H. Vanderhaeghe, J. Med. Chem. 1987, 30,
1270–1278.
A. Matsuda, J. Med. Chem. 1999, 42, 2901–2908; f) L. A. Pa- [18] a) J. von Braun, P. Engelbertz, Ber. Dtsch. Chem. Ges. 1923, 56,
quette, R. T. Bibart, C. K. Seekamp, A. L. Kahana, Org. Lett.
2001, 3, 4039–4041; g) S. M. Daluge, M. T. Martin, B. R. Sick-
les, D. A. Livingston, Nucleosides, Nucleotides Nucleic Acids
2000, 19, 297–327.
1573–1577; b) J. von Braun, A. Friedsam, Ber. Dtsch. Chem.
Ges. 1930, 63, 2407–2413.
[19] M. Bessodes, D. Komiotis, K. Antonakis, Tetrahedron Letters
1986, 27, 579–580.
[20] a) C. K. Chu, B. Doboszewski, W. Schmidt, G. V. Ullas, J. Org.
Chem. 1989, 54, 2767–2769; b) J. Fiandor, S. Y. Tam, Tetrahe-
dron Lett. 1990, 31, 597–600.
[3] a) E. De Clercq, J. Med. Chem. 1986, 29, 1561–1569; b) C.
Périgaud, G. Gosselin, J.-L. Imbach, Nucleosides Nucleotides
1992, 11, 903–945.
[4] a) H. Mitsuya, K. J. Weinhold, P. A. Furman, M. H. St. Clair,
S. N. Lehrman, R. C. Gallo, D. Bolognesi, D. W. Barry, S.
[21] G. E. Keck, J. B. Jates, J. Am. Chem. Soc. 1982, 104, 5829–
5831.
Broder, Proc. Nat. Acad. Sci. U. S. A. 1985, 82, 7096–7100; b) [22] M. J. Robins, J. S. Wilson, F. Hansske, J. Am. Chem. Soc. 1983,
M. H. St. Clair, C. A. Richards, T. Spector, K. J. Weinhold,
W. H. Miller, A. J. Langlois, P. A. Furman, Antimicrob. Agents
Chemother. 1987, 31, 1972–1977.
105, 4059–4065.
[23] J. Béres, G. Sagi, I. Tömösközi, L. Gruber, E. Gulacsi, L.
Ötvös, Tetrahedron Lett. 1988, 29, 2681–2684.
[24] C. Sahlberg, Tetrahedron Lett. 1992, 33, 679–682.
[25] a) C. Meier, M. Lorey, E. De Clercq, J. Balzarini, J. Med.
Chem. 1998, 41, 1417–1427; b) J. Balzarini, S. Aquaro, T. Knis-
pel, C. Rampazzo, V. Bianchi, C.-F. Perno, E. De Clercq, C.
Meier, Mol. Pharmacol 2000, 58, 928–935.
[26] a) C. Meier, T. Knispel, V. E. Marquez, M. A. Siddiqui, E.
De Clercq, J. Balzarini, J. Med. Chem. 1999, 42, 1615–1624; b)
J. Balzarini, F. Haller-Meier, E. De Clercq, C. Meier, Antiviral
Chem. Chemother. 2002, 12, 301–306; c) C. Meier, A. Lomp,
A. Meerbach, P. Wutzler, J. Med. Chem. 2002, 45, 5157–5172;
d) C. Meier, L. Habel, F. Haller-Meier, A. Lomp, M. Herder-
ich, R. Klöcking, A. Meerbach, P. Wutzler, Antiviral Chem.
Chemother. 1998, 9, 389–402.
[5] a) P. Herdewijn, J. Balzarini, E. De Clercq, in: Advances in
Antiviral Drug Design (Ed.: E. De Clercq), JAI Press: Green-
wich, CT, 1993, vol. 1, pp. 233–318; b) P. Herdewijn, J. Balzar-
ini, E. De Clercq, R. Pauwels, M. Baba, S. Broder, H. Vander-
haeghe, J. Med. Chem. 1987, 30, 1270–1278; c) H. Mitsuya, S.
Broder, Proc. Nat. Acad. Sci. U. S. A. 1986, 83, 1911–1915.
[6] P. A. Furman, J. A. Fyfe, M. H. St. Clair, K. Weinhold, J. L.
Rideout, G. A. Freeman, S. N. Lehrmann, D. P. Bolognesi, S.
Broder, H. Mitsuya, Proc. Nat. Acad. Sci. U. S. A. 1986, 83,
8333–8337.
[7] a) J. Balzarini, Pharm. World Sci. 1994, 16, 113–126; b) Z. Hao,
D. A. Cooney, N. R. Hartman, C. F. Perno, A. Fridland, A. L.
DeVico, M. G. Sarngadharan, S. Broder, D. G. Johns, Mol.
Pharmacol. 1988, 34, 431–435.
[27] S.-Y. Wu, J. E. Casida, Chem. Res. Toxicol. 1992, 5, 680–684.
Received: September 22, 2005
[8] a) J. Balzarini, P. Herdewijn, E. De Clercq, J. Biol. Chem. 1989,
264, 6127–6133; b) J. Balzarini, G. J. Kang, M. Dalal, P. Herde-
Published Online: December 5, 2005
940
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 932–940