Synthesis of a bicyclic analogue of AZT restricted in an unusual O4′-endo conformation

Article abstract of DOI:10.1021/jo010299j

The [3.2.0]bicyclic β-nucleoside analogue 5 has been designed as a conformationally restricted analogue of the anti-HIV drug AZT. The synthesis of 5 as well as its α-anomer 29 is hereby described. The synthesis was accomplished from D-arabinose via a modified Corey-Link procedure stereo-selectively incorporating the azide moiety as well as a methyl ester function. When the tertbutyldiphenylsilyl group was used as a permanent protecting group, a selective formation of an oxetane ring failed. When using the p-methoxyphenyl group as a permanent protecting group, 5 and 29 were efficiently obtained via a selective reduction of the ester, a nucleobase coupling followed by separation of the anomers and ring-closing procedures. The nucleoside 5 is conformationally restricted in an unusual O4′-endo (East) conformation, which is an intermediate between the North- and South-type conformations. Nevertheless, neither 5 nor 29 displayed any anti-HIV activity.

Full text of DOI:10.1021/jo010299j

4878
J . Org. Chem. 2001, 66, 4878-4886
Syn th esis of a Bicyclic An a logu e of AZT Restr icted in a n Un u su a l
O4′-En d o Con for m a tion
Marianne H. Sørensen,† Claus Nielsen,‡ and Poul Nielsen*,†
Department of Chemistry, University of Southern Denmark, Odense University,
DK-5230 Odense, Denmark, and Retrovirus Laboratory, Department of Virology, Statens Serum Institut,
DK-2300 Copenhagen, Denmark
pon@chem.sdu.dk
Received March 19, 2001
The [3.2.0]bicyclic â-nucleoside analogue 5 has been designed as a conformationally restricted
analogue of the anti-HIV drug AZT. The synthesis of 5 as well as its R-anomer 29 is hereby described.
The synthesis was accomplished from D-arabinose via a modified Corey-Link procedure stereo-
selectively incorporating the azide moiety as well as a methyl ester function. When the tert-
butyldiphenylsilyl group was used as a permanent protecting group, a selective formation of an
oxetane ring failed. When using the p-methoxyphenyl group as a permanent protecting group, 5
and 29 were efficiently obtained via a selective reduction of the ester, a nucleobase coupling followed
by separation of the anomers and ring-closing procedures. The nucleoside 5 is conformationally
restricted in an unusual O4′-endo (East) conformation, which is an intermediate between the North-
and South-type conformations. Nevertheless, neither 5 nor 29 displayed any anti-HIV activity.
In tr od u ction
In the treatment of AIDS, 2′,3′-dideoxynucleosides are
very important drugs that are used in monotherapy as
well as in combination therapy with other types of
drugs.1,2 These nucleoside analogues are phosphorylated
in vivo to give their 5′-O-triphosphates, which are effec-
tive inhibitors of the HIV-encoded enzyme HIV-1 reverse
transcriptase (HIV-1 RT).1,2 The first drug to be approved
for the treatment of AIDS was 3′-azido-3′-deoxythymidine
(AZT, 1, Figure 1).1 However, this and other 2′,3′-
dideoxynucleoside analogues have toxic side effects and
lead to the emergence of resistance.1 Therefore, there is
a continuous need for improved anti-HIV drugs and for
new insight into the structure-activity relations between
different nucleoside analogues and their pharmacological
effects.
Recently, conformationally restricted nucleoside ana-
logues have received considerable attention as monomers
in oligonucleotide sequences with enhanced affinities for
complementary nucleic acid sequences3 as well as in
studies on the interactions of nucleoside/nucleotide sub-
strates with corresponding receptors and enzymes.4,5
Furthermore, a plethora of conformationally restricted
nucleosides has been synthesized for potential antiviral
activity.4,6
F igu r e 1. Chemical structures of AZT and related bicyclic
analogues.
The conformational behavior of natural as well as
modified nucleosides is of immense importance for their
biological activities.7,8 The puckering of the furanose rings
of nucleosides can be described by the pseudorotational
cycle (Figure 2),7,9 which correlates all possible twist (T)
and envelope (E) conformations of the furanose to the so-
called pseudorotational angle P.7,9 Thus, unmodified
† Odense University.
‡ Statens Serum Institut.
(1) (a) De Clercq, E. Pure Appl. Chem. 1998, 70, 567. (b) De Clercq,
E. J . Med. Chem. 1995, 38, 2491.
(2) Huryn, D. M.; Okabe M. Chem. Rev. 1992, 92, 1745.
(3) (a) Kool, E. T. Chem. Rev. 1997, 97, 1473. (b) Herdewijn, P.
Biochim. Biophys. Acta 1999, 1489, 167. (c) Meldgaard, M.; Wengel,
J . J . Chem. Soc., Perkin Trans. 1 2000, 3539.
(4) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.; Ford,
H., J r.; Feldman, R. J .; Mitsuya, H.; George, C.; Barchi, J . J ., J r. J .
Am. Chem. Soc. 1998, 120, 2780.
(5) (a) Marquez, V. E.; Russ, P.; Alonso, R.; Siddiqui, M. A.;
Hernandez, S.; George, C.; Nicklaus, M. C.; Dai, F.; Ford, H., J r. Helv.
Chim. Acta 1999, 82, 2119. (b) J acobson, K. A.; J i, X.; Li, A.-H.;
Melman, N.; Siddiqui, M. A.; Shin, K.-J .; Marquez, V. E.; Ravi, R. G.
J . Med. Chem. 2000, 43, 2196.
(6) For recent examples of bicyclic nucleoside analogues, see: (a)
Lescop, C.; Huet, F. Tetrahedron 2000, 56, 2995. (b) Kværnø, L.;
Nielsen, C.; Wightman, R. H. Chem. Commun. 2000, 2903. (c) Wang,
G. Tetrahedron Lett. 2000, 41, 7139.
(7) Saenger, W. Principles of Nucleic Acid Structure; Springer: New
York, 1984.
(8) Ford, H., J r.; Dai, F.; Mu, L.; Siddiqui, M. A.; Nicklaus, M. C.;
Anderson, L.; Marquez, V. E.; Barchi, J . J ., J r. Biochemistry 2000, 39,
2581.
(9) For definitions, nomenclature, and conformational behavior of
nucleosides and nucleotides, see ref 7 as well as: (a) Altona, C.;
Sundaralingam, M. J . Am. Chem. Soc. 1972, 94, 8205. (b) Altona, C.;
Sundaralingam, M. J . Am. Chem. Soc. 1973, 95, 2333.
10.1021/jo010299j CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/08/2001

Synthesis of a Bicyclic Analogue of AZT
J . Org. Chem., Vol. 66, No. 14, 2001 4879
to adopt an S-type conformation for phosphorylation and
an N-type conformation for inhibiting HIV-1 RT.4
Very recently, Obika et al.14 and Olsen et al.15 inde-
pendently synthesized the AZT analogue 4 (Figure 1),
which is a perfect N-type conformational mimic.14,15 Thus,
this bicyclic nucleoside adopts a C-3′-endo conformation
with P ) 18° (Figure 2) as determined by NMR16b and
X-ray crystallography16c for the original LNA monomer.16
In line with the former results, this compound shows no
antiviral activity, perhaps due to its very inflexible
structure.15
To obtain further insight into the relationship between
the conformation of the furanose ring and biological
activity, we decided to synthesize a bicyclic analogue of
AZT that is conformationally restricted into a conforma-
tional range on the path between the N- and S-type
conformations. On the basis of a [3.2.0]bicyclic structure,
the nucleoside 5 would be a 3′-azido-3′-deoxy analogue
of a bicyclic nucleoside, which has been suggested to have
an O4′-endo or East (E)-type conformation with a pseu-
dorotational angle P around 90° (Figures 1 and 2).17 Due
to the constrained bicyclic structure, 5 would be an
analogue of AZT prevented from taking a conformation
resembling any of the two low-energy N- or S-type
conformations. Therefore, this molecule might give fur-
ther and valuable insight into the structure-activity
relationships of the involved enzymes and to the postu-
lated demand for conformational flexibility for anti-HIV
nucleoside analogues. On the other hand, it cannot be
precluded in advance that this E-type conformational
mimic of AZT will be recognized by phosphorylating
enzymes and/or as its triphosphate by HIV-1 RT, thus
revealing a new potent anti-HIV drug. Thus, in the
related anti-HIV drug 2′,3′-didehydro-2′,3′-dideoxy-
thymidine (d4T)1 the C1′-C2′-C3′-C4′ moiety adopts a
similar inflexible planarity.18
F igu r e 2. Pseudorotational cycle of the furanose ring in
nucleosides (E ) envelope, T ) twist).
nucleosides are known to exist in an equilibrium between
two major conformational ranges, the C-3′-endo confor-
mations centered around P ) 18° and the C-2′-endo
conformations centered around P ) 162°.7 Due to their
positions in the pseudorotational cycle, these are known
as North (N) and South (S) conformations, respectively
(Figure 2).7,9 The same equilibrium between N- and
S-conformations, driven by the interplay of stereoelec-
tronic effects, exists for most 2′,3′-dideoxynucleosides.10
Thus, AZT has been shown to crystallize in a high S-type
conformation with P ) 215°,11 while a study on the
interaction between the triphosphate of AZT (AZTTP)
and the target viral enzyme HIV-1 RT has shown AZTTP
to bind to the enzyme with a pseudorotational angle P
around 60°.12 The natural substrate thymidine triphos-
phate (TTP) binds with P around 55°,12 and both of these
are C-4′-exo conformations that in a broad definition can
be recognized as N-type conformations (Figure 2).
Resu lts
Retr osyn th etic Con sid er a tion s. For the construc-
tion of the bicyclic skeleton of 5, an oxetane ring should
be connected to a furanose ring with a 3′-azido moiety.
The oxetane ring formation should be relatively straight-
forward from a furanose substrate with the 2′-OH group
preorganized for nucleophilic attack on the 3′-C methyl-
ene group connected to a good leaving group like a
methylsulfonic ester (a , Figure 3).17 The ring formation
should await the nucleobase coupling in order to avoid
any Lewis acid mediated ring opening of the strained
[3.2.0]bicyclic ring system.19 However, the compound a
could have both arabino and ribo configurations, as the
Recently, Marquez et al. have presented a comprehen-
sive study on two analogues of AZT that are conforma-
tionally restricted due to the replacement of the furanose
rings with bicyclic moieties.4 Thus, the analogue 2 (Figure
1) can be considered as a good mimic of AZT in an N-type
conformation as P has been established to be approxi-
mately 342° corresponding to a C-2′-exo conformation
(Figure 2). On the other hand, 3 is an S-type conforma-
tional mimic with P ≈ 198° i.e., a C-3′-exo conformation
(Figures 1 and 2). Neither 2 nor 3 display any antiviral
activity.4 However, when transformed into the corre-
sponding triphosphates, 2 shows an inhibition of HIV-1
RT comparable to that observed for unmodified AZTTP,
whereas the triphosphate of 3 remains inactive. These
results confirm the postulate of Van Roey et al. that the
biotransformation of nucleoside drugs into the active
triphosphates demands S-type conformations13 and leads
to the conclusion that active anti-HIV nucleoside ana-
logues must display an appropriate flexibility in order
(14) Obika, S.; Andoh, J .; Sugimoto, T.; Miyashita, K.; Imanishi, T.
Tetrahedron Lett. 1999, 40, 6465.
(15) Olsen, A. G.; Rajwanshi, V. K.; Nielsen, C.; Wengel, J . J . Chem.
Soc., Perkin Trans. 1 2000, 3610.
(16) LNA is defined as oligonucleotides containing the [2.2.1]bicyclic
nucleoside monomers corresponding to the analogues of 4 containing
a
3′-hydroxy group instead of a 3′-azido group and a variety of
nucleobases; see: (a) Singh, S. K.; Nielsen, P.; Koshkin, A. A.; Wengel,
J . Chem. Commun. 1998, 455. (b) Koshkin, A. A.; Singh, S. K.; Nielsen,
P.; Rajwanshi, V. K.; Kumar, R.; Meldgaard, M.; Olsen, C. E.; Wengel,
J . Tetrahedron 1998, 54, 3607. (c) Obika, S.; Nanbu, D.; Hari, Y.; Morio,
K.; In, Y.; Ishida, T.; Imanishi, T. Tetrahedron Lett. 1997, 38, 8735.
(d) Obika, S.; Nanbu, D.; Hari, Y.; Andoh, J .; Morio, K.; Doi, T.;
Imanishi, T. Tetrahedron Lett. 1998, 39, 5401.
(17) (a) Christensen, N. K.; Petersen, M.; Nielsen, P.; J acobsen, J .
P.; Olsen, C. E.; Wengel, J . J . Am. Chem. Soc. 1998, 120, 5458.
(18) Harte, W. E., J r.; Starrett, J . E., J r.; Martin, J . C.; Mansuri,
M. M. Biochem. Biophys. Res. Commun. 1991, 175, 298.
(10) Plavec, J .; Tong, W.; Chattopadhyaya, J . J . Am. Chem. Soc.
1993, 115, 9734.
(11) Van Roey, P.; Salerno, J . M.; Duax, W. L.; Chu, C. K.; Ahn, M.
K.; Schinazi, R. F. J . Am. Chem. Soc. 1988, 110, 2277.
(12) Painter, G. R.; Aulabaugh, A. E.; Andrews, C. W. Biochem.
Biophys. Res. Commun. 1993, 191, 1166.
(13) Van Roey, P.; Taylor, E. W.; Chu, C. K.; Schinazi, R. F. Ann.
N. Y. Acad. Sci. 1990, 616, 29.

4880 J . Org. Chem., Vol. 66, No. 14, 2001
Sørensen et al.
Sch em e 1a
F igu r e 3. Retrosynthetic considerations. Pg ) varying pro-
tecting groups.
C-2′ configuration might be easily converted from ribo
to arabino taking advantage of the pyrimidine nucleobase
in the so-called anhydro approach.17,20 The 3′-C-hy-
droxymethyl group in a might be obtained by reduction
of an ester group. The R-azido ester moiety in b can be
obtained by a modification of the Corey-Link amino acid
synthesis21 developed by Dominguez et al.22 Thus, a basic
azide treatment of a trichloromethyl-substituted tertiary
alcohol c should give b in a single step with inversion of
configuration due to the illustrated mechanism (Figure
3). The alcohol c should be obtained from a ketone using
a simple reaction with the trichloromethyl anion. Ste-
reoselective control of this reaction can only be obtained
on a sterically constrained substrate like d where the
isopropylidine group directs the nucleophile to attach
from the R-face of the furanose ring. Thus, an arabino-
or lyxo-configured furanose derivative was preferred as
the starting material. In the end, this would give a sugar
a
Reagents: (a) KF, 18-crown-6, H2O, DMF; (b) p-methoxyphe-
nol, DEAD, Ph3P, THF, (63%, two steps); (c) CrO3, Ac2O, pyridine,
CH2Cl2 (8: 90%; 19: 99%); (d) CHCl3, LHMDS, THF (9: 54%; 20:
74%); (e) NaN3, 18-crown-6, DBU, MeOH (10: 68%; 21: 87%); (f)
NaBH4, THF (11: 66%) or NaBH4, THF, EtOH (22: 80%); (g)
MsCl, pyridine (12: 77%; 23: 87%); (h) (i) TBAF, THF, (ii) MsCl,
pyridine (96%); (i) HCl, MeOH, H2O, CH2Cl2 (14: 79%) or AcCl,
MeOH, H2O, CH2Cl2 (24: 94%). TBDPS ) tert-butyldiphenylsilyl.
a
with arabino configuration, and after nucleobase
coupling, two anomeric nucleoside products should be
expected.
Ch em ica l Syn th esis. As an appropriate carbohydrate
precursor possessing the preferred stereochemistry, D-
arabinose 6 was chosen as a very cheap starting material
(Scheme 1). As a conveniently protected arabinofuranose
derivative, the isopropylidene-protected silyl ether 7 has
been well described in the literature.23,24 Thus, 6 has been
converted to 7 using two subsequent protecting steps23
or, alternatively, three steps including a diethyl mercap-
tal intermediate.24 The latter method24 was superior in
our hands, and we chose to investigate the feasibility of
the silyl group as a permanent protecting group in our
synthetic strategy. Thus, a chromium-mediated oxidation
of 7 afforded the ketone 824 in a high yield. The reaction
with the trichloromethyl anion was accomplished using
a strong base, and the product 9 was obtained in a
reasonable yield and with absolute stereoselectivity.25
Following the reported modification of the Corey-Link
reaction,22 9 was converted to the â-azido methyl ester
10 in good yield, taking advantage of the in situ formation
of a dichloroepoxide, the reaction with the azide ion and
the methanolysis of the intermediate acyl chloride (Fig-
ure 3). The reaction was absolutely stereoselective, and
only one compound was obtained. However, the absolute
configuration was not exclusively verified at this stage.
Selective reduction of the methyl ester without simulta-
neous reduction of the azide was accomplished using a
cold treatment with sodium boronhydride26 affording the
primary alcohol 11 in a good yield. As a preparation for
the formation of the oxetane ring, the alcohol group was
subsequently converted to a leaving group. Hence, the
methanesulfonic ester 12 was obtained, and at this stage
the expected C-3 configuration was confirmed using
NOE-difference spectroscopy. Thus, a mutual NOE-
contact was observed between the H-1′ signal of the
methylene group and one of the H-5 signals and not the
H-4 signal, hereby confirming this group (C-1′) to be at
the concave site (the â-face) of the bicyclic structure.
Nevertheless, the isopropylidene group could not be
removed without affecting the silyl ether and, therefore,
the silyl protecting group had to be exchanged at this
stage. However, all attempts to replace the silyl group
(19) Lewis acid mediated ring opening reactions in connection to
nucleobase couplings have been reported with a [3.2.0]bicyclic methyl
furanoside: (a) Obika, S.; Morio, K.; Hari, Y.; Imanishi, T. Chem.
Commun. 1999, 2423. With a [2.2.1]bicyclic methyl furanoside: (b)
Nielsen, P.; Wengel, J . Chem. Commun. 1998, 2645.
(20) Fox, J . J .; Miller, N. C. J . Org. Chem. 1963, 28, 936.
(21) Corey, E. J .; Link, J . O. J . Am. Chem. Soc. 1992, 114, 1906.
(22) Dominguez, C.; Ezquerra, J .; Baker, S. R.; Borrelly, S.; Prieto,
L.; Espada, M.; Pedregal, C. Tetrahedron Lett. 1998, 39, 9305.
(23) Dahlman, O.; Garegg, P. J .; Mayer, H.; Schramek, S. Acta
Chem. Scand., Ser. B 1986, 40, 15.
(25) Very recently, another study suggested the use of weaker bases
(e.g., DBU) for this reaction type: Aggarwal, V. K.; Mereu, A. J . Org.
Chem. 2000, 65, 7211.
(24) Va´zquez-Tato, M. P.; Seijas, J . A.; Fleet, G. W. J .; Mathews, C.
J .; Hemmings, P. R.; Brown, D. Tetrahedron 1995, 51, 959.
(26) Mori, K.; Kinsho, T. Liebigs Ann. 1991, 1309.

Synthesis of a Bicyclic Analogue of AZT
J . Org. Chem., Vol. 66, No. 14, 2001 4881
Sch em e 2a
As the first step, 7 was desilylated to give the known
arabinose derivative 1731,32 and then directly reacted with
p-methoxyphenol under Mitsunobu conditions to give the
p-methoxyphenyl ether 18 in a reasonable overall yield
(Scheme 1). We still consider the present route as
superior even though 17 has also been obtained through
other 5′-O-protected compounds.31 The new arabinose
derivative 18 was oxidized quantitatively to give the
ketone 19 and subsequently reacted with chloroform to
give the alcohol 20. The same modified Corey-Link
procedure22 was applied giving 21 in a high yield, and
mild reduction gave efficiently the primary alcohol 22.
In all the four latter steps, the yields were improved
compared to the steps converting 7 to 11. In the reaction
of 19 with chloroform, the probable explanation was a
very slow addition of the strong base.25 Esterification of
22 to give 23 and treatment with methanolic hydrochloric
acid gave the mixture of methyl furanosides 24 in a high
yield.
At this stage, two options appeared possible. Thus,
cyclization of 24 would give two bicyclic methyl furano-
sides (similar to R- and â-analogues of 15) on which a
coupling reaction with a nucleobase following a modified
Vorbru¨ggen method might give the target R- and â-ano-
meric bicyclic nucleosides. However, as similar conditions
have been reported to afford ring-opening reactions (vide
supra),19 we decided to perform the coupling reaction
before the ring closure. Thus, with a protocol used
successfully with similar methyl furanosides,33 simulta-
neous trimethylsilylation of the secondary alcohol of 24
and thymine and subsequent coupling of these with TMS-
triflate as a Lewis acid catalyst, after separation afforded
the two anomeric nucleosides 25 and 26 in good yields
and in an almost equimolar ratio (Scheme 3). As the
R-anomer might be a very useful side product, we did
not investigate a variety of solvents and Lewis acids in
order to change this ratio in favor of the â-anomer.
Instead, both anomers were reacted with a strong base
to give the bicyclic nucleosides 27 and 28. Finally, the
deprotections using CAN30 afforded smoothly the target
nucleoside 5 as well as its R-anomer 29.
a
Reagents: (a) NaH, DMF (15: 12% and 16: 57%).
with alternative protecting groups without affecting the
sulfonic ester of 12 or, alternatively, the ester of 10,
failed, and we decided to explore another strategy. Thus,
the preference for the formation of four-membered rings
over five-membered rings has been observed on related
structures in the construction of other [3.2.0]bicyclic
nucleoside analogues.19a,27 Therefore, we converted 11 to
the bismethanesulfonic ester 13 in two very efficient
steps. Treatment with methanolic hydrochloric acid af-
forded the two separated anomeric methyl furanosides
14 in a good yield. The elucidation of the anomeric
configurations were performed by 13C NMR by comparing
the signals of C-1 with known methyl furanosides,28 as
3
well as from the J H1′H2′ coupling constants, as the
geometry forces the θH1H2 torsion angle of the R-anomer
3
to be near 90° and, thus, J H1H2 to be ∼0 Hz. To explore
the selectivity in a ring-closing procedure, the major
R-anomer of 14 was treated with a strong base affording
two bicyclic methyl furanosides 15 and 16 in a 1:5 ratio
1
(Scheme 2). These were separated and analyzed by H
NMR. The major isomer displayed very small J H4H5
coupling constants (<1 Hz) corresponding to the [2.2.1]-
bicyclic system in 16, whereas the minor isomer displayed
larger J H4H5 coupling constants (4.7 and 6.5 Hz) corre-
3
3
sponding to the [3.2.0]bicyclic system in 15. Furthermore,
in 13C NMR the C-2′ signal has shifted downfield to 91
ppm for 15 as observed for the similar [3.2.0]bicyclic
system in the original nucleoside analogue17 compared
to 78 ppm for C-2′ in 16. Thus, the preferred formation
of an oxetane ring was disfavored in this case, and in a
preliminary similar experiment also the â-anomer of 14
gave two bicyclic products. As nucleoside derivatives
potentially obtained by coupling of, e.g., thymine to 14
are expected to behave similarly, we decided to reconsider
the entire strategy.
When reconsidering the synthetic strategy, it appeared
obvious that a more stable permanent protecting group
for the 5′-hydroxy group was needed. Thus, a group that
is less labile toward both basic and acidic conditions,
compared to the silyl ether, might form the basis of
successful synthesis of the target bicyclic nucleoside.
Furthermore, some of the modest yields obtained with
the silyl ether might be improved (e.g., the conversions
of 8 to 11). The protecting group should also be stable
toward oxidative and reductive conditions, and as it
should be removable without affecting the azide moiety,
a benzyl ether could be excluded. Therefore, we chose the
p-methoxyphenyl ether as this can be selectively reacted
with primary alcohols, removed with mild oxidation using
cerium(IV) ammonium nitrate (CAN), and fulfills all
other criteria.29 To our knowledge, this protecting group
has been used in the construction of only few other
nucleoside derivatives.30
The anomeric configurations of the two products were
elucidated using NOE-difference spectroscopy in addition
to the information covered in the 3J HH coupling constants.
3
Thus, for the two anomers 25/26 the J H1′H2′ coupling
constants were <1 Hz and 3.3 Hz, respectively. For both
compounds, C-2′-endo conformations are expected, due
to the preference of the 2′-OH group for adopting a
pseudoaxial position and the 3′-carbon substituent for
adopting a pseudoequatorial position. Therefore, the
3
isomer with the very small J H1′H2′ constant can be
deduced to the R-anomer 26, as in this case a torsion
angle θH1′H2′ very close to 90° is expected. The coupling
constants for the bicyclic compounds further verified
these assignments as the R-anomers 28 and 29 displayed
3
very small coupling constants J H1′H2′ < 1 Hz, whereas
3
the â-anomers 27 and 5 displayed larger J H1′H2′ coupling
constants, 2.4 and 2.7 Hz, respectively. The characteristic
13C chemical shifts for the C-2′ between 86 and 92 ppm
(30) (a) Czernecki, S.; Ezzitouni, A.; Krausz, P. Synthesis 1990, 651.
(b) Czernecki, S.; Ezzitouni, A. J . Org. Chem. 1992, 57, 7325.
(31) J arell, H. C.; Ritchie, R. G. S.; Szarek, W. A.; J ones, J . K. N.
Can. J . Chem. 1973, 51, 1767.
(32) Martin, O. R.; Rao, S. P.; El-Shenawy, H. A.; Kurz, K. G.; Cutler,
A. B. J . Org. Chem. 1988, 53, 3287.
(27) Obika, S.; Morio, K.; Nanbu, D.; Imanishi, T. Chem. Commun.
1997, 1643.
(28) Bock, K.; Pedersen, C. Adv. Carbohydr. Chem. Biochem. 1983,
41, 27.
(29) Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett.
1985, 26, 6291.
(33) Nielsen, P.; Dalskov, J . K. Chem. Commun. 2000, 1179.

4882 J . Org. Chem., Vol. 66, No. 14, 2001
Sørensen et al.
Sch em e 3a
NMR. Thus, the presence of the oxetane ring demands
the torsion angle ν2 describing the C2′-C3′ torsion to be
relatively close to 0°. Hereby, the pseudorotation angle
P must be near 270° or 90° (Figure 2).7,9 From a
generalized Karplus equation, the relation between P and
3
the coupling constant J H1′H2′ can be found.34 Thus, for 5,
3
our experimental coupling constant J H1′H2′ ) 2.7 Hz,
confirms a conformation with P ∼90° as a conformation
3
with P ∼270° would demand a J H1′H2′ ∼7 Hz. Neverthe-
less, some flexibility in an oxetane ring can be expected.
However, from vibrational spectroscopy on simple oxet-
ane this ring type has been reported to be essentially
planar in contrast to the cyclobutane ring.35 Thus, for the
simple oxetane molecule the O-C-C-C torsion angle
has been estimated to be a maximum of 2.5°.35 Therefore,
as a supposition we can claim that ν2 e (7°. From the
definitions of ν2 ) Φmax cos P, where Φmax is the puckering
amplitude,7,9 this suggests that P can be found in the
following interval [90 ( 11°] if Φmax ) 36° as standard
for unmodified nucleosides7 and if compensated by a
lower puckering amplitude, e.g., Φmax ) 20°, the interval
is enlarged to [90 ( 20°]. Therefore, the bicyclic nucleo-
sides 5 and 29 are in all probability restricted in
conformations very close to pure E-type (O4′-endo) con-
formations. Furthermore, an ab initio calculation was
performed on 5, i.e., a geometry optimization at the
6-31G* level using the Gaussian94 program.36 This
confirmed the bicyclic nucleoside to adopt an E-conforma-
tion with P ) 91.4° (ν2 ) -1.1°) and Φmax ) 46.8°. The
θH1′H2′ ) 38.7° is in perfect agreement34 with our experi-
a
Reagents: (a) thymine, TMS-Cl, bis(trimethylsilyl)acetamide,
TMS-OTf, CH3CN (25: 32% and 26: 35%); (b) NaH, DMF
(27: 79%; 28: 93%); (c) CAN, CH3CN, H2O (5: 96%; 29: 80%).
PMP ) p-methoxyphenyl.
were observed for all the four bicyclic nucleosides. Finally,
mutual NOE contacts were seen for 5 between the
oxetane H-1′′ and the thymine H-6 (3%), between H-1′
and H-4′ (4%), and between H-1′′ and H-5′ (3%). These
contacts verify the â-configuration of the nucleoside as
well as the position of the oxetane ring on the â-face of
the furanose moiety. For 29, the mutual NOE contacts
between H-1′′ and H-5′ (2%) as well as the lack of contacts
between H-1′′ and H-6 and between H-1′ and H-4′
indicate the corresponding R-configuration. Finally, the
strong NOE contacts between the oxetane H-1′′ and the
thymine H-6 for 5 indicate an anti conformation7 of the
nucleobase moiety.
3
mental coupling constant J H1′H2′ ) 2.7 Hz.
The bicyclic nucleosides 5 and 29 were evaluated for
antiviral activity against HIV-1 in MT-4 cells (HIV-IIIB)
as described previously.37 Unfortunately, both compounds
were inactive against HIV-1 at 300 µM. Thus, the
conformational restriction of the furanose moiety of AZT
by the [3.2.0]bicyclic structure of 5 is unfavorable for anti-
HIV activity. This might be due to a decreased biotrans-
formation of 5 into its corresponding triphosphate or,
alternatively, to a low affinity of the triphosphate for
HIV-1 RT. Hence, these results confirm the results of
Marquez et al. suggesting that the conformational flex-
ibility is essential for the activity of AZT.4 Thus, the lack
of anti-HIV activity of 5 is not opposed to the results with
other bicyclic analogues of AZT (vide supra),4,15 confirm-
ing that the viral enzyme binds AZT in an N-conforma-
tion,12 whereas the enzymes performing the phosphory-
Discu ssion
The present synthesis of the target bicyclic derivative
5 has been accomplished in 6.4% overall yield from the
starting material 7 taking advantage of the p-methoxy-
phenyl protecting group. In addition, the same reaction
sequence afforded the R-anomer 29 in a similar 6.8%
overall yield. Thus, the yield limiting step toward 5 was
the nucleobase coupling reaction giving a mixture of
anomeric nucleosides. All other steps were performed in
satisfying yields. According to the retro-synthetic strategy
(Figure 3), the addition of a trichloromethyl group and
the subsequent Corey-Link-type reaction were per-
formed in high yields and with perfect stereoselectivity.
Furthermore, all other steps were performed successfully
setting up a convenient substrate 24 for nucleobase
coupling reactions. The key point in the synthesis has
been the choice of the p-methoxyphenyl ether as a
permanent protecting group for the primary alcohol
moiety. To our opinion, this simple ether group deserves
much greater attention in carbohydrate and nucleoside
chemistry as a very stable, easily removable, and selec-
tive protecting group for primary hydroxyl groups.
The conformational restriction of 5 in an O4′-endo
conformation can be confirmed by simple modeling and
3
(34) The Karplus relationship correlating J H1′H2′ and the pseudoro-
tational angle P was constructed employing a generalised Karplus
equation for nucleosides developed by Altona and co-workers, which
accounts for the electronegativity of substituents: (a) Donders, L. A.;
de Leeuw F. A. A. M.; Altona, C. Magn. Reson. Chem. 1989, 27, 556.
(b) Altona, C.; Ippel, J . H.; Westra Hoekzema, A. J . A.; Erkelens, C.;
Groesbeek, M.; Donders, L. A. Magn. Res. Chem. 1989, 27, 564. (c)
Altona, C.; Francke, R.; de Haan, R.; Ippel, J . H.; Daalmans, G. J .;
Westra Hoekzema, A. J . A.; van Wijk, J . Magn. Reson. Chem. 1994,
32, 670.
(35) (a) Chan, S. I.; Zinn, J .; Fernandez, J .; Gwinn, W. D. J . Chem.
Phys. 1960, 33, 1643. (b) Chan, S. I.; Zinn, J .; Gwinn, W. D. J . Chem.
Phys. 1961, 34, 1319.
(36) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.; Petersson,
G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.;
Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .;
Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala,
P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .;
Stewart, J . P.; Head-Gordon, M.; Gonzalez, C.; Pople, J . A. Gaussian
94, revision D.3; Gaussian, Inc.: Pittsburgh, PA, 1995.
(37) Danel, K.; Pedersen, E. B.; Nielsen, C. J . Med. Chem. 1998,
41, 191.

Synthesis of a Bicyclic Analogue of AZT
J . Org. Chem., Vol. 66, No. 14, 2001 4883
5-O-ter t-Bu tyld ip h en ylsilyl-1,2-O-isop r op ylid en e-â-D-
a r a bin ofu r a n -3-u lose (8).24 To a mixture of anhydrous
pyridine (15 mL, 187 mmol) and anhydrous CH2Cl2 (150 mL)
was added CrO3 (9.4 g, 94 mmol), and the mixture was stirred
for 15 min. After the mixture was cooled to 0 °C, a solution of
the secondary alcohol 7 (10 g, 23 mmol) in CH2Cl2 (70 mL)
was added dropwise. Acetic anhydride (9.0 mL, 94 mmol) was
added, and the mixture was stirred for 30 min. The mixture
was poured into a mixture of toluene and ethyl acetate (500
mL, 1:4 (v/v)), stirred for 20 min, and filtered through a layer
of silica. The filter was rinsed three times with ethyl acetate,
and the filtrate was evaporated under reduced pressure to give
the ketone 8 (8.70 g, 90%) as an oil: 1H NMR (CDCl3) δ 7.74-
7.68 (4H, m), 7.43-7.37 (6H, m), 6.03 (1H, d, J 4.5 Hz), 4.39
(1H, d, J 4.5 Hz), 4.30 (1H, t, J 4.6 Hz), 3.96-3.93 (2H, m),
1.38 (3H, s), 1.36 (3H, s), 1.07 (9H, s); 13C NMR (CDCl3) δ
207.11, 135.72, 132.93, 129.73, 127.70, 114.74, 102.57, 82.29,
76.73, 64.47, 27.43, 26.59, 19.20.
lation reactions recognize the substrates in S-confor-
mations.13 On the other hand, the well-established anti-
HIV activity of d4T1 indicates that some conformational
restriction in a conformation between N- and S-type
conformations can be accepted. Therefore, the inactivity
of 5 might be due to the molecular geometry, e.g., the
sterical effect of the oxetane ring, more than the confor-
mationally constrained structure. In forthcoming biologi-
cal studies, we might be able to deduce the low anti-HIV
activity to either low affinity for the target viral enzyme
or to insufficient biotransformation. Hence, 5 might be
a very important compound in the understanding of the
conformational preferences of these important enzymes.
Finally, we plan to use compounds 5 and 29 in our
ongoing study of conformationally restricted oligonucle-
otide analogues.3,16,17,33 Thus, oligonucleotide sequences
with so-called N3′-P5′-phosphoramidite internucleotide
linkages have revealed very promising results concerning
the recognition of complementary RNA sequences.38 As
the azide moiety of 5 and 29 should be easily converted
to a primary amine, these bicyclic nucleosides will be very
useful building blocks for the construction of conforma-
tionally restricted oligonucleotide sequences with N3′-
P5′-phosphoramidite linkages and evaluated with both
the R- and â-geometry for their properties in nucleic acid
recognition.
5-O-ter t-Bu tyld ip h en ylsilyl-3-C-tr ich lor om eth yl-1,2-O-
isop r op ylid en e-â-D-lyxofu r a n ose (9). The ketone 8 (2.5 g,
5.9 mmol) was dissolved in anhydrous THF (25 mL) and
anhydrous CHCl3 (2.6 mL, 32 mmol). The solution was stirred
at -78 °C, and a 1 M solution of LiHMDS in THF (21.3 mL,
21.3 mmol) was added slowly. The solution was stirred at -78
°C for 3 h, and the reaction was poured into an ice-cold
saturated aqueous solution of NaHCO3. The mixture was
extracted with CH2Cl2, and the combined organic phases were
dried (Na2SO4) and evaporated to dryness under reduced
pressure. The residue was purified by silica gel chromatogra-
phy using hexanes/ethyl acetate (9:1 (v/v)) as eluent affording
the tertiary alcohol 9 (1.72 g, 54%) as an oil after evaporation
of the solvents: FAB-MS m/z 487 [M - t-Bu]+; 1H NMR
(CDCl3) δ 7.73-7.71 (4H, m, Ph), 7.43-7.36 (6H, m, Ph), 5.95
(1H, d, J 4.3 Hz, 1-H), 4.80 (1H, d, J 4.3 Hz, 2-H), 4.64 (1H,
dd, J 4.7, 7.3 Hz, 4-H), 4.36 (1H, s, OH), 4.09 (1H, dd, J 4.7,
11.1 Hz, 5-H), 3.93 (1H, dd, J 7.3, 11.1 Hz, 5-H), 1.49 (3H, s,
CH3), 1.42 (3H, s, CH3), 1.10 (9H, s, CH3); 13C NMR (CDCl3) δ
135.73, 135.61, 133.16, 132.86, 129.68, 129.71, 127.67, 114.14,
105.54, 103.90, 87.50, 84.28, 82.17, 65.13, 27.06, 26.82, 19.16.
3-C-Azid o-5-O-ter t-b u t yld ip h en ylsilyl-1,2-O-isop r op -
ylid en e-3-C-m eth oxyca r bon yl-â-D-a r a bin ofu r a n ose (10).
The tertiary alcohol 9 (2.9 g, 5.3 mmol) was dissolved in
anhydrous MeOH (25 mL), and NaN3 (1.04 g, 16.0 mmol) and
18-crown-6 (15 mg, 0.057 mmol) were added. DBU (4.00 mL,
26.7 mmol) was added dropwise, and the mixture was stirred
at 50 °C for 1 h and poured into a saturated aqueous solution
of NH4Cl (50 mL). The mixture was extracted with ether, and
the combined organic extracts were dried (Na2SO4) and
evaporated to dryness under reduced pressure. The residue
was purified by silica gel chromatography using hexanes/ethyl
acetate (9:1 (v/v)) as eluent affording the azido ester 10 (1.83
g, 68%) as an oil after evaporation of the solvents: FAB-MS
Con clu sion
The synthesis of a bicyclic AZT analogue 5 and its
anomer 29 has been successfully accomplished using, e.g.,
a modified Corey-Link procedure. The nucleoside ana-
logue 5 is conformationally restricted in the unusual
E-type (O4′-endo) conformation but inactive against
HIV-1 in MT-4 cells. These results are in line with the
results by Marquez et al.4 indicating that conformational
flexibility is essential for the anti-HIV activity of 2′,3′-
dideoxynucleoside analogues. On the other hand, the
inactivity of 5 might also be due to steric effects. In
general, the present [3.2.0]bicyclic structure might find
wider applicability in other nucleoside analogues for the
study of the correlation between conformational behavior
of nucleoside substrates and their affinity for nucleoside/
nucleotide converting enzymes and receptors.
m/z 496 [M - Me]+; IR (KBr) 2114, 1756 cm-1 1H NMR
;
Exp er im en ta l Section
(CDCl3) δ 7.69-7.65 (4H, m, Ph), 7.42-7.35 (6H, m, Ph), 5.84
(1H, d, J 3.5 Hz, 1-H), 4.50 (1H, d, J 3.5 Hz, 2-H), 4.25 (1H, t,
J 6.2 Hz, 4-H), 4.09 (1H, dd, J 6.2, 10.4 Hz, 5-H), 3.95 (1H,
dd, J 6.5, 10.4 Hz, 5-H), 3.74 (3H, s, OCH3), 1.36 (3H, s, CH3),
1.30 (3H, s, CH3), 1.06 (9H, s, CH3); 13C NMR (CDCl3) δ 166.04
(1′-C), 135.60, 135.49, 133.27, 132.96, 129.70, 129.68, 127.68,
127.67 (Ph), 114.77 (C(CH3)2), 105.20 (1-C), 85.78 (4-C), 84.95
(2-C), 73.59 (3-C), 63.27 (5-C), 52.71 (OCH3), 26.73 (CH3), 26.35
(CH3), 19.14 (C(CH3)3).
3-C-Azid o-5-O-ter t-b u t yld ip h en ylsilyl-1,2-O-isop r op -
yliden e-3-C-h ydr oxym eth yl-â-D-ar abin ofu r an ose (11). The
azido ester 10 (1.75 g, 3.42 mmol) was dissolved in 96% EtOH
(25 mL), and the solution was stirred at 0 °C. NaBH4 (0.26 g,
6.8 mmol) was added, and the mixture was stirred at 5 °C for
12 h and poured into an ice-cold saturated aqueous solution
of NaHCO3. The mixture was extracted with CH2Cl2, and the
combined organic extracts were dried (Na2SO4) and evaporated
to dryness under reduced pressure. The residue was purified
by silica gel chromatography using hexanes/ethyl acetate (9:1
(v/v)) as eluent affording the primary alcohol 11 (1.08 g, 66%)
as a white solid after evaporation of the solvents: FAB-MS
m/z 484 [M + H]+; IR (KBr) 3446, 2114 cm-1; 1H NMR (CDCl3)
Reactions were performed under an atmosphere of nitrogen
when anhydrous solvents were used. Column chromatography
was carried out on glass columns using silica gel 60 (0.040-
0.063 mm). Chemical shifts are reported in ppm relative to
1
tetramethylsilane as internal standard for H NMR (250, 300,
or 500 MHz) and 13C NMR (62.5 or 75 MHz). 1H NOE
difference spectra were recorded for compounds 12, 5, and 29.
Assignments of NMR spectra when given are based on 2D
spectra and follow standard carbohydrate and nucleoside style;
i.e., the carbon atom next to a nucleobase is assigned C-1′, etc.
In nucleosides, C-1′′ designates the carbon atom in the 3′-C
branch; otherwise, C-1′ designates the carbon atom in the 3-C
branch. Compound names given in this section for the bicyclic
compounds are given according to the von Baeyer nomencla-
ture. Fast-atom bombardment mass spectra (FAB-MS) were
recorded in positive-ion mode. Microanalyses were performed
at The Microanalytical Laboratory, Department of Chemistry,
University of Copenhagen.
(38) For a review, see: Gryaznov, S. M. Biochim. Biophys. Acta 1999,
1489, 131.

4884 J . Org. Chem., Vol. 66, No. 14, 2001
Sørensen et al.
δ 7.68-7.62 (4H, m, Ph), 7.46-7.37 (6H, m, Ph), 5.80 (1H, d,
J 3.9 Hz, 1-H), 4.40-4.29 (3H, m, 2-H, 4-H, 1′-H), 4.15-4.01
(2H, m, 5-H, 1′-H), 3.73 (1H, dd, J 3.8, 10.6 Hz, H-5), 3.13
(1H, dd, J 4.1, 10.1 Hz, OH), 1.25 (3H, s, CH3), 1.21 (3H, s,
CH3), 1.08 (9H, s, CH3); 13C NMR (CDCl3) δ 135.47, 135.44,
132.06, 131.61, 130.20, 128.01, 128.00, 112.86, 105.82, 85.36,
84.11, 74.60, 64.01, 62.56, 26.79, 26.12, 25.42, 19.03. Anal.
Calcd for C25H33N3O5Si: C, 62.09; H, 6.88; N, 8.69. Found: C,
61.99; H, 6.92; N, 8.47.
(1H, m, H-4), 4.19 (1H, m, H-2), 3.59 (3H, s, OCH3), 3.14 (3H,
s, SO2CH3) 3.09 (3H, s, SO2CH3); 13C NMR (CDCl3) δ 102.89
(C-1), 80.13 (C-4), 75.93 (C-2), 71.00 (C-3), 67.57, 66.79 (C-5,
C-1′), 56.92 (OCH3), 37.70, 37.60 (2 × SO2CH3).
(1R,2S,4S,5S)-1-Azid o-2-m et h a n su lfon yloxym et h yl-4-
m eth oxy-3,6-d ioxa bicyclo[3.2.0]h ep ta n e (15) a n d (1S,3S,-
4S,7R)-7-Azid o-7-m eth a n su lfon yloxym eth yl-3-m eth oxy-
2,5-d ioxa bicyclo[2.2.1]h ep ta n e (16). The methyl furanoside
14R (69 mg, 0.18 mmol) was dissolved in anhydrous DMF (1
mL), and a 60% oily dispersion of NaH (12.5 mg, 0.31 mmol)
was added. The mixture was stirred at room temperature for
30 min, and water (1 mL) was added. The mixture was
neutralized with a 0.1 M aqueous solution of HCl and poured
into CH2Cl2 (10 mL). The organic phase was washed with a
saturated aqueous solution of NaHCO3, dried (Na2SO4), and
evaporated to dryness under reduced pressure. The residue
was purified by silica gel chromatography using hexanes/ethyl
acetate (7:3 (v/v)) as eluent affording the bicyclic compounds
15 (6 mg, 12%) and 16 (29 mg, 57%) as clear oils after
evaporation of the solvents. 15: FAB-MS m/z 280 [M + H]+;
1H NMR (CDCl3) δ 5.01, 5.00 (2H, 2 × s, 1-H, 2-H), 4.76 (1H,
d, J 7.8 Hz, 1′-H), 4.69 (1H, d, J 7.8 Hz, 1′-H), 4.56 (1H, dd J
6.5, 11.3 Hz, 5-H), 4.42 (1H, dd J 4.7, 11.3 Hz, 5-H), 4.15 (1H,
m, 4-H) 3.41 (3H, s, OCH3), 3.11 (3H, s, SO2CH3); 13C NMR
(CDCl3) δ 105.86, 91.30, 76.92, 73.07, 67.17, 65.86, 54.93, 37.84.
16: 1H NMR (CDCl3) δ 5.03 (1H, s, 1-H), 4.56 (1H, s, 4-H),
4.51 (1H, d, J 11.0 Hz, 5-H), 4.44 (1H, d, J 11.0 Hz, 5-H), 4.10
(1H, s, 2-H), 4.00 (1H, d, J 9.3 Hz, 1′-H), 3.87 (1H, d, J 9.3 Hz,
1′-H), 3.52 (3H, s, OCH3), 3.13 (3H, s, SO2CH3); 13C NMR
(CDCl3) δ 106.82 (1-C), 78.39 (4-C), 77.98 (2-C), 71.21 (1′-C),
69.86 (3-C), 69.39 (5-C), 56.79 (OCH3), 37.59 (SO2CH3).
1,2-O-Isop r op ylid en e-5-O-p -m et h oxyp h en yl-â-D-a r a -
bin ofu r a n ose (18). The silyl ether 7 (20 g, 47 mmol) was
dissolved in anhydrous THF (150 mL), and KF (16.2 g, 280
mmol), water (10 mL, 560 mmol), and 18-crown-6 (3.6 g, 14
mmol) were added. The mixture was stirred at room temper-
ature for 18 h and evaporated to dryness under reduced
pressure. The residue was purified by silica gel chromatogra-
phy using CH2Cl2/MeOH (9:1 (v/v)) as eluent affording the
dialcohol 1732 (7.93 g) as a white solid after evaporation of the
solvents. This solid was redissolved in anhydrous THF (50
mL), and triphenylphosphine (14.2 g, 54.1 mmol) and 4-meth-
oxyphenol (14.9 g, 121 mmol) were added. The mixture was
stirred at 0 °C, and DEAD (8.5 mL, 54 mmol) was added
dropwise. The mixture was stirred at 0 °C for 30 min and at
50 °C for 16 h. The solvent was removed by evaporation under
reduced pressure, and the residue was purified by silica gel
chromatography using hexanes/ether (1:1 (v/v)) as eluent
affording the phenyl ether 18 (8.75 g, 63%) as a white solid
3-C-Azid o-5-O-ter t-b u t yld ip h en ylsilyl-1,2-O-isop r op -
ylidene-3-C-methansulfonyloxymethyl-â-D-arabinofuranose
(12). The primary alcohol 11 (300 mg, 0.62 mmol) was
dissolved in anhydrous pyridine (5 mL) and the solution was
stirred at 0 °C. Methanesulfonyl chloride (0.1 mL, 1.2 mmol)
was added and the mixture was stirred at room temperature
for 1 h and evaporated to dryness under reduced pressure. The
residue was redissolved in CH2Cl2 and washed with a satu-
rated aqueous solution of NaHCO3. The organic phase was
dried (Na2SO4), and evaporated to dryness under reduced
pressure. The residue was purified by silica gel chromatogra-
phy using CH2Cl2/MeOH (98:2 (v/v)) as eluent affording the
sulfonic ester 12 (227 mg, 77%) as an white solid after
evaporation of the solvents: FAB-MS m/z 466 [M - MsO]+;
1H NMR (CDCl3) δ 7.69-7.64 (4H, m, Ph), 7.48-7.41 (6H, m,
Ph), 5.88 (1H, d, J 3.8 Hz, 1-H), 4.67 (2H, s, 2 × 1′-H), 4.54
(1H, d, J 3.8 Hz, 2-H), 4.24 (1H, dd, J 4.5, 10.1 Hz, 4-H), 3.94
(1H, t, J 10.2 Hz, 5-H), 3.78 (1H, dd, J 4.4, 10.4 Hz, 5-H), 3.03
(3H, s, SO2CH3), 1.26 (6H, s, CH3), 1.09 (9H, s, CH3); 13C NMR
(CDCl3) δ 135.55, 135.47, 132.40, 132.11, 130.03, 130.00,
127.95, 127.89 (Ph), 112.95 (C(CH3)2), 105.60 (1-C), 85.75 (4-
C), 82.97 (2-C), 72.09 (3-C), 67.98 (1′-C), 62.93 (5-C), 37.26 (SO2-
CH3), 26.81 (C(CH3)3), 25.96 (CH3), 25.56 (CH3), 19.00 (C(CH3)3).
3-C-Azid o-5-O-m eth a n su lfon yl-1,2-O-isop r op ylid en e-3-
C-m et h a n su lfon yloxym et h yl-â-D-a r a b in ofu r a n ose (13).
The primary alcohol 11 (300 mg, 0.62 mmol) was dissolved in
anhydrous THF (5 mL), and a 1 M solution of TBAF in THF
(0.68 mL, 0.68 mmol) was added. The mixture was stirred at
room temperature for 30 min and evaporated to dryness under
reduced pressure. The residue was redissolved in anhydrous
pyridine (2 mL), and methanesulfonyl chloride (0.2 mL, 2.5
mmol) was added. The mixture was stirred at room temper-
ature for 30 min and evaporated to dryness under reduced
pressure. The residue was redissolved in CH2Cl2 and washed
with a saturated aqueous solution of NaHCO3. The organic
phase was dried (Na2SO4) and evaporated to dryness under
reduced pressure. The residue was purified by silica gel
chromatography using CH2Cl2 as eluent affording the sulfonic
ester 13 (240 mg, 96%) as an off-white solid after evaporation
of the solvents: FAB-MS m/z 402 [M + H]+; 1H NMR (CDCl3)
δ 6.00 (1H, d, J 3.5 Hz), 4.58-4.40 (6H, m), 3.15 (6H, s), 1.63
(3H, s), 1.33 (3H, s); 13C NMR (CDCl3) δ 113.79, 106.06, 83.26,
82.41, 71.37, 67.32, 66.65, 38.07, 37.68, 25.88, 25.33.
Meth yl 3-C-Azid o-5-O-m eth a n su lfon yl-1,2-O-isop r op -
ylid en e-3-C-m eth a n su lfon yloxym eth yl-D-a r a bin ofu r a n o-
sid e (14). The sulfonic ester 13 (276 mg, 0.69 mmol) was
dissolved in CH2Cl2 (1 mL). MeOH (2.6 mL) and water (1.4
mL) were added, and the mixture was stirred at 0 °C. A
solution of HCl in MeOH (7 mL, 26% (w/w)) was added, and
the reaction mixture was stirred at room temperature for 16
h. Water (5 mL) was added, and the mixture was neutralized
by NaHCO3(s) and extracted with CH2Cl2. The combined
organic extracts were dried (Na2SO4) and evaporated to
dryness under reduced pressure. The residue was purified by
silica gel chromatography using CH2Cl2/MeOH (98:2 (v/v)) as
eluent affording the two anomeric methyl furanoside 14R (153
mg, 59%) and 14â (51 mg, 20%) as clear oils after evaporation
of the solvents. 14R: FAB-MS m/z 376 [M + H]+; 1H NMR
(CDCl3) δ 4.99 (1H, s, H-1), 4.68 (1H, d, J 11.1 Hz, H-1′), 4.49-
4.32 (5H, m, H-2, 2 x H-5, H-1′ og H-4), 3.44 (3H, s, OCH3),
3.16 (3H, s, SO2-CH3) 3.11 (3H, s, SO2-CH3); 13C NMR
(CDCl3) δ 108.86 (C-1), 80.87 (C-4), 79.89 (C-2), 70.17 (C-3),
67.38, 67.04 (C-5, C-1′), 55.83 (OCH3), 37.82, 37.58 (2 × SO2-
CH3). 14â: FAB-MS m/z 376 [M + H]+; 1H NMR (CDCl3) δ
5.17 (1H, d, J 4.5 Hz, H-1), 4.65 (1H, d, J 11.1 Hz, H-1′), 4.57,
(1H, d, J 11.1 Hz, H-1′), 4.41 (2H, d, J 5.9 Hz, 2 x H5), 4.29
1
after evaporation of the solvents: FAB-MS m/z 296 [M]+; H
NMR (CDCl3) δ 6.84 (4H, s), 5.97 (1H, d, J 3.8 Hz), 4.60 (1H,
d, J 3.8 Hz), 4.43 (1H, br s), 4.30 (1H, m), 4.25-4.10 (3H, m),
3.79 (3H, s), 2.46 (1H, br s), 1.55 (3H, s), 1.34 (3H, s); 13C NMR
(CDCl3) δ 154.07, 152.52, 115.51, 114.67, 112.71, 105.75, 86.91,
85.56, 76.42, 68.38, 55.67, 26.94, 26.02. Anal. Calcd for
C
15H20O6: C, 60.81; H, 6.76. Found: C, 61.07; H, 6.76.
1,2-O-Isop r op ylid en e-5-O-p -m et h oxyp h en yl-â-D-a r a -
bin ofu r a n -3-u lose (19). To a mixture of anhydrous pyridine
(2.0 mL, 27 mmol) and anhydrous CH2Cl2 (15 mL) was added
CrO3 (1.3 g, 14 mmol), and the mixture was stirred for 15 min.
After the mixture was cooled to 0 °C, a solution of the
secondary alcohol 18 (1.0 g, 3.4 mmol) in CH2Cl2 (10 mL) was
added dropwise. Acetic anhydride (1.3 mL, 14 mmol) was
added, and the mixture was stirred for 30 min. The mixture
was poured into a mixture of toluene and ethyl acetate (50
mL, 1:3 (v/v)), stirred for 20 min, and filtered through a layer
of silica. The filter was rinsed three times with ethyl acetate,
and the filtrate was evaporated under reduced pressure to give
the ketone 8 (0.99 g, 99%) as an oil: 1H NMR (CDCl3) δ 6.88-
6.79 (4H, m), 6.08 (1H, d, J 4.0 Hz), 4.50-4.48 (2H, m), 4.26-
4.15 (2H, m), 3.75 (3H, s), 1.56 (3H, s), 1.42 (3H, s); 13C NMR
(CDCl3) δ 207.05, 154.34, 152.29, 116.02, 115.11, 114.60,
102.74, 80.27, 76.67, 68.89, 55.61, 27.43, 26.93.
1,2-O-Isopr opyliden e-5-O-p-m eth oxyph en yl-3-C-tr ich lo-
r om eth yl-â-D-lyxofu r a n ose (20). The ketone 19 (0.99 g, 3.4

Synthesis of a Bicyclic Analogue of AZT
J . Org. Chem., Vol. 66, No. 14, 2001 4885
mmol) was dissolved in anhydrous THF (10 mL) and anhy-
drous CHCl3 (0.75 mL, 9.3 mmol). The solution was stirred at
-78 °C, and a 1 M solution of LiHMDS in THF (6.0 mL, 6.0
mmol) was added slowly. The solution was stirred at -78 °C
for 3 h, and the reaction mixture was poured into an ice-cold
saturated aqueous solution of NaHCO3. The mixture was
extracted with CH2Cl2, and the combined organic phases were
dried (MgSO4), and evaporated to dryness under reduced
pressure. The residue was purified by silica gel chromatogra-
phy using CH2Cl2 as eluent affording the tertiary alcohol 20
(1.03 g, 74%) as a white solid after evaporation of the
solvents: FAB-MS m/z 412 [M]+; 1H NMR (CDCl3) δ 6.92-
6.81 (4H, m), 6.00 (1H, d, J 4.2 Hz), 4.90-4.86 (2H, m), 4.39
(1H, dd, J 2.9, 10.8 Hz), 4.16 (1H, dd, J 8.2, 10.8 Hz), 4.11
(1H, s), 3.76 (3H, s), 1.66 (3H, s), 1.47 (3H, s); 13C NMR (CDCl3)
δ 154.05, 152.66, 115.68, 114.84, 114.59, 105.53, 86.94, 82.76,
82.22, 69.95, 55.69, 27.27, 27.03. Anal. Calcd for C16H19O6Cl3:
C, 46.60; H, 4.61. Found: C, 46.65; H, 4.47.
(1H, d, J 10.8 Hz, 1′-H), 4.58 (1H, d, J 10.8 Hz, 1′-H), 4.56
(1H, d, J 3.8 Hz, 2-H), 4.47 (1H, dd, J 5.1, 8.9 Hz, 4-H), 4.24
(1H, t, J 9.5 Hz, 5-H), 4.14 (1H, dd, J 5.1, 9.9 Hz, 5-H), 3.77
(3H, s, OCH3), 3.08 (3H, s, SO2CH3), 1.58 (3H, s, CH3), 1.34
(3H, s, CH3); 13C NMR (CDCl3) δ 154.50, 151.68, 115.51,
114.83, 113.37, 105.77, 83.34, 83.22, 71.90, 67.49, 67.38, 55.67,
37.56, 26.42, 25.59.
Meth yl 3-C-Azid o-3-C-m eth a n su lfon yloxym eth yl-5-O-
p -m et h oxyp h en yl-D-a r a b in ofu r a n osid e (24). Anhydrous
MeOH (10 mL) was stirred at -30 °C, and acetyl chloride (2
mL) was added slowly. The mixture was stirred at -30 °C for
30 min and warmed to room temperature. A solution of 23
(540 mg, 1.26 mmol) in CH2Cl2/MeOH/water (2:2:1 (v/v/v), 12.5
mL) was stirred at 0 °C, and the first solution was added
dropwise. The mixture was stirred at room temperature for
16 h, and water (12 mL) was added. The mixture was
neutralized with NaHCO3(s) and extracted with CH2Cl2. The
combined organic extracts were dried (MgSO4) and evaporated
to dryness under reduced pressure. The residue was purified
by silica gel chromatography using CH2Cl2/MeOH (97:3 (v/v))
as eluent affording the anomeric mixture 24 (510 mg, 94%) as
a clear oil after evaporation of the solvents: FAB-MS m/z 403
[M]+; 1H NMR (CDCl3) δ 6.90-6.83 (m), 5.16 (d, J 4.8 Hz),
5.05 (s), 4.72-4.56 (m), 4.45-4.11 (m), 3.77 (s), 3.45 (s), 3.08
(s); 13C NMR (CDCl3) δ 154.94, 154.64, 151.97, 151.35, 116.08,
115.69, 114.86, 114.74, 109.59, 102.65, 82.36, 80.92, 79.33,
76.00, 71.26, 70.83, 68.19, 67.84, 67.81, 67.34, 56.68, 55.78,
55.68, 37.53, 37.46.
3-C-Azid o-1,2-O-isop r op ylid en e-3-C-m eth oxyca r bon yl-
5-O-p-m eth oxyp h en yl-â-D-a r a bin ofu r a n ose (21). The ter-
tiary alcohol 20 (1.08 g, 2.62 mmol) was dissolved in anhydrous
MeOH (15 mL), and NaN3 (0.42 g, 6.5 mmol) and 18-crown-6
(5 mg, 0.019 mmol) were added. DBU (1.6 mL, 11 mmol) was
added dropwise, and the mixture was stirred at 40 °C for 1 h
and poured into a saturated aqueous solution of NH4Cl (25
mL). The mixture was extracted with ether, and the combined
organic extracts were dried (MgSO4) and evaporated to dryness
under reduced pressure. The residue was purified by silica gel
chromatography using CH2Cl2 as eluent affording the azido
ester 21 (0.87 g, 87%) as a clear oil after evaporation of the
1-(3-C-Azido-3-C-m eth an su lfon yloxym eth yl-5-O-p-m eth -
oxyp h en yl-r/â-D-a r a bin ofu r a n osyl)th ym in e (25 a n d 26).
The anomeric mixture of methyl furanosides 24 (320 mg, 0.80
mmol) was coevaporated with anhydrous CH3CN (3 × 20 mL).
Thymine (0.2 g, 1.6 mmol) was added, and the mixture was
dried under reduced pressure and dissolved under an Ar
atmosphere in anhydrous CH3CN (4 mL). N,O-Bis(trimethyl-
silyl)acetamide (BSA) (1.5 mL, 6.5 mmol) and TMS-Cl (0.10
mL, 0.80 mmol) were added, and the mixture was stirred at
60 °C for 1 h. After the mixture was cooled to 0 °C, TMS-triflate
(0.73 mL, 4.0 mmol) was added dropwise, and the mixture was
stirred at 70 °C for 24 h. An additional portion of TMS-triflate
(0.3 mL, 1.6 mmol) was added, and after being stirred for
another 24 h, the mixture was poured into a saturated aqueous
solution of NaHCO3 (30 mL). CH2Cl2 was added, and the
organic phase was washed with a saturated aqueous solution
of NaHCO3, dried (MgSO4), and evaporated to dryness under
reduced pressure. The residue was redissolved in anhydrous
THF (10 mL), and a 1 M solution of TBAF in THF (1.2 mL,
1.2 mmol) was added. The solution was stirred at room
temperature for 1 h and diluted with CH2Cl2. The mixture was
washed with a saturated aqueous solution of NaHCO3 and
water, dried (MgSO4), and evaporated to dryness under
reduced pressure. The residue was purified by silica gel
chromatography using CH2Cl2/MeOH (19:1 (v/v)) as eluent
affording the R-anomer 26 (139 mg, 35%) as a white foam and
the â-anomer 25 (126 mg, 32%) as an oil after evaporation of
solvents: FAB-MS m/z 379 [M]+; IR (KBr) 2119, 1751 cm-1
;
1H NMR (CDCl3) δ 6.87-6.80 (4H, m, PMP), 5.93 (1H, d, J
3.6 Hz, 1-H), 4.59 (1H, d, J 3.6 Hz, 2-H), 4.47 (1H, t, J 6.1 Hz,
4-H), 4.39 (1H, dd, J 5.8, 9.8 Hz, 5-H), 4.29 (1H, dd, J 6.7, 9.8
Hz, 5-H), 3.82 (3H, s, OCH3), 3.77 (3H, s, OCH3), 1.58 (3H, s,
CH3), 1.36 (3H, s, CH3); 13C NMR (CDCl3) δ 165.85 (1′-C),
154.13, 152.24, 115.55, 114.59 (PMP), 114.99 (C(CH3)2), 105.30
(1-C), 85.07 (2-C), 83.14 (4-C), 73.97 (3-C), 67.50 (5-C), 55.62
(OCH3), 52.91 (OCH3), 26.60, 26.34 (CH3). Anal. Calcd for
C
17H21O7N3: C, 53.83; H, 5.54; N, 11.08. Found: C, 53.78; H,
5.50; N, 10.93.
3-C-Azid o-1,2-O-isop r op ylid en e-3-C-h yd r oxym eth yl-5-
O-p-m eth oxyp h en yl-â-D-a r a bin ofu r a n ose (22). The azido
ester 21 (0.91 g, 2.41 mmol) was dissolved in THF (5 mL) and
96% EtOH (15 mL), and the solution was stirred at 0 °C.
NaBH4 (0.27 g, 7.22 mmol) was added, and the mixture was
stirred at 5 °C for 14 h and poured into an ice-cold saturated
aqueous solution of NaHCO3. The mixture was extracted with
CH2Cl2, and the combined organic extracts were dried (Na2-
SO4) and evaporated to dryness under reduced pressure. The
residue was purified by silica gel chromatography using
hexanes/ethyl acetate (9:1 (v/v)) as eluent affording the
primary alcohol 22 (0.67 g, 80%) as a clear oil after evaporation
of the solvents: FAB-MS m/z 351 [M]+; IR (KBr) 3440, 2131
cm-1; 1H NMR (CDCl3) δ 6.88-6.82 (4H, m), 5.94 (1H, d, J 3.8
Hz), 4.57-4.02 (6H, m), 3.78 (3H, s), 1.57 (3H, s), 1.31 (3H, s);
13C NMR (CDCl3) δ 154.69, 151.45, 115.54, 114.87, 113.10,
105.94, 84.16, 83.07, 74.43, 68.36, 62.29, 55.69, 26.57, 25.45.
Anal. Calcd for C16H21O6N3: C, 54.70; H, 5.98; N, 11.96.
Found: C, 54.68; H, 5.87; N, 11.72.
3-C-Azid o-1,2-O-isop r op ylid e n e -3-C-m e t h a n su lfon -
yloxym eth yl-5-O-p-m eth oxyp h en yl-â-D-a r a bin ofu r a n ose
(23). The primary alcohol 22 (649 mg, 1.85 mmol) was
dissolved in anhydrous pyridine (7 mL), and the solution was
stirred at 0 °C. Methanesulfonyl chloride (0.43 mL, 5.6 mmol)
was added, and the mixture was stirred at room temperature
for 1 h and evaporated to dryness under reduced pressure. The
residue was redissolved in CH2Cl2 and washed with a satu-
rated aqueous solution of NaHCO3. The organic phase was
dried (Na2SO4) and evaporated to dryness under reduced
pressure. The residue was purified by silica gel chromatogra-
phy using CH2Cl2/MeOH (98:2 (v/v)) as eluent affording the
sulfonic ester 23 (690 mg, 87%) as a white solid after evapora-
tion of the solvents: FAB-MS m/z 429 [M]+; 1H NMR (CDCl3)
δ 6.87-6.80 (4H, m, PMP), 5.99 (1H, d, J 3.8 Hz, 1-H), 4.66
1
the solvents. 26: FAB-MS m/z 497 [M]+; H NMR (CDCl3) δ
10.45 (1H, s, NH), 7.49 (1H, d, J 1.0 Hz, 6-H), 6.90-6.83 (4H,
m, PMP), 6.03 (1H, br s, 2′-OH), 5.91 (1H, s, 1′-H), 4.79-4.67
(3H, m, 4′-H, 5′-H′, 1′′-H), 4.47 (1H, br s, 2′-H), 4.28-4.24 (2H,
m, 5′-H, 1′′-H), 3.78 (3H, s, OCH3) 3.09 (3H, s, SO2CH3), 1.95
(3H, s, CH3); 13C NMR (CDCl3) δ 164.73 (4-C), 154.60 (3-C),
151.72, 150.57 (PMP), 135.23 (6-C), 115.70, 114.83 (PMP),
110.36 (5-C), 94.23 (1′-C), 85.23 (4′-C), 78.92 (2′-C), 71.12 (3′-
C), 67.55, 67.29 (1′′-C, 5′-C), 55.73 (OCH3), 37.51 (SO2CH3),
12.64 (CH3). Anal. Calcd for C19H23N5O9S: C, 45.87; H, 4.66;
N, 14.08; s, 6.44. Found: C, 45.62; H, 4.52; N, 13.52; S, 6.21.
25: FAB-MS m/z 498 [M + H]+; 1H NMR (CDCl3) δ 11.08 (1H,
s, NH), 7.38 (1H, s, 6-H), 6.88 (4H, br s, PMP), 6.26 (1H, d, J
2.9 Hz, 1′-H), 5.57 (1H, d, J 5.4 Hz, 2′-OH), 4.79-4.63 (3H,
m, 2 × 1′′-H, 2′-H), 4.44 (1H, t, J 6.2 Hz, 4′-H), 4.24 (2H, m, 2
× 5′-H), 3.78 (3H, s, OCH3), 3.12 (3H, s, SO2CH3), 1.58 (3H, s,
CH3); 13C NMR (CDCl3) δ 166.01 (4-C), 154.71 (2-C), 151.86,
150.42 (PMP), 138.79 (6-C), 115.84, 114.91 (PMP), 107.95 (5-
C), 88.11 (1′-C), 82.39 (4′-C), 73.44 (3′-C), 71.81 (2′-C), 67.34,
(1′′-C, 5′-C), 55.75 (OCH3), 37.63 (SO2CH3), 12.17 (CH3).

4886 J . Org. Chem., Vol. 66, No. 14, 2001
Sørensen et al.
(1R,2S,4R,5S)-1-Azid o-2-(p-m eth oxyp h en oxy)m eth yl-4-
(th ym in -1-yl)-3,6-dioxabicyclo[3.2.0]h eptan e (27). The â-nu-
cleoside 25 (181 mg, 0.36 mmol) was dissolved in anhydrous
DMF (3 mL), and a 60% oily dispersion of NaH (36 mg, 0.91
mmol) was added. The mixture was stirred at room temper-
ature for 1 h and quenched with water (3 mL). The mixture
was neutralized with a 0.1 M aqueous solution of HCl and
extracted with CH2Cl2 . The organic phase was washed with
a saturated aqueous solution of NaHCO3, dried (MgSO4), and
evaporated to dryness under reduced pressure. The residue
was purified by silica gel chromatography using CH2Cl2/MeOH
(97:3 (v/v)) as eluent affording the bicyclic â-nucleoside 27
(115.5 mg, 79%) as a white solid after evaporation of the
solvents: FAB-MS m/z 402 [M + H]+; 1H NMR (CDCl3) δ 8.50
(1H, s, NH), 7.52 (1H, s, 6-H), 6.91-6.85 (4H, m, PMP), 6.03
(1H, d, J 2.4 Hz, 1′-H), 5.21 (1H, d, J 2.4 Hz, 2′-H), 4.96 (1H,
d, J 7.8 Hz, 1′′-H), 4.88 (1H, d, J 7.8 Hz, 1′′-H), 4.41 (1H, dd,
J 5.7, 10.2 Hz, 5′-H), 4.27 (1H, dd, J 5.7, 10.2 Hz, 5′-H), 4.18
(1H, t, J 5.7 Hz, 4′-H) 3.79 (3H, s, OCH3) 1.93 (3H, s, CH3);
13C NMR (CDCl3) δ 163.57,154.56, 151.88, 150.20, 137.01,
115.39, 114.75, 110.19, 87.16, 83.41, 78.47, 73.07, 66.90, 65.37,
55.68, 12.54. Anal. Calcd for C18H19N5O6: C, 53.86; H, 4.77;
N, 17.45. Found: C, 53.68; H, 4.85; N, 17.04.
(1R,2S,4S,5S)-1-Azid o-2-(p-m eth oxyp h en oxy)m eth yl-4-
(th ym in -1-yl)-3,6-dioxabicyclo[3.2.0]h eptan e (28). The same
procedure as in the preparation of 27 was used applying the
R-nucleoside 26 (114 mg, 0.23 mmol), anhydrous DMF (3 mL)
and a 60% oily dispersion of NaH (18.4 mg, 0.46 mmol)
affording the bicyclic R-nucleoside 28 (85.1 mg, 93%) as a white
solid: FAB-MS m/z 402 [M + H]+;1H NMR (CDCl3) δ 9.39 (1H,
s, NH), 7.00 (1H, s, 6-H), 6.84-6.83 (4H, m, PMP), 5.58, 5.56
(2H, 2 × s, 1′-H, 2′-H), 4.91 (1H, d, J 7.3 Hz, 1′′-H), 4.74 (1H,
t, J 5.6 Hz, 4′-H), 4.66 (1H, d, J 7.3 Hz, 1′′-H), 4.27 (1H, dd, J
6.0, 10.0 Hz, 5′-H), 4.11 (1H, dd, J 6.0, 10.0 Hz, 5′-H), 3.75
(3H, s, OCH3) 1.92 (3H, s, CH3); 13C NMR (CDCl3) δ 163.84,
154.37, 152.09, 151.01, 139.10, 115.42, 114.65, 111.60, 95.09,
91.82, 82.40, 73.41, 69.70, 66.24, 55.63, 12.28.
after the solution was stirred for 1 h, MgSO4(s) was added.
After being stirred for another 30 min, the mixture was filtered
and the filtrate evaporated to dryness under reduced pressure.
The residue was purified by silica gel chromatography using
CH2Cl2/MeOH (19:1 (v/v)) as eluent affording the bicyclic
nucleoside 5 (42 mg, 96%) as an off-white solid after evapora-
tion of the solvents: FAB-MS m/z 296 [M + H]+; HR MALDI
FT-MS m/z 318.0844, calcd 318.0809 [M + Na+]; IR (KBr)
3432, 2115, 1699 cm-1 1H NMR (DMSO-d6) δ 11.43 (1H, s,
;
NH), 7.71 (1H, s, 6-H), 6.03 (1H, d, J 2.7 Hz, 1′-H), 5.15 (1H,
t, J 5.6 Hz, 5′-OH) 5.14 (1H, d, J 2.7 Hz, 2′-H), 5.00 (1H, d, J
7.9 Hz, 1′′-H), 4.63 (1H, d, J 7.9 Hz, 1′′-H), 3.96 (1H, t, J 5.7
Hz, 4′-H), 3.87 (1H, m, 5′-H), 3.73 (1H, m, 5′-H), 1.80 (3H, s,
CH3); 13C NMR (DMSO-d6) δ 163.48 (4-C), 149.90 (2-C), 137.71
(6-C), 108.03 (5-C), 86.73 (2′-C), 82.46 (1′-C), 79.30 (4′-C), 72.87
(3′-C), 66.49 (1′′-C), 58.32 (5′-C), 12.07 (CH3).
(1R,2S,4S,5R)-1-Azid o-2-h yd r oxym et h yl-4-(t h ym in -1-
yl)-3,6-d ioxa bicyclo[3.2.0]h ep ta n e (29). The same proce-
dure as in the preparation of 5 was used with the nucleoside
28 (39 mg, 0.10 mmol), CH3CN/water (4:1 (v/v), 2 mL), and
CAN (106 mg 0.20 mmol) affording the bicyclic nucleoside 29
(23 mg, 80%) as an off-white solid: FAB-MS m/z 296 [M +
H]+; HR MALDI FT-MS m/z 318.0846, calcd 318.0809 [M +
Na+]; IR (KBr) 3435, 2118, 1690 cm-1; 1H NMR (DMSO-d6) δ
11.47 (1H, s, NH), 7.57 (1H, s, 6-H), 5.59, 5.56 (2H, 2 × s, 1′-
H, 2′-H), 5.06 (1H, t, J 5.5 Hz, 5′-OH), 4.82 (1H, d, J 7.7 Hz,
1′′-H) 4.43 (1H, d, J 7.7 Hz, 1′′-H), 4.37 (1H, t, J 6.0 Hz, 4′-H),
3.77 (1H, m, 5′-H), 3.60 (1H, m, 5′-H), 1.76 (3H, s, CH3); 13C
NMR (DMSO-d6) δ 163.95, 151.22, 140.31, 109.06, 93.97, 91.59,
83.41, 72.79, 69.07, 59.03, 11.82.
Ack n ow led gm en t. The Danish Natural Science
Research Council is thanked for financial support. Dr.
M. Petersen and Dr. J . P. J acobsen are thanked for
assistance with molecular modeling.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
compounds 5, 8-10, 12-14, 16, 19, 23-25, 28, and 29. 1H
NMR spectra of compounds 5 and 29. This material is
available free of charge via the Internet at http://pubs.acs.org.
(1R,2S,4R,5S)-1-Azid o-2-h yd r oxym et h yl-4-(t h ym in -1-
yl)-3,6-d ioxa bicyclo[3.2.0]h ep ta n e (5). The nucleoside 27
(58 mg, 0.14 mmol) was dissolved in CH3CN/water (4:1 (v/v),
3 mL), and the solution was stirred at 0 °C. Cerium(IV)-
ammonium nitrate (CAN) (158 mg 0.29 mmol) was added, and
J O010299J