Synthesis and conformational analysis of C-4′-modified (2-oxabicyclo-[3.1.0]hexyl)pyrimidine nucleosides

Article abstract of DOI:10.1002/ejoc.200600550

We report on the synthesis of hitherto unknown pyrimidine nucleoside analogues bearing the 2-oxabicyclo[3.1.0]hexane scaffold (5, 6, 8, 13-17 and 19) with various modifications at the C-4′ position including methylene, azido, and arabinolike configuration

Full text of DOI:10.1002/ejoc.200600550

FULL PAPER
DOI: 10.1002/ejoc.200600550
Synthesis and Conformational Analysis of C-4Ј-Modified (2-Oxabicyclo-
[3.1.0]hexyl)pyrimidine Nucleosides[‡]
Julien Gagneron,[a] Gilles Gosselin,[a] and Christophe Mathé*[a]
Keywords: Nucleosides / Conformational restriction / Bicyclic ring systems / Molecular modeling
We report on the synthesis of hitherto unknown pyrimidine
nucleoside analogues bearing the 2-oxabicyclo[3.1.0]hexane
scaffold (5, 6, 8, 13–17 and 19) with various modifications at
the C-4Ј position including methylene, azido, and arabino-
like configuration. Conformational analysis on the nucleo-
side analogues 6, 14 and 17 indicates that the conformation
of such C-4Ј-modified nucleoside analogues was restricted in
the South-East hemisphere of the pseudorotation cycle (be-
0
2
tween a T1 and a E conformation).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
cleotide-interacting enzymes and receptors. In this regard,
several nucleoside analogues with fixed furanose-ring puck-
ering have been synthesized and evaluated for their bio-
logical activities. Numerous synthetic strategies have been
used to lock the puckering of the furanose ring into a N-
type or S-type conformation by adding various fused
rings.[6] As a part of our ongoing research on conformation-
ally restricted nucleoside analogues, we have recently re-
ported the synthesis of locked nucleosides built on the 2-
oxabicyclo[3.1.0]hexane template and incorporating the ca-
nonical nucleic acid bases.[7] Herein, we report on the syn-
thesis of hitherto unknown pyrimidine nucleoside ana-
logues bearing the 2-oxabicyclo[3.1.0]hexane scaffold (5, 6,
8, 13–17 and 19) with various modifications at the C-4Ј po-
sition, including methylene, azido, and the arabino-like con-
figuration (Figure 1). Additionally, the effect of such struc-
tural modifications on the resulting sugar conformation was
studied on nucleosides 6, 14 and 17 as model compounds
by means of molecular modeling.
Introduction
Over several decades, numerous nucleoside analogues
with modifications in the sugar moiety have been designed
with the hope of obtaining new antiviral and antitumor
agents.[1,2] Such nucleoside analogues generally have to be
metabolized by cellular kinases to their 5Ј-triphosphate
forms, which finally interact with viral or cellular polymer-
ases, leading to a biological activity. In order to discover
new nucleoside derivatives endowed with biological activi-
ties, modifications of the base and/or sugar moiety of natu-
ral nucleosides can be attempted.[3] Recently, the conforma-
tional behaviour of natural as well as modified nucleosides,
and in particular the sugar puckering, has been considered
of great importance throughout their metabolic pathway, as
well as in the final interaction with the target polymerases.
Normally, the ribofuranose ring of natural nucleosides ex-
ists in a dynamic equilibrium covering a range of conforma-
tions, which can be easily described with the concept of the
pseudorotation cycle.[4] The North- (N-) and South- (S-)
type conformations are the most relevant to the biological
activities observed for nucleosides and nucleotides in associ-
ation with various enzymes and receptors.[5] For these
reasons, the design of conformationally restricted nucleo-
side analogues has drawn considerable attention, because
they adopt a determined conformation that can be useful
in probing the conformational preferences of nucleoside/nu-
[‡] This work has been presented in preliminary form at the Chem-
iedozententagung 2006, March 19–22, 2006, Hamburg, Ger-
many
Figure 1. C-4Ј-modified pyrimidine nucleosides built on a 2-oxabi-
cyclo[3.1.0]hexane scaffold. Numbering used as shown for 16–19.
[a] Laboratoire de Chimie Organique Biomoléculaire de Synthèse,
UMR 5625 CNRS-Université Montpellier II,
Case courrier 008, Place Eugène Bataillon, 34095 Montpellier
Cedex 5, France
Results and Discussion
Chemical Synthesis
Fax: +33-4-670042029
E-mail: cmathe@univ-montp2.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
The synthesis of starting materials 1 and 2 was achieved
through the preparation of a suitable sugar precursor bear-
Eur. J. Org. Chem. 2006, 4891–4897
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J. Gagneron, G. Gosselin, C. Mathé
FULL PAPER
ing the 2-oxabicyclo[3.1.0]hexane scaffold,[7] followed by pounds 16 and 17 with the C-4Ј hydroxy group in the arab-
glycosylation reactions and deprotection (Scheme 1). Com- ino configuration.[15] After an acetylation step, derivative 18
pounds 1 and 2 were selectively converted into their corre- was converted into the target nucleoside 19 by a thionation
sponding protected derivatives 3 and 4, which were oxidized reaction with Lawesson’s reagent and treatment of the re-
with the Dess–Martin periodinane reagent.[8] The resulting sulting thioamide intermediate with methanolic ammonia.
4Ј-keto nucleoside intermediates were not isolated but di-
rectly used in the Wittig reaction.[9] The nucleosides 5 and
6 (Figure 1) were obtained after a final deprotection step
and purification by silica gel column chromatography. The
synthesis of the corresponding cytosine nucleoside 8 was
accomplished in a two-step procedure from 5. After an
acetylation step, compound 7 was treated with Lawesson’s
reagent,[10] to give a thioamide intermediate, which was
treated with methanolic ammonia, affording nucleoside 8.
In order to prepare the target nucleosides 13–17 and 19
(Figure 1), compounds 1 and 2 were converted into the key
anhydro derivatives 9 and 10 by a one-pot transformation
involving a tandem Mitsunobu reaction (Scheme 2).[11] Nu-
cleophilic ring opening of the anhydro derivatives was
achieved with sodium azide in the presence of 18-crown-6
and provided compounds 11 and 12, which upon treatment
with sodium methoxide in methanol gave the desired nucle-
osides 13 and 14. The synthesis of the corresponding C-
4Ј-azido cytosine nucleoside 19 was not accomplished with
Lawesson’s reagent. Indeed, the use of Lawesson’s reagent
Scheme 2. a) i. DEAD, PPh3, BzOH, DMF; ii. DEAD, PPh3; b)
NaN3, 18-crown-6, DMF, reflux; c) MeOH, MeONa; d) i. 1,2,4-
triazole, pyridine, 4-chlorophenyl phosphorodichloridate; ii.
on azido nucleosides has been reported to promote the re-
duction of the azido function.[12] Instead, Sung’s methodol-
ogy,[13] successfully applied in the conversion of uracil into
NH4OH, dioxane; iii. MeOH, MeONa.
cytosine azido nucleosides,[14] was used. Thus, reaction of
11 with 4-chlorophenyl phosphorodichloridate and 1,2,4-
triazole provided the triazolylpyrimidinone derivative,
which upon treatment with aqueous ammonia, followed by
sodium methylate, gave the cytosine derivative 15. Finally,
alkaline treatment of 9 and 10 (Scheme 3) yielded com-
Scheme 3. a) 1  NaOH, MeOH; b) Ac2O, pyridine; c) i. Lawes-
son’s reagent, 1,2-dichloroethane, reflux; ii. MeOH/NH3, 100 °C.
Conformational Analysis
Briefly, the definition of the conformational behaviour of
natural, as well as modified nucleosides, involves the deter-
mination of three principal structural parameters.[16] The
Scheme 1. a) BzCl, DMF, pyridine, 0 °C; b) i. periodinane, CH2Cl2,
glycosidic torsion angle χ determines the syn or anti disposi-
0 °C; ii. C2H5C(CH3)2ONa, PPh3MeBr, THF; iii. MeOH, MeONa;
tion of the base relative to the sugar moiety (syn when the
c) Ac2O, pyridine; d) i. Lawesson’s reagent, 1,2-dichloroethane, re-
flux; ii. MeOH/NH3.
C-2 carbonyl of pyrimidines or N-3 of purines lies over the
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C-4Ј-Modified (2-Oxabicyclo[3.1.0]hexyl)yrimidine Nucleosides
FULL PAPER
sugar ring, anti when these atoms are oriented in the oppo- 2-oxabicyclo[3.1.0.]hexane scaffold.[7] This modification of
site direction). The torsion angle γ determines the orienta- the sugar moiety is able to restrict the dynamic equilibrium
tion of the 5Ј-OH with respect to C-3Ј, as represented by between the N-type and S-type geometry that normally
the three main rotamers γ+, γt and γ–. The conformation characterizes the sugar moiety of standard nucleosides in
of the furanose ring and its deviation from planarity are solution. Using nucleoside 2 as a model compound, we have
described by the pseudorotational phase angle P (0–360°) previously established that the conformation was restricted
and the maximal puckering amplitude νmax (0–50°). A con- toward a 0T1 conformation (P = 107.2°, νmax = 17.2°,
formationally unrestricted furanose ring in solution can Table 1).[7] Herein, the conformation of the thymine nucleo-
adopt a number of envelope or twist forms, which are con- sides 6, 14 and 17 bearing various modifications at C-4Ј
veniently described by the value of P in the pseudorotation (including methylene, azido and the arabino configuration,
cycle (Figure 2). By convention, P = 0° corresponds to an respectively) were analyzed by molecular modeling and
absolute N conformation possessing a symmetrical twist compared with compound 2. An ab initio calculation was
3
form T2 (C2Ј-exo-C3Ј-endo), whereas the S antipode twist, performed on the compound of interest by performing ge-
2T3 (C2Ј-endo-C3Ј-exo), corresponds to P = 180°. Every ometry optimization at the 3-21 G level with the basis set
18°, the conformation of the furanose ring along the pseu- implemented in the HyperChem 7.5 software. A root-
dorotation cycle alternates between envelope and twist con- mean-square gradient termination cut-off of 0.05 kcalÅ–1
formations. For the typical N geometry, the conformations mol–1 was used for geometry optimization with the Polak–
fluctuate between C2Ј-exo (2E) and C3Ј-endo (3E), whereas Ribiere conjugate gradient algorithm. The torsion angles γ
for an antipodal S geometry, the conformations range be- and χ on the nucleoside structure were initially located in
tween C3Ј-exo (3E) and C2Ј-endo (2E). These two ranges the γ and anti ranges, respectively. The results of the calcula-
are separated by two pseudorotational barriers that occur tions are illustrated in Table 1. Introduction of an exocyclic
approximately in the Eastern (O4Ј-endo, E) and Western double bond in position 4Ј on the 2-oxabicyclo[3.1.0]hexane
0
0
(O4Ј-exo, E) regions. Preference for any of these specific scaffold (compound 6) drives the resulting conformation (P
conformations in solution is determined by the interplay of = 156.6° for 6 vs. 107.2° for 2) toward a more markedly S-
important interactions resulting from steric and stereoelec- type conformation with a sugar puckering close to a C2Ј-
tronic effects. The latter consist mainly of the anomeric and endo envelope conformation (2E). Additionally, the double
gauche effects.[17] Recently, we have reported the synthesis bond reduces the puckering amplitude (νmax) to 10.9°, con-
of conformationally locked nucleoside analogues built on a ferring a certain degree of planarity to the 2-oxabicy-
Figure 2. Pseudorotation cycle for nucleosides showing the characterisic North, South, East and West conformations. The units of P and
νmax values are degrees. Envelope (E) and twist (T) forms alternate every 18°. The shaded area indicates the preferred pseudorotational
region for nucleosides 2, 6, 14 and 17.
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J. Gagneron, G. Gosselin, C. Mathé
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Table 1. Selected torsion angles, pseudorotational phase angle P and maximum torsion angle νmax of compound 2, 6, 14 and 17, as
determined from ab initio calculations.
Analogue
2[7]
6
14
17
ν0 [°]
– 17.2
– 7.2
– 19.1
– 23.1
ν1 [°]
ν2 [°]
ν3 [°]
ν4 [°]
νmax [°][22]
17.2
10.9
19.2
25.9
P [°][22]
107.2
156.6
114.0
128.1
13.8
10.7
16.6
24.9
– 5.1
– 5.5
5.6
– 4.0
0.9
14.1
1.0
14.3
14.4
– 10.0
– 7.8
– 16.0
clo[3.1.0]hexane scaffold. An increase of the planarity has osides. Models (6, 14 and 17) bearing the thymine base sug-
been recently reported in the case of methanocarbanucleos- gest that the conformations of such C-4Ј-modified 2-oxa-
ides built on a bicyclo[3.1.0]hexane template following the bicyclo[3.1.0]hexane nucleoside analogues were restricted
introduction of a double bond within the bicyclic ring sys- into the S-E hemisphere of the pseudorotation cycle (be-
0
2
tem.[18] Introduction of an azido function (compound 14) tween a T1 and a E conformation). Thus, through appro-
in place of the hydroxy group (compound 2) at C-4Ј in a priate chemical modifications at the C-4Ј position, we have
ribo-like configuration (4ЈR) afforded similar sugar pucker- modulated by degrees the conformation of the resulting nu-
ing (P = 114° for 14 vs. 107.2° for 2) and νmax (19.2°for 14 cleosides. These new nucleoside analogues built on a 2-oxa-
0
vs. 17.2° for 2), and both conformations are close to a T1 bicyclo[3.1.0]hexane scaffold may find wider applicability to
conformation. In this case, the presence of the azido func- probe the conformational preferences of nucleoside/nucleo-
tion does not greatly influence the sugar puckering and the tide-converting enzymes and receptors.
νmax. In the case of compound 17, inversion of stereochem-
istry at C-4Ј (4ЈR Ǟ 4ЈS, ribo- to arabino-like configura-
tion) drives the resulting conformation (P = 128° for 17 vs.
107.2° for 2) toward a sugar puckering close to a C1Ј-exo
envelope conformation (1E) with a larger puckering ampli-
Experimental Section
General Remarks: Evaporation of solvents was carried out with a
rotary evaporator under reduced pressure. Melting points were de-
termined in open capillary tubes with a Gallenkamp MFB-595–
010 M apparatus and are uncorrected. UV spectra were recorded
tude (νmax = 25.9° for 17 vs. 17.2° for 2). This E type con-
1
formation may be ascribed to a preferential pseudo-axial
orientation of the hydroxy group in regard to a favourable
O2Ј–C3Ј–C4Ј–O4Ј gauche effect[19] and a preferential
pseudo-equatorial orientation of the base due to the 2-oxa-
bicyclo[3.1.0]hexane scaffold, leading to minimal steric hin-
drance between the base and the hydroxymethyl residue in
position 1. The vicinal (3JH4Ј–H3Ј) coupling constants were
estimated[20] from the torsion angles φ (H3Ј–C3Ј–C4Ј–H4Ј)
obtained from molecular modeling of selected nucleoside
analogues 2 and 17 (Table 2), according to the Diez–Al-
tona–Donders equation, as implemented in the MestRe-J
program.[21] A good agreement was observed between esti-
with a Uvikon 931 (Kontron) spectrophotometer. NMR spectra
were recorded at 400 MHz (1H) and 100 MHz (13C) in (CD3)2SO
at ambient temperature with a Bruker DRX 400 spectrometer.
Chemical shifts (δ) are quoted in parts per million (ppm), refer-
enced to the residual solvent peak at 2.49 δ (1H) and 39.5 δ (13C)
relative to tetramethylsilane (TMS). Deuterium exchange and
COSY experiments were performed in order to confirm proton as-
signments. Coupling constants, J, are reported in Hz. 2D 1H-13C
heteronuclear COSY was performed for the attribution of 13C sig-
nals. FAB mass spectra were recorded in the positive-ion or nega-
tive-ion mode with a JEOL SX 102 spectrometer. The matrix was
a mixture (50:50, v/v) of glycerol and thioglycerol (G-T), or 3-ni-
trobenzyl alcohol (NBA). IR spectra were recorded with a Perkin–
Elmer FT-IR paragon 1000 spectrometer. Specific rotations were
measured with a Perkin–Elmer Model 241 spectropolarimeter (path
length 1 cm) and are given in units of 10–1 deg cm2 g–1. Elemental
analyses were carried out by the Service de Microanalyses du
CNRS, Division de Vernaison (France). Thin-layer chromatog-
raphy was performed on precoated aluminium sheets of Silica Gel
60 F254 (Merck, Art. 5554), and product spots were visualised by
UV absorbency followed by charring with 5% ethanolic sulfuric
acid. Column chromatography was carried out on Silica Gel 60
(Merck, Art. 9385). All moisture-sensitive reactions were carried
out under rigorous anhydrous conditions under an argon atmo-
sphere in oven-dried glassware. Solvents were dried and distilled
prior to use, and solids were dried with P2O5 under reduced pres-
sure.
3
mated and experimental JH4Ј–H3Ј values, showing that the
solution conformations of nucleosides 2 and 17 match the
lowest energy structure from molecular modeling.
Table 2. Torsion angles of lowest energy structures from ab initio
calculations and estimated and experimental 3JH3Ј–H4Ј values of se-
lected compounds 2 and 17.
Analogue
φ
3Jestd., H3Ј–H4Ј
3Jexp., H3Ј–H4Ј
H3Ј–C3Ј–C4Ј–H4Ј
[°]
[Hz]
[Hz]
2
17
133
27
5.1
4.7
5.0[a]
4.8
[a] Data from ref.[7]
Conclusions
[(1S,3R,4R,5S)-3-[2,4-Dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-hy-
droxy-2-oxabicyclo[3.1.0]hex-1-yl]methyl Benzoate (3): Yield
710 mg (50%). M.p. 69 °C. [α]2D0 = –88.6 (c = 0.44, DMSO). 1H
NMR (300 MHz, [D6]DMSO): δ = 11.38 (br. s, 1 H, NH), 8.04–
7.53 (m, 6 H, C6H5, 6-H), 5.52 (m, 3 H, 5-H, 3Ј-H and 4Ј-OH),
4.80 (m, 2 H, 4Ј-H and 7Јa-H), 4.50 (d, J = 12.7 Hz, 1 H, 7Јb-H),
The synthesis of conformationally restricted pyrimidine
nucleoside analogues with various structural modifications
at the C-4Ј position (including methylene, azido and the
arabino-like modifications) was achieved, starting from
their corresponding 2-oxabicyclo[3.1.0]hexane parent nucle- 1.96 (m, 1 H, 5Ј-H), 1.35 (t, J = 5.4 Hz, 1 H, 6Јa-H), 0.95 (dd, J =
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C-4Ј-Modified (2-Oxabicyclo[3.1.0]hexyl)yrimidine Nucleosides
FULL PAPER
6.5, 9.4 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO): H, 5Ј-H), 2.01 (s, 3 H, CH3), 1.18 (t, J = 5.2 Hz, 1 H, 6Јa-H), 1.10
δ = 165.6 (C=O), 162.9 (C-4), 150.2 (C-2), 141.5 (C-6), 133.5–128.8 (dd, J = 5.8, 9.6 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]-
(Car), 102.3 (C-5), 90.6 (C-3Ј), 75.1 (C-1Ј), 67.8 (C-4Ј), 66.3 (C-7Ј), DMSO): δ = 170.7 (COCH3), 163.5 (C-4), 150.5 (C-2), 146.8 (C-
23.6 (C-5Ј), 12.7 (C-6Ј) ppm. FAB-MS: m/z = 345 [M + H]+. 4Ј), 141.5 (C-6), 109.7 (CH=CH2), 102.8 (C-5), 85.5 (C-3Ј), 68.3
HRMS: calcd. for C17H17N2O6 [M+H]+ 345.1087; found 345.1073.
(C-1Ј), 65.8 (C-7Ј), 24.2 (C-5Ј), 20.5 (CH3CO), 19.1 (C-6Ј) ppm.
FAB-MS: m/z = 279 [M + H]+. HRMS: calcd. for C13H15N2O5
[M+H]+ 279.0981; found 279.0969.
[(1S,3R,4R,5S)-4-Hydroxy-3-[5-methyl-2,4-dioxo-3,4-dihydro-
1(2H)-pyrimidinyl]-2-oxabicyclo[3.1.0]hex-1-yl]methyl Benzoate (4):
Yield 505 mg (50%). M.p. 177 °C. [α]2D0 = –97 (c = 1.00, DMSO).
4-Amino-1-[(1S,3R,5S)-1-(hydroxymethyl)-4-methylene-2-oxabi-
1H NMR (300 MHz, [D6]DMSO): δ = 11.36 (br. s, 1 H, NH), 8.04– cyclo[3.1.0]hex-3-yl]-2(1H)-pyrimidinone (8): Yield 50 mg (50%).
7.53 (m, 5 H, C6H5), 7.37 (d, J = 1.1 Hz, 1 H, 6-H), 5.52 (m, 2 H, UV (EtOH 95%): λmax (ε) = 269 nm (9000). [α]2D0 = –94.9 (c = 0.59,
3Ј-H and 4Ј-OH), 4.70 (m, 2 H, 4Ј-H and 7Јa-H), 4.49 (d, J = DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 7.49 (d, J = 7.4 Hz,
12.7 Hz, 1 H, 7Јb-H), 1.94 (m, 1 H, 5Ј-H), 1.62 (s, 3 H, CH3), 1.36 1 H, 6-H), 7.25 (d, J = 13.6 Hz, 2 H, NH2), 6.39 (s, 1 H, 3Ј-H),
(t, J = 6.6 Hz, 1 H, 6Јa-H), 0.94 (dd, J = 6.6, 9.1 Hz, 1 H, 6Јb-H) 5.75 (d, J = 7.4 Hz, 1 H, 5-H), 5.34 (d, J = 1.9 Hz, 1 H, CH=CH2),
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 165.6 (CO), 163.5 (C-
4), 150.4 (C-2), 136.5 (C-6), 133.5–128.8 (Car), 110.2 (C-5), 89.2 (C-
3Ј), 74.8 (C-4Ј), 67.2 (C-1Ј), 66.1 (C-7Ј), 23.2 (C-5Ј), 12.3 (C-6Ј),
11.7 (CH3) ppm. FAB-MS: m/z = 359 [M + H]+. C18H18N2O6
(358.35): calcd. C 60.33, H 5.06, N 7.82; found C 60.16, H 5.27, N
7.61.
5.04 (t, J = 5.8 Hz, 1 H, 7Ј-OH), 4.65 (s, 1 H, CH=CH2), 3.95 (dd,
J = 6.2, 12.6 Hz, 1 H, 7Јa-H), 3.49 (dd, J = 5.2, 12.6 Hz, 1 H, 7Јb-
H), 2.19 (dd, J = 4.5, 9.3 Hz, 1 H, 5Ј-H), 1.12 (t, J = 5.2 Hz, 1 H,
6Јa-H), 1.07 (dd, J = 5.9, 9.3 Hz, 1 H, 6Јb-H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 165.50 (C-4), 155.1 (C-2), 149.9 (C-
4Ј), 142.1 (C-6), 107.3 (CH=CH2), 94.9 (C-5), 85.5 (C-3Ј), 71.4 (C-
1Ј), 61.9 (C-7Ј), 23.6 (C-5Ј), 18.3 (C-6Ј) ppm. FAB-MS: m/z = 471
[2M+H]+, 236 [M+H]+. HRMS: calcd. for C11H14N3O3 [M+H]+
236.1035; found 236.1027.
1-[(1S,3R,5S)-1-(Hydroxymethyl)-4-methylene-2-oxabicyclo[3.1.0]-
hex-3-yl]-2,4(1H,3H)-pyrimidinedione (5): Yield 140 mg (36% from
3). UV (EtOH 95%): λmax (ε) = 260 nm (9100). [α]2D0 = –28.6 (c =
1
0.14, DMSO). H NMR (300 MHz, [D6]DMSO): δ = 11.39 (br. s,
[(5aR,6aS,7aS,7bS)-2-Oxo-5a,7,7a,7b-tetrahydro-2H,6aH-cyclopro-
pa[4Ј,5Ј]furo[2Ј,3Ј:4,5][1,3]oxazolo[3,2-a]pyrimidin-6a-yl]methyl
1 H, NH), 7.50 (d, J = 8.1 Hz, 1 H, 6-H), 6.33 (s, 1 H, 3Ј-H), 5.69
(d, J = 8.1 Hz, 1 H, 5-H), 5.32 (d, J = 1.8 Hz, 1 H, CH=CH2), Benzoate (9): Yield 504 mg (59%). UV (EtOH 95%): λmax (ε) =
5.06 (t, J = 6.1 Hz, 1 H, 7Ј-OH), 4.82 (s, 1 H, CH=CH2), 3.95 (dd, 252 nm (8000). [α]2D0 = –134 (c = 0.94, DMSO). 1H NMR
J = 6.1, 12.7 Hz, 1 H, 7Јa-H), 3.48 (dd, J = 5.1, 12.7 Hz, 1 H, 7Јb- (300 MHz, [D6]DMSO): δ = 7.80 (d, J = 7.4 Hz, 1 H, 6-H), 7.40–
H), 2.22 (dd, J = 4.5, 9.6 Hz, 1 H, 5Ј-H), 1.18 (t, J = 5.2 Hz, 1 H,
6Јa-H), 1.08 (dd, J = 5.9, 9.6 Hz, 1 H, 6Јb-H) ppm. 13C NMR 8.0 Hz, 1 H, 5-H), 5.58 (d, J = 5.5 Hz, 1 H, 4Ј-H), 4.83 (d, J =
(100 MHz, [D6]DMSO): δ = 163.0 (C-4), 150.6 (C-2), 148.6 (C-4Ј), 12.9 Hz, 1 H, 7Јa-H), 4.21 (d, J = 12.9 Hz, 1 H, 7Јb-H), 2.23 (dd,
7.71 (m, 5 H, Car), 6.09 (d, J = 5.5 Hz, 1 H, 3Ј-H), 5.81 (d, J =
141.3 (C-6), 108.3 (CH=CH2), 102.7 (C-5), 84.8 (C-3Ј), 71.9 (C-1Ј), J = 5.6, 10.5 Hz, 1 H, 5Ј-H), 1.29 (dd, J = 5.6, 6.5 Hz, 1 H, 6Јa-
61.8 (C-7Ј), 23.5 (C-5Ј), 18.4 (C-6Ј) ppm. FAB-MS: m/z = 237 H), 1.14 (t, J = 7.2 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz,
[M+H]+. C11H12N2O4 (0.1 dioxane, 254.04): calcd. C 55.88, H
5.27, N 11.43; found C 55.73, H 5.23, N 11.22.
[D6]DMSO): δ = 170.9 (CO), 165.2 (C-4), 159.5 (C-2), 136.7 (C-6),
128.7–133.4 (Car), 108.9 (C-5), 93.2 (C-3Ј), 84.7 (C-4Ј), 70.0 (C-1Ј),
64.4 (C-7Ј), 23.7 (C-5Ј), 17.0 (C-6Ј) ppm. FAB-MS: m/z = 327
[M+H]+. C17H14N2O5 (326.31): calcd. C 62.57, H 4.32, N 8.59;
found C 62.27, H 4.33, N 8.34.
1-[(1S,3R,5S)-1-(Hydroxymethyl)-4-methylene-2-oxabicyclo[3.1.0]-
hex-3-yl]-5-methyl-2,4(1H,3H)-pyrimidinedione (6): Yield 120 mg
(36% from 3). UV (EtOH 95%): λmax (ε) = 263 nm (8900). [α]2D0
= –100.0 (c = 0.6, DMSO).1H NMR (300 MHz, [D6]DMSO): δ = [(5aR,6aS,7aS,7bS)-3-Methyl-2-oxo-5a,7,7a,7b-tetrahydro-2H,6aH-
11.38 (br. s, 1 H, NH), 7.38 (d, J = 1.2 Hz, 1 H, 6-H), 6.33 (s, 1 H, cyclopropa[4Ј,5Ј]furo[2Ј,3Ј:4,5][1,3]oxazolo[3,2-a]pyrimidin-6a-yl]-
3Ј-H), 5.31 (d, J = 1.9 Hz, 1 H, CH=CH2), 5.09 (t, J = 6.4 Hz, 1
H, 7Ј-OH), 4.79 (d, J = 0.9 Hz, 1 H, CH=CH2), 3.96 (dd, J = 5.8,
methyl Benzoate (10): Yield 475 mg (60%). M.p. 238 °C. UV (EtOH
95%): λmax (ε) = 263 nm (7000). [α]2D0 = –97 (c = 1.00, DMSO). 1H
12.7 Hz, 1 H, 7Јa-H), 3.49 (dd, J = 5.0, 12.7 Hz, 1 H, 7Јb-H), 2.22 NMR (300 MHz, [D6]DMSO): δ = 7.50–7.40 (m, 6 H, C6H5 and
(dd, J = 4.5, 9.6 Hz, 1 H, 5Ј-H), 1.75 (d, J = 1.2 Hz, 3 H, CH3),
1.17 (t, J = 5.2 Hz, 1 H, 6Јa-H), 1.08 (dd, J = 5.8, 9.6 Hz, 1 H,
6-H), 6.08 (d, J = 5.1 Hz, 1 H, H-3Ј), 5.55 (d, J = 5.1 Hz, 1 H, 4Ј-
H), 4.87 (d, J = 12.9 Hz, 1 H, 7Јa-H), 4.18 (d, J = 12.9 Hz, 1 H,
6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.8 (C-4), 7Јb-H), 2.22 (dd, JH5Ј–H6Јa = 5.5, 10.2 Hz, 1 H, 5Ј-H), 1.65 (s, 3 H,
149.7 (C-2), 147.8 (C-4Ј), 135.9 (C-6), 109.2 (C-5), 107.3 CH3), 1.28 (dd, J = 6.4, 10.2 Hz, 1 H, 6Јb-H), 1.12 (t, J = 5.8 Hz,
(CH=CH2), 83.7 (C-3Ј), 70.9 (C-1Ј), 60.9 (C-7Ј), 22.7 (C-5Ј), 17.6
(C-6Ј), 11.3 (CH3 ) ppm. FAB-MS: m/z = 251 [M + H]+ .
C12H14N2O4 (0.3 H2O, 255.66): calcd. C 56.38, H 5.76, N 10.96;
found C 56.20, H 5.48, N 10.91.
1 H, 6Јa-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 171.3
(CO), 165.2 (C-4), 159.0 (C-2), 128.6–133.3 (C-6 and Car), 117.1
(C-5), 93.7 (C-3Ј), 84.2 (C-4Ј), 69.8 (C-1Ј), 64.2 (C-7Ј), 23.9 (C-
5Ј), 17.0 (C-6Ј), 13.3 (CH3) ppm. FAB-MS: m/z = 341 [M+H]+.
C18H16N2O5 (340.33): calcd. C 63.52, H 4.74, N 8.23; found C
63.37, H 4.40, N 8.48.
[(1S,3R,5S)-3-[2,4-Dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-methyl-
ene-2-oxabicyclo[3.1.0]hex-1-yl]methyl Acetate (7): To a solution of
compound 5 (150 mg, 0.635 mmol) in pyridine (4 mL) was added
acetic anhydride (0.9 mL, 9.5 mmol). After 12 h, the solution was
evaporated, co-evaporated with toluene, and the residue was puri-
fied by silica gel column chromatography (CH2Cl2/methanol, 97:3)
[(1S,3R,4R,5S)-4-Azido-3-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidin-
yl]-2-oxabicyclo[3.1.0]hex-1-yl]methyl Benzoate (11): Yield 50 mg
(44 %). UV (EtOH 95 %): λmax (ε) = 260 (10500). 1H NMR
(300 MHz, [D6]DMSO): δ = 11.45 (br. s, 1 H, NH), 8.00–7.63 (m,
J = 8.0 Hz, 6 H, C6H5 and 6-H), 5.62 (d, J = 5.2 Hz, 1 H, 3Ј-H),
to give compound 7 (170 mg, 96%) as a colourless syrup. [α]2D0
=
–163 (c = 0.92, DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 5.53 (d, J = 8.0 Hz, 1 H, H-5), 5.00 (t, J = 5.6 Hz, 1 H, 4Ј-H), 4.67
11.41 (br. s, 1 H, NH), 7.35 (d, J = 8.1 Hz, 1 H, 6-H), 6.28 (s, 1 H, (d, J = 12.7 Hz, 1 H, 7Јa-H), 4.63 (d, J = 12.7 Hz, 1 H, 7Јb-H),
3Ј-H), 5.74 (d, J = 8.1 Hz, 1 H, 5-H), 5.38 (d, J = 1.9 Hz, 1 H,
2.20 (m, 1 H, 5Ј-H), 1.38 (t, J = 5.5 Hz, 1 H, 6Јa-H), 1.11 (dd, J =
CH=CH2), 4.86 (s, 1 H, CH=CH2), 4.47 (d, J = 12.8 Hz, 1 H, 7Јa- 6.8, 9.1 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO):
H), 4.20 (d, J = 12.8 Hz, 1 H, 7Јb-H), 2.36 (dd, J = 5.1, 9.2 Hz, 1 δ = 165.5 (C=O), 162.8 (C-4), 149.9 (C-2), 140.9 (C-6), 133.5–128.8
Eur. J. Org. Chem. 2006, 4891–4897
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4895

J. Gagneron, G. Gosselin, C. Mathé
FULL PAPER
(Car), 102.4 (C-5), 89.5 (C-3Ј), 68.7 (C-1Ј), 66.5 (C-4Ј), 65.8 (C-7Ј), gel column chromatography with a stepwise gradient of MeOH (6–
21.3 (C-5Ј), 13.9 (C-6Ј) ppm. FAB-MS: m/z = 369 [M+H]+. IR:
= 2108 cm–1. C17H15N5O5 (369.33): calcd. C 55.28, H 4.09, N
10%) in CH2Cl2. The appropriate fractions were collected (50 mg)
and treated with sodium methylate (22 mg, 0.41 mmol) in methanol
(2.2 mL). The reaction mixture was stirred at room temperature
overnight and neutralized with a 2  HCl solution and evaporated
to dryness. The residue was purified by silica gel column
chromatography with a stepwise gradient of MeOH (10–16%) in
CH2Cl2 to give compound 15 (30 mg, 29% overall yield from 11),
which was lyophylised from water. UV (EtOH 95%): λmax (ε) =
270 nm (9400). 1H NMR (300 MHz, [D6]DMSO): δ = 7.74 (d, J =
7.4 Hz, 1 H, 6-H), 7.26 (br. s, 2 H, NH2), 5.61 (d, J = 7.4 Hz, 1 H,
5-H), 5.61 (d, J = 4.7 Hz, 1 H, 3Ј-H), 5.04 (t, J = 5.5 Hz, 1 H, 7Ј-
OH), 4.70 (t, J = 4.7 Hz, 1 H, 4Ј-H), 3.89 (dd, J = 5.9, 12.6 Hz, 1
H, 7Јa-H), 3.48 (dd, J = 5.0, 12.6 Hz, 1 H, 7Јb-H), 1.92 (m, 1 H,
5Ј-H), 1.10 (t, J = 5.0 Hz, 1 H, 6Јa-H), 0.89 (dd, J = 6.5, 9.0 Hz, 1
H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 165.6 (C-
4), 154.6 (C-2), 141.6 (C-6), 94.6 (C-5), 90.5 (C-3Ј), 72.2 (C-1Ј),
68.2 (C-4Ј), 61.8 (C-7Ј), 20.7 (C-5Ј), 13.7 (C-6Ј) ppm. FAB-MS: m/z
= 265 [M+H]+. HRMS: calcd. for C10H13N6O3 [M+H]+ 265.1049;
found 265.1052.
ν
˜
N3
18.96; found C 55.07, H 3.89, N 18.78.
[(1S,3R,4R,5S)-4-Azido-3-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-py-
rimidinyl]-2-oxabicyclo[3.1.0]hex-1-yl]methyl Benzoate (12): Yield
150 mg (53%). UV (EtOH 95%): λmax (ε) = 263 nm (10300). [α]2D0
1
= –105.5 (c = 0.54, DMSO). H NMR (300 MHz, [D6]DMSO): δ
= 11.4 (br. s, 1 H, NH), 8.05–7.53 (m, 5 H, C6H5), 7.35 (d, J =
1.1 Hz, 1 H, 6-H), 5.64 (d, J = 5.7 Hz, 1 H, 3Ј-H), 4.98 (t, J =
5.8 Hz, 1 H, 4Ј-H), 4.77 (d, J = 12.8 Hz, 1 H, 7Јa-H), 4.54 (d, J =
12.8 Hz, 1 H, 7Јb-H), 2.19 (m, 1 H, 5Ј-H), 1.59 (d, J = 1.1 Hz, 3
H, CH3), 1.43 (t, J = 5.6 Hz, 1 H, 6Јa-H), 1.10 (dd, J = 6.8, 9,1 Hz,
1 H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 165.6
(C=O), 163.5 (C-4), 150.0 (C-2), 135.9 (C-6), 133.6–128.8 (Car),
110.5 (C-5), 87.8 (C-3Ј), 68.0 (C-1Ј), 66.2 (C-4Ј), 65.7 (C-7Ј), 20.9
(C-5Ј), 13.3 (CH3), 11.8 (C-6Ј) ppm. FAB-MS: m/z = 384
[M+H]+. IR: ν = 2107 cm–1. C18H17N5O5 (383.36): calcd. C
56.39, H 4.47, N 18.27; found C 56.07, H 4.49, N 17.98.
˜
N3
1-[(1S,3R,4R,5S)-4-Azido-1-(hydroxymethyl)-2-oxabicyclo[3.1.0]-
hex-3-yl]-2,4(1H,3H)-pyrimidinedione (13): Yield 130 mg (90%).
1-[(1S,3R,4S,5S)-4-Hydroxy-1-(hydroxymethyl)-2-oxabicyclo[3.1.0]-
hex-3-yl]-2,4(1H,3H)-pyrimidinedione 16: Yield 120 mg (80%). M.p.
173 °C. UV (EtOH 95%): λmax (ε) = 260 nm (11800). [α]2D0 = +85.4
(c = 1.03, DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 11.23
(br. s, 1 H, NH), 7.64 (d, J = 8.1 Hz, 1 H, 6-H), 5.79 (d, J = 4.7 Hz,
1 H, 3Ј-H), 5.56 (d, J = 8.1 Hz, 1 H, 5-H), 5.44 (d, J = 4.7 Hz, 1
H, 4Ј-OH), 4.97 (t, J = 5.0 Hz, 1 H, 7Ј-OH), 4.24 (t, J = 4.7 Hz, 1
H, 4Ј-H), 3.87 (dd, J = 5.2, 12.5 Hz, 1 H, 7Јa-H), 3.60 (dd, J = 4.8,
12.5 Hz, 1 H, 7Јb-H), 1.49 (dd, J = 4.9, 9.7 Hz, 1 H, 5Ј-H), 0.89 (t,
J = 5.4 Hz, 1 H, 6Јa-H), 0.72 (dd, J = 6.6, 9.7 Hz, 1 H, 6Јb-H)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 163.3 (C-4), 150.1 (C-
2), 143.2 (C-6), 99.6 (C-5), 86.4 (C-3Ј), 70.9 (C-4Ј), 69.7 (C-1Ј), 61.8
(C-7Ј), 23.3 (C-5Ј), 11.6 (C-6Ј) ppm. FAB-MS: m/z = 241
[M+H]+. C10H12N2O5 (240.21): calcd. C 50.00, H 5.04, N 11.66;
found C 49.94, H 5.03, N 11.56.
M.p. 178 °C. UV (EtOH 95%): λmax (ε) = 260 nm (9800). [α]2D0
=
1
–95.3 (c = 0.64, DMSO). H NMR: (300 MHz, [D6]DMSO): δ =
11.41 (br. s, 1 H, NH), 7.79 (d, J = 8.1 Hz, 1 H, 6-H), 5.71 (d, J =
8.1 Hz, 1 H, 5-H), 5.61 (d, J = 4.7 Hz, 1 H, 3Ј-H), 5.09 (t, J =
5.3 Hz, 1 H, 7Ј-OH), 4.83 (t, J = 4.7 Hz, 1 H, 4Ј-H), 3.89 (dd, J =
6, 12.7 Hz, 1 H, 7Јa-H), 3.49 (dd, J = 4.8, 12.7 Hz, 1 H, 7Јb-H),
1.94 (m, 1 H, 5Ј-H), 1.15 (dd, J = 5.2, 6.6 Hz, 1 H, 6Јa-H), 0.88
(dd, J = 6.6, 9.0 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 163.0 (C-4), 150.0 (C-2), 140.7 (C-6), 102.4 (C-5), 89.2
(C-3Ј), 72.6 (C-1Ј), 67.7 (C-4Ј), 61.7 (C-7Ј), 20.5 (C-5Ј), 13.6 (C-6Ј)
ppm. FAB-MS: m/z = 266 [M+H]+. C10H11N5O4 (265.23): calcd.
C 45.28, H 4.18, N 26.41; found C 45.24, H 4.10, N 26.25.
1-[(1S,3R,4R,5S)-4-Azido-1-(hydroxymethyl)-2-oxabicyclo[3.1.0]-
hex-3-yl]-5-methyl-2,4(1H,3H)-pyrimidinedione (14): Yield 60 mg
(69%). UV (EtOH 95%): λmax (ε) = 264 nm (11700). [α]2D0 = –123.5
(c = 0.51, DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 11.40
(br. s, 1 H, NH), 7.66 (d, J = 1.1 Hz, 1 H, 6-H), 5.62 (d, J = 5.0 Hz,
1 H, 3Ј-H), 5.12 (t, J = 5.5 Hz, 1 H, 7Ј-OH), 4.81 (t, J = 5.0 Hz, 1
H, 4Ј-H), 3.90 (dd, J = 6.0, 12.7 Hz, 1 H, 7Јa-H), 3.51 (dd, J = 5.0,
12.7 Hz, 1 H, 7Јb-H), 1.94 (m, 1 H, 5Ј-H), 1.79 (s, 3 H, CH3), 1.17
(t, J = 5.8 Hz, 1 H, 6Јa-H), 0.89 (dd, J = 6.8, 9.0 Hz, 1 H, 6Јb-H)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 163.6 (C-4), 150.0 (C-
2), 136.2 (C-6), 110.0 (C-5), 88.4 (C-3Ј), 72.2 (C-1Ј), 67.5 (C-4Ј),
61.7 (C-7Ј), 20.4 (C-5Ј), 13.3 (CH3), 12.1 (C-6Ј) ppm. FAB-MS: m/z
= 280 [M+H]+. C11H13N5O4 (279.25): calcd. C 47.31, H 4.69, N
25.08; found C 47.47, H 4.70, N 24.77.
1-[(1S,3R,4S,5S)-4-Hydroxy-1-(hydroxymethyl)-2-oxabicyclo[3.1.0]-
hex-3-yl]-5-methyl-2,4(1H,3H)-pyrimidinedione (17): Yield 220 mg
(86%). M.p. 75 °C. UV (EtOH 95%): λmax (ε) = 263 nm (9500).
[α]2D0 = +66.9 (c = 1.21, DMSO). 1H NMR (300 MHz, [D6]DMSO):
δ = 11.25 (br. s, 1 H, NH), 7.53 (d, J = 1.1 Hz, 1 H, 6-H), 5.78 (d,
J = 4.8 Hz, 1 H, 3Ј-H), 5.41 (d, J = 4.8 Hz, 1 H, 4Ј-OH), 5.00 (t,
J = 5.8 Hz, 1 H, 7Ј-OH), 4.24 (t, J = 4.8 Hz, 1 H, 4Ј-H), 3.89 (dd,
J = 5.9, 12.6 Hz, 1 H, 7Јa-H), 3.62 (dd, J = 5.7, 12.6 Hz, 1 H, 7Јb-
H), 1.76 (d, J = 1.1 Hz, 3 H, CH3), 1.49 (dd, J = 4.9, 9.7 Hz, 1 H,
5Ј-H), 0.87 (t, J = 5.4 Hz, 1 H, 6Јa-H), 0.72 (dd, J = 6.6, 9.7 Hz, 1
H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 163.9 (C-
4), 150.1 (C-2), 138.9 (C-6), 106.7 (C-5), 86.4 (C-3Ј), 71.0 (C-4Ј),
69.7 (C-1Ј), 61.8 (C-7Ј), 23.4 (C-5Ј), 12.1 (CH3), 11.7 (C-6Ј) ppm.
FAB-MS: m/z = 509 (2M + H)+, 255 [M + H]+. C11H14N2O5
(254.24): calcd. C 51.97, H 5.55, N 11.02; found C 51.86, H 5.35,
N 10.83.
4-Amino-1-[(1S,3R,4R,5S)-4-azido-1-(hydroxymethyl)-2-oxabicy-
clo[3.1.0]hex-3-yl]-2(1H)-pyrimidinone (15): To a cooled (ice/water
bath) solution of compound 11 (120 mg, 0.325 mmol) in dry pyri-
dine (2 mL) was added 1,2,4-triazole (295 mg, 4.27 mmol) followed
by the addition of 4-chlorophenyl phosphorodichloridate
(0.231 mL, 1.43 mmol). The reaction mixture was stirred at room
temperature for 48 h, and the solvent was evaporated to dryness.
The residue was dissolved in CH2Cl2 (30 mL) and washed with
water. The organic layer was dried (Na2SO4), concentrated to dry-
ness, and the residue was purified by silica gel column chromatog-
[(1S,3R,4S,5S)-4-(Acetyloxy)-3-[2,4-dioxo-3,4-dihydro-1(2H)-
pyrimidinyl]-2-oxabicyclo[3.1.0]hex-1-yl]methyl acetate (18): To a
solution of compound 16 (120 mg, 0.5 mmol) in pyridine (3 mL)
was added acetic anhydride (0.7 mL, 7.4 mmol). After stirring over-
night, the solution was evaporated, co-evaporated with toluene, and
the crude product was purified by silica gel column chromatog-
raphy with a stepwise gradient of MeOH (3–5%) in CH2Cl2 to raphy with a stepwise gradient of MeOH (3–5%) in CH2Cl2 to give
afford to the 4-triazolyl intermediate (85 mg). This compound was
then dissolved in NH4OH/dioxane (2.7 mL, 1:3, v/v), and the reac-
tion mixture was stirred overnight at room temperature. The mix-
ture was evaporated, and the crude product was purified by silica
compound 18 (140 mg, 86%) as a white foam. 1H NMR (300 MHz,
[D6]DMSO): δ = 11.37 (br. s, 1 H, NH), 7.50 (d, J = 8.1 Hz, 1 H,
6-H), 6.06 (d, J = 4.8 Hz, 1 H, 3Ј-H), 5.70 (d, J = 8.1 Hz, 1 H, 5-
H), 5.30 (d, J = 4.8 Hz, 1 H, 4Ј-H), 4.47 (s, 2 H, 7Јa-H and 7Јb-H),
4896
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4891–4897

C-4Ј-Modified (2-Oxabicyclo[3.1.0]hexyl)yrimidine Nucleosides
FULL PAPER
quez, T. K. Harden, K. A. Jacobson, J. Med. Chem. 2005, 48,
8108–8111; f) P. L. Boyer, J. G. Julias, V. E. Marquez, S. H. Hu-
gues, J. Mol. Biol. 2005, 345, 441–450.
2.09 (s, 3 H, CH3), 1.94 (s, 3 H, CH3), 1.77 (dd, J = 5.1, 10.1 Hz, 1
H, 5Ј-H), 1.38 (dd, J = 5.1, 7.1 Hz, 1 H, 6Јa-H), 1.00 (dd, J = 7.1,
10.1 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
170.2 (COCH3), 168.9 (COCH3), 162.8 (C-4), 149.6 (C-2), 141.2
(C-6), 100.9 (C-5), 84.5 (C-3Ј), 72.6 (C-4Ј), 66.9 (C-1Ј), 64.6 (C-7Ј),
21.4 (C-5Ј), 20.6 (CH3CO), 20.4 (CH3CO), 12.3 (C-6Ј) ppm. FAB-
MS: m/z = 649 [2M + H]+, 325 [M + H]+. HRMS: calcd. for
C14H17N2O7 [M+H]+ 325.1036; found 325.1045.
[6] For recent examples, see: a) J. Ravn, P. Nielsen, J. Chem. Soc.,
Perkin Trans. 1 2001, 985–993; b) M. H. Sorensen, C. Nielsen,
P. Nielsen, J. Org. Chem. 2001, 66, 4878–4886; c) T. Bryld,
M. H. Sorensen, P. Nielsen, T. Koch, C. Nielsen, J. Wengel, J.
Chem. Soc., Perkin Trans. 1 2002, 1655–1662; d) M. Montem-
bault, N. Bourgougnon, J. Lebreton, Tetrahedron Lett. 2002,
43, 8091–9094; e) M. J. Kim, H. O. Kim, H.-D. Kim, J. H.
Kim, L. S. Jeong, M. W. Chun, Bioorg. Med. Chem. Lett. 2003,
13, 3499–3501; f) S. Obika, J.-I. Andoh, M. Onoda, O. Naka-
gawa, A. Hiroto, T. Sugimoto, T. Imanishi, Tetrahedron Lett.
2003, 44, 5267–5270; g) M. K. Gurjar, D. S. Reddy, M.
Bhadbhade, R. G. Gonnade, Tetrahedron 2004, 60, 10269–
10275; h) N. Kifli, T. T. Htar, E. De Clercq, J. Balzarini, C.
Simmons, Bioorg. Med. Chem. 2004, 12, 3247–3257; i) P. J.
Hrdlicka, N. K. Andersen, J. S. Jepsen, F. G. Hansen, K. F.
Haselmann, C. Nielsen, J. Wengel, Bioorg. Med. Chem. 2005,
13, 2597–2621.
4-Amino-1-[(1S,3R,4S,5S)-4-hydroxy-1-(hydroxymethyl)-2-oxabicy-
clo[3.1.0]hex-3-yl]-2(1H)-pyrimidinone (19): Yield 70 mg (83%). UV
(EtOH 95%): λmax (ε) = 270 nm (9100). [α]2D0 = +86.6 (c = 0.78,
DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 7.61 (d, J = 7.4 Hz,
1 H, 6-H), 7.37 (br. s, 1 H, NH), 7.16 (br. s, 1 H, NH), 5.79 (d, J
= 4.5 Hz, 1 H, 3Ј-H), 5.71 (d, J = 7.4 Hz, 1 H, 5-H), 5.29 (d, J =
5.3 Hz, 1 H, 4Ј-OH), 4.92 (t, J = 5.6 Hz, 1 H, 7Ј-OH), 5.09 (t, J =
4.5 Hz, 1 H, 4Ј-H), 3.83 (dd, J = 5.7, 12.5 Hz, 1 H, 7Јa-H), 3.66
(dd, J = 5.5, 12.5 Hz, 1 H, 7Јb-H), 1.51 (dd, J = 4.9, 9.7 Hz, 1 H,
5Ј-H), 0.87 (t, J = 6.6 Hz, 1 H, 6Јa-H), 0.71 (dd, J = 6.6, 9.7 Hz, 1
H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 164.9 (C-
4), 154.0 (C-2), 144.0 (C-6), 92.2 (C-5), 86.8 (C-3Ј), 70.3 (C-4Ј),
69.1 (C-1Ј), 61.9 (C-7Ј), 23.6 (C-5Ј), 11.2 (C-6Ј) ppm. FAB-MS: m/z
= 240 [M+H]+. HRMS: calcd. for C10H14N3O4 [M+H]+ 240.0984;
found 240.1021.
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Acknowledgments
J.G. is particularly grateful to the Ministère de l’Education Nation-
ale, de la Recherche et de la Technologie (France) for a doctoral
fellowship. Sidaction (France) is gratefully acknowledged for finan-
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Received: June 26, 2006
Published Online: September 7, 2006
Eur. J. Org. Chem. 2006, 4891–4897
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4897