Synthesis and biological evaluation of 4′-C,3′-O-propylene- linked bicyclic nucleosides

Article abstract of DOI:10.1002/ejoc.201100859

A set of pyrimidine nucleosides fused with a 4′-C,3′-O- propylene bridge was successfully synthesised in 12 steps from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, an inexpensive starting material, based on a ring-closing metathesis (RCM) reaction followed by Vorbrueggen-type nucleobase coupling. Antiviral and cytotoxicity activities of the targeted modified nucleosides, as well as their phosphoramidate prodrugs, are described. An efficient route to a set of pyrimidine nucleosides fused with a 4′-C,3′-O-propylene bridge has been developed. Antiviral and cytotoxicity activities of these bicyclic nucleosides, as well as their phosphoramidate prodrugs, are presented. Copyright

Full text of DOI:10.1002/ejoc.201100859

FULL PAPER
DOI: 10.1002/ejoc.201100859
Synthesis and Biological Evaluation of 4Ј-C,3Ј-O-Propylene-Linked Bicyclic
Nucleosides
Wilfried Hatton,[a] Julie Hunault,[a] Maxim Egorov,[a] Christophe Len,[b] Muriel Pipelier,[a]
Virginie Blot,[a] Virginie Silvestre,[a] Valérie Fargeas,[a] Adjou Ané,[c] Tami McBrayer,[d]
Mervi Detorio,[d] Jong-Hyun Cho,[d] Nathalie Bourgougnon,[e] Didier Dubreuil,[a]
Raymond F. Schinazi,[d] and Jacques Lebreton*[a]
Keywords: Medicinal chemistry / Antiviral agents / Nucleosides / Metathesis / Glycosylation / Nitrogen heterocycles
A set of pyrimidine nucleosides fused with a 4Ј-C,3Ј-O-prop-
ylene bridge was successfully synthesised in 12 steps from
1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, an inexpen-
sive starting material, based on a ring-closing metathesis
(RCM) reaction followed by Vorbrüggen-type nucleobase
coupling. Antiviral and cytotoxicity activities of the targeted
modified nucleosides, as well as their phosphoramidate pro-
drugs, are described.
fied nucleosides, various restricted analogues on the sugar
ring, with a bridge of different sizes containing one oxygen
atom, have been evaluated for their biological activities.
In the antisense field, the most intriguing examples are
the 2Ј-O,4Ј-C-methylene-bridged nucleic acids (named
locked nucleic acids, or LNA,[4] now commercially avail-
able) and ENA[5] (2Ј-O,4Ј-C-ethylene-bridged nucleic acids)
as outlined in Figure 1. It is worth pointing out that LNA
are conformationally restricted RNA mimics, with an N-
type sugar pucker that is present exclusively in A-form du-
plexes. LNA display a markedly increased duplex stability
with complementary RNA and a greater nuclease resistance
compared to native DNA. In addition, some bicyclic nu-
cleoside analogues containing a fused oxirane (1),[6] oxetane
(2)[7] and tetrahydrofuran (3–4[8] and 5)[9] rings (Figure 1)
have been reported to exhibit anti-HIV activity.
Introduction
There has been a continuing interest in the synthesis of
modified nucleosides as potent antiviral and antitumor
agents, and a plethora of compounds has been evaluated
over the years.[1] In this context, various bridged nucleo-
sides, in which the carbohydrate conformation is restricted
or locked by the introduction of an additional link on the
carbohydrate moiety, have been reported.[2] Some of these
carbohydrate-modified nucleosides have also been incorpo-
rated into oligonucleotides to increase resistance toward en-
zymatic degradation and to form stable duplexes with com-
plementary DNA and RNA strands.[3] All these modified
nucleosides have been designed to optimise their recogni-
tion by their target enzymes or oligonucleotide strands
based on a preorganisation of the sugar moiety to an ap-
propriate conformation. Among the large number of modi-
[a] Université de Nantes, CNRS, Laboratoire CEISAM-UMR
6230, Faculté des Sciences et des Techniques,
2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3,
France
Fax: +33-2-51125562
E-mail: Jacques.Lebreton@univ-nantes.fr
[b] Université de Technologie de Compiègne, Ecole Supérieure de
Chimie Organique Minérale,
EA 4297, Transformations Intégrées de la Matière
Renouvelable,
1 allée du Réseau Jean-Marie Buckmaster, 60200 Compiègne,
France
[c] Laboratoire de Chimie Organique, UFR SSMT, Université de
Cocody 22,
BP 582, Abidjan 22, Cote d’Ivoire
[d] Center for AIDS Research, Department of Pediatrics, Emory
University School of Medicine/Veterans Affair Medical Center,
Decatur, Georgia 30033, USA
[e] Université de Bretagne-Sud Laboratoire de Biotechnologie et
Chimie Marines, Campus de Tohannic,
56017 Vannes, France
Figure 1. Structures of LNA, ENA and nucleoside derivatives 1–5
(T = thymin-1-yl, C = cytosin-1-yl, B = pyrimidin-1-yl and purin-
9-yl).
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100859.
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Synthesis and Biological Evaluation of Bicyclic Nucleosides
Besides LNA and ENA, some oxygenated bicyclic nu-
cleosides, such as 6,[10] 7,[11] 8,[12] 9[13] and 1014 (Figure 2),
have been incorporated into oligonucleotides and evaluated
for antisense application. To the best of our knowledge,
since our previous work[15] on the synthesis of the 4Ј-C,3Ј-
O-propylene-bridged nucleosides 11 and 12 starting from
thymidine (Scheme 1), no effort to prepare such bicyclic nu-
cleosides has been described in the literature, with the ex-
ception of a publication by Morita et al.[14]
Figure 3. Targeted bicyclic nucleosides 13–18.
Results and Discussion
Chemical Synthesis
For the synthesis of the 4Ј-C-,3Ј-O-bridged nucleosides
13–18, a convergent strategy was used in which the modi-
fied glycosyl donor 20 was synthesised from the inexpensive
1,2:5,6-di-O-isopropylidene-α-d-glucofuranose and then
coupled to the nucleobase, leading to the targeted d-ribo
analogues. This strategy was designed based on the retro-
Figure 2. Selected oxygenated bicyclic nucleoside derivatives 6–10
incorporated into oligonucleosides (T = thymin-1-yl, B = pyrim-
idin-1-yl and purin-9-yl and A = adenin-9-yl).
synthetic analysis involving
a ring-closing metathesis
(RCM)[16] reaction as the key step (Scheme 2). RCM is a
useful method in organic chemistry for the synthesis of dif-
ferent nucleoside analogues that have restricted conforma-
tions, such as bicyclonucleosides[2f] and cyclonucleosides.[2g]
Scheme 1. Structure of 3Ј-O,4Ј-C-propylene-bridged nucleosides 11
and 12 in the 2Ј-deoxyribose series.
These authors reported the biological evaluation of 2Ј,5Ј-
oligoadenylate-5Ј-triphosphate analogues containing 4Ј-
C,3Ј-O-bridged adenosine as potent RNase L agonists, but
without any information about the preparation of the bicy-
clic nucleoside derivative 10.
Scheme 2. Retrosynthetic scheme.
As the entry on the d-ribo derivatives, we envisaged that
As a continuation of our interest in the preparation of the chiral compound 20 could serve as the common glycosyl
new nucleoside analogues, we herein report full details re- donor to reach our target nucleosides, as outlined in
lated to the synthesis of bicyclic nucleosides 13–18 (Fig- Scheme 3. The precursor of our key glycosyl donor 20 was
ure 3) in the d-ribose series containing natural pyrimidine synthesised via the diene 19 according to a known sequence
nucleobases (thymine, uracil and cytosine) and present their described for the 3-O-benzyl derivative.[17] In our case, the
biological evaluation.
choice to use diacetoneglucose as the starting material led
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us to invert the absolute configuration of the carbon atom dehyde and sodium hydroxide afforded the corresponding
in position 3 [(S) to (R)] to have the d-allose configuration. aldol, which was then trapped by reduction with sodium
Then the oxidative cleavage of the diol in position 5,6 would borohydride to yield the desired diol 23.[19] According to
furnish the pentose analogue in similar configuration with previously reported examples, the less hindered 5Јβ-hydroxy
that of the natural nucleoside. The chiral starting material group of diol 23 was stereoselectively protected as a silyl
21 was prepared on a large scale in 4 steps from a glucose ether in 64% yield.[11b,17] The structure of 24 was confirmed
derivative following known procedures.[18] Oxidative cleav- by NOE correlation between the methylene bearing the free
age of the diol 21 by treatment with NaIO4 in a mixture hydroxy function and the methyl of the isopropylidene
of dioxane and water furnished the aldehyde 22. Without group oriented toward the endo face of the bicyclic system
isolation, treatment of the aldehyde 22 with excess formal- (see Supporting Information).[17a] Next, Swern oxidation of
Scheme 3. Reagents and conditions: (a) see ref.[18], 4 steps, 50% overall yield. (b) NaIO4, H2O/dioxane (1:1), 0 °C, 30 min. (c) HCHO
aq., NaOH aq., room temp., dioxane, 6 h, then NaBH4, room temp., 30 min., 51% yield for the three steps. (d) TBDPSCl, Et3N, CH2Cl2,
0 °C then r.t., overnight, 64%. (e) ClCOCOCl, DMSO, DIPEA, CH2Cl2, –78 °C. (f) Ph3P=CH2, THF, –78 °C, room temp., 3 h, 45% for
the two steps. (g) Grubbs’ catalyst second generation, CH2Cl2, room temp., 16 h, 97%. (h) AcOH, Ac2O, cat. H2SO4, room temp., 3 h,
77%. (i) Uracil, BSA, TMSOTf, CH3CN, 0 °C then r.t., 12 h, for 26 73%, for 30 same conditions with cytosine, 77%. (j) Thymine,
HMDS, TMSCl, TMSOTf, DCE, –35 °C, then r.t., 24 h, 76%. (k) K2CO3, MeOH, room temp., for 27, 3 h, 88%; for 29, 3 h, 79%; for
31, 2 h, 85%. (l) TBAF, THF, room temp., for 13, 4 h, 95%; for 14, 4 h, 95%; for 15, 4 h, 76%. (m) 1 atm. H2, 10% Pd/C, EtOH, r.t.
for 16, 24 h, 93%; for 17, 24 h, 87%; for 18, 24 h, 79%.
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Synthesis and Biological Evaluation of Bicyclic Nucleosides
Scheme 4. Reagents and conditions: (a) compound 32, N-methylimidazole, THF, –78 °C, 2 h, then r.t., 12 h, 65%. (b) 1,4-cyclohexadiene,
Pd/C, EtOH, room temp., 3 h, 98%. (c) tert-BuMgCl, THF, 30 min, –78 °C, then compound 32, –78 °C, 2 h, then r.t., 12 h, 48%. (d) 1
atm. H2, Pd/C, EtOH, room temp., 3 h, 94%.
the remaining primary alcohol of 24 gave the corresponding
In addition to this work, the aryl phosphoramidate deriv-
aldehyde, which was treated with methylenetriphenylphos- atives of 13, 15, 16 and 18 were prepared according to re-
phorane to afford the diene 19 in 45% overall yield for the ported methodology[22] to evaluate the importance of the
two-step sequence. The subsequent RCM reaction per- rate-limiting monophosphorylation step on the antiviral ac-
formed with the second generation Grubbs’ catalyst at tivity (Scheme 4). It should be also pointed out that the
room temperature in dichloromethane on compound 19 led resulting less polar aryl phosphoramidites prodrugs 33–36
to the desired cyclised intermediate 25 in high yield.
may more efficiently cross the plasma membrane. The
Successive hydrolysis of the acetonide group of com- masking groups are then cleaved by chemical or enzymatic
pound 25 and acetylation of the resulting diol with acidic hydrolysis to liberate the charged phosphates inside the cell.
treatment in a one-pot reaction delivered the diacetate 20 Starting from nucleoside analogue 13, the phosphoramidate
as an anomeric mixture. It should be noted that the two 33 was prepared by addition of compound 32 in the pres-
anomers have been separated on silica gel chromatography ence of N-methylimidazole. The later compound 33 was
for NMR analysis. At this point, from this key intermediate then subjected to hydrogenation by catalytic hydrogen
20 as an α,β-anomeric mixture, the desired β-nucleoside an- transfer to minimize reduction of the double bound of the
alogues could be efficiently obtained in around 75% yield uracil base,[23] affording the pronucleotide 34 in 65% yield
after purification by stereoselective coupling in the presence for the two steps. Starting from nucleoside analogue 15, the
of TMSOTf with the silylated pyrimidines formed in situ phosphoramidate 35 was obtained following the Uchigawa
following the method of Vorbrüggen.[20] The attack of the procedure[24] in the presence of tert-butylmagnesium chlo-
nucleobase from the favourable β-face is due to anchimeric ride in 48% yield. Then, classical hydrogenation of nucleo-
assistance by neighbouring group participation of the 2Ј-O- tide analogue 35 furnished the target pronucleotide 36 in
Ac to give only the β-anomer. From 26, 28 and 30, subse- 94% yield. All of the phosphoramidate derivatives 33–36
quent methanolysis and cleavage of the TBDPS group with were obtained as diastereomeric mixtures (RP:SP = 1:1), as
1
TBAF afforded the first bicyclic nucleosides 13, 14 and 15, measured by H and 31P NMR spectra.
respectively, and the hydrogenation of the double bond of
the compounds so obtained gave the saturated analogues
16–18 in around 60% yield for the three steps. In our hands,
standard hydrogenation of 13 [1 atm. H2 (balloon) 10% Pd/
Conformational Analysis of Nucleosides 13 and 16
C, EtOH, room temp., 24 h] furnished the target uridine
We performed the conformational analysis of both dihy-
analogue 16 without the unwanted reduction of the C5–C6 dro- and tetrahydro-2H-pyrano-fused uridines 13 and 16 to
uracil double bond.[17b,21b–21d] Nevertheless, some reports study their ribofuranose sugar conformations. In both
in the literature[21a] mention the hydrogenation of the uracil cases, our proton NMR studies (Bruker 500 MHz Avance
nucleobase under these later conditions, which could de- III spectrometer) in D2O from 283 to 323 K showed no
pend on the quality of Pd/C. Also, the use of transfer hy- variation of the J1Ј,2Ј values: 8.45Ϯ0.15 Hz and
drogenation conditions prevents this potential side reaction 8.25Ϯ0.15 Hz for 13 and 16, respectively. These results
(vide infra).
indicated unambiguously that their ribofuranose ring puck-
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J. Lebreton, et al.
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ering was restricted in the S-type conformation by the 3Ј- phates (if they are formed) are not recognized by the viral
O,4Ј-C-bridge, which is the appropriate conformation for DNA or RNA polymerases.
phosphorylation.[9,25]
Experimental Section
Biological Evaluation
All reactions were performed using anhydrous solvents and moni-
tored by TLC (Kieselgel 60F254 MERCK aluminium sheet) with
All final nucleoside analogs and phosphoramidates were
detection by UV light and/or with ethanolic phosphomolybdic acid
tested against HIV-1 (strain LAI) in an assay using human
solution. Flash column chromatography was performed on silica
peripheral blood mononuclear (PBM) cells and demon-
gel 60 ACC 40–63 μm (SDS). 1H NMR and 13C NMR spectra were
strated no significant activity (median effective concentra-
recorded at 300 MHz and 75 MHz, respectively, with a Bruker Av-
tion, EC50 Ͼ 100 μm) when compared with 3Ј-azido-3Ј-de-
ance 300 MHz spectrometer. Chemical shifts (δ) are quoted in ppm,
oxythymidine (AZT, zidovudine) which had an EC50 value
and are referenced to TMS as an internal standard. Coupling con-
of 0.004 μm.[26] These compounds were also evaluated for
stants (J) are quoted in Hz. Mass spectra and HRMS spectra were
their potential toxic effects on uninfected phytohaemagglu-
tinin-stimulated human PBM cells, and also in lymphoblas- Claude Bernard, University of Lyon, with a Thermo-Finnigan
recorded at the Centre Commun de Spectrométrie de Masse-
MAT 95 XL apparatus. Melting points (m.p.) were measured on a
Stuart Scientific apparatus 7SMP3 or Kofler Heating Plate (type
WME). Optical rotations were measured with a Perkin–Elmer 241
MC polarimeter.
toid CEM cells as well as anchored Vero (African green
monkey kidney) cells: no cytotoxicity up to 100 μm was de-
tected for any of the compounds.[27] Although none of these
3Ј-O,4Ј-C-propylene-bridged nucleosides presented any
cytotoxicity, they had no anti-HIV activity when tested up
to 100 μm. Therefore, we also evaluated the compounds for
activity against HCV, an RNA virus, using a well defined
Huh-7 replicon assay system.[28] Unfortunately, none of the
compounds were effective, but they were also not cytotoxic
toward Huh-7 cells, whereas the positive control 2Ј-C-meth-
ylcytidine had significant antiviral activity (EC50 = 3 μm).
Concerning the aryl phosphoramidate derivatives of 13, 15,
16 and 18, the biological data showed no appreciable differ-
3-O-Allyl-4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-erythrofur-
anose (23): To a stirred solution of diol 21 (14.2 g, 54.6 mmol) in
water and dioxane (1:1, 38 mL), NaIO4 (14.0 g, 65.5 mmol,
1.2 equiv.) was added at 0 °C. After stirring for 30 min, 1.5 mL of
ethylene glycol was added, and the resulting mixture was extracted
with AcOEt (3ϫ50 mL) and then with CH2Cl2. The organic layer
was then dried with MgSO4, filtered and concentrated under re-
duced pressure to obtain the aldehyde 22. To the crude aldehyde
dissolved in dioxane (185 mL) was added an aqueous formaldehyde
solution (37%, 6.0 mL) and an aqueous solution of NaOH (2 m,
ences in antiviral potency compared to their parent struc- 27.3 mL). After stirring for 6 h at room temp., the mixture was
cooled to 0 °C, and NaBH4 (3.8 g, 99.1 mmol, 2.0 equiv.) was
slowly added. The solution was stirred for 30 min at room temp.,
and a pyridine/acetic acid mixture (4:1, 200 mL) was added. After
stirring for an additional 30 min at 0 °C, the crude mixture was
concentrated under reduced pressure. Purification by chromatog-
raphy on silica gel (petroleum ether/AcOEt, 30:70) afforded the diol
23 as a colourless syrup (6.6 g, 51% over two steps). Spectroscopic
data of this compound were consistent with those reported by Kier-
tures against HIV-1 or HCV. All final nucleoside analogues
and phosphoramidates were tested against Herpes simplex
virus type 1 (HSV-1) by cell viability.[29,30] After 3 days of
treatment, microscopically visible alteration of normal Vero
cell morphology was observed and viability assay showed
destruction of cell layer. For those compounds, the 50%
cytotoxic concentration (CC50) fell within the range of 0.49
to 3.0 μm. The cytosine analogues 15 and 18 showed the
lowest toxicity (3.0 and 2.2 μm respectively), compared with
zek et al., see ref.[19]. [α]2D5 = +78.3 (c = 1.0, CHCl ). IR (neat): ν
˜
3
= 3429, 2975, 2930, 2880, 1644, 1456, 1386, 1377, 1106, 1055,
Acyclovir [Zovirax®, 2-amino-9-(propoxymethyl)-1H-pu- 876 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.94–5.84 (m, 1 H,
H2C=CH-CH2), 5.73 (d, J = 3.6 Hz, 1 H, H1Ј), 5.28 [syst. ABMXY,
rin-6(9H)-one], which has a CC50 above 4.4 μm. No anti-
HSV activity was observed for any of the final nucleoside
J = 17.1, 1.2 Hz, 1 H, H-(H)C=CH-CH2], 5.20 [syst. ABMXY, J
= 10.5, 1.2 Hz, 1 H, H-(H)C=CH-CH2], 4.63 (dd, J = 5.1, 3.6 Hz,
analogues 13–18 nor phosphoramidates 33–36. The lack of
1 H, H2Ј), 4.22 (d, J = 5.1 Hz, 1 H, H3Ј), 4.21 and 4.06 (syst.
recognition of the corresponding 5Ј-triphosphate of these
ABMXY, J = 12.7, 5.8 Hz, 2 H, H2C=CH-CH2), 3.92 and 3.60
bicyclic nucleosides by viral polymerases or lack of conver-
sion to the triphophates by cellular kinases are the most
likely explanations for the lack of antiviral activity.
(syst. AB, J = 12.0 Hz, 2 H, H5Јα), 3.83 and 3.78 (syst. AB, J =
5.8 Hz, 2 H, H5Јβ), 1.57 {s, 3 H, [C(CH3)-CH3(endo)]}, 1.29 {s, 3
H, [C(CH3)-CH3(exo)]} ppm. 13C NMR (75 MHz, CDCl3): δ =
134.0 (H2C=CH-), 118.3 (H2C=CH-), 113.5 [2 ϫO-C(O)CH3],
104.3 (C1Ј), 86.2 (C4Ј), 78.5 (C2Ј), 78.2 (C3Ј), 71.9 (O-CH2-
CH=CH2), 64.0, 63.1 (2ϫCH2-OH), 26.5 [C(CH3)-CH3(endo)],
25.8 [C(CH3)-CH3(exo)] ppm.
Conclusions
In summary, we have prepared a set of novel pyrimidine
ribonucleosides fused with a 4Ј-C,3Ј-O-propylene bridge in
12 steps from diacetonide-α-d-glucose using a simple and
flexible synthetic route. None of the synthesised nucleoside
analogues were cytotoxic, but they exhibited no significant
anti-HIV or anti-HCV activities, suggesting that these com-
pounds are probably not substrates for the various cellular
3-O-Allyl-5-tert-butyldiphenylsilyl-4-C-hydroxymethyl-1,2-O-iso-
propylidene-α-D-erythrofuranose (24): Diol 23 (6.6 g, 25.4 mmol)
was dissolved in dry CH2Cl2 (150 mL), and then Et3N (11.3 mL,
93.9 mmol, 3.7 equiv.) and tert-butyldiphenylsilylchloride
(19.7 mL, 76.2 mmol, 3.0 equiv.) were added at 0 °C. After stirring
overnight at room temp., a saturated aqueous solution of NaHCO3
was added, and the aqueous layer was extracted three times with
kinases, or alternatively, their corresponding 5Ј-triphos- CH2Cl2. The organic layers were combined, dried with MgSO4,
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Synthesis and Biological Evaluation of Bicyclic Nucleosides
filtered and concentrated under reduced pressure. After purifica-
tion by chromatography on silica gel (petroleum ether/AcOEt,
90:10), the monoprotected alcohol 24 was obtained as white crys-
CH=CH2), 66.3 (CH2-O-Si), 26.8 [(CH3)3C-Si], 26.2 [C(CH3)-
CH3(endo)], 25.8 [C(CH3)-CH3(exo)], 19.3 [(CH3)3C-Si] ppm.
(3ξ)-3,7-Anhydro-5,6-dideoxy-1,2-O-(1-methylethylidene)-4-{[(tert-
butyldiphenylsilyl)oxy]methyl}-β-L-threo-hept-5-enofuranose (25):
To a solution of compound 19 (3.7 g, 7.5 mmol) in dry CH2Cl2
(850 mL) was added Grubbs’ type-II catalyst (670 mg, 0.75 mmol,
0.1 equiv.). The reaction mixture was stirred for 16 h at room temp.,
and then the solvent was evaporated. The crude residue was puri-
fied by chromatography on silica gel (petroleum ether/AcOEt, 95:5)
to give the bicyclic compound 25 as a brown oil (3.4 g, 97 %).
tals (8.3 g, 64%); m.p. 67–69 °C. IR (KBr): ν = 3500, 3133, 2987,
˜
2952, 2857, 1471, 1429, 1385, 1136, 1007 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 7.68–7.65 (m, 4 H, HAr), 7.43–7.38 (m, 6
H, HAr), 5.99–5.86 (syst. ABMXY, 1 H, H2C=CH-CH2), 5.83 (d,
J = 3.3 Hz, 1 H, H1Ј), 5.30 [syst. ABMXY, J = 17.1, 1.5 Hz, 1 H,
H-(H)C=CH-CH2], 5.24 [syst. ABMXY, J = 10.3, 1.5 Hz, 1 H, H-
(H)C=CH-CH2], 4.70 (dd, J = 5.1, 3.8 Hz, 1 H, H2Ј), 4.43 (d, J =
5.1 Hz, 1 H, H3Ј), 4.22 and 4.02 (syst. ABMXY, J = 12.6, 5.4,
1.5 Hz, 2 H, H2C=CH-CH2), 3.84 and 3.78 (syst. AB, J = 11.9 Hz,
2 H, -CH2OH), 3.82 and 3.75 (syst. AB, J = 9.0 Hz, 2 H, H5Ј), 1.64
{s, 3 H, [C(CH3)-CH3(endo)]}, 1.37 {s, 3 H, [C(CH3)-CH3(exo)]},
1.06 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.6
(CHAr), 134.1 (H2C=CH-), 133.3, 133.0 (CAr-Si), 129.8, 127.7
(CHAr), 118.2 (H2C=CH-), 113.7 [2 ϫO-C(O)CH3], 104.4 (C1Ј),
87.3 (C4Ј), 79.2 (C2Ј), 78.1 (C3Ј), 71.9 (O-CH2-CH=CH2), 65.5
(CH2-O-Si), 63.2 (CH2-OH), 26.8 [(CH3)3C-Si], 26.7 [C(CH3)-
CH3(endo)], 26.3 [C(CH3)-CH3(exo)], 19.3 [(CH3)3C-Si] ppm.
[α]2D5 = –3.1 (c = 1.0, CHCl ). IR (neat): ν = 2931, 2857, 1428, 1381,
˜
3
1372, 1113, 1018 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.63–7.72
(m, 4 H, HAr), 7.35–7.45 (m, 6 H, HAr), 5.97 (d, J = 4.3 Hz, 1 H,
H1Ј), 6.00–5.93 (m, 1 H, H2C=CH-CH2), 5.73 [syst. ABMX, J =
10.6, 2.2 Hz, 1 H, H-(H)C=CH-CH2], 4.94 (dd, J = 5.9, 4.3 Hz, 1
H, H2Ј), 4.50 and 4.04 (syst. ABMX, J = 16.4, 3.0, 2.2 Hz, 2 H,
HC=CH-CH2), 4.39 (d, J = 5.9 Hz, 1 H, H3Ј), 3.65 and 3.43 (syst.
AB, J = 10.8 Hz, 2 H, H5Ј), 1.54 {s, 3 H, [C(CH3)-CH3(endo)]},
1.38 {s, 3 H, [C(CH3)-CH3(exo)]}, 1.05 (s, 9 H, tBu) ppm. 13C
NMR (75 MHz, CDCl3): δ = 135.7 (CHAr), 133.0, 132.8 (CAr-Si),
129.8 (CHAr, HC=CH-CH2), 127.8 (CHAr), 124.3 (HC=CH-CH2),
114.1 [O-C(O)(CH3)2], 105.4 (C1Ј), 82.2 (C2Ј), 80.2 (C4Ј), 74.4 (C3Ј),
68.1 (C5Ј), 63.8 (HC=CH-CH2-O), 27.2 [C(CH3)-CH3], 26.8 [(CH3)3-
C-Si], 26.4 [C(CH3)-CH3], 19.2 [(CH3)3C-Si] ppm.
3-O-Allyl-5-(tert-butyldiphenylsilyl)-1,2-O-isopropylidene-4-C-vinyl-
α-D-erythrofuranose (19): To a solution of oxalyl chloride (2.9 mL,
33.1 mmol, 2.0 equiv.) in anhydrous CH2Cl2 (70 mL) at –78 °C was
added a solution of dry DMSO (3.9 mL, 10.3 mmol, 3.3 equiv.) in
anhydrous CH2Cl2 (35 mL). After stirring for 20 min at –78 °C,
alcohol 24 (8.3 g, 16.5 mmol) in anhydrous CH2Cl2 (35 mL) was
added dropwise. The reaction mixture was stirred for 30 min at
–78 °C, Et3N (12.4 mL, 102.5 mmol, 6.2 equiv.) was added, and the
reaction was warmed to room temp. before being cooled to 0 °C
for addition of H2O. After extraction with CH2Cl2, the organic
layer was washed with H2O and brine, dried with MgSO4, filtered
and concentrated under reduced pressure. The aldehyde (8.2 g) was
then used crude for the next reaction. To a suspension of triphenyl-
phosphonium bromide (23.6 g, 66.1 mmol, 4.0 equiv.) in dry THF
(300 mL) at 0 °C was added nBuLi (1.6 m in hexanes, 23.8 mL,
59.5 mmol, 3.6 equiv.). After stirring for 5 min at 0 °C and 1 h at
room temp., the reaction mixture was cooled to –78 °C. A solution
of the previous crude aldehyde (8.2 g, 16.5 mmol) in dry THF
(200 mL) was added dropwise. The reaction was stirred for 30 min
at –78 °C then for 2 h at 0 °C and finally for 1 h at room tempera-
ture before being cooled to 0 °C for the addition of a saturated
aqueous solution of NH4Cl. After extraction with CH2Cl2, the
combined organic layers were washed with brine, dried with
MgSO4, filtered and concentrated under reduced pressure. The
crude residue was purified by chromatography on silica gel (petro-
leum ether/AcOEt, 95:5), and the unsaturated compound 19 was
obtained as a colourless oil (3.7 g, 45% over two steps). [α]2D5 = –1.0
1,2-Di-O-acetyl-3,7-anhydro-5,6-dideoxy-4-{[(tert-butyldiphenylsil-
yl)oxy]methyl}-α/β-L-lyxo-hept-5-enofuranose (20): To a solution of
the bicyclic compound 25 (3.4 g, 7.3 mmol) in acetic acid (95 mL)
was added acetic anhydride (10.2 mL, 87.5 mmol, 12.0 equiv.) and
a concentrated solution of H2SO4 (95 μL, 14 μmol, 0.002 equiv.).
After stirring for 3 h at room temp., an aqueous saturated solution
of NaHCO3 was added, and the aqueous layer was extracted with
CH2Cl2. The organic layer was dried with MgSO4, filtered and con-
centrated under reduced pressure. The crude residue was purified
by chromatography on silica gel (petroleum ether/AcOEt, 80:20) to
give anomer β-20 as a colourless oil (1.7 g, 46%) and anomer α-20
as a colourless oil (1.2 g, 31%). β-Anomer: [α]2D5 = +67.0 (c = 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.74–7.66 (m, 4 H, HAr),
7.46–7.36 (m, 6 H, HAr), 6.51 (d, J = 5.1 Hz, 1 H, H1Ј), 6.15–6.08
(syst. ABMX, J = 10.4, 4.3, 1.6 Hz, 1 H, HC=CH-CH2), 5.70–5.66
(m, 2 H, HC=CH-CH2, H2Ј), 4.38 (d, J = 5.0 Hz, 1 H, H3Ј), 4.28
and 3.90 (syst. ABMX, J = 16.4, 4.3, 2.0 Hz, 2 H, HC=CH-CH2),
3.59 and 3.38 (syst. AB, J = 11.0 Hz, 2 H, H5Ј), 2.19, 2.11 [s, 3 H,
O-C(=O)-CH3], 1.10 (s, 9 H, tBu) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.6, 170.0 [2ϫO-C(=O)-CH3], 135.6, 132.7 (CHAr),
132.3 (CAr), 130.8 (HC=CH-CH2), 129.9, 127.8 (CHAr), 124.7
(HC=CH-CH2), 94.5 (C1Ј), 81.5 (C4Ј), 74.3 (C3Ј), 72.6 (C2Ј), 68.0
(C5Ј), 62.8 (HC=CH-CH2), 26.8 [(CH3)3C-Si], 21.4, 20.7 [2ϫO-
C(=O)-CH3], 19.1 [(CH3)3C-Si] ppm. α-Anomer: [α]2D5 = –59.0 (c =
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.74–7.66 (m, 4 H,
HAr), 7.46–7.36 (m, 6 H, HAr), 6.38 (d, J = 5.4 Hz, 1 H, H1Ј), 6.08
(syst. ABMX, J = 10.4, 4.3, 1.5 Hz, 1 H, HC=CH-CH2), 5.64 (syst.
ABMX, J = 10.4, 2.0 Hz, 1 H, HC=CH-CH2), 5.60 (dd, J = 5.3,
5.0 Hz, 1 H, H2Ј), 4.50 and 4.04 (syst. ABMX, J = 16.4, 4.3, 2.0 Hz,
2 H, HC=CH-CH2), 4.40 (d, J = 5.0 Hz, 1 H, H3Ј), 3.66 and 3.43
(syst. AB, J = 11.0 Hz, 2 H, H5Ј), 2.18, 2.00 [s, 3 H, O-C(=O)-
CH3], 1.10 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.7, 170.1 [2ϫO-C(=O)-CH3], 135.6 (CHAr), 132.6 (CAr), 130.0
(HC=CH-CH2) 129.9, 127.8 (CHAr), 124.1 (HC=CH-CH2), 99.2
(C1Ј), 82.0 (C4Ј), 80.2 (C3Ј), 75.2 (C2Ј), 67.6 (C5Ј), 63.0 (HC=CH-
CH2), 26.7 [(CH3)3C-Si], 21.0 [2ϫO-C(=O)-CH3], 19.2 [(CH3)3C-
Si] ppm.
(c = 1.0, CHCl ). IR (neat): ν = 2980, 2858, 1472, 1428, 1265, 1250,
˜
3
1113, 1028 cm–1. H NMR (300 MHz, CDCl3): δ = 7.75–7.66 (m,
1
4 H, HAr), 7.45–7.35 (m, 6 H, HAr), 6.14 (syst. ABX, J = 17.3,
11.0 Hz, 1 H, HC=CH2 vinyl), 6.08–5.94 (m, 1 H, H2C=CH-CH2
allyl), 5.85 (d, J = 3.8 Hz, 1 H, H1Ј), 5.45 [syst. ABX, J = 17.3,
1.8 Hz, 1 H, HC=C(H)-H vinyl], 5.35 [syst. ABMXY, J = 17.3, 1.4,
1.1 Hz, 1 H, H-(H)C=CH-CH2 allyl], 5.25–5.22 [m, 1 H, H-(H)-
C=CH-CH2 allyl], 5.18 [syst. ABX, J = 11.0, 1.8 Hz, 1 H, H-
C=C(H)-H vinyl], 4.72 (dd, J = 4.9, 3.8 Hz, 1 H, H2Ј), 4.48 (d, J =
4.9 Hz, 1 H, H3Ј), 4.30–4.12 (m, 2 H, H2C=CH-CH2 allyl), 3.57 (s,
2 H, H5Ј), 1.54 {s, 3 H, [C(CH3)-CH3(endo)]}, 1.38 {s, 3 H,
[C(CH3)-CH3(exo)]}, 1.05 (s, 9 H, tBu) ppm. 13C NMR (75 MHz,
CDCl3): δ = 135.7, 135.5 (CHAr), 134.8 (H2C=CH- vinyl), 133.9
(H2C=CH- allyl), 133.5, 133.0 (CAr-Si), 129.7, 127.7 (CHAr), 117.9
(H2C=CH- allyl), 116.2 (H2C=CH- vinyl), 113.5 [2ϫO-C(O)CH3],
Uridine Derivative 26: To
a suspension of uracil (203 mg,
103.9 (C1Ј), 87.1 (C4Ј), 79.5 (C2Ј), 77.0 (C3Ј), 72.0 (O-CH2- 0.37 mmol, 1.5 equiv.) in freshly distilled CH3CN (3 mL) was
Eur. J. Org. Chem. 2011, 7390–7399
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7395

J. Lebreton, et al.
FULL PAPER
added BSA [N,O-bis(trimethylsilyl)acetamide] (185 μL, 0.75 mmol,
3.0 equiv.). The mixture was stirred for 20 min at room temp., and
a solution of glycoside 20 (116 mg, 0.25 mmol, 1 equiv.) in freshly
distilled CH3CN (2 mL) was added. After cooling to 0 °C,
TMSOTf (46 μL, 0.25 mmol) was added, and the reaction was
stirred at room temp. overnight. After dilution with CH2Cl2, an
aqueous saturated solution of NaHCO3 was added. The aqueous
layer was extracted three times with CH2Cl2, and then the organic
layers were recombined, dried with Na2SO4, filtered and concen-
trated under reduced pressure. The crude mixture was purified by
chromatography on silica gel (petroleum ether/AcOEt, 60:40) to
afford compound 26 (181 mg, 73%) as a white solid; m.p. 61–62 °C.
(syst. ABMX, J = 16.2, 4.8, 1.8 Hz, 2 H, HC=CH-CH2), 4.01 (d,
J = 4.8 Hz, 1 H, H3Ј), 3.60 and 3.49 (syst AB, J = 11.7 Hz, 2 H,
H5Ј) ppm. 13C NMR (75 MHz, CD3OD): δ = 168.1, 152.8 (C=O),
142.9 [N-(H)C=CH], 132.5 (HC=CH-CH2), 125.2 (HC=CH-CH2),
103.4 [N-(H)C=CH], 88.4 (C1Ј), 80.9 (C4Ј), 78.5 (C3Ј), 75.3 (C2Ј),
67.4 (C5Ј), 63.8 (HC=CH-CH2) ppm. HRMS (CI): calcd. for
C12H15N2O6 [M + H]+ 283.0930; found 283.0931.
Uridine Derivative 16: To a solution of nucleoside analogue 14
(83 mg, 0.38 mmol) in EtOH (17 mL) was added Pd/C 10%
(17 mg). After 24 h of stirring at room temp. under H2 atmosphere
(balloon), the reaction mixture was filtered through Celite and con-
centrated under reduced pressure. The crude residue was purified
by chromatography on silica gel (AcOEt and AcOEt/MeOH, 70:30)
to give the diol 16 as a white powder (75 mg, 93%); m.p. 224–
1
[α]2D5 = +46.5 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ =
9.20 (s, 1 H, NH), 7.79 [d, J = 8.1 Hz, 1 H, N-(H)C=CH], 7.70–
7.63 (m, 4 H, HAr), 7.47–7.38 (m, 6 H, HAr), 6.46 (d, J = 8.4 Hz 1
H, H1Ј), 6.13 (syst ABMX, J = 10.3, 4.7, 1.6 Hz, 1 H, HC=CH-
CH2), 5.58–5.49 (m, 2 H, HC=CH-CH2, H2Ј), 5.37 [d, J = 8.1 Hz,
1 H, N-(H)C=CH], 4.35 (d, J = 4.8 Hz, 1 H, H3Ј), 4.23 [syst.
ABMX, J = 16.4, 4.7, 1.2 Hz, 1 H, HC=CH-C(H)-H], 3.88–3.81
[m, 1 H, HC=CH-C(H)-H], 3.83 and 3.50 (syst. AB, J = 11.3 Hz,
2 H, H5Ј), 2.16 [s, 3 H, H3C-C(=O)], 1.13 (s, 9 H, tBu) ppm. 13C
NMR (75 MHz, CDCl3): δ = 170.3, 163.0, 150.6 (C=O), 140.0 [N-
(H)C=CH], 135.7, 135.3 (CHAr), 131.6 (HC=CH-CH2), 130.3,
130.2 (CAr-Si), 128.1, 127.8 (CHAr), 123.2 (HC=CH-CH2), 102.9
[N-(H)C=CH], 84.1 (C1Ј), 79.6 (C4Ј), 75.2 (C3Ј), 74.6 (C2Ј), 68.5
(C5Ј), 62.6 (HC=CH-CH2), 27.0 [(CH3)3C-Si], 20.6 [O-C(=O)-
CH3], 19.3 [(CH3)3C-Si] ppm. HRMS (CI): calcd. for
C30H35N2O7Si [M + H]+ 563.2214; found 563.2214.
1
225 °C. [α]2D5 = –39.8 (c = 1.0, MeOH). H NMR (300 MHz, [D6]-
DMSO): δ = 11.27 (s, 1 H, NH), 8.02 [d, J = 8.1 Hz, 1 H, N-(H)-
C=CH], 6.02 (d, J = 8.4 Hz, 1 H, H1Ј), 5.67 [d, J = 8.1 Hz, 1 H,
N-(H)C=CH], 5.35 (t, J = 1.2 Hz, 1 H, CH2-OH), 5.15 (d, J =
7.5 Hz, 1 H, CH-OH), 4.57–4.50 (m, 1 H, H2Ј), 3.90–3.86 (m, 1 H,
CH2-CH2-O), 3.83 (d, J = 3.9 Hz, 1 H, H3Ј), 3.39–3.37 (m, 2 H,
H5Ј), 3.30–3.27 (m, 1 H, CH2-CH2-O), 1.59–1.51 [m, 4 H, H2C-
CH2-O, H2C-(CH2)2-O] ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 162.9, 151.1 (C=O), 141.0 [N-(H)C=CH], 102.0 [N-(H)C=CH],
86.8 (C1Ј), 81.6 (C4Ј), 76.4 (C3Ј), 73.2 (C2Ј), 66.4 (C5Ј), 63.7 (CH2-
CH2-O), 28.1 (CH2-CH2-O), 20.5 [CH2-(CH2)2-O] ppm. HRMS
(CI): calcd. for C12H17N2O6 [M + H]+ 285.1087; found 285.1088.
Thymidine Derivative 28: To a suspension of thymine (475 mg,
3.8 mmol, 2.1 equiv.) in dry HMDS (50 mL) was added trimethyl-
silyl chloride (7.5 mL, 59.0 mmol, 33.0 equiv.). The reaction mix-
ture was heated under reflux overnight and then concentrated un-
der reduced pressure. The crude mixture was diluted with dry 1,2-
dichloroethane (5 mL) and a solution of compound 20 (935 mg,
1.8 mmol) in dry 1,2-dichloroethane (10 mL) was added. The reac-
tion mixture was cooled to –35 °C and TMSOTf (720 μL,
4.0 mmol, 2.0 equiv.) was added dropwise. After 24 h of stirring at
room temp., an aqueous saturated solution of NaHCO3 was added,
and the resulting mixture was stirred for 40 min at room temp.
After extraction with CH2Cl2, the organic layers were dried with
MgSO4, filtered and concentrated under reduced pressure. The
crude residue was purified by chromatography on silica gel (petro-
leum ether/AcOEt, 40:60) to give the thymidine derivative 28 as a
white solid (790 mg, 76%); m.p. 82–83 °C. [α]2D5 = +103.3 (c = 1.0,
Uridine Derivative 27: Compound 26 (181 mg, 0.32 mmol) was dis-
solved in MeOH (14 mL), and K2CO3 (126 mg, 0.96 mmol,
3 equiv.) was added. After stirring for 3 h at room temp., an aque-
ous solution of HCl (1 n) was added until neutral pH, and then
the solvent was evaporated under reduced pressure. The crude mix-
ture was purified by chromatography on silica gel (petroleum ether/
AcOEt, 50:50) to obtain alcohol 27 (147 mg, 88%) as a white solid;
m.p. 90–91 °C. [α]2D5 = +51.4 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 9.58 (br. s, 1 H, NH), 7.73 [d, J = 8.1 Hz, 1 H, N-(H)-
C=CH], 7.65–7.59 (m, 4 H, HAr), 7.47–7.38 (m, 6 H, HAr), 6.17 (d,
J = 8.4 Hz, 1 H, H1Ј), 6.12 (syst ABMX, J = 10.5, 3.9 Hz, 1 H,
HC=CH-CH2), 5.57 (d, J = 10.5 Hz, 1 H, HC=CH-CH2), 5.42 [dd,
J = 8.1, 1.5 Hz, 1 H, N-(H)C=CH], 4.54 (dd, J = 8.4, 4.8 Hz, 1 H,
H2Ј), 4.28 and 3.94 (syst. ABMX, J = 16.5, 3.9 Hz, 2 H, HC=CH-
CH2), 4.07 (d, J = 4.8 Hz, 1 H, H3Ј), 3.79 and 3.47 (syst. AB, J =
11.1 Hz, 2 H, H5Ј), 1.10 (s, 9 H, tBu) ppm. 13C NMR (75 MHz,
CDCl3): δ = 163.2, 151.1 (C=O), 140.0 [N-(H)C=CH], 135.6, 135.2,
130.2, 128.0 (CHAr), 135.3, 131.6 (CAr-Si), 123.7 (HC=CH-CH2),
102.8 [N-(H)C=CH], 86.9 (C1Ј), 79.0 (C4Ј), 76.1 (C3Ј), 75.3 (C2Ј),
68.3 (C5Ј), 62.7 (HC=CH-CH2), 27.0 [(CH3)3C-Si], 19.2 [(CH3)3C-
Si] ppm. HRMS (CI): calcd. for C28H33N2O6Si [M + H]+ 521.2108;
found 521.2109.
CHCl ). IR (KBr): ν = 3360, 2874, 1700, 1458, 1129, 1060 cm–1.
˜
3
1H NMR (300 MHz, CDCl3): δ = 8.90 (br. s, 1 H, NH), 7.72–7.66
(m, 4 H, HAr), 7.53 (s, 1 H, HC=Cthy), 7.47–7.37 (m, 6 H, HAr),
6.40 (d, J = 8.6 Hz, 1 H, H1Ј), 6.18–6.10 (syst. ABMX, J = 10.3,
3.8 Hz, 1 H, HC=CH-CH2), 5.61–5.51 (m, 2 H, H2Ј, HC=CH-
CH2), 4.40 (d, J = 4.9 Hz, 1 H, H3Ј), 4.23 [syst. ABMX, J = 16.3,
4.7 Hz, 1 H, HC=CH-C(H)-H], 3.91–3.82 [m, 1 H, HC=CH-C(H)-
H], 3.86 and 3.50 (syst. AB, J = 11.2 Hz, 2 H, H5Ј), 2.16 [s, 3 H,
O-C(=O)-CH3], 1.68 (s, 3 H, CH3thy), 1.11 (s, 9 H, tBu) ppm. 13C
NMR (75 MHz, CDCl3): δ = 170.6 [O-C(=O)-CH3], 163.6, 150.7
(C=O), 135.6 (CHAr), 135.3 (CHthy), 131.8, 132.6 (CAr), 131.5
(HC=CH-CH2), 128.1, 130.2, 130.3 (CHAr), 123.4 (HC=CH-CH2),
111.8 (Cthy), 83.7 (C1Ј), 79.3 (C4Ј), 75.0 (C3Ј), 74.3 (C2Ј), 62.6 (C5Ј),
Uridine Derivative 13: Alcohol 27 (147 mg, 0.28 mmol) was dis-
solved in THF (4 mL), and a solution of TBAF (1 m in THF,
565 μL, 0.56 mmol, 2 equiv.) was added. The mixture was stirred
for 4 h at room temp. and then concentrated under reduced pres-
sure. Purification of the crude mixture by chromatography on silica
gel (AcOEt/MeOH, 70:30) afforded nucleoside analogue 13 con-
taminated with a small amount of TBAF-derived materials (83 mg,
95%) as a white powder; m.p. 197–198 °C. [α]2D5 = +70.8 (c = 1.0,
60.4 (HC=CH-CH2), 27.1 [(CH3)3C-Si], 20.7 [O-C(=O)-CH3], 19.4
thy
[(CH3)3C-Si], 11.7 (CH3
) ppm. HRMS (CI): calcd. for
C31H37N2O7Si [M + H]+ 577.2371; found 577.2370.
1
MeOH). H NMR (300 MHz, CD3OD): δ = 8.10 [d, J = 8.1 Hz, 1
H, N-(H)C=CH], 6.23 (syst. ABMX, J = 10.5, 4.8, 1.8 Hz, 1 H, Thymidine Derivative 29: To a solution of thymidine derivative 28
HC=CH-CH2), 6.11 (d, J = 8.1 Hz, 1 H, H1Ј), 5.75 [d, J = 8.1 Hz, (380 mg, 0.7 mmol) in MeOH (30 mL) was added K2CO3 (288 mg,
1 H, N-(H)C=CH], 5.67 (syst. ABMX, J = 10.5, 2.4, 1.8 Hz, 1 H,
HC=CH-CH2), 4.62 (dd, J = 8.1, 4.8 Hz, 1 H, H2Ј), 4.27 and 3.99
2.1 mmol, 3.2 equiv.). After stirring for 3 h at room temp., the reac-
tion mixture was neutralised with an aqueous solution of HCl (1 m)
7396
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7390–7399

Synthesis and Biological Evaluation of Bicyclic Nucleosides
until neutral pH, and then concentrated under reduced pressure.
The crude residue was purified by chromatography on silica gel
(petroleum ether/AcOEt, 60:40) to give the alcohol 29 as a white
cooling to 0 °C, TMSOTf (40 μL, 0.22 mmol) was added, and the
reaction mixture was stirred at room temp. overnight. After di-
lution with CH2Cl2, an aqueous saturated solution of NaHCO3
was added. The aqueous layer was extracted three times with
solid (278 mg, 79%); m.p. 89–90 °C. [α]2D5 = +106.4 (c = 1.0,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 8.21 (br. s, 1 H, NH), CH2Cl2, and then the organic layers were recombined, dried with
7.66–7.63 (m, 4 H, HAr), 7.49–7.39 (m, 7 H, HC=Cthy, HAr), 6.17–
Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was purified by chromatography on silica gel (CHCl3/
6.10 (m, 2 H, H1Ј, HC=CH-CH2), 5.58 (syst. ABMX, J = 10.2 Hz,
1 H, HC=CH-CH2), 4.58 (m, 1 H, H2Ј), 4.25 and 3.95 (syst. MeOH, 97:3) to afford compound 30 as a white solid (95 mg, 77%);
ABMX, J = 16.4, 4.5 Hz, 1 H, HC=CH-CH2), 4.11 (d, J = 5.0 Hz, m.p. 69–70 °C. [α]2D5 = +70.7 (c = 1.0, CHCl3). 1H NMR (300 MHz,
1 H, H3Ј), 3.83 and 3.50 (syst. AB, J = 11.0 Hz, 2 H, H5Ј), 3.02 (d, CDCl3): δ = 7.73 [d, J = 7.5 Hz, 1 H, N-(H)C=CH], 7.66–7.60 (m,
J = 11.0 Hz, 1 H, OH), 1.52 (s, 3 H, CH3thy), 1.11 (s, 9 H, tBu) 4 H, HAr), 7.42–7.34 (m, 6 H, HAr), 6.49 (d, J = 8.4 Hz, 1 H, H1Ј),
ppm. 13C NMR (75 MHz, CDCl3): δ = 163.2, 150.8 (C=O), 135.6 6.34, 6.24 (br. s, 2 H, NH2), 6.10 (syst ABMX, J = 10.5, 4.5 Hz, 1
(CHAr), 135.4 (HC=Cthy), 135.3, 132.6, 131.9 (CAr), 131.1
H, HC=CH-CH2), 5.56–5.43 [m, 3 H, N-(H)C=CH, H2Ј, HC=CH-
(HC=CH-CH2), 130.4, 130.3, 128.1 (CHAr), 124.0 (HC=CH-CH2), CH2], 4.30 (d, J = 5.1 Hz, 1 H, H3Ј), 4.16 [syst. ABMX, J = 16.8,
111.6 (Cthy), 86.7 (C1Ј), 78.8 (C4Ј), 75.9 (C3Ј), 74.8 (C2Ј), 68.4 (CH2-
O-Si), 62.7 (H-C=CH-CH2), 27.1 [(CH3)3C-Si], 19.4 [(CH3)3C-Si],
11.8 (CH3thy) ppm. HRMS (CI): calcd. for C29H35N2O6Si [M +
H]+ 534.2264; found 535.2263.
4.5 Hz, 1 H, HC=CH-C(H)-H], 3.82–3.76 [m, 1 H, HC=CH-C(H)-
H], 3.75 and 3.43 (syst. AB, J = 11.1 Hz, 2 H, H5Ј), 2.07 [s, 3 H,
O-C(=O)-CH3], 1.07 (s, 9 H, tBu) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.2 (CH3C=O), 165.6, 156.0 (C=N and C=O), 140.9
[N-(H)C=CH], 135.6, 135.3 (CHAr), 132.3, 131.6 (CAr), 131.3
(HC=CH-CH2), 130.1–129.8, 123.5 (CHAr), 113.9 (HC=CH-CH2),
95.6 [N-(H)C=CH], 84.2 (C1Ј), 78.9 (C4Ј), 75.1 (C3Ј), 75.0 (C2Ј),
68.2 (C5Ј), 62.5 (HC=CH-CH2), 26.9 [(CH3)3C-Si], 20.6 [O-C(=O)-
CH3], 19.1 [(CH3)3C-Si] ppm. HRMS (CI): calcd. for
C30H36N3O6Si [M + H]+ 562.2373; found 562.2374.
Thymidine Derivative 14: To a solution of alcohol 29 (200 mg,
0.37 mmol) in dry THF (5 mL) was added TBAF (1 m in THF,
750 μL, 0.75 mmol, 2 equiv.). After 4 h of stirring at room temp.,
the reaction mixture was concentrated under reduced pressure. The
crude mixture was purified by chromatography on silica gel (Ac-
OEt/MeOH, 85:15) to give the diol 14 as a white solid contami-
nated with a small amount of TBAF-derived materials (110 mg,
95%); m.p. 210–211 °C. [α]2D5 = +69.5 (c = 1.0, MeOH). IR (KBr):
Cytidine Derivative 31: Compound 30 (135 mg, 0.24 mmol) was dis-
solved in MeOH (10 mL), and K2CO3 (100 mg, 0.72 mmol,
3 equiv.) was added. After stirring for 2 h at room temp., an aque-
ous solution of HCl (1 n) was added until neutral pH, and then
the solvent was evaporated under reduced pressure. The crude mix-
ture was purified by chromatography on silica gel (CHCl3/MeOH,
95:5) to obtain alcohol 31 as a white solid (107 mg, 85%); m.p. 82–
83 °C. [α]2D5 = +53.9 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.71 [d, J = 7.2 Hz, 1 H, N-(H)C=CH], 7.60–7.57 (m,
4 H, HAr), 7.45–7.34 (m, 6 H, HAr), 6.21 (m, 4 H, H1Ј, HC=CH-
CH2, NH2), 5.62–5.57 [m, 2 H, N-(H)C=CH, HC=CH-CH2], 4.46
(dd, J = 7.5, 5.1 Hz, 1 H, H2Ј), 4.25 and 3.90 (syst. ABMX, J =
16.5, 4.5 Hz, 2 H, HC=CH-CH2), 4.07 (d, J = 5.1 Hz, 1 H, H3Ј),
3.68 and 3.46 (syst. AB, J = 11.1 Hz, 2 H, H5Ј), 1.03 (s, 9 H, tBu)
ppm. 13C NMR (75 MHz, CDCl3): δ = 165.7, 157.0 (C=N and
C=O), 140.8 [N-(H)C=CH], 135.5, 135.4 (CHAr), 132.3, 132.0
(CAr), 131.4 (HC=CH-CH2), 130.1, 127.9 (CHAr), 123.9 (HC=CH-
CH2), 95.0 [N-(H)C=CH], 89.1 (C1Ј), 79.8 (C4Ј), 76.8 (C3Ј), 76.5
(C2Ј), 67.9 (C5Ј), 62.9 (HC=C-CH2), 26.9 [(CH3)3C-Si], 19.1 [(CH3)3-
C-Si] ppm. HRMS (CI): calcd. for C28H33N3O5Si [M + H]+
520.2268; found 520.2266.
ν = 3465, 3257, 2925, 1724, 1658, 1477, 1368, 1259, 1129, 1060,
˜
1040 cm–1. 1H NMR (300 MHz, CD3OD): δ = 7.82 (s, 1 H, CHthy),
6.12 (syst. ABMX, J = 10.0, 5.0, 1.0 Hz, 1 H, HC=CH-CH2), 6.00
(d, J = 8.4 Hz, 1 H, H1Ј), 5.57 (syst. ABMX, J = 10.0 Hz, 1 H,
HC=CH-CH2), 4.54 (dd, J = 5.8 Hz, 1 H, H2Ј), 4.16 and 3.87 (syst.
ABMX, J = 16.3, 4.6 Hz, 1 H, C=CH-CH2-H), 3.95 (d, J = 5.0 Hz,
1 H, H3Ј), 3.52 and 3.37 (syst. AB, J = 11.0, 7.0 Hz, 2 H, H5Ј) 1.8
(s, 3 H, CH3thy) ppm. 13C NMR (75 MHz, CD3OD): δ = 166.3,
153.1 (C=O), 138.5 (CHthy), 132.4 (HC=CH-CH2), 125.3
(HC=CH-CH2), 112.1 (Cthy), 88.3 (C1Ј), 80.7 (C4Ј), 78.4 (C3Ј), 75.0
(C2Ј), 67.5 (H-C=CH-CH2), 63.9 (C5Ј), 12.5 (CH3thy) ppm. HRMS
(CI): calcd. for C13H17N2O6 [M + H]+ 297.1087; found 297.1087.
Thymidine Derivative 17: To a solution of diol 14 (110 mg,
0.37 mmol) in MeOH (20 mL) was added Pd/C 10% (26 mg). After
24 h of stirring at room temp. under H2 atmosphere (balloon), the
reaction mixture was filtered through Celite and concentrated un-
der reduced pressure. The crude residue was purified by chromatog-
raphy on silica gel (AcOEt and AcOEt/MeOH, 95:5) to give the
diol 17 as a white powder (95 mg, 87%); m.p. 123–124 °C. [α]2D5
=
Cytidine Derivative 15: Alcohol 31 (107 mg, 0.33 mmol) was dis-
solved in THF (4 mL), and a solution of TBAF 1 m in THF
(654 μL, 0.66 mmol, 2 equiv.) was added. The mixture was stirred
for 4 h at room temp., and then concentrated under reduced pres-
sure. Purification of the crude mixture by chromatography on silica
gel (AcOEt/MeOH, 80:20) afforded nucleoside analogue 15 as a
white powder (70 mg, 76%); m.p. 159–160 °C. [α]2D5 = +89.1 (c =
1.0, MeOH). 1H NMR (300 MHz, CD3OD): δ = 7.99 [d, J =
7.5 Hz, 1 H, N-(H)C=CH], 6.23 (syst. ABMX, J = 10.2, 4.5,
1.5 Hz, 1 H, HC=CH-CH2), 6.10 (d, J = 8.4 Hz, 1 H, H1Ј), 5.94
[d, J = 7.5 Hz, 1 H, N-(H)C=CH], 5.69 (syst. ABMX, J = 10.2,
2.4, 1.5 Hz, HC=CH-CH2), 5.68 (dd, J = 8.4, 4.8 Hz, 1 H, H2Ј),
4.27 and 4.00 (syst. ABMX, J = 16.2, 4.5, 1.5 Hz, 2 H, HC=CH-
CH2), 4.06 (d, J = 4.8 Hz, 1 H, H3Ј), 3.61 and 3.47 (syst. AB, J =
11.7 Hz, 2 H, H5Ј) ppm. 13C NMR (75 MHz, CD3OD): δ = 167.5,
158.9 (C=N and C=O), 143.9 [N-(H)C=CH], 132.4 (HC=CH-
CH2), 125.3 (HC=CH-CH2), 96.8 [N-(H)C=CH], 90.2 (C1Ј), 80.8
(C4Ј), 78.5 (C3Ј), 75.5 (C2Ј), 67.5 (C5Ј), 61.6 (HC=C-CH2) ppm.
–40.7 (c = 1.0, CD OD). IR (KBr): ν = 3429, 3064, 2928, 1696,
˜
3
1473, 1283, 1074 cm–1. H NMR (300 MHz, CD3OD): δ = 8.00 (s,
1
1 H, CHthy), 6.13 (d, J = 8.0 Hz, 1 H, H1Ј), 4.73–4.69 (m, 1 H,
H2Ј), 3.95–3.92 (m, 1 H, CH2-CH2-O), 3.91 (d, J = 4.2 Hz, 1 H,
H3Ј), 3.52 (syst. AB, J = 11.7 Hz, 2 H, H5Ј), 3.38–3.27 (m, 1 H,
CH2-CH2-O), 1.90 (s, 3 H, CH3thy), 1.80–1.75 {m, 2 H, [HC(H)-
CH2-O, HC(H)-(CH2)2-O]}, 1.64–1.54 {m, 2 H, [HC(H)-CH2-O,
HC(H)-(CH2)2-O]} ppm. 13C NMR (75 MHz, MeOD): δ = 166.3,
153.2 (C=O), 138.8 (CHthy), 111.8 (Cthy), 89.5 (C1Ј), 83.6 (C4Ј), 78.3
(C3Ј), 75.6 (C2Ј), 68.5 (C5Ј), 65.7 (CH2-CH2-O), 29.6, 22.0 [CH2-
(CH2)2-O, CH2-CH2-O], 12.5 (CH3thy) ppm. HRMS (CI): calcd.
for C13H19N2O6 [M + H]+ 299.1243; found 299.1241.
Cytidine Derivative 30: To a suspension of cytosine (36 mg,
0.33 mmol, 1.5 equiv.) in freshly distilled CH3CN (2.5 mL) was
added BSA (163 μL, 0.67 mmol, 3 equiv.). The mixture was stirred
for 30 min at room temp., and a solution of glycoside 20 (102 mg,
0.22 mmol) in freshly distilled CH3CN (1.5 mL) was added. After
Eur. J. Org. Chem. 2011, 7390–7399
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7397

J. Lebreton, et al.
FULL PAPER
HRMS (CI): calcd. for C12H16N3O5 [M + H]+ 282.1090; found
282.1090.
added in anhydrous THF (5 mL) under argon. After stirring for
2 h at –78 °C, the reaction mixture was maintained for 12 h at room
temp. The solution was treated with saturated NH4Cl (0.2 mL) at
0 °C and then concentrated under reduced pressure. The residue
was dissolved in CH2Cl2 (20 mL), washed with cold water (10 mL)
and brine (5 mL). The organic layer was dried with Na2SO4, fil-
tered and concentrated under reduced pressure. The residue was
purified by flash silica gel chromatography (CH2Cl2/MeOH, 20:1
to 10:1) to give 35 (74 mg, 0.138 mmol) in 48% yield as a dia-
Cytidine Derivative 18: To a solution of nucleoside analogue 15
(70 mg, 0.25 mmol) in EtOH (14 mL) was added Pd/C 10%
(14 mg). After stirring for 24 h at room temp. under H2 atmosphere
(balloon), the reaction mixture was filtered through Celite and con-
centrated under reduced pressure. The crude residue was purified
by chromatography on silica gel (AcOEt/MeOH, 80:20) to give the
diol 18 as a white powder (56 mg, 79%); m.p. 190–191 °C. [α]2D5
=
1
stereomeric mixture (RP/SP = 1:1). H NMR (400 MHz, CD3OD):
–31.4 (c = 1.0, MeOH). 1H NMR (300 MHz, [D6]DMSO): δ = 7.87
[d, J = 7.5 Hz, 1 H, N-(H)C=CH], 7.19, 7.11 (br. s, 2 H, NH2),
6.04 (d, J = 8.4 Hz, 1 H, H1Ј), 5.74 [d, J = 7.5 Hz, 1 H, N-(H)-
C=CH], 5.26 (t, J = 5.4 Hz, 1 H, HO-CH5Ј), 4.99 (d, J = 7.8 Hz,
1 H, HO-CH2Ј), 4.50 (m, 1 H, H2Ј), 3.89–3.87 (m, 1 H, CH2-CH2-
O), 3.82 (d, J = 4.2 Hz, 1 H, H3Ј), 3.41–3.23 (m, 3 H, H5Ј, CH2-
CH2-O), 1.64–1.57 [m, 3 H, H2C-(CH2)2-O, CH2-CH2-O], 1.48–
1.42 (m, 1 H, CH2-CH2-O) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 7.83–7.69 (br. s, 1 H), 7.68–7.64 (m, 1 H), 7.35–7.30 (m, 2 H),
7.22–7.12 (m, 3 H), 6.34–6.31 (m, 1 H), 6.27–6.24 (m, 1 H), 5.96–
5.90 (m, 1 H), 5.85–5.65 (m, 1 H), 4.37–3.84 (m, 8 H), 3.43 (s, 1
H), 3.18 (m, 1 H), 3.10 (m, 1 H), 1.29–1.15 (m, 6 H) ppm. 31P
NMR (162 MHz, CD3OD): δ = 4.53, 4.37 ppm. MS-ESI+: m/z =
537 [M + H+]. HRMS-ESI+: m/z calcd. for C23H30N4O9P [M +
H+] 537.1741; found 537.1745.
δ = 165.3, 155.8 (C=N and C=O), 141.9 [N-(H)C=CH], 94.3 [N- Cytidine Derivative 36: To a solution of 35 (30 mg, 0.056 mmol) in
(H)C=CH], 88.2 (C1Ј), 81.2 (C4Ј), 76.3 (C3Ј), 73.6 (C2Ј), 68.4 (C5Ј),
EtOH (5 mL) was added 10% Pd/C (5 mg) at room temp. The mix-
63.7 (CH2-CH2-O), 28.1, 20.6 [CH2-CH2-O, CH2-(CH2)2-O] ppm. ture was stirred for 3 h under an H2 atmosphere (1 atm), and then
HRMS (CI): calcd. for C12H18N3O5 [M + H]+ 284.1246; found
284.1245.
treated with Celite (1.0 g) and stirred for 30 min with the septa
removed. The suspension was filtered, and the resulting solid was
washed with MeOH (5ϫ5 mL). The collected solution was concen-
trated under reduced pressure, and the residue was purified by silica
gel column chromatography (CH2Cl2/MeOH, 10:1) to give 36
Uridine Derivative 33: To a solution of 13 (100 mg, 0.35 mmol) and
32 (130 mg, 0.44 mmol, 1.3 equiv.) in anhydrous THF (10 mL) at
–78 °C was added N-methylimidazole (0.14 mL, 1.75 mmol,
5 equiv.) over 5 min under argon. After stirring for 2 h at –78 °C,
the reaction was maintained for 12 h at room temp. The solvent
was removed under reduced pressure and the residue was dissolved
in CH2Cl2 (20 mL), washed with cold 0.5 m HCl (5 mL ϫ2), cold
water (10 mL), and brine (5 mL). The organic layer was dried with
Na2SO4, filtered and concentrated under reduced pressure. The res-
idue was purified by flash silica gel chromatography (CH2Cl2/
MeOH, 20:1) to give 33 (120 mg, 65%) as a diastereomeric mixture
1
(28 mg, 94%) as a diastereomeric mixture (RP/SP = 1:1). H NMR
(400 MHz, CD3OD): δ = 8.02–7.99 (m, 1 H), 7.37–7.33 (m, 2 H),
7.24–7.13 (m, 3 H), 6.42–6.38 (m, 1 H), 5.93–5.90 (m, 1 H), 4.14–
3.83 (m, 8 H), 3.64 (m, 1 H), 3.58 (br. s, 1 H), 3.30 (m, 1 H), 1.95–
1.88 (m, 1 H), 1.84–1.79 (m, 2 H), 1.59–1.50 (m, 1 H), 1.33–1.14
(m, 6 H) ppm. 31P NMR (162 MHz, CD3OD): δ = 4.36, 4.31 ppm.
MS-ESI+: m/z = 539 [M + H+]. HRMS-ESI+: m/z calcd. for
C23H32N4O9P [M + H+] 539.1897; found 539.1901.
1
Supporting Information (see footnote on the first page of this arti-
(RP/SP = 1:1). H NMR (400 MHz, CD3OD): δ = 8.14–7.98 (m, 1
1
cle): Copies of H- and 13C-NMR spectra for compounds 13–18,
H), 7.33–7.24 (m, 2 H), 7.21–7.07 (m, 3 H), 6.30–6.17 (m, 2 H),
5.71–5.60 (m, 2 H), 5.39–5.23 (m, 1 H), 4.21–3.84 (m, 7 H), 3.60–
3.56 (m, 1 H), 3.45–3.42 (m, 1 H), 1.36–1.34–1.15 (m, 6 H) ppm.
31P NMR (162 MHz, CD3OD): δ = 4.30, 4.17 ppm. MS-ESI+: m/z
= 538 [M + H+]. HRMS-ESI+: m/z calcd. for C23H29N3O10P [M +
H+] 538.1582; found 538.1585.
1
NOESY data for compound 24 and copies of H-, 31P-NMR and
mass spectra for compounds 33–36.
Acknowledgments
Uridine Derivative 34: To a solution of 33 (50 mg, 0.09 mmol) in
EtOH (5 mL) was added 1,4-cyclohexadiene (0.50 mL) and 10%
Pd/C (5 mg) at room temp. After stirring for 3 h at room temp.,
the reaction mixture was treated with Celite (1.0 g) and stirred for
30 min with the septa removed. The suspension was filtered, and
the resulting solid was washed with MeOH (3ϫ15 mL). The col-
lected solution was concentrated under reduced pressure, and the
residue was purified by silica gel column chromatography (CH2Cl2/
MeOH, 20:1) to give 34 (490 mg, 98%) as a diastereomeric mixture
This work was finacially supported by the Centre National de la
Recherche Scientifique (CNRS) and the Université de Nantes. This
work was also supported in part by the US National Institutes of
Health (NIH), grant numbers 2P30-AI-050409, 5R37-AI-025899,
5R37-AI-041980, and the Department of Veterans Affairs (to
R. F. S.). The authors wish to thank Dr Jean-Marc Escudier (Uni-
versité de Toulouse, UMR-CNRS 506.8, France) for useful com-
ments.
1
(RP/SP = 1:1). H NMR (400 MHz, CD3OD): δ = 8.26–8.14 (m, 1
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Cytidine Derivative 35: To a solution of 15 (80 mg, 0.285 mmol) in
anhydrous THF (5 mL) at –78 °C was added tBuMgCl (1.0 m in
THF, 0.65 mL, 0.650 mmol, 2.3 equiv.) under argon. After stirring
for 30 min at –78 °C followed by 30 min at 0 °C, the solution was
cooled to –78 °C, and 32 (110 mg, 0.377 mmol, 1.3 equiv.) was
7398
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: June 14, 2011
Published Online: October 28, 2011
Eur. J. Org. Chem. 2011, 7390–7399
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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