Click azide-alkyne cycloaddition for the synthesis of D-(-)-1,4- disubstituted triazolo-carbanucleosides

Article abstract of DOI:10.1002/ejoc.200801124

A revisited and improved synthesis of an optically active azido-carbanucleoside is reported. This azido precursor is used in the successful and versatile synthesis of enantiomerically pure D-(-)-1,4- disubstiluted 1,2,3-lriazolo-carbanuclcosides via coppe

Full text of DOI:10.1002/ejoc.200801124

FULL PAPER
DOI: 10.1002/ejoc.200801124
Click Azide-Alkyne Cycloaddition for the Synthesis of
Triazolo-Carbanucleosides
D
-(–)-1,4-Disubstituted
Julie Broggi,[a,b,c] Hiroki Kumamoto,[a] Sabine Berteina-Raboin,[a] Steven P. Nolan,[b,c] and
Luigi A. Agrofoglio*[a]
Dedicated to Professor J. M. Robins on the occasion of his 70th birthday
Keywords: Nucleosides / Carbanucleosides / Antiviral agents / Olefin metathesis / Huisgen cycloaddition / Ribavirin /
Poxvirus
A revisited and improved synthesis of an optically active
azido-carbanucleoside is reported. This azido precursor is
used in the successful and versatile synthesis of enantiomeri-
sides via copper(I)-catalyzed and microwave-assisted
Huisgen 1,3-dipolar cycloaddition.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
cally pure D-(–)-1,4-disubstituted 1,2,3-triazolo-carbanucleo- Germany, 2009)
We report here the revisited and improved large-scale
synthesis of an optically active azido-carbanucleoside as a
flexible building block for further synthetic elaboration[8]
This azido-precursor was used in the successful and versa-
tile synthesis of 1,4-disubstituted -(–)-1,2,3-triazolo-car-
banucleosides via copper(I)-catalyzed and microwave-as-
sisted Huisgen 1,3-dipolar cycloaddition.[9] Previously, we
and others had reported the synthesis of diverse carbanu-
cleosides bearing a 1,2,3-triazole moiety, structurally related
to ribavirin,[10,11] with interesting antiviral activities against
HIV-1,[12] varicella-zoster virus,[13] or vaccinia virus.[14] In
Introduction
Natural -nucleosides and their -counterparts usually
exhibit different antiviral activities and toxicities.[1] Regard-
ing carbocyclic nucleosides,[2,3] enantiomers with a β--con-
figuration exhibited significantly better antiviral effects
than their -analogues as they appear to be better candidate
for enzyme targeting and enzyme activation (phosphoryla-
tion). In the search for less toxic and more potent inhibitors
of the S-adenosylhomocysteine SAH hydrolase, an enzyme
involved in methyl transfer reactions,[4] many -carbocyclic
analogues have emerged as effective inhibitors of vaccinia
virus.[5,6] Therefore, the enantiospecific syntheses of carban-
ucleosides are crucial for further exploration of this class of
compounds.[7] The synthetic approach deals principally
with access to the enantiomerically pure highly oxygenated
cyclopentane skeleton. However, the overall availability of
optically active derivatives remains limited due to the lack
of convenient methodologies for large-scale and stereospec-
ific preparation of key intermediates. Thus, new synthetic
intermediates for enantiomerically pure carbocyclic nucleo-
sides are of significant interest.
[a] Institut de Chimie Organique et Analytique (ICOA) UMR-
6005 CNRS, Université de Orléans,
45067 Orléans, France
Fax: +33-2-38417281
E-mail: luigi.agrofoglio@univ-orleans.fr
[b] Institute of Chemical Research of Catalonia (ICIQ),
16, Av. Països Catalans, 43007 Tarragona, Spain
[c] School of Chemistry, University of St Andrews,
St Andrews, KY16 9ST, UK
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Structure–activity relationship.
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Synthesis of 1,4-Disubstituted Triazolo-Carbanucleosides
order to examine structure-activity relationships and in- tions brought to the approach, we chose to follow the sec-
clude former results, we opted to study a 2Ј,3Ј-dihydroxy- ond procedure[19] for the larger-scale synthesis of 3 taking
4Ј-hydroxymethyl-substituted carbocyclic moiety structur- advantage of the existing stereogenic centers of -ribose
ally related to the anti-pox agent ribavirin and to carbocy- (Scheme 1).
clic 3-deazaadenosine (Figure 1).
In both Jeong’s and Chu’s procedures, the ring-closing
metathesis (RCM)[18] reaction of the diene 1 was performed
using Grubbs’ catalyst.[20] In our case, the RCM reaction to
afford the -cyclopentenol 2 was carried out using 1.5 mol-
% of the Ru catalyst 9 developed by Nolan et al.[21] (Fig-
ure 2). Diene 1 was completely converted to 2 within 1 h of
reaction at 25 °C. However, since the ring-closed cyclopen-
tenol 2 is highly volatile, the desired -2-cyclopentenone 3
was directly obtained in 79% overall yield from 1 by oxi-
dation of the secondary alcohol under PCC oxidation con-
ditions without isolation of cyclopentenol 2.
Results and Discussion
To the best of our knowledge, the only synthesis of the
-azido-carbanucleoside 8 was reported in 1988 by Tadano
et al.[15] and it was used as precursor for the synthesis of
carbocyclic nucleoside antibiotics. The synthetic approach
used consisted in targeting the optically active carbocyclic
skeleton using carbohydrates as starting materials. How-
ever, the enantioselectivity across numerous steps could not
be controlled and tedious purifications by repeated column
chromatography were necessary to separate the different ep-
imers. Herein, we present an enantiomerically controlled
synthesis of 8 in 16 steps (Scheme 1). To access the key op-
tically active azide intermediate 8, we selected the -2-cyclo-
pentenone 3 known as a versatile synthon for various -
carbocyclic nucleosides.[16] The first practical procedures to
obtain 3 were reported by Jeong et al.[17] starting from inex-
pensive -isoascorbic acid and then by Chu et al.[19] from
-ribose. The first method was problematic in large-scale
Figure 2. Ruthenium catalyst 9.
Compound 3 was then easily converted to unstable exo-
preparation due to the extreme sensitivity of many interme- olefin 4 following Schneller’s method (Scheme 1).[22] This
diates as well as difficulties in controlling the stereoselective synthetic approach consists in using a vinyl group as a mask
oxidation and reduction steps. Hence in spite of some varia- for the hydroxymethyl group of carbocyclic nucleosides.
Scheme 1. Reagents and conditions: (a) [Ru] = 9 (1.5 mol-%), anhydrous CH2Cl2, 24 °C, 1 h; (b) pyridinium chlorochromate, CH2Cl2,
room temp., 12 h; (c) vinylmagnesium bromide, CuBr·Me2S, TMSCl, HMPA, THF, –78 °C, 3 h; (d) (i) LiAlH4, THF, 0 °C to room
temp., 2 h; (ii) BzCl, DMAP, iPr2NEt, CH3CN, 0 °C to room temp., 2 h; (e) (i) OsO4, NaIO4, MeOH/acetone/H2O, room temp., 30 min;
(ii) NaBH4, MeOH, –78 °C to room temp., 40 min; (iii) tert-butylchlorodiphenylsilane, imidazole, DMAP, CH3CN, room temp., 1 h;
(iv) NaOMe, MeOH, 0 °C to room temp., 15 h; (f) TsCl, iPr2NEt, DMAP, CH3CN, 0 °C to room temp., 24 h; (g) NaN3, 18-crown-6,
DMF, 140 °C, 2 h; (h) DIAD, DPPA, PPh3, THF, 0 °C to room temp., 7 h.
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FULL PAPER
The incorporation of a vinyl group onto a cyclopentyl ring In a mixture water/tert-butyl alcohol under microwave irra-
by 1,4-enone addition is known to be a high-yielding reac- diation,[31] Cu0/CuSO4-catalyzed reactions were performed
tion.[23]
with complete conversion of 8 into the desired 1,4-disubsti-
Copper(I) bromide–dimethyl sulfide complex induces the tuted triazoles 10–15 in extremely short reaction times
formation of an organocuprate via transmetallation with vi- (Ͻ15 min) and with no observable formation of by-prod-
nylmagnesium bromide.[24] This less reactive organocuprate ucts (Table 1). These results demonstrated that this pre-
leads to a regioselective 1,4-addition of the vinyl group to viously developed method[28] was also applicable to dif-
α,β-unsaturated ketones. On the other hand, addition of ferent azido-carbanucleosidic substrates even if the latter
TMSCl-HMPA promotes the conjugate addition by trap- contained protecting groups. According to the “click”
ping the magnesium enolate intermediate with TMSCl.[25] chemistry prerogatives,[32] the reaction was stereoselective,
The role of HMPA may be to cleave the dimer frequently versatile, and insensitive to oxygen and water. Even, the
engendered by cuprates.[26] Thus, 1,4-addition of vinylmag- electron-deficient 1-heptyne reacted within a few minutes
nesium bromide to 3 cleanly afforded ketone 4 in 82% yield. (Table 1, entry 3). Compounds 10–15 were isolated in high
Freshly opened vinylmagnesium bromide (not chloride!) is yield and purity by simple liquid-liquid extraction.
essential to successfully carry out this reaction. After
Table 1. Microwave assisted 1,3-dipolar cycloaddition of azido de-
rivative 8.
stereoselective reduction of ketone 4 and subsequent benzo-
ylation, benzoate 5 was afforded in moderate yield. The silyl
ether 6 was obtained in good yield from 5 by i) oxidative
glycol cleavage of exo-olefin using osmium tetroxide/so-
dium periodate, ii) sodium borohydride reduction of the re-
sulting aldehyde, iii) protection of primary alcohol, and iv)
debenzoylation sequence. Finally, we first tried to introduce
an azide function by simple tosylation and SN2 azidation.
However, the overall yield of the desired 8 was only 60% for
two steps. On the other hand, the application of Mitsunobu
azidation[27] appeared to be more convenient for the synthe-
sis of 8. Alcohol 6 was treated with diisopropyl azodicar-
boxylate (DIAD) and diphenyl phosphoryl azide (DPPA) in
the presence of PPh3. Azide 8 was obtained in 95% yield
as the single stereoisomer. The enantioselective addition of
azide function with inversion of configuration was con-
firmed by NOESY spectroscopy (Figure 3). Unlike the cor-
relation observed between H1Ј and H2Ј in the α-cyclopenta-
nol 6, only correlations between H1Ј and the two H6Ј were
detected in the β-oriented azido carbocycle 8.
The regioselectivity of the cycloaddition reaction under
Figure 3. NOESY correlations of 6 and 8.
1
microwave irradiation was confirmed by using H and 13C
long-range NMR experiments (HMBC). The selective for-
Then, we performed the Huisgen 1,3-dipolar cycload- mation of 1,4-disubstituted 1,2,3-triazoles was confirmed
dition[9] between enantiomerically pure azidocarbocycle 8 by a long-range correlation between the H1Ј of the sugar
and various terminal alkynes under the optimized reaction and the carbon bearing the 1H-triazole H5 (Figure 4).
conditions previously reported for racemic series of 1,4-di-
Finally, deprotection of the isopropylidene and the sil-
substituted (Ϯ)-1,2,3-triazolo-4Ј-hydroxymethyl-carbanu- yloxy groups afforded the final optically active compounds
cleosides.[28] A mixture copper Cu0/copper sulfate CuII- 16–21 in moderate to quantitative yields (Table 2). Accord-
SO4,[29] in situ comproportionated to form CuI, was used ing to NOESY experiments, the β-configuration is con-
as a water soluble catalyst to obtain selectively the 1,4-di- served during the 1,3-dipolar cycloaddition. As for azide 8,
substituted regioisomer.[30] This option is particularly at- only correlations between H1Ј and the two H6Ј were de-
tractive, as copper metal and copper sulfate are inexpensive. tected in the β-oriented triazolo-carbanucleosides.
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Synthesis of 1,4-Disubstituted Triazolo-Carbanucleosides
in refluxing ethanol, the starting material 8 was almost
completely recovered (Scheme 2). Nevertheless, 5% of the
expected compound 22 could be isolated and characterized.
Conclusions
Figure 4. HMBC correlation for 1,4-disubstituted 1,2,3-triazoles
10–15.
In conclusion, we have explored the syntheses of -con-
figured 1,4-disubstituted 1,2,3-triazolo-carbanucleosides via
optimized copper(I)-catalyzed microwave-assisted alkyne–
azide Huisgen cycloaddition. The preparation of an enan-
tiomerically pure cyclopentane azide derivative was
achieved using an optically active enone intermediate, read-
ily obtained by published procedure on a multi-gram scale.
Final Mitsunobu azidation proved a superior method com-
pared to traditional tosylation and SN2 azidation sequence.
The -azide was then sucessfully reacted with different ter-
minal alkynes to afford the corresponding 1,4-disubstituted
-(–)-1,2,3-triazolo-carbanucleosides, confirming the effi-
ciency of the developed tool for different azido-carbanu-
cleosidic substrates. Despite a carbocyclic 3-deazaadenos-
ine-like carbocycle moiety, none of the synthesized com-
pounds showed any cytotoxicity or significant antiviral ac-
tivity on infected vaccinia virus cells. Comparing the evalu-
ated compounds to known anti-pox nucleosides, the struc-
ture-activity relationship study suggests that 1,4-disubsti-
tuted 1,2,3-triazoles are not adequate bases for smallpox
inhibition. In the domain of nucleoside chemistry, this orig-
inal azido compound could be an important candidate and
versatile precursor not only for cycloaddition with diverse
dipolarophiles but also for various transformations involv-
ing azides.
Table 2. Deprotection of 1,4-disubstituted 1,2,3-triazolo-carbanu-
cleosides 10–15.[a]
Experimental Section
General: Commercially available chemicals were used as received.
Microwave reactions were carried out in a Biotage Initiator with a
maximum power of 300 W and temperatures were measured by IR
sensor. Reactions were monitored by thin-layer chromatography
(TLC) analysis using silica gel plates (Kieselgel 60 F254). Com-
pounds were visualized by UV irradiation and/or spraying with eth-
anol solution 2.5% in phosphomolybdic acid, followed by charring
at 150 °C. Column chromatography was performed on Silica Gel
60 M (0.040–0.063 mm). 1H NMR spectra were recorded on
250 MHz or 400 MHz spectrometers, and 13C NMR on 62.9 MHz
or 125 MHz spectrometers at room temperature, using deuterated
The synthesis of an optically pure 1,4,5-trisubstituted tri-
azolo-carbanucleoside was also attempted. To achieve the
synthesis of 22, we applied our protocol previously opti-
mized for 1,2,3-triazolo-3Ј-deoxy-carbanucleosides,[33] in-
spired by the reported 1,3-dipolar cycloaddition of azides
and 2-cyanoacetamide.[34] In spite of reaction times of 48 h solvents as the internal standard. Chemical shifts are given in ppm
Scheme 2. Reagents and conditions: (a) EtONa, EtOH, reflux, N2, 48 h.
Eur. J. Org. Chem. 2009, 1880–1888
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L. A. Agrofoglio et al.
FULL PAPER
and signals are reported as s (singlet), d (doublet), t (triplet), q
(quartet), qi (quintuplet) and m (multiplet). Assignments of NMR
spectra follow standard nucleosides nomenclature: triazole bases
are numbered from N-1 to C-5 and carbocycles are numbered from
C-1Ј to C-6Ј with C-5Ј for the 4-hydroxymethyl chain. Similar con-
ventions apply for the corresponding hydrogen atoms.
15.6 mmol) and NaIO4 (6.69 g, 31.3 mmol, 2 equiv.) in MeOH/ace-
tone/H2O (1:1:1, 240 mL), a solution of OsO4 (2.5 wt.-% in
tBuOH) (1 mL) was added at room temperature. After 1.5 h of stir-
ring, the reaction mixture was filtered through a celite pad and
concentrated. The resulting residue was diluted with CH2Cl2 and
then washed with brine. The aqueous phases were extracted with
CH2Cl2 and the combined organic layers were dried with MgSO4.
The crude A aldehyde was obtained as an oil and directly used in
the next step without further purification. To a MeOH (100 mL)
solution of crude A, NaBH4 (1.18 g, 31.3 mmol, 2 equiv.) was
added at –78 °C. After 40 min of stirring at room temperature,
AcOH (2 mL) and acetone (100 mL) were added and the resulting
reaction mixture was concentrated. The reaction mixture was di-
luted with CH2Cl2 and then washed with an aqueous saturated
NaHCO3 solution. The aqueous phases were extracted with
CH2Cl2 and the combined organic layers were dried with MgSO4.
This crude alcohol B was used in the next step without further
purification. To the MeCN (50 mL) solution of crude alcohol B, 4-
(dimethylamino)pyridine (2.11 g, 17.2 mmol, 1.1 equiv.), imidazole
(1.38 g, 20.3 mmol, 1.3 equiv.) and tert-butylchlorodiphenylsilane
(5.26 mL, 20.3 mmol, 1.3 equiv.) were added at room temperature
under N2. After 1 h of stirring, the reaction mixture was diluted
with EtOAc and then washed with an aqueous saturated NaHCO3
solution. The aqueous phases were extracted with EtOAc and the
combined organic layers were dried with MgSO4, filtered and con-
centrated to give the crude C. Freshly prepared 0.5  NaOMe solu-
tion in MeOH (100 mL) was added to crude C at 0 °C and stirred
for 16 h at room temperature. AcOH (8.6 mL) was added and the
reaction mixture was concentrated. The resulting residue was di-
luted with CH2Cl2 and then washed with an aqueous saturated
NaHCO3 solution. The aqueous phases were extracted with
CH2Cl2 and the combined organic layers were dried with MgSO4.
The oily residue was purified by silica gel column chromatography
(petroleum ether/EtOAc, 3:1). Compound 6 (5.01 g, 76 % for 4
steps) was obtained as a colourless oil. [α]2D7 = –47.7 (c = 0.1,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.64–7.61 (m, 4 H, HAr),
7.45–7.36 (m, 6 H, HAr), 4.50 (d, J = 5.8 Hz, 1 H, H3Ј), 4.44 (t, J
= 5.8 Hz, 1 H, H2Ј), 4.25–4.18 (m, 1 H, H1Ј), 3.58 (dd, J = 10.3
and 5.6 Hz, 1 H, H5Ј), 3.51 (dd, J = 10.3 and 5.6 Hz, 1 H, H5Ј),
2.41 (d, J = 8.3 Hz, 1 H, OH), 2.24–2.23 (m, 1 H, H4Ј), 1.93–1.82
(m, 2 H, H6Ј), 1.50 (s, 3 H, CH3), 1.32 (s, 3 H, CH3), 1.04 (s, 9 H,
tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.8 (CH, 2CAr),
135.7 (CH, 2CAr), 133.3 (C, 2CAr), 129.9 (CH, 2CAr), 127.9 (CH,
4CAr), 111.3 (C), 82.9 (CH, C3Ј), 79.7 (CH, C2Ј), 71.9 (CH, C1Ј),
65.3 (CH2, C5Ј), 44.1 (CH, C4Ј), 35.5 (CH2, C6Ј), 27.0 (tBu), 26.3
(CH3), 24.4 (CH3), 19.3 (C-Si) ppm. HRMS (ESI) m/z calcd. for
(4R,5R)-(–)-4,5-Isopropylidenedioxy-2-cyclopenten-1-one (3): -Ri-
bose was converted into the diene 1 in six steps according to Chu’s
procedure.[19] A solution of diene 1 (7.0 g, 38 mmol) in anhydrous
CH2Cl2 (200 mL) was added to [Ru] = catalyst 9 (0.48 g, 1.5 mol-
%) under N2 atmosphere. After 1 h of stirring at 24 °C, pyridinium
chlorochromate (12.3 g, 57 mmol, 1.5 equiv.) was added to the re-
sulting dark brown mixture. The reaction mixture was stirred at
room temperature for 12 h and filtered through a silica gel pad
(EtOAc). The filtrate was concentrated in vacuo, and the resulting
residue was purified by column chromatography on silica gel (pe-
troleum ether/EtOAc, 9:1), to give the unstable compound 3
(4.63 g, 79%) as a white crystalline solid. [α]2D7 = –74.5 (c = 0.35,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.60 (dd, J = 5.9 and
2.3 Hz, 1 H, H3Ј), 6.21 (d, J = 5.9 Hz, 1 H, H2Ј), 5.26 (dd, J = 5.5
and 2.3 Hz, 1 H, H4Ј), 4.46 (d, J = 5.5 Hz, 1 H, H5Ј), 1.42 (s, 6 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 202.9 (C, CO), 159.5
(CH, C3Ј), 134.2 (CH, C2Ј), 115.5 (C), 78.6 (CH, C4Ј), 76.5 (CH,
C5Ј), 27.4 (CH3), 26.1 (CH3) ppm. MS (ESI): (M+ + Na) m/z 177.0.
CAS: 115509-13-2.
(1S,2S,3R,4R)-2,3-Isopropylidenedioxy-4-vinylcyclopentyl Benzoate
(5): Compound 3 was converted into 4 according to Schneller’s
procedure.[22] A THF (40 mL) solution of 4 (4.46 g, 24.5 mmol)
was added dropwise to a suspension of LiAlH4 (1.67 g, 44.1 mmol,
1.8 equiv.) in THF (100 mL) at 0 °C under Ar. After 5 min of stir-
ring, the reaction mixture was warmed to room temperature and
stirred a further 3 h. H2O (1 mL), 15% NaOH aqueous solution
(1 mL) and H2O (1 mL) were added in turn at 0 °C. The solution
was filtered through a short celite pad and the filtrate was concen-
trated under reduced pressure. To a MeCN (40 mL) solution of the
resulting residue, 4-(dimethylamino)pyridine (6.01 g, 49.0 mmol,
2 equiv.), N,N-diisopropylethylamine (8.54 mL, 49.0 mmol,
2 equiv.) and benzoyl chloride (5.6 mL, 49.0 mmol, 2 equiv.) were
added at 0 °C under Ar. After 2 h of stirring at room temperature,
the reaction mixture was diluted with EtOAc and then washed with
aqueous saturated NaHCO3 solution. The aqueous phases were ex-
tracted with EtOAc and the combined organic layers were dried
with MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (petro-
leum ether/EtOAc, 5:1). 5 (5.54 g, 79% for 2 steps) was obtained
as a colourless oil. [α]2D7 = –66.6 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.09 (d, J = 8.5 Hz, 2 H, HAr), 7.57 (t, J
= 7.4 Hz, 1 H, HAr), 7.45 (t, J = 7.8 Hz, 2 H, HAr), 5.83 (ddd, J =
17.1, 10.5 and 6.6 Hz, 1 H, H5Ј), 5.20–5.12 (m, 3 H, H2C = +H1Ј),
4.80 (t, J = 5.6 Hz, 1 H, H2Ј), 4.54 (d, J = 5.6 Hz, 1 H, H3Ј), 2.88
(br. s, 1 H, H4Ј), 2.36–2.29 (m, 1 H, H6Ј), 2.09–2.03 (m, 1 H, H6Ј),
1.43 (s, 3 H, CH3), 1.32 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.3 (C, CO), 137.8 (CH, C5Ј), 133.1 (CH, CAr), 130.3
(C, CAr), 129.9 (CH, 2CAr), 128.4 (CH, 2CAr), 115.8 (CH2, H2C=),
111.9 (C), 84.4 (CH, C3Ј), 78.3 (CH, C2Ј), 73.8 (CH, C1Ј), 44.2 (CH,
C4Ј), 32.5 (CH2, C6Ј), 26.3 (CH3), 24.7 (CH3) ppm. HRMS (ESI)
m/z calcd. for C17H20NaO4 (M+ + Na) 311.1259, found 311.1259.
C25H34O4NaSi (M+ + Na) 449.2124, found 449.2121. IR (neat): ν
˜
= 3520 (OH), 1471, 1427, 1381 (C=C aromatic), 1209–1040 (C–O)
cm–1. CAS: 112543-76-7.
(1S,2R,3R,4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,3-isopropyl-
idenedioxy-1-tosyloxycyclopentane (7): To a CH3CN (15 mL) solu-
tion of 6 (0.5 g, 1.17 mmol), 4-dimethylaminopyridine (0.2 g,
1.76 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (0.3 mL,
1.76 mmol, 1.5 equiv.) at 0 °C, p-toluenesulfonyl chloride (0.34 g,
1.76 mmol, 1.5 equiv.) was added. After 10 min of stirring, the reac-
tion mixture was warmed to room temperature. After 24 h of stir-
ring, the reaction mixture was diluted with CH2Cl2 and then
washed with an aqueous saturated NaHCO3 solution. The aqueous
phases were extracted with CH2Cl2 and the combined organic lay-
ers were dried with MgSO4. The oily residue was purified by silica
gel column chromatography (petroleum ether/EtOAc, 6:1). 7
(0.59 g, 87%) was obtained as a colourless oil. The compound was
pure enough by TLC to be directly engaged into the next reaction.
IR (neat): ν = 1710 (C=O), 1637 (C=C), 1491, 1453, 1372 (C=C
˜
aromatic), 1268–1047 (C–O) cm–1.
(1S,2S,3R,4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,3-isopropyl-
idenedioxycyclopentan-1-ol (6): To a solution of 5 (4.51 g,
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Synthesis of 1,4-Disubstituted Triazolo-Carbanucleosides
(1R,2S,3R,4R)-1-Azido-4-[(tert-butyldiphenylsilyloxy)methyl]-2,3-
isopropylidenedioxycyclopentane (8). Procedure from 7: A DMF
147.9 (C, C4), 135.7 (CH, 4CAr–Si), 133.5 (C, 2CAr–Si), 130.8 (C,
CAr), 129.9 (CH, 2CAr–Si), 128.9 (CH, 2CAr), 128.3 (CH, CAr),
(4 mL) solution of 7 (0.22 g, 0.38 mmol), sodium azide (0.12 g, 127.9 (CH, 4CAr–Si), 125.9 (CH, 2CAr), 119.4 (CH, C5), 113.6 (C),
1.9 mmol, 5 equiv.) and 18-crown-6 ether (0.12 g, 0.46 mmol, 85.1 (CH, C2Ј), 81.2 (CH, C3Ј), 66.5 (CH, C1Ј), 64.3 (CH2, C5Ј),
1.2 equiv.) was heated for 3 h at 140 °C. The reaction mixture was
diluted with EtOAc and then washed with brine. The aqueous
phases were extracted with EtOAc and the combined organic layers
were dried with MgSO4. The oily residue was purified by silica gel
column chromatography (petroleum ether/EtOAc, 9:1). 8 (0.12 g,
69%) was obtained as a yellow oil. Procedure from 6: To a THF
(80 mL) solution of 6 (2.0 g, 4.72 mmol) and PPh3 (3.82 g,
14.16 mmol, 3 equiv.), a mixture of diisopropyl azodicarboxylate
(2.8 mL, 14.16 mmol, 3 equiv.) and diphenylphosphoryl azide
(3.07 mL, 14.16 mmol, 3 equiv.) in THF (20 mL) was added drop-
wise at 0 °C under Ar. After 7 h of stirring at room temperature,
EtOH (30 mL) was added and stirred for 30 min. After evaporation
of all volatiles, the oily residue was purified by silica gel column
chromatography (petroleum ether/EtOAc, 100:1 to 50:1). 8 (2.03 g,
95%) was obtained as yellow oil. [α]2D6 = –19.0 (c = 0.1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.68–7.65 (m, 4 H, HAr), 7.46–
7.37 (m, 6 H, HAr), 4.46 (dd, J = 6.2 and 2.5 Hz, 1 H, H3Ј), 4.31
(dd, J = 6.2 and 3.5 Hz, 1 H, H2Ј), 3.92 (td, J = 6.0 and 2.8 Hz, 1
H, H1Ј), 3.69 (dd, J = 10.3 and 7.0 Hz, 1 H, H5Ј), 3.63 (dd, J =
10.3 and 7.0 Hz, 1 H, H5Ј), 2.37 (qid, J = 7.0 and 2.5 Hz, 1 H, H4Ј),
2.22 (dt, J = 13.8 and 7.0 Hz, 1 H, H6Ј), 1.75 (dt, J = 13.8 and
5.7 Hz, 1 H, H6Ј), 1.46 (s, 3 H, CH3), 1.27 (s, 3 H, CH3), 1.07 (s, 9
H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.8 (CH, 2CAr),
135.7 (CH, 2CAr), 133.6 (C, 2CAr), 129.9 (CH, 2CAr), 127.9 (CH,
4CAr), 111.7 (C), 85.1 (CH, C2Ј), 82.1 (CH, C3Ј), 67.0 (CH, C1Ј),
64.3 (CH2, C5Ј), 47.0 (CH, C4Ј), 31.7 (CH2, C6Ј), 27.0 (tBu + CH3),
24.6 (CH3), 19.4 (C Si) ppm. 29Si NMR (79.5 MHz, CDCl3): δ =
– 1 0 4 . 4 ( b r. s, S i ) p p m . H R M S ( E S I ) m / z c a l c d . fo r
C25H33N3NaO3Si (M+ + Na) 474.2189, found 474.2207. IR (neat):
45.9 (CH, C4Ј), 33.7 (CH2, C6Ј), 27.6 (CH3), 27.0 (tBu), 25.1 (CH3),
19.5 (C Si) ppm. 29Si NMR (79.5 MHz, CDCl3): δ =-103.9 (br. s,
Si) ppm. HRMS (ESI) m/z calcd. for C33H39N3NaO3Si (M+ + Na)
576.2658, found 576.2642.
(1R,2S,3R,4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,3-isopropyl-
idenedioxy-1-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]cyclopentane
(11): The title compound was prepared from 2-ethynyl pyridine
(12 µL) after 1 min of microwave irradiation. Compound 11
(61 mg, Ͼ99%) was obtained as a light brown foam. [α]2D7 = –25.7
1
(c = 0.16, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.58 (br. s, 1
H, N-CH), 8.24 (s, 1 H, H5), 8.18 (d, J = 7.6 Hz, 1 H, =C-CH=),
7.78 (t, J = 7.6 Hz, 1 H, =C-CH=CH), 7.64 (dd, J = 6.4 and 1.2 Hz,
4 H, HAr–Si), 7.44–7.36 (m, 6 H, HAr–Si), 7.23 (br. s, 1 H, N-
CH=CH), 4.87–4.81 (m, 2 H, H2Ј + H1Ј), 4.59 (dd, J = 6.4 and
4.0 Hz, 1 H, H3Ј), 3.81–3.74 (m, 2 H, H5Ј), 2.66–2.59 (m, 1 H, H6Ј),
2.49–2.40 (m, 2 H, H4Ј + H6Ј), 1.55 (s, 3 H, CH3), 1.30 (s, 3 H,
CH3), 1.07 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ =
150.5 (C, =C), 149.5 (CH, N-CH), 148.5 (C, C4), 137.0 (CH, =C-
CH=CH), 135.7 (CH, 4CAr–Si), 133.5 (C, 2CAr–Si), 129.9 (CH,
2CAr–Si), 127.9 (CH, 4CAr–Si), 123.0 (CH, N-CH=CH), 121.8 (CH,
C5), 120.4 (CH, =C-CH=), 113.7 (C), 85.0 (CH, C2Ј), 81.1 (CH,
C3Ј), 66.6 (CH, C1Ј), 64.2 (CH2, C5Ј), 45.8 (CH, C4Ј), 33.9 (CH2,
C6Ј), 27.6 (CH3), 27.0 (tBu), 25.1 (CH3), 19.4 (C-Si) ppm. HRMS
(ESI) m/z calcd. for C32H38N4NaO3Si (M+ + Na) 577.2635, found
577.2629.
(1R,2S,3R,4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,3-isopropyl-
idenedioxy-1-(4-pentyl-1H-1,2,3-triazol-1-yl)cyclopentane (12): The
title compound was prepared from 1-heptyne (15 µL) after 15 min
of microwave irradiation. Compound 12 (60 mg, Ͼ99%) was ob-
tained as a colourless oil. [α]2D7 = –22.5 (c = 0.4, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.64 (dd, J = 7.8 and 1.4 Hz, 4 H, HAr–Si),
7.45–7.35 (m, 6 H, HAr–Si), 7.33 (s, 1 H, H5), 4.80–4.77 (m, 1 H,
H2Ј), 4.74–4.70 (m, 1 H, H1Ј), 4.56 (dd, J = 6.8 and 4.0 Hz, 1 H,
H3Ј), 3.79–3.74 (m, 2 H, H5Ј), 2.70 (t, J = 7.6 Hz, 2 H, =C-CH2),
2.56–2.52 (m, 1 H, H6Ј), 2.51–2.37 (m, 2 H, H4Ј + H6Ј), 1.68–1.64
(m, 2 H, =C-CH2-CH2), 1.54 (s, 3 H, CH3), 1.37–1.33 [m, 4 H,
(CH2)2-CH3], 1.29 (s, 3 H, CH3), 1.06 (s, 9 H, tBu), 0.89 [t, J =
7.2 Hz, 3 H, (CH2)2-CH3] ppm. 13C NMR (100 MHz, CDCl3): δ =
148.6 (C, C4), 135.7 (CH, 4CAr–Si), 133.5 (C, 2CAr–Si), 129.9 (CH,
2CAr–Si), 127.9 (CH, 4CAr–Si), 120.2 (CH, C5), 113.5 (C), 85.1 (CH,
C2Ј), 81.2 (CH, C3Ј), 66.2 (CH, C1Ј), 64.3 (CH2, C5Ј), 45.8 (CH,
C4Ј), 33.9 (CH2, C6Ј), 31.6 (CH2, CH2-CH2-CH3), 29.3 (CH2, =C-
CH2-CH2), 27.6 (CH3), 27.0 (tBu), 25.8 (CH2, =C-CH2), 25.1
(CH3), 22.5 (CH2, CH2-CH3), 19.4 (C-Si), 14.1 (CH2, CH2-CH3)
ppm. HRMS (ESI) m/z calcd. for C32H45N3NaO3Si (M+ + Na)
570.3128, found 570.3125.
ν = 2102 (N ), 1472, 1427, 1382 (C=C aromatic), 1160–1043 (C–
˜
3
O) cm–1. CAS: 112543-78-9.
General Procedures for the 1,3-Dipolar Cycloaddition Under Micro-
wave Irradiation. Synthesis of (–)-10–15: A solution of azide 8
(50 mg, 0.1 mmol) in a 1:1 mixture of water and tBuOH (1 mL)
was prepared in a glass vial equipped with a magnetic stirring bar.
Then, copper powder (5.6 mg, 80 mol-%), a water solution 1  of
copper sulfate (22 µL, 20 mol-%) and the alkyne (1.05 equiv.) were
added in turn. The vial was sealed with an aluminum/Teflon®
crimp cap and the reaction mixture was then irradiated at 125 °C.
Upon completion of the reaction, the vial was cooled to 50 °C by
air jet cooling before being opened. The reaction mixture was then
filtered through a plug of celite (EtOAc) and the filtrate was con-
centrated under reduced pressure. The oily residue was then dis-
solved in 20 mL of EtOAc and washed twice with a saturated
NaHCO3 solution (5 mL) and once with brine (5 mL). The aque-
ous phases were extracted twice with EtOAc (20 mL) and the com-
bined organic layers were dried with MgSO4, filtered and concen-
trated under reduced pressure.
(1R,2S,3R,4R)-1-[4-(Acetoxymethyl)-1H-1,2,3-triazol-1-yl]-4-[(tert-
butyldiphenylsilyloxy)methyl]-2,3-isopropylidenedioxycyclopentane
(13): The title compound was prepared from propargyl acetate
(12 µL) after 1 min of microwave irradiation. Compound 13
(60 mg, Ͼ99%) was obtained as a colourless oil. [α]2D7 = –20.7 (c =
0.4, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.67–7.63 (m, 5 H,
(1R,2S,3R,4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,3-isopropyl-
idenedioxy-1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclopentane (10): The
title compound was prepared from phenylacetylene (13 µL) after
5 min of microwave irradiation. Compound 10 (61 mg, Ͼ99%) was
obtained as a colourless oil. [α]2D7 = –25.7 (c = 0.4, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.85 (dd, J = 8.5 and 1.4 Hz, 2 H, H5 + HAr–Si), 7.45–7.36 (m, 6 H, HAr–Si), 5.21 (s, 2 H, =C-CH2),
HAr), 7.84 (s, 1 H, H5), 7.65 (dd, J = 7.8 and 1.4 Hz, 4 H, HAr–Si), 4.8–4.70 (m, 2 H, H2Ј + H1Ј), 4.57 (dd, J = 6.8 and 4.4 Hz, 1 H,
7.46–7.31 (m, 9 H, 6HAr–Si + 3HAr), 4.86–4.77 (m, 2 H, H2Ј + H1Ј), H3Ј), 3.80–3.73 (m, 2 H, H5Ј), 2.57–2.52 (m, 1 H, H6Ј), 2.48–2.35
4.61 (dd, J = 6.9 and 4.0 Hz, 1 H, H3Ј), 3.82–3.75 (m, 2 H, H5Ј),
(m, 2 H, H4Ј + H6Ј), 2.08 (s, 3 H, CO-CH3), 1.54 (s, 3 H, CH3),
2.64–2.42 (m, 3 H, H4Ј + H6Ј), 1.57 (s, 3 H, CH3), 1.32 (s, 3 H, 1.29 (s, 3 H, CH3), 1.07 (s, 9 H, tBu) ppm. 13C NMR (100 MHz,
CH3), 1.08 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = CDCl3): δ = 171.0 (CO), 142.9 (C, C4), 135.7 (CH, 4CAr–Si), 133.4
Eur. J. Org. Chem. 2009, 1880–1888
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1885

L. A. Agrofoglio et al.
FULL PAPER
(C, 2CAr–Si), 129.9 (CH, 2CAr–Si), 127.9 (CH, 4CAr–Si), 123.5 (CH, H2Ј), 4.03 (dd, J = 5.0 and 3.5 Hz, 1 H, H3Ј), 3.67 (d, J = 6.0 Hz,
C5), 113.7 (C), 85.0 (CH, C2Ј), 81.1 (CH, C3Ј), 66.6 (CH, C1Ј), 64.3 2 H, H5Ј), 2.52 (dt, J = 13.5 and 8.5 Hz, 1 H, H6Ј), 2.29–2.23 (m,
(CH2, C5Ј), 57.7 (CH2, =C-CH2), 45.7 (CH, C4Ј), 33.9 (CH2, C6Ј), 1 H, H4Ј), 1.99–1.93 (m, 1 H, H6Ј) ppm. 13C NMR (62.9 MHz,
27.6 (CH3), 27.0 (tBu), 25.1 (CH3), 21.0 (CH3, CO-CH3), 19.4 (C- CD3OD): δ = 148.6 (C, C4), 131.7 (C, CAr), 130.0 (CH, 2CAr), 129.3
Si) ppm. HRMS (ESI) m/z calcd. for C30H39N3NaO5Si (M+ + Na)
(CH, CAr), 126.6 (CH, 2CAr), 121.7 (CH, C5), 78.2 (CH, C2Ј), 73.8
(CH, C3Ј), 66.7 (CH, C1Ј), 64.4 (CH2, C5Ј), 46.8 (CH, C4Ј), 31.0
(CH2, C6Ј) ppm. HRMS (ESI) m/z calcd. for C14H17N3NaO3 (M+
+ Na) 298.1168, found 298.1181.
572.2557, found 572.2554. IR (neat): ν = 1741 (C=O), 1471, 1427,
˜
1381 (C=C aromatic), 1229 (C–O), 1111–1030 (C–O) cm–1.
(1R,2S,3R,4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-1-[4-(2-hydroxy-
ethyl)-1H-1,2,3-triazol-1-yl]-2,3-isopropylidenedioxycyclopentane
(14): The title compound was prepared from 3-butyn-1-ol (9 µL)
after 1 min of microwave irradiation. Compound 14 (57 mg,
Ͼ99%) was obtained as a colourless oil. [α]2D7 = –13.3 (c = 0.17,
(1R,2S,3R,4R)-2,3-Dihydroxy-4-(hydroxymethyl)-1-[4-(pyridin-2-
yl)-1H-1,2,3-triazol-1-yl]cyclopentane (17): The title compound was
prepared from 11 (59 mg, 0.1 mmol). After purification by column
chromatography, the obtained precipitate was washed with CH2Cl2
to eliminate the colour. Compound 17 (29 mg, 98%) was isolated
as a white solid. [α]2D7 = –33.6 (c = 0.3, CH3OH). 1H NMR
(400 MHz, [D6]DMSO): δ = 8.65 (s, 1 H, H5), 8.59 (d, J = 4.4 Hz,
1 H, N-CH), 8.02 (d, J = 7.6 Hz, 1 H, =C-CH=), 7.89 (td, J = 7.6
and 1.6 Hz, 1 H, =C-CH=CH), 7.34 (ddd, J = 7.6, 4.4 and 0.8 Hz,
1 H, N-CH=CH), 5.09 (d, J = 6.8 Hz, 1 H, C2Ј-OH), 4.87–4.82 (m,
1 H, H1Ј), 4.78–4.76 (m, 2 H, C3Ј-OH + C5Ј-OH), 4.16–4.10 (m, 1
H, H2Ј), 3.84–3.81 (m, 1 H, H3Ј), 3.47–3.42 (m, 2 H, H5Ј), 2.35 (dt,
J = 13.2 and 8.6 Hz, 1 H, H6Ј), 2.10–2.03 (m, 1 H, H4Ј), 1.81–1.73
(m, 1 H, H6Ј) ppm. 13C NMR (100 MHz, [D6]DMSO): δ= 150.2
(C, =C), 149.8 (CH, N-CH), 147.3 (C, C4), 137.6 (CH, =C-
CH=CH), 123.3 (CH, N-CH=CH), 122.7 (CH, C5), 119.8 (CH,
=C-CH=), 76.9 (CH, C2Ј), 72.2 (CH, C3Ј), 65.0 (CH, C1Ј), 63.0
(CH2, C5Ј), 45.5 (CH, C4Ј), 30.0 (CH2, C6Ј) ppm. HRMS (ESI) m/z
calcd. for C13H16N4NaO3 (M+ + Na) 299.1120, found 299.1120.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.65 (dd, J = 8.0 and
1.2 Hz, 4 H, HAr–Si), 7.46 (s, 1 H, H5), 7.44–7.36 (m, 6 H, HAr–Si),
4.80–4.69 (m, 2 H, H2Ј + H1Ј), 4.57 (dd, J = 6.8 and 4.0 Hz, 1 H,
H3Ј), 3.95 (t, J = 5.4 Hz, 2 H, CH2-OH), 3.80–3.73 (m, 2 H, H5Ј),
2.95 (t, J = 5.4 Hz, 2 H, =C-CH2), 2.63 (s, 1 H, OH), 2.57–2.52
(m, 1 H, H6Ј), 2.48–2.35 (m, 2 H, H4Ј + H6Ј), 1.54 (s, 3 H, CH3),
1.29 (s, 3 H, CH3), 1.07 (s, 9 H, tBu) ppm. 13C NMR (100 MHz,
CDCl3): δ = 145.7 (C, C4), 135.7 (CH, 4CAr–Si), 133.4 (C, 2CAr–Si),
129.9 (CH, 2CAr–Si), 127.9 (CH, 4CAr–Si), 121.3 (CH, C5), 113.6
(C), 85.0 (CH, C2Ј), 81.1 (CH, C3Ј), 66.4 (CH, C1Ј), 64.3 (CH2, C5Ј),
61.8 (CH2, CH2-OH), 45.8 (CH, C4Ј), 33.8 (CH2, C6Ј), 28.8 (CH2,
=C-CH2), 27.6 (CH3), 27.0 (tBu), 25.1 (CH3), 19.4 (C-Si) ppm.
HRMS (ESI) m/z calcd. for C29H39N3NaO4Si (M+ + Na) 544.2608,
found 544.2614. IR (neat): ν = 3390 (OH), 1471, 1427, 1380 (C=C
˜
aromatic), 1210–1064 (C–O) cm–1.
(1R,2S,3R,4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,3-isopropyl-
idenedioxy-1-(4-methoxycarbonyl-1H-1,2,3-triazol-1-yl)cyclopen-
tane (15): The title compound was prepared from methyl propiolate
(10 µL) after 1 min of microwave irradiation. Compound 15
(59 mg, Ͼ99%) was obtained as an orange oil. [α]2D7 = –20.8 (c =
(1R,2S,3R,4R)-2,3-Dihydroxy-4-(hydroxymethyl)-1-(4-pentyl-1H-
1,2,3-triazol-1-yl)cyclopentane (18): The title compound was pre-
pared from 12 (58 mg, 0.1 mmol). The residue was purified by silica
gel column chromatography (EtOAc). Compound 18 (25 mg, 88%)
1
was obtained as a white solid. [α]2D7 = –13.2 (c = 0.2, CH3OH). H
1
0.15, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1 H, H5),
NMR (250 MHz, CD3OD): δ = 7.81 (s, 1 H, H5), 4.94–4.77 (m, 1
H, H1Ј), 4.21 (dd, J = 8.0 and 5.0 Hz, 1 H, H2Ј), 3.99 (dd, J = 5.3
and 3.5 Hz, 1 H, H3Ј), 3.65 (d, J = 6.0 Hz, 2 H, H5Ј), 2.69 (t, J =
7.5 Hz, 2 H, =C-CH2), 2.46 (dt, J = 13.5 and 8.5 Hz, 1 H, H6Ј),
2.26–2.19 (m, 1 H, H4Ј), 1.91–1.84 (m, 1 H, H6Ј), 1.70–1.62 (m, 2
H, =C-CH2-CH2), 1.38–1.32 [m, 4 H, (CH2)2-CH3], 0.91 [t, J =
6.6 Hz, 3 H, (CH2)2-CH3] ppm. 13C NMR (62.9 MHz, CD3OD): δ
= 149.0 (C, C4), 122.5 (CH, C5), 78.0 (CH, C2Ј), 73.8 (CH, C3Ј),
66.4 (CH, C1Ј), 64.4 (CH2, C5Ј), 46.7 (CH, C4Ј), 32.5 (CH2, CH2-
CH2-CH3), 31.0 (CH2, C6Ј), 30.3 (CH2, =C-CH2-CH2), 26.3 (CH2,
=C-CH2), 23.4 (CH2, CH2-CH3), 14.3 (CH2, CH2-CH3) ppm.
HRMS (ESI) m/z calcd. for C13H23N3NaO3 (M+ + Na) 292.1637,
found 292.1626.
7.63 (dd, J = 6.4 and 1.2 Hz, 4 H, HAr–Si), 7.45–7.36 (m, 6 H,
HAr–Si), 4.80–4.73 (m, 2 H, H2Ј + H1Ј), 4.57 (dd, J = 6.2 and 4.2 Hz,
1 H, H3Ј), 3.95 (s, 3 H, OCH3), 3.77–3.76 (m, 2 H, H5Ј), 2.62–2.54
(m, 1 H, H6Ј), 2.49–2.37 (m, 2 H, H4Ј + H6Ј), 1.54 (s, 3 H, CH3),
1.29 (s, 3 H, CH3), 1.07 (s, 9 H, tBu) ppm. 13C NMR (100 MHz,
CDCl3): δ = 161.3 (C, CO), 140.0 (C, C4), 135.7 (CH, 4CAr–Si),
133.4 (C, 2CAr–Si), 130.0 (CH, 2CAr–Si), 127.9 (CH, 4CAr–Si), 127.3
(CH, C5), 113.8 (C), 85.0 (CH, C2Ј), 81.1 (CH, C3Ј), 67.0 (CH, C1Ј),
64.1 (CH2, C5Ј), 52.3 (OCH3), 45.6 (CH, C4Ј), 33.7 (CH2, C6Ј), 27.6
(CH3), 27.0 (tBu), 25.1 (CH3), 19.5 (C-Si) ppm. HRMS (ESI) m/z
calcd. for C29H37N3NaO5Si (M+ + Na) 558.2400, found 558.2394.
IR (neat): ν = 1727 (C=O), 1471, 1427, 1382 (C=C aromatic), 1239
˜
(C–O), 1066–1042 (C–O) cm–1.
General Procedure for Deprotection. Synthesis of (–)-16–21: The
protected triazole (0.1 mmol) was stirred overnight in an aqueous
solution of trifluoroacetic acid (60% v/v) (2 mL) at room tempera-
ture. After evaporation of all volatiles, the resulting oil was dis-
solved in THF (2 mL) and tetrabutyl ammonium fluoride trihydr-
ate (33 mg, 0.1 mmol, 1.05 equiv.) was added. The reaction mixture
was stirred for 1 h at room temperature. After evaporation of all
volatiles, the residue was purified by silica gel column chromatog-
raphy (EtOAc/MeOH, 98:2).
(1R,2S,3R,4R)-1-[4-(Acetoxymethyl)-1H-1,2,3-triazol-1-yl]-2,3-di-
hydroxy-4-(hydroxymethyl)cyclopentane (19): The title compound
was prepared from 13 (58 mg, 0.1 mmol). The residue was purified
by silica gel column chromatography (EtOAc). Compound 19
(22 mg, 76%) was obtained as a colorless oil. 1H NMR (250 MHz,
CD3OD): δ = 8.09 (s, 1 H, H5), 5.18 (s, 2 H, =C-CH2), 4.92–4.81
(m, 1 H, H1Ј), 4.22 (dd, J = 8.3 and 5.3 Hz, 1 H, H2Ј), 3.99 (dd, J
= 5.3 and 3.5 Hz, 1 H, H3Ј), 3.64 (d, J = 5.6 Hz, 2 H, H5Ј), 2.47
(dt, J = 13.2 and 8.5 Hz, 1 H, H6Ј), 2.29–2.16 (m, 1 H, H4Ј), 2.06 (s,
3 H, CO-CH3), 1.97–1.83 (m, 1 H, H6Ј) ppm. 13C NMR (62.9 MHz,
CD3OD): δ = 172.3 (CO), 143.8 (C, C4), 125.3 (CH, C5), 78.2 (CH,
C2Ј), 73.8 (CH, C3Ј), 66.6 (CH, C1Ј), 64.4 (CH2, C5Ј), 58.2 (CH2,
=C-CH2), 46.8 (CH, C4Ј), 31.0 (CH2, C6Ј), 20.6 (CH3, CO-CH3)
(1R,2S,3R,4R)-2,3-Dihydroxy-4-(hydroxymethyl)-1-(4-phenyl-1H-
1,2,3-triazol-1-yl)cyclopentane (16): The title compound was pre-
pared from 10 (55 mg, 0.1 mmol) and was obtained as a white solid
16 (24 mg, 86%). [α]2D7 = –65.0 (c = 0.2, CH3OH). 1H NMR
(500 MHz, CD3OD): δ = 8.39 (s, 1 H, H5), 7.81 (d, J = 7.5 Hz, 2 ppm. HRMS (ESI) m/z calcd. for C11H17N3NaO5 (M+ + Na)
H, HAr), 7.43 (t, J = 7.5 Hz, 2 H, HAr), 7.34 (t, J = 7.5 Hz, 1 H,
HAr), 4.95–4.90 (m, 1 H, H1Ј), 4.29 (dd, J = 8.0 and 5.0 Hz, 1 H,
294.1066, found 294.1073. IR (neat): ν = 3360 (OH), 1731 (C=O),
˜
1229 (C–O), 1160–1042 (C–O) cm–1.
1886
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1880–1888

Synthesis of 1,4-Disubstituted Triazolo-Carbanucleosides
(1R,2S,3R,4R)-2,3-Dihydroxy-1-[4-(2-hydroxyethyl)-1H-1,2,3-tri-
azol-1-yl]-4-(hydroxymethyl)]cyclopentane (20): The title compound
was prepared from 14 (57 mg, 0.1 mmol). After purification by col-
umn chromatography, the obtained precipitate was washed with
CH2Cl2 to eliminate the colour. Compound 20 (21 mg, 80%) was
obtained as a white solid. [α]2D7 = –26.6 (c = 0.15, CH3OH). 1H
NMR (400 MHz, CD3OD): δ = 7.87 (s, 1 H, H5), 4.87–4.80 (m, 1
H, H1Ј), 4.21 (dd, J = 8.4 and 5.3 Hz, 1 H, H2Ј), 3.99 (dd, J = 5.3
and 3.6 Hz, 1 H, H3Ј), 3.82 (br. s, 2 H, CH2-OH), 3.65 (d, J =
6.0 Hz, 2 H, H5Ј), 2.91 (t, J = 6.6 Hz, 2 H, =C-CH2), 2.46 (dt, J =
13.2 and 8.5 Hz, 1 H, H6Ј), 2.27–2.19 (m, 1 H, H4Ј), 1.93–1.85 (m,
1 H, H6Ј) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.3 (C, C4),
123.4 (CH, C5), 78.2 (CH, C2Ј), 73.9 (CH, C3Ј), 66.5 (CH, C1Ј),
64.4 (CH2, C5Ј), 62.1 (CH2, CH2-OH), 46.7 (CH, C4Ј), 31.0 (CH2,
C6Ј), 29.9 (CH2, =C-CH2) ppm. HRMS (ESI) m/z calcd. for
Acknowledgments
These studies were supported by a grant from Aventis Pharma
(Sanofi-Aventis group) and Bayer Pharma as part of a multi-organ-
ism call for proposals. The ICIQ Foundation is gratefully acknowl-
edged for financial support. S. P. N. is an ICREA Research Pro-
fessor. Authors acknowledge Dr D. Deville-Bonne (Institut J.
Monod, Paris, France) Pr D. Garin (CRSSA, La Tronche, France),
Pr R. Snoeck (Rega Institute, Leuven, Belgium) for biological
evaluations.
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C10H17N3NaO4 (M+ + Na) 266.1117, found 266.1111. IR (neat): ν
˜
= 3294 (OH), 1201–1050 (C–O) cm–1.
(1R,2S,3R,4R)-2,3-Dihydroxy-4-(hydroxymethyl)-1-[4-(methoxycar-
bonyl)-1H-1,2,3-triazol-1-yl]cyclopentane (21): The title compound
was prepared from 15 (59 mg, 0.1 mmol). After purification by col-
umn chromatography, the obtained precipitate was washed with
CH2Cl2 to eliminate the colour. Compound 21 (15 mg, 52%) was
obtained as a white solid. [α]2D7 = –28.0 (c = 0.2, CH3OH). 1H NMR
(250 MHz, CD3OD): δ = 8.62 (s, 1 H, H5), 4.97–4.78 (m, 1 H, H1Ј),
4.25 (dd, J = 8.5 and 5.3 Hz, 1 H, H2Ј), 4.00 (dd, J = 5.3 and
3.2 Hz, 1 H, H3Ј), 3.92 (s, 3 H, OCH3), 3.65 (d, J = 6.0 Hz, 2 H,
H5Ј), 2.57–2.45 (m, 1 H, H6Ј), 2.30–2.19 (m, 1 H, H4Ј), 1.99–1.87
(m, 1 H, H6Ј) ppm. 13C NMR (62.9 MHz, CD3OD): δ = 162.4 (C,
CO), 140.3 (C, C4), 129.2 (CH, C5), 78.2 (CH, C2Ј), 73.8 (CH, C3Ј),
66.9 (CH, C1Ј), 64.3 (CH2, C5Ј), 52.5 (OCH3), 46.8 (CH, C4Ј), 30.8
(CH2, C6Ј) ppm. HRMS (ESI) m/z calcd. for C10H15N3NaO5 (M+
+ Na) 280.0909, found 280.0913. IR (neat): ν = 3363 (OH), 1731
˜
(C=O), 1226 (C–O), 1142–1055 (C–O) cm–1.
(1R,2S,3R,4R)-1-(5-Amino-4-carbamoyl-1H-1,2,3-triazol-1-yl)-2,3-
isopropylidenedioxy-4-[(tert-butyldiphenylsilyloxy)methyl]cyclopentane
(22): In a dry flask, sodium metal (11 mg, 0.48 mmol, 2 equiv.) was
dissolved in dry EtOH (1 mL) under N2. To a solution of 8
(100 mg, 0.22 mmol) in dry EtOH (10 mL) under N2, the prepared
sodium ethoxide solution was added dropwise. After the addition
of 2-cyanoacetamide (21 mg, 0.25 mmol, 1.1 equiv.), the reaction
mixture was refluxed for 48 h. The residue was purified by silica
gel column chromatography (petroleum ether/EtOAc, 1:3). Com-
pound 22 (6 mg, 5%) was obtained as a colourless oil. [α]2D7 = –32.4
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1
(c = 0.1, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.66 (dd, J =
7.6 and 1.6 Hz, 4 H, HAr–Si), 7.46–7.37 (m, 6 H, HAr–Si), 6.68 (br.
s, 1 H, CONHH), 5.64 (s, 2 H, NH2), 5.30 (br. s, 1 H, CONHH),
4.57 (dd, J = 7.2 and 4.4 Hz, 1 H, H3Ј), 4.52–4.49 (m, 1 H, H2Ј),
4.33 (dt, J = 12.4 and 6.4 Hz, 1 H, H1Ј), 3.84–3.76 (m, 2 H, H5Ј),
2.76 (dd, J = 25.2 and 12.4 Hz, 1 H, H6Ј), 2.61–2.54 (m, 1 H, H6Ј),
2.52–2.46 (m, 1 H, H4Ј), 1.59 (s, 3 H, CH3), 1.30 (s, 3 H, CH3),
1.07 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.7
(CO), 145.5 (C, C4), 135.7 (CH, 4CAr–Si), 133.5 (C, 2CAr–Si), 130.0
(CH, 2CAr–Si), 127.9 (CH, 4CAr–Si), 122.9 (C, C5), 114.2 (C), 85.1
(CH, C2Ј), 81.5 (CH, C3Ј), 64.3 (CH2, C5Ј), 63.7 (CH, C1Ј), 45.3
(CH, C4Ј), 31.2 (CH2, C6Ј), 27.6 (CH3), 27.0 (tBu), 25.1 (CH3), 19.5
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˜
(C=O), 1458, 1421, 1380 (C=C aromatic), 1254 (C–N), 1210–1003
(C–O) cm–1.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of all new compounds.
Eur. J. Org. Chem. 2009, 1880–1888
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1887

L. A. Agrofoglio et al.
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Received: November 13, 2008
Published Online: February 26, 2009
1888
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1880–1888