Synthesis of Novel Triazolo Cyclobutane Nucleoside Analogs

Article abstract of DOI:10.1002/bkcs.10270

Synthesis of triazolo-cyclobutane nucleosides analogs is reported. These molecules have been obtained by a short and efficient sequence involving a click azide-alkyne cycloaddition following by cis-hydroxylation in the key step.

Full text of DOI:10.1002/bkcs.10270

Article
DOI: 10.1002/bkcs.10270
BULLETIN OF THE
T. T. T. Tran et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Novel Triazolo Cyclobutane Nucleoside Analogs
†
†
‡
§
Thi Thu Thuy Tran,†, Ngoc Thang Ngo, Thi Ha Dinh, Giang Vo-Thanh, and Stéphanie Legoupy
*
†Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, Hanoi, Vietnam.
*E-mail: thuytran.inpc@gmail.com
‡Equipe de Catalyse Moléculaire-ICMMO, Bât 420 Université Paris-Sud 11, 91405 Orsay Cedex, France
§LUNAM Université, Université d'Angers, CNRS UMR 6200, Laboratoire MOLTECH-Anjou, 49045
ANGERS cedex, France
Received October 3, 2014, Accepted January 10, 2015, Published online April 24, 2015
Synthesis of triazolo-cyclobutane nucleosides analogs is reported. These molecules have been obtained by a
short and efficient sequence involving a click azide-alkyne cycloaddition following by cis-hydroxylation in the
key step.
Keywords: Nucleoside analogs, Click chemistry, cis-Dihydroxylation, Triazolo-cyclobutane
Introduction
In course of our research program toward nucleoside ana-
logs, we have already prepared cyclobutene analogs of carbo-
vir 1,8 compounds 2 with a methylene spacer between the
carbocycle and the heterocycle,9 nucleosides analogs with a
methylene unit10 3 and 4, and mono- and polyhydroxylated
analogs11 6 and 7 (Figure 2). We then planned to prepare tri-
hydroxylated nucleoside analogs bearing a 1,2,3-triazole moi-
ety I and II via click azide-alkyne cycloaddition12 following
by cis-dihydroxylation.
Nucleoside analogs have interesting biological activities espe-
cially asantiviral oranticancer agents. Besides modificationof
the ribosyl ring byvarious five-memberedcarbasugars,1 atten-
tion has been directed toward carbocyclic derivatives such as
abacavir,2 carbovir,3 entecavir,4 cyclobut-A, and cyclobut-G5
(Figure 1). However, as ribavirin6 was reported as therapeutic
agent in HCV infection, synthesis of various triazolo-
nucleoside analogs have been reported.7
Experimental
Commercially available reagents and solvents were purified
and dried, when necessary, by standard methods just prior
to use. NMR spectra were recorded on a Bruker AV500
(Rheinstetten, Germany) spectrometer at 500 and 125 MHz
for 1H and 13C, respectively, with TMS as internal standard.
EI-MS spectra were recorded on a LC/MSD Agilent Series
1100(Santa Clara, CA, USA)instrument. HR-EIS-MSspectra
were recorded on a microTOF-QII 10027 (Bruker Daltonics,
Bremen, Germany). Elemental analyses were performed at
CNRS ISCN, Gif sur Yvette. The optical rotation was deter-
mined with a Perkin-Elmer (Waltham, MA, USA) automatic
HN
N
O
N
O
N
N
N
N
N
N
N
N
NH
NH2
NH
NH2
HO
HO
HO
NH2
Abacavir
Carbovir
Entecavir
OH
O
HO
B
N
N
NH2
HO
N
HO
Cyclobut-A, B = Adenine
Cyclobut-G, B = Guanine
Ribavirin
HO OH
Figure 1. Carbocyclic nucleoside analogs.
B
OH
HO
B
HO
B
HO
B
HO
B
1
2
3
4
5
OH
B = adenine
or thymine
B = adenine
or thymine
B = adenine
or thymine
B = adenine
or thymine
B = various bases
N
N
N
N
N
N
HO
B
HO
B
HO
HO
R
R
HO
HO
OH
OH
OH
HO
OH
HO
7
I
II
6
B = adenine
or thymine
B = adenine
or thymine
Figure 2. Cyclobutene and cyclobutane nucleoside analogs.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1390–1395
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Triazolo-Cyclobutane Nucleoside Analogs
KOREAN CHEMICAL SOCIETY
polarimeter. Melting points were recorded on a Buchi B-545
(Switzerland) apparatus and uncorrected.
4-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(((1S,4R)-4-
(((tert-butyldiphenylsilyl)oxy)methyl) cyclobut-2-en-1-yl)
methyl)-1H-1,2,3-triazole (12). Yield: 97%. White solid,
mp 97–98 ꢀC.1H NMR (500 MHz, CDCl3) δ 7.70–7.66 (m,
8H), 7.46–7.37 (m, 12H), 7.33 (s, 1H), 6.06 (2d overlap,
2H, J = 2.5 Hz), 4.89 (s, 2H), 4.77 (dd, 1H, J = 13.5 and 5.0
Hz), 4.42 (dd, 1H, J = 13.5 and 10.5 Hz), 3.80 (dd, 1H, J =
11.5 and 5.5 Hz), 3.78 (dd, 1H, J = 11.5 and 8.5 Hz),
3.46–3.43 (m, 1H), 3.27–3.26 (m, 1H), 1.09 (s, 18H). 13C
NMR (125 MHz, CDCl3) δ 148.1, 138.4, 138.2, 135.6 (2C),
135.5 (2C), 133.4, 133.2, 129.8 (2C), 127.7 (4C), 121.6,
63.4, 58.7, 51.0, 47.5, 45.5, 26.9 (3C), 26.8 (3C), 19.24,
19.22. HRMS: C41H49N3O2Si2 calcd. for [M + H]+:
672.3436, found: 672.3441.
((1S,4R)-4-((tert-Butyldiphenylsilyloxy)methyl-2)-cyclo-
butenyl)methyl methane-sulfonate (10). To a cold solution
(0 ꢀC) of alcohol 9 (10 g, 28.4 mmol) and methanesulfonyl
chloride (4.39 g, 38.3 mmol) in CH2Cl2 (20 mL) was added
slowly triethylamine (5.7 g, 56.4 mmol) under argon. The
resulting mixture was stirred at rt for 1 h. Water (3 mL) was
added and the aqueous layer was extracted with EtOAc (3 ×
15 mL). The combined organic phase was dried over Na2SO4
and evaporated to dryness. The residue was purified by column
chromatography on silica gel (n-hexane/ethyl acetate 4:1) to
yield 10 (8.3 g, 85%) as a colorless oil. 1H NMR (500 MHz,
CDCl3) δ 7.66 (dd, 4H, J = 6.0 and 2.0 Hz), 7.44–7.38 (m,
6H), 6.18 (d, 1H, J = 2.5 Hz), 6.10 (d, 1H, J = 2.5 Hz), 4.57
(dd, 1H, J = 9.5 and 6.5 Hz), 4.38 (dd, 1H, J = 9.5 and 8.0 Hz),
3.82 (dd, 1H, J = 11.5 and 6.0 Hz), 3.75 (dd, 1H, J = 11.5 and
8.0 Hz), 3.84–3.30 (m, 1H), 3.23–3.20 (m, 1H), 2.90 (s, 3H),
1.05 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 139.0, 137.1,
135.6 (4C), 133.5, 133.3, 129.8, 129.7, 127.7 (4C), 70.8,
63.4, 47.5, 44.4, 37.2, 26.9 (3C), 19.2. Anal. calcd. for
C23H30SiSO4: C, 64.15, H, 7.02, S, 7.49. Found C, 64.11, H,
7.05, S, 7.43.
(((1R,4S)-4-(Azidomethyl)cyclobut-2-enyl)methoxy) (tert-
butyl)diphenylsilane (11). To a solution of mesylate 10 (8.3 g,
24.4 mmol) in anhydrous DMF (50 mL) was added sodium
azide (6.3 g, 97.6 mmol) under argon atmosphere. The reac-
tion mixture was then stirred at 55 ꢀC for 12 h. After cooling
toroomtemperature, icewater(100 mL)wasadded. Theaque-
ous layer was extracted with EtOAc (4 × 70 mL). The com-
bined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. Purification of the crude
product by column chromatography on silica gel (n-hexane/
ethyl acetate 95:5) afforded azide 11 (7.6 g, 82%) as colorless
oil. 1H NMR (500 MHz, CDCl3) δ 7.68–7.66 (m, 4H),
7.46–7.38 (m, 6H), 6.22 (d, 1H, J = 2.5 Hz), 6.08 (d, 1H,
J = 2.5 Hz), 3.83–3.75 (m, 2H), 3.62 (dd, 1H, J = 12.0 and
6.0 Hz), 3.41 (dd, 1H, J = 12.0 and 8.5 Hz), 3.23–3.17 (m,
2H), 1.05 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 138.5,
138.4, 135.6 (4C), 133.7, 133.6, 129.7 (2C), 127.7 (4C),
63.6, 52.0, 48.0, 45.0, 26.9 (3C), 19.2. MS m/z = 399 (M +
Na)+. Anal. calcd. for C22H27SiN3O: C, 69.98, H, 7.21, N,
11.13. Found C, 69.75, H, 7.25, N, 10.82.
Benzyl
1-(((1S,4R)-4-(((tert-butyldiphenylsilyl)oxy)
methyl)cyclobut-2-en-1-yl) methyl)-1H-1,2,3-triazole-4-
carboxylate (13). Yield: 95%. White solid, mp 63–64 ꢀC
.1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.65 (dd, J =
9.0 and 3.5 Hz, 4H), 7.50–7.31 (m, 11H), 6.07 (m, 2H),
5.40 (s, 2H), 4.85 (dd, 1H, J = 14.0 and 6.0 Hz), 4.51 (dd,
1H, J = 14.0 and 10.5 Hz), 3.87 (dd, 1H, J = 11.0 and 5.0
Hz), 3.75 (dd, 1H, J = 11.0 and 8.5 Hz), 3.48 (dt, 1H, J =
10.0 and 5.0 Hz), 3.25 (dt, 1H, J = 10.0 and 5.0 Hz), 1.07 (s,
9H). 13C NMR (125 MHz, CDCl3) δ 160.6, 139.9, 138.6,
137.7, 135.6 (2C), 135.5 (2C), 133.3, 133.2, 129.9, 129.8,
128.6 (3C), 128.5 (2C), 128.4, 127.80 (4C), 127.5, 66.8,
63.3, 51.4, 47.6, 45.3, 26.9 (3C), 19.2. HRMS: C32H35N3O3Si
calcd. for [M + H]+: 538.2520, found: 538.2525.
1-(((1S,4R)-4-(((tert-Butyldiphenylsilyl)oxy)methyl
cyclobut-2-enyl)methyl)-4-(3-(trifluoromethyl)phenyl)-1H-
1,2,3-triazole (14). Yield: 98%. Colorless oil. 1H NMR (500
MHz, CDCl3) δ 7.79 (s, 1H), 7.68–7.66 (m, 5H), 7.59–7.53
(m, 2H), 7.46–7.43 (m, 2H), 7.41–7.38 (m, 5H), 6.14 (d, 1H,
J = 2.5 Hz), 6.10 (d, 1H, J = 2.5 Hz), 4.86 (dd, 1H, J = 13.5
and 6.0 Hz), 4.55 (dd, 1H, J = 13.5 and 10.0 Hz), 3.90 (dd,
1H, J = 11.0 and 5.0 Hz), 3.80 (dd, 1H, J = 11.0 and 8.0 Hz),
3.57–3.53 (m, 1H), 3.30–3.27 (m, 1H), 1.05 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ 146.3, 138.5, 138.0, 135.6 (2C),
135.5 (2C), 133.4, 133.2, 131.6, 129.9, 129.8, 129.3, 128.9,
127.8 (4C), 125.1, 124.6, 123.0, 122.5, 120.1, 63.4, 51.2,
47.6, 45.5, 26.9 (3C), 19.3. HRMS: C31H32N3OF3Si calcd.
for [M + H]+: 548.2340, found: 548.2345.
1-(((1S,4R)-4-((tert-Butyldiphenylsilyl)oxy)methyl)
cyclobut-2-en-1-yl)methyl)-4-(3,5-difluorophenyl)-1H-1,2,3-
triazole (15). Yield: 94%. Colorless oil. 1H NMR (500 MHz,
CDCl3) δ 7.63 (s, 1H); 7.60–7.58 (m, 4H), 7.37–7.35 (m, 2H),
7.33–7.31 (m, 4H), 7.25–7.23 (m, 2H), 6.70–6.67 (m, 1H),
6.05 (d, 1H, J = 2.5 Hz), 6.02 (d, 1H, J = 2.5 Hz), 4.77 (dd,
1H, J = 13.5 and 6.0 Hz), 4.46 (dd, 1H, J = 13.5 and 10.0
Hz), 3.82 (dd, 1H, J = 11.0 and 5.0 Hz), 3.73 (dd, 1H, J =
11.0 and 8.5 Hz), 3.47–3.45 (m, 1H), 3.20–3.18 (m, 1H),
1.01 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 164.3 (d, J =
13.0 Hz), 162.4 (d, J = 13.2 Hz), 145.7, 138.5, 137.9, 135.6
(2C), 135.5 (2C), 133.8, 133.3, 133.2, 129.9 (2C), 127.8
(4C), 120.4, 108.5 (d, J = 6.5 Hz), 108.3 (d, J = 6.0 Hz),
103.2 (t, J = 25.0 Hz), 63.4, 51.2, 47.6, 45.5, 26.9 (3C),
General Procedure for the Azide-Alkyne Huisgen
Cycloaddtion. To a solution of azide 11 (0.3 g, 0.79 mmol)
t
and selected alkyne (1.2 eq) in BuOH (2 mL) were added
sodium ascorbate 200 mol% (0.32 g, 1.58 mmol, in 1 mL
H2O) and 20 mol% CuSO4.5H2O (40.5 mg, 0.16 mmol, in
1 mL H2O) under argon atmosphere. The reaction mixture
was stirred overnight at room temperature and then saturated
NH4OH solution (5 mL) was added. The mixture was
extracted with ethyl acetate (3 × 15 mL). The combined
organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel (n-hexane/EtOAc) to afford
the 1,2,3-triazolocyclobutene.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1390–1395
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Triazolo-Cyclobutane Nucleoside Analogs
KOREAN CHEMICAL SOCIETY
19.2. HRMS: C30H31N3OF2Si calcd. for [M + H]+: 516.2277,
found: 516.2283.
C9H15N3O4Na calcd. for [M + Na]+: 252.0955, found:
252.0957.
tert-Butyl-(1-(((1S,4R)-4-((tert-butyldiphenylsily-
loxy) methyl)cyclobut-2-enyl)methyl)-1H-1,2,3-triazol-4-
yl)methylcarbamate (16). Yield: 82%. White solid, mp
Benzyl 1-(((1S,2R,3S,4R)-2,3-dihydroxy-4-(hydroxyl
methyl)cyclobutyl)methyl)-1H-1,2,3-triazole-4-carbo-xylate
(18c). Yield: 28%. White solid, mp 216–217 ꢀC. ½αꢁD20 + 19
1
101–102 ꢀC. H NMR (500 MHz, CDCl3) δ 7.66–7.64 (m,
1
(c 1.200, MeOH). H NMR (500 MHz, CD3OD) δ 8.55 (s,
4H), 7.51 (s, 1H), 7.46–7.38 (m, 6H), 7.12–7.08 (m, 1H),
6.08 (d, J = 2.5 Hz, 1H), 6.06 (d, J = 2.5 Hz, 1H), 4.78 (dd,
J = 14.0 and 6.0 Hz, 1H), 4.45 (dd, J = 14.0 and 10.5 Hz,
1H), 4.39 (m, 2H), 3.86 (dd, J = 11.0 and 5.0 Hz, 1H), 3.76
(dd, J = 11.0 and 8.5 Hz, 1H), 3.45 (ddd, J = 5 Hz, 1H), 3.25
(ddd, J = 5 Hz, 1H), 1.44 (s, 9H), 1.07 (s, 9H). 13C NMR
(125 MHz, CDCl3) δ 158.8, 156.9, 138.3, 138.2,135.6,
135.55, 133.4, 133.3, 129.84, 129.82, 127.8, 64.4, 51.1(2C),
47.5, 45.4, 36.1, 28.4, 26.9, 19.2 (2C) . HRMS: C30H40N4O3Si
calcd. for [M + H]+: 53.2942, found: 533.2948.
1H), 7.47 (d, J = 7.0 Hz, 2H), 7.40–7.35 (m, 3H), 5.38 (s,
2H), 4.85 (dd, J = 14.0 and 9.0 Hz, 1H), 4.73 (dd, J = 14.0
and 5.5 Hz, 1H), 4.37–4.34 (m, 1H), 4.30–4.28 (m, 1H),
3.91 (d, J = 7.0 Hz, 2H), 2.94–2.90 (m, 1H), 2.69–2.66 (m,
1H). 13C NMR (125 MHz, CD3OD) δ 161.9, 140.2, 137.2,
130.2, 129.6 (2C), 129.5 (2C), 129.4, 70.1, 69.2, 67.7, 59.2,
48.0, 43.1, 39.9. HRMS: C16H20N3O5 calcd. for [M + H]+:
334.1397, found: 334.1396.
Benzyl
1-(((1S,2S,3R,4R)-2,3-dihydroxy-4-(hydroxyl-
methyl)cyclobutyl)methyl)-1H-1,2,3-triazole-4carboxy-late
General Procedure for Dihydroxylation of Cyclobutene
(18d). Yield: 52%. White solid, mp 171–172 ꢀC. ½αꢁD20 − 123
Nucleoside Analogs Following by Desilylation.
4-
1
(c 2.300, MeOH). H NMR (500 MHz, CD3OD) δ 8.60 (s,
Methylmorpholine N-oxide (102 mg, 0.870 mmol) and a 4%
aqueous solution of OsO4 (76 μL, 3.05 mg, 0.012 mmol) were
added to a solution of cyclobutene (0.58 mmol) in a THF:H2O
(10:1) mixture (2.5 mL). The reaction mixture was stirred at
room temperature for 4 h then 20% NaHSO3 solution (5
mL) was added at 0 ꢀC. The mixture was extracted with ethyl
acetate (5 × 10 mL). The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The
residue containing two isomers was submitted to the deprotec-
tion reaction.
To the crude mixture of silylated diols (0.4 mmol) THF (4
mL) was added a solution of TBAF 1 M in THF (800 μL). The
reaction mixture was stirred at room temperature for 30 min
then saturated NH4Cl and ethyl acetate were added.
The organic layer was separated, dried over Na2SO4 and con-
centrated under reduced pressure. The residue was purified
by column chromatography (dichloromethane/methanol
10:1) to successively lead to isomer cis-isomer c then to
trans-isomer d.
1H), 7.47 (d, J = 7.0 Hz, 2H), 7.40–7.33 (m, 3H), 5.39 (s,
2H), 4.74 (dd, J = 14.0 and 7.5 Hz, 1H), 4.65 (dd, J = 14.0
and 9.0 Hz, 1H), 4.15–4.11 (m, 2H), 3.79–3.72 (m, 2H),
3.00–2.93 (m, 1H), 2.41–2.37 (m, 1H). 13C NMR (125 MHz,
CD3OD) δ 161.8, 140.4, 137.2, 129.8, 129.6 (2C), 129.5
(2C), 129.4, 70.9 (2C), 67.7, 60.7, 51.0, 45.1, 44.3. HRMS:
C16H20N3O5 calcd. for [M + H]+: 334.1397, found: 334.1399.
(1R,2S,3R,4S)-3-(Hydroxymethyl)-4-((4-(3-(trifluoro-
methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)cyclo butane-
1,2-diol (19c). Yield: 34%. White solid, mp 222–223 ꢀC.
20
1
½αꢁD + 22 (c 0.750, MeOH). H NMR (500 MHz, DMSO
d6) δ 8.67 (s, 1H), 8.14 (m, 2H), 7.68 (m, 2H), 5.10 (d, J =
5.0 Hz, 1H), 4.85 (d, J = 5.0 Hz, 1H), 4.68 (dd, J = 14.0 and
9.0 Hz, 1H), 4.61 (dd, J = 14.0 and 6.0 Hz, 1H), 4.44 (dd,
J = 5.0 and 4.5 Hz, 1H), 4.20 (m, 2H), 3.74–3.69 (m, 1H),
3.69–3.64 (m, 1H), 2.86–2.79 (m, 1H), 2.54–2.47 (m, 1H).
13C NMR (125 MHz, DMSO d6) δ 144.5, 132.0, 130.1,
129.6 (q, J = 32.0 Hz), 128.8, 125.2, 124.1, 122.4, 121.3,
68.4, 67.7, 57.3, 46.3, 41.6, 38.4. HRMS: C15H17F3N3O3
calcd. for [M + H]+: 344.1217, found: 344.1208.
(1R,2S,3R,4S)-3-(Hydroxymethyl)-4-((4-(hydroxyl-
methyl)-1H-1,2,3-triazol-1-yl)methyl) cyclobutane-1,2diol
(17c). Yield: 27%. White solid, mp 208–209 ꢀC. ½αꢁD20 + 104
(1S,2R,3R,4S)-3-(Hydroxymethyl)-4-((4-(3-(trifluoro-
methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)cyclo butane-
1,2-diol (19d). Yield: 41%. White solid, mp 178–179 ꢀC.
1
(c 1.450, MeOH). H NMR (500 MHz, CD3OD) δ 7.96 (s,
1H), 4.77 (dd, J = 14.0 and 9.5 Hz, 1H), 4.68 (s, 2H), 4.67
(dd, J = 14.0 and 5.5 Hz, 1H), 4.39–4.36 (m, 1H), 4.33–4.30
(m, 1H), 3.96–3.88 (m, 2H), 2.91–2.87 (m, 1H), 2.71–2.67
(m, 1H). 13C NMR (125 MHz, CD3OD) δ 148.8, 124.5,
70.5, 69.0, 59.2, 56.5, 47.4, 43.5, 39.9. HRMS: C9H16N3O4,
calcd. for [M + H]+: 230.1135, found: 230.1138.
20
1
½αꢁD − 28 (c 1.300, MeOH). H NMR (500 MHz, CD3OD)
δ 8.51 (s, 1H), 8.16 (s, 1H), 8.09 (dd, J = 4.0 and 3.0 Hz,
1H), 7.65 (m, 2H), 4.76 (dd, J = 14.0 and 7.5 Hz, 1H), 4.66
(dd, J = 14.0 and 9.0 Hz, 1H), 4.20–4.16 (m, 2H), 3.84–3.77
(m, 2H), 3.05–2.99 (m, 1H), 2.46–2.42 (m, 1H). 13C NMR
(125 MHz, CD3OD) δ 147.3, 133.0, 132.3 (q, J 32.2 Hz),
130.8, 130.1, 125.6 (d, J 3.7 Hz), 124.5, 123.2 (d, J 3.7 Hz),
123.0, 71.0, 70.9, 60.7, 50.8, 45.2, 44.4. HRMS:
C15H17F3N3O3 calcd. for [M + H]+: 344.1217, found:
344.1211.
(1S,2R,3R,4S)-3-(Hydroxymethyl)-4-((4-(hydroxyl
methyl)-1H-1,2,3-triazol-1-yl)methyl) cyclobutane-1,2diol
(17d). Yield: 33%. White solid, mp 165–166 ꢀC. ½αꢁD20 − 8
1
(c 2.800, MeOH). H NMR (500 MHz, CD3OD) δ 7.97 (s,
1H), , 4.69 (s, 2H), 4.68 (dd, J = 14.0 and 7.5 Hz, 1H), 4.58
(dd, J =14.0 and 9.0 Hz, 1H), 4.17 (dd, J = 6.0 and 3.0 Hz,
1H), 4.13 (dd, J = 6.0 Hz, 1H), 3.77 (m, 2H), 2.96–2.91 (m,
1H), 2.47–2.34 (m, 1H). 13C NMR (125 MHz, CD3OD) δ
149.0, 124.2, 70.9, 70.9, 60.7, 56.5, 50.5, 45.2, 44.4. HRMS:
(1S,2R,3S,4R)-3-((4-(3,5-Difluorophenyl)-1H-1,2,3-tria-
zol-1-yl)methyl)-4-(hydroxymethyl) cyclobutane-1,2-diol
(20c). Yield: 31%. White solid, mp 219–220 ꢀC. ½αꢁD20 + 95
1
(c 2.300, MeOH). H NMR (500 MHz, CD3OD) δ 8.43 (s,
Bull. Korean Chem. Soc. 2015, Vol. 36, 1390–1395
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Triazolo-Cyclobutane Nucleoside Analogs
KOREAN CHEMICAL SOCIETY
1H), 7.47–7.42 (m, 2H), 6.95–6.90 (m, 1H), 4.84 (dd, J = 14.0
and 9.5 Hz, 1H), 4.73 (dd, J = 14.0 and 6.0 Hz, 1H), 4.39 (ddd,
J = 7.0, 5.5 and 1.5 Hz, 1H), 4.34 (ddd, J = 6.0 and 2.0 Hz,
1H), 4.98–3.92 (m, 2H), 2.99–2.94 (m, 1H), 2.75–2.70 (m,
1H). 13C NMR (125 MHz, CD3OD) δ 165.9 (d, J = 13.0
Hz), 164.0 (d, J = 13.5 Hz), 146.4, 135.5 (t, J = 10 Hz),
123.8, 109.4 (d, J = 6.6 Hz), 109.2 (d, J = 6.6 Hz), 103.9 (t,
J = 26.0 Hz), 70.4, 69.1, 59.2, 47.8, 43.4, 40.0. HRMS:
C14H16F2N3O3 calcd. for [M + H]+: 312.1154, found:
312.1153.
effects have been observed between the proton of triazole's
ring and the N-CH2 proton, suggesting the 1,4-disubstituted
triazole with 1 proton which is close to this CH2 proton
(Figure 3).
cis-Hydroxylation of cyclobutene compounds 12–16 by
reaction with N-methylmorpholine N-oxide in the presence
of osmium tetroxide as catalyst led to a mixture of cis-a and
trans-isomers b (Scheme 3). The subsequent desilylation
without purification of the crude mixture provided a mixture
of triazolo-cyclobutane nucleoside analogs 17–20c and
17–20d, which were separated by chromatography on silica
gel (Table 2). The hydroxylated products of compound 16
could not be separated and purified properly by chromatogra-
phy on silica gel.
(1R,2S,3S,4R)-3-((4-(3,5-Difluorophenyl)-1H-1,2,3-tria-
zol-1-yl)methyl)-4-(hydroxymethyl) cyclobutane-1,2-diol
(20d). Yield: 39%. White solid, mp 182–183 ꢀC. ½αꢁD20 − 11
1
(c 1.650, MeOH). H NMR (500 MHz, CD3OD) δ 8.46 (s,
The structures of triazolo-cyclobutane nucleoside analogs
have been unequivocally assigned by NMR experiments.
The phase-sensitive NOESY experiments of trans-isomers
d showed correlations between H-3/H-6 and H-2/H-5. Similar
correlations were absent in cis-isomers c (Figure 4).
Compounds 17–20c and 17–20d were subjected to antimi-
crobial evaluation against E.coli, P.aeruginosa, B. subtillis,
S. aureus, A. niger, F. oxysporum, S. cerevisiae, and C. albi-
can, cytotoxicity in KB cells, VSV, HSV-1 and 2, HIV-1 and
2, and H5N1 virus. No significant activity was observed for
antimicrobial and antiviral activity. However, compounds
17d, 18d, 19c, 19d, and 20c showed moderate cytotoxic activ-
ity with IC50 of 39.6–52.4 μg/mL against KB cell lines
(Table 3, an anticancer agent ellipticine was used as positive
control).
1H), 7.47–7.42 (m, 2H), 6.95–6.90 (dddd, J = 9.0 and 2.0
Hz, 1H), 4.74 (dd, J = 14.0 and 7.0 Hz, 1H), 4.65 (dd, J =
14.0 and 9.0 Hz, 1H), 4.20–4.16 (m, 2H), 3.84–3.76 (m,
2H), 3.02–2.97 (m, 1H), 2.46–2.41 (m, 1H). 13C NMR
(125 MHz, CD3OD) δ 165.9 (d, J = 13.3 Hz), 163.9 (d, J =
13.3 Hz), 146.7, 135.4 (t, J = 10 Hz) 123.4, 109.4 (d, J =
6.6 Hz), 109.2 (d, J = 6.6 Hz), 104.0 (t, J = 25.9 Hz), 71.0
70.9, 60.7, 50.8, 45.1, 44.4. HRMS: C14H16F2N3O3 calcd.
for [M + H]+: 312.1154, found: 312.1148.
Results and Discussion
The starting material was the monoacetate 8 which is available
in high enantiomeric excess by an enzymatic acylation as pre-
viously described by Huet et al.13 Protection of this alcohol
as a silyl derivative followed by removal the acetyl group in
presence of NH3/MeOH gave the alcohol 9 in good yield
(Scheme 1). Treatment of 9 with methanesulfonyl chloride
and triethylamine afforded mesylate 10 in 85%. Nucleophilic
substitution of10withsodiumazideat55 ꢀCinDMFprovided
azide 11 in 82% isolated yield.
N
N
N
CuSO4.5H2O (20 mol%)
NaAsc (200 mol%)
OTBDPS
N3
TBDPSO
R
R
+
tBuOH/H2O 1/1, r.t.,12h
11
12-16
Scheme 2. Click reactions.
Azide 11 was subjected to azide-alkyne Huisgen cycloaddi-
tion reaction with various alkynes. The cycloaddition reaction
was carried out under different solvent systems such as EtOH,
EtOH:H2O (1:1), MeOH, MeOH:H2O (1:1), propanol, propa-
nol:H2O (1:1), BuOH and BuOH:H2O (1:1). The best result
was obtained after stirring the reaction mixture overnight at
Table 1. Click azide-alkyne cycloaddition.
Entry
R
Product
Yield %a
1
2
3
4
TBDPSO CH2
COOBn
m CF3C6H5
12
13
14
15
97
95
98
94
t
room temperature in BuOH:H2O (1:1) solvent system with
F
Cu(I) (CuSO4.5H2O and sodium ascorbate) as catalyst.
Applying this procedure, we successfully synthesized 1,2,3-
triazolocyclobutene 12–16 in good yields (Scheme 2 and
Table 1).
The regiochemistry of the azide-alkyne cycloaddition pro-
ducts was established by NOESY experiments. Strong NOE
F
5
-CH2-N-Boc
16
82
a Isolated yield.
CF3
OH
OTBDPS
OTBDPS
OMs
OTBDPS
a,b
c
d
82%
TBDPSO
N
85%
70%(2steps)
(ref 9)
4
N
8
9
10
11
OAc
>96.8% ee
OH
N
3
1
N
5
H
Scheme 1. Reagents and conditions: (a) tBuPh2SiCl, imidazole,
DMF; (b) NH3/MeOH; (c) MsCl, Et3N, CH2Cl2; (d) NaN3, DMF,
55 ꢀC.
14
Figure 3. NOESY correlation for 14.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1390–1395
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Triazolo-Cyclobutane Nucleoside Analogs
KOREAN CHEMICAL SOCIETY
N
N
N
N
N
N
N
TBDPSO
HO
HO
R
R
R
a
c
N
N
HO
HO
OH
OH
N
OsO , NMO
TBDPSO
4
TBAF
R
+
+
N
N
N
THF/H O
2
N
N
TBDPSO
R
12-15
b
d
HO
OH
HO
OH
Scheme 3. cis-Dihydroxylations and desilylations of 12–16.
Table 2. Synthesis of triazolo-cyclobutane nucleoside analogs.
References
Ratio
a/b
cis-
isomer c
trans-
isomer d
Yield %a
c/d
1. (a) V. E. Marquez, M. I. Lim, Med. Res. Rev. 1986, 6, 1;
(b) D. M. Huryn, M. Okabe, Chem. Rev. 1992, 92, 1745;
(c) L. A. Agrofoglio, E. Suhas, A. Farese, R. Condom, S. R.
Challand, R. A. Earl, R. Guedj, Tetrahedron 1994, 50, 10611;
(d) M. T. Crimmins, Tetrahedron 1998, 54, 9229; (e) J. B.
Rodriguez, M. J. Comin, Mini Rev. Med. Chem. 2003, 3, 95;
(f ) L. S. Jeong, J. A. Lee, Antivir. Chem. Chemother. 2004,
15, 235.
Entry Triazole
1
2
3
4
12
13
14
15
45/55
35/65
45/55
44/56
17c
18c
19c
20c
17d
18d
19d
20d
27/33
28/52
34/41
31/39
a Isolated yield.
2. W. Hugues, J. A. McDowell, J. Shenep, P. Flynn, M. W. Kline,
R. Yogev, W. Symonds, H. Lou, S. Hetherington, Antimicrob.
Agents Chemother. 1999, 43, 609.
CF3
CF3
3. J. A. V. Coates, H. J. Inggall, B. A. Pearson, C. R. Penn, R. Storer,
C. Williamson, J. M. Cameron, Antiviral Res. 1991, 15, 161.
4. S. F. Innaimo, M. Sieffer, G. S. Bisacchi, N. Standring,
R. Zahler, R. J. Colonno, Antimicrob. Agents Chemother.
1997, 41, 1444.
5. S. Hayashi, D. W. Norbeck, W. Rosenbrook, R. L. Fine, M. Mat-
sukura, J. J. Plattner, S. B. Broder, H. Mitsuya, Antimicrob.
Agents Chemother. 1990, 34, 287.
HO
N
HO
N
5
5
N
N
1
HO
H
1
N
N
4
4
H
HO
2
6
2
6
3
3
OH
H
19c
19d
H
OH
Figure 4. NOESY correlations for 19c and 19d.
6. (a) P. Borowski, M. Lang, A. Niebuhr, A. Haag, H. Schmitz,
J. Schulze zurWiesch, J. Choe, M. A. Siwecka, T.
Kulikowski, Acta Biochim. Pol. 2001, 48, 739; (b) S. Crotty,
C. E. Cameron, R. Andino, Proc. Natl. Acad. Sci. U.S.A.
2001, 98, 6895; (c) J. Y. Lau, R. C. Tam, T. J. Liang, Z. Hong,
Hepatology 2002, 35, 1002; (d) A. M. Contreras, Y. Hiasa, W.
He, A. Terella, E. V. Schmidt, R. T. Chung, J. Virol. 2002,
76, 8505.
7. (a) Y. Saito, V. Escuret, D. Durantel, F. Zoulim, R. F.
Schinazi, L. A. Agrofoglio, Bioorg. Med. Chem. 2003, 11,
3633; (b) P. Wang, L. Hollecker, K. W. Pankiewicz, S. E. Patter-
son, T. Whitaker, T. R. McBrayer, P. M. Tharnish, R. W.
Sidwell, L. J. Stuyver, M. J. Otto, R. F. Schinazi, K. A. Wata-
nabe, J. Med. Chem. 2004, 47, 6100; (c) R. Guezguez,
K. Bougrin, K. El Akri, R. Benhida, Tetrahedron Lett.
2006, 47, 4807; (d) K. El Akri, K. Bougrin, J. Balzarini, A. Faraj,
R. Benhida, Bioorg. Med. Chem. Lett. 2007, 17, 6656;
(e) U. Pradere, V. Roy, T. R. McBrayer, R. F. Schinazi, L. A.
Agrofoglio, Tetrahedron 2008, 64, 9044; (f ) J. Broggi, H.
Kumamoto, S. Berteina-Raboin, S. P. Nolan, L. A.
Agrofoglio, Eur. J. Org. Chem. 2009, 12, 1880; (g) A. Montagu,
V. Roy, J. Balzarini, R. Snoeck, G. Andrei, L. Agrofoglio,
Eur. J. Med. Chem. 2011, 46, 778; (h) M. Koszytkowska-Sta-
winska, E. Mironiuk-Puchalska, T. Rowicki, Tetrahedron
2012, 68, 214.
Table 3. Cytotoxic activity of triazolo-cyclobutane nucleoside
analogs.
C (μg/mL)
17d
18d
19c
19d
20c
Ellipticine
100
20
4
0.8
IC50
80.9
40.9
28.0
9.4
67.1
36.6
13.3
11.5
45.9
69.5
40.9
16.1
12.9
39.8
73.2
39.1
9.4
8.5
39.6
65.9
30.5
11.1
4.5
95.4a
66.8
15.7
−5.4
1.01
38.5
52.4
a % inhibition on KB cell lines.
Conclusion
In summary, several triazolo-nucleoside analogs were synthe-
sized by a short route involving the Huisgen 1,3-dipolar cyclo-
addition. Compounds 17d, 18d, 19c, 19d, and 20c showed
moderate cytotoxic activity against KB cell lines.
Acknowledgments. We thank the Vietnam National
Foundation for Science and Technology Development
(NAFOSTED) for financially supporting under project No.
104.01.91.09.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1390–1395
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
Article
Triazolo-Cyclobutane Nucleoside Analogs
KOREAN CHEMICAL SOCIETY
8. (a) M.-E. Gourdel, F. Huet, J. Org. Chem. 1997, 62, 2166; (b) M.-
E. Gourdel, F. Huet, Nucleosides Nucleotides 1999, 18, 645.
9. C. Hubert, C. Alexandre, A.-M. Aubertin, F. Huet, Tetrahedron
2002, 58, 3775.
10. (a) S. Danappe, F. Boeda, C. Alexandre, A.-M. Aubertin,
N. Bourgougnon, F. Huet, Synth. Commun. 2006, 36, 3225;
(b) S. Danappe, A. Pal, C. Alexandre, A.-M. Aubertin, N.
Bourgougnon, F. Huet, Tetrahedron 2005, 61, 5782.
11. Y. Marsac, A. Nourry, S. Legoupy, M. Pipelier, D. Dubreuil, A.-
M. Aubertin, N. Bourgougnon, R. Benhida, F. Huet, Tetrahe-
dron 2005, 61, 7607.
12. (a) R. Huisgen, Angew. Chem., Int. Ed. Engl. 1963, 2, 565;
(b) R. Huisgen, A. Padwa Eds., 1,3-Dipolar Cycloaddition
Chemistry, Vol. 1, Wiley, New York, 1984.
13. C. Pichon, C. Hubert, C. Alexandre, F. Huet, Tetrahedron:
Asymmetry 2000, 11, 2429.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1390–1395
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1395