Corey lactone as key precursor for a facile synthesis of novel 1,2,3-triazole carbocyclic nucleosides via Click Chemistry

Article abstract of DOI:10.1016/j.tetlet.2013.03.069

Corey lactone (2) and Click Chemistry allowed for an efficient and facile approach to the synthesis of novel 1,2,3-triazole carbocyclic nucleosides (11 and 17) in good overall yields.

Full text of DOI:10.1016/j.tetlet.2013.03.069

Tetrahedron Letters 54 (2013) 2726–2728
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Corey lactone as key precursor for a facile synthesis of novel 1,2,3-triazole
carbocyclic nucleosides via Click Chemistry
Carlos A. González-González a, Aydeé Fuentes-Benítez a, Erick Cuevas-Yáñez b, David Corona-Becerril b,
a,
Carlos González-Romero a, , Davir González-Calderón
⇑
⇑
a Departamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón/Paseo Tollocan s/n, Toluca, Estado de Mexico 50120, Mexico
b Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM, Toluca-Atlacomulco Km. 14.5, San Cayetano, Toluca, Estado de Mexico 50200, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Corey lactone (2) and Click Chemistry allowed for an efficient and facile approach to the synthesis of
novel 1,2,3-triazole carbocyclic nucleosides (11 and 17) in good overall yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 26 February 2013
Revised 11 March 2013
Accepted 15 March 2013
Available online 24 March 2013
Keywords:
Carbocyclic nucleosides
Click Chemistry
Corey lactone
Ribavirin (Fig. 1) was the first triazole nucleoside with a potent
broad-spectrum antiviral1 approved by the FDA for therapy against
Hepatitis C Virus (HCV), and is currently being used clinically
worldwide.2 The discovery of Ribavirin in 19721a sparked a new
burst in research for the design and synthesis of novel triazole
nucleosides,3 resulting in some compounds with promising
biological potential. For instance, recently reported ETCAR has
exhibited cytostatic activity,4 while TSAO has shown anti-HIV
activity.5
CONH2
CONH2
N
N
N
N
N
N
O
O
HO
HO
OH
Ribavirin
HO
HO
OH
ETCAR
R
N
Carbocyclic nucleosides (also named ‘carbonucleosides’ in short
form) are compounds in which a methylene group has replaced the
oxygen atom of the furanose ring. These compounds have potent
metabolic stability because they are unaffected by phosphorylase
and hydrolase enzymes that cleave the glycosidic bond of natural
nucleosides.6 For this reason, 1,2,3-triazole carbocyclic nucleosides
are peculiar compounds, and efforts by some research groups7
have led to interesting biological agents. For instance, compound
A has displayed activity against HIV-18 and compound B against
Vaccinia Virus, SARSCoV, and Cowpox Virus.9 Meanwhile, com-
pound C has shown a specific inhibitory potential against Varicella
Zoster Virus (TK+VZV).10
N
CONH2
N
N
N
O
N
TBSO
H2N
NH2
HO
OTBS
O
S
O
OH
A
TSAO
O
CONH2
N
N
N
N
OCH3
N
N
HO
HO
OH
HO
I
The emerging field of Click Chemistry (Pioneered by Huisgen11
and brought back by Sharpless12), involving the Cu alkyne-azide
cycloaddition (CuAAC), has become a powerful tool to obtain
1,2,3-triazoles which are well known as important biological
B
C
Figure 1. Representative bioactive triazole nucleosides and triazole carbocyclic
nucleosides.
agents.13 In last decade the use of Click Chemistry was explored
in the synthesis of 1,2,3-triazole nucleosides, nucleotides, and
oligonucleotides.14
⇑
Corresponding authors. Tel.: +52 722 2175 109x113; fax: +52 722 2173 890.
E-mail addresses: cgonzalezr@uaemex.mx (C. González-Romero), qfb_dgonzale-
z@yahoo.com.mx (D. González-Calderón).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.069

C. A. González-González et al. / Tetrahedron Letters 54 (2013) 2726–2728
2727
Ph
O
O
N
N
HO
OR1
O
OTBS
OTBS
O
N
x
OR2
OTBS ix
OTBS
OTBS
OTBS
vii
v
i
HO
OR2
OTBS
RO
viii
N3
R1O
THPO
vi
1
HO
Corey Lactone
10
11
8, R= H
6
, R1= R2= H
2
3
4
5
, R1= R2= Ac
9
, R= Ts
7
, R1= R2= TBS
ii
iii
iv
, R1= R2= H
, R1= H, R2= TBS
, R1= THP, R2= TBS
Ph
N
N
O
O
N3
OR1
N
OR2
OTBS
HO
HO
xv
xvi
xii
xi
3
OTBS
OTBS
OTBS
TBSO
TBSO
TBSO
12
17
16
13, R1= R2= H
14, R1= H, R2= TBS
15, R1= Ts, R2= TBS
OH
xiii
xiv
Scheme 1. Reagents and conditions: (i) paraformaldehyde, AcOH, H2SO4, 80 °C, 24 h, 70%; (ii) DBN, MeOH, rt, 12 h, 80%; (iii) TBSCl, Im, DMF, rt, 8 h, 75%; (iv) DHP, p-TsOH
anh, DCM anhyd, rt, 1 h, 98%; (v) LAH, THF anhyd, rt, 4 h, 84%; (vi) TBSCl, Im, DMF, rt, 12 h, 88%; (vii) Me2AlCl, DCM anhyd, rt, 3 h, 82%; (viii) TsCl, Py, rt, 24 h, 85%; (ix) NaN3,
DMF, MW, 150 °C, 15 min, 85%; (x) CuSO4ꢁ5H2O, MeOH, 50 °C, 8 h, then, CuI, phenylacetylene, NaOH aq 0.5 M, 50 °C, overnight, 73%; (xi) TBSCl, Im, DMF, rt, 12 h, 90%; (xii)
LAH, THF anhyd, rt, 4 h, 78%; (xiii) TBSCl, Im, DMF, rt, 8 h, 70%; (xiv) TsCl, Py, rt, 24 h, 80%; (xv) NaN3, DMF, MW, 150 °C, 15 min, 80%; (xvi) CuSO4ꢁ5H2O, MeOH, 50 °C, 8 h, then,
CuI, phenylacetylene, NaOH aq 0.5 M, 50 °C, overnight, 70%.
Hence, in our pursuit of new strategies for producing 1,2,3-tri-
azole carbocyclic nucleosides, we herein report a new simple route
were unsuccessful. Therefore, we decided to use the tosyl-azida-
tion procedure. Alcohols 8 and 14 were treated with p-toluenesul-
fonyl chloride (TsCl) in pyridine (Py). Crude tosylates22 were
successfully purified by column chromatography to obtain the cor-
responding tosylates 9 and 15 (in 85% and 80% yields, respectively).
Replacement of the tosyl group (9 and 15) by introduction of an
azide group (NaN3 in dry DMF) was possible with a microwave-as-
sisted reaction (150 °C, 15 min) leading to compounds 10 and 16
(in 75% and 80% yields, respectively). On the other hand, there
were not any reactions at room temperature, and sluggish reac-
tions were observed (ꢀ60%) when using conventional heating
(100 °C, 24 h). Since temperature seemed to be the main limiting
factor in the aforementioned methods;18–21 Shioiri’s method was
carried out with MW (150 °C, 15 min), resulting in a complete reac-
tion (67% yield). Purification of tosylates was crucial; reaction with
crude tosylates gave low yields (>30%).
Recently our collaborative research group reported a novel
method for triazole formation through Click Chemistry.23 Depro-
tection of silyl protecting groups and CuAAC of substrates 10 and
16 were subjected to a one-pot system. Firstly, silyl ethers (10
and 16) were treated with CuSO4ꢁ5H2O in methanol at 50 °C until
total deprotection of silyl groups was observed (monitored by
TLC). Then, CuI, phenylacetylene and NaOH aq 0.5 M were added
and the mixture reactions were stirred at 60–65 °C overnight.
The corresponding 1,2,3-triazole carbocyclic nucleosides 11 and
17 were achieved in good yields (73% and 70% respectively). The
regiochemistry and structure of the target compounds (11 and
17) were assigned by 1D and 2D NMR techniques (1H, 13C, DEPT,
COSY, HETCOR and NOESY experiments).
for the synthesis of novel
and b-
a-D
-20-deoxy-homocarbanucleoside (11)
L
-20-deoxy analog (17) via Click Chemistry (Scheme 1). Fur-
thermore, we propose Corey lactone15 as the key precursor, being
an excellent supplier of the required pseudosugar ring (cyclopen-
tane) that allows for the high stereospecific configuration of all
suitable functional groups.
The Corey lactone bis-acetate 2 was prepared in one step from
commercially available unsaturated lactone 1 by stereospecific
Prins Reaction according to the Tömösközi’s method.16 Structural
confirmation for 2 was determined by 2D NMR techniques (COSY
and HETCOR spectrum). This reaction led to a compound with four
required and highly defined stereocenters along with two carbonyl
functionalities. Transesterification of 2 by treatment with DBN in
MeOH gave the corresponding Corey lactone diol (3) in 80% yield.
Diol 3 became the key intermediate and provided two pathways
for the synthesis of triazole carbocyclic nucleosides.
The strategic protection of hydroxyl groups with tert-butyldi-
methylsilyl chloride (TBSCl) played an important role in the syn-
thesis. The conversions of alcohols (3, 6, and 13) to silyl ethers
(4, 7, 12, and 14) were achieved using TBS and imidazole (Im) in
dry DMF with good yields (75, 88, 90, and 70%, respectively). The
use of TBS allowed for the selective protection of primary over sec-
ondary alcohols. On the other hand, acid-catalyzed protection of
hydroxyl lactone 4 with dihydropyrane (DHP) in the presence of
p-TsOH catalyst afforded the tetrahydropyranyl (THP) ether 5 in
excellent yield (98%) within 1 h. Lactones 5 and 12 were reduced
by employing LiAlH4 in dry THF, furnishing the corresponding
dioles 6 and 13 in 84% and 78% yields, respectively. Selective
deprotection of THP ether 7 was attained by employing dimethyl
aluminum chloride (Me2AlCl) according to Shibasaki’s method.17
Alcohol 8 was isolated in 82% yield.
In summary, we have developed the first approach to the syn-
thesis of 1,2,3-triazole carbocyclic nucleosides
(a-D
-20-deoxy-
homocarbanucleoside 11 and b-L
-20-deoxy analog 17) from Corey
lactone.
For introduction of the azide group into a pseudosugar ring (8
and 14), we tested some methods for the one-pot conversion of
alcohols to azides, including the procedures by Gómez-Vidal and
Silverman (DPPA, DEAD, THF, 0 °C —Mitsunobu Reaction—),18
Thompson et al. (DPPA, DBU, toluene, rt),19 Mizuno and Shioiri
(p-NO2DPPA, DBU, toluene, rt),20 and Gouin-Kovensky (NaN3,
PPh3, CBr4, DMF, rt).21 Unfortunately the aforementioned methods
Acknowledgments
Financial support from UAEMéx (project No.2441) and CONA-
CyT (postgraduate scholarship) is gratefully acknowledged. The
authors would like to thank the referee and S. Jaime-Figueroa
(Roche, USA) for his valuable comments and suggestions,

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