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B. Bhatt et al. / Tetrahedron Letters 52 (2011) 2741–2743
Herein we describe the synthesis of a series of triazole-contain-
the C-1 bromide by azide providing the key C-1 azide derivative 11
in 73% yield. Importantly, each step in Scheme 1 was optimized to
obtain 11 from 5, in a reaction sequence amenable to scale-up for
generating a library of 10-homo-N-nucleoside mimetics.
Having established an efficient synthesis of the versatile build-
ing block 11, we next examined the model copper-catalyzed ‘click’
reaction between unprotected azide 11 and the alkyne, 2-ethynyl-
pyridine, in aqueous isopropanol (Scheme 2). The reaction went
smoothly, however, purification of triazole derivative 12 proved
problematic and the triazole product was isolated in 34% yield
only, with some impurities still present.
With compound 12, aqueous work-up was not possible and
even column purification was problematic. Therefore, acetylation
of 1-azido derivative 11 was carried-out using standard acetylation
conditions (Ac2O, pyridine) to give pure acetylated derivative 13 in
90% yield (Scheme 3). The tri-O-acetylated C-1 azide 13 was then
utilized as the starting material for ‘click’ chemistry with different
alkynes to prepare a series of 18 differently substituted triazole
derivatives 14a–r (Table 1).
The triazole derivatives were obtained in excellent yields gener-
ally after purification. The only exception was the synthesis of
compound 14l, with the free amino group on the alkyne, which re-
sulted in formation of a complex mixture. Subsequently, the 3,4,6-
tri-O-acetylated triazole derivatives 14a–l were deacetylated using
1 M sodium methoxide solution at room temperature. As indicated
by TLC analysis, the reaction in each case was complete within
15 min and the final products 15a–l (Table 1) were obtained in
yields ranging from 71% to 89%.
It was found that the triazole derivatives with large hydropho-
bic substituents on the triazole ring (e.g., 15a and 15b) had limited
aqueous solubility. It was anticipated that the introduction of a
charged moiety at the primary C-6 hydroxy group on the carbohy-
drate residue would improve this solubility. Furthermore, it was
thought that O-sulfation at C-6 would introduce an appropriate
negative charge that would in part mimic the corresponding 6-O-
phosphate group of nucleosides. Therefore, selective sulfation of
the C-6 hydroxy group of the triazole derivatives was performed
using sulfur trioxide–pyridine complex.24 By way of example, com-
pound 15a was treated with two molar equivalents of sulfur triox-
ide–pyridine complex in anhydrous pyridine solution for 12 h
ing 10-homo-N-nucleoside mimetics (Fig. 1) based on the 2,5-anhy-
dro-glucitol scaffold of general structure 3 utilizing azide–alkyne
‘click’ chemistry.15 We chose a 2,5-anhydro-glucitol template,
where the stereochemistry at C-3 (equivalent to C-2 of the ribose
unit of the RNA nucleosides 1) is reversed from the natural config-
uration. With the glucitol stereochemistry at C-3/C-4, introduction
of modifications at these position should be simple, for example,
through epoxide formation,16 including inversion of the C-3 config-
uration to give the ribose-based mimetic. Our preference for the
five-membered heterocycles, 1,2,3-triazoles, was based on a num-
ber of factors including their higher stability toward acidic and ba-
sic hydrolysis as well as harsh reductive/oxidative conditions.15 It
is also known that triazoles are capable of actively participating
in hydrogen bonding, as well as dipole–dipole and
p-stacking
interactions.17 Moreover, the apparent general antiviral activity
of ribavirin (4), which is a 1,2,4-triazole-containing nucleoside,18
provides a further validation for the preparation of 10-homo-N-
nucleoside mimetics bearing a triazole moiety. A ribavirin-based
10-homo-N-nucleoside has also been reported, although to the best
of our knowledge, no biological data has been published to date.19
Our initial study toward the preparation of 10-homo-N-nucleo-
side mimetics 3 involved the synthesis of the 2,5-anhydro-glucitol
derivative with a C-1 azide. The C-1 azide building block could then
undergo a 1,3-dipolar cycloaddition with substituted alkynes pos-
sessing lipophilic, hydrophilic, acidic or basic functionalities. The
synthesis of 1-azido-2,5-anhydro-glucitol is shown in Scheme 1.
The key intermediate 1,2:5,6-dianhydro-3,4-di-O-benzyl-
mannitol 8 was prepared from commercially available 1,2:5,6-di-
O-isopropylidene- -mannitol (5), as described by Le Merrer
D-
D
et al.20 Based on the work of Kuszmann in which brominated hex-
itols were prepared from protected 1,2:5,6-bisepoxides,21 com-
pound 8 was then treated with HBr in acetic acid to afford 1-
bromo-2,5-anhydro-glucitol intermediate 9 (Scheme 1) through
2,5-O-heterocyclization. The high regioselectivity of the O-hetero-
cyclization in favor of the 5-exo-tet process22,23 leads to ring clo-
sure at the more substituted atom of the second epoxide
resulting in the facile formation of 2,5-anhydro-D-glucitol 9. Thus,
the intermediate 1-bromo-glucitol derivative 9 could be readily
synthesized from the commercially available starting material 5
in 45% yield over seven steps. Successful de-O-benzylation was
achieved by treatment of 9 with formic acid in the presence of
Pd/C under a hydrogen gas atmosphere and resulted in the isola-
tion of the desired deprotected 1-bromo derivative 10 in a satisfac-
tory 87% yield. This was followed by nucleophilic displacement of
Scheme 2. Reagents and conditions: (a) 2-ethynylpyridine, CuSO4ꢀH2O, sodium
ascorbate, iPrOH:H2O, 40–50 °C, 1 h (34%).
O
O
a
b
R
R2O
R2O
N
N3
11
N
N
R1O
OR1
R1O
OR1
13
14
c
O
S
O
O
d
R
R
N
HO
O
N
HO
Scheme 1. Reagents and conditions: (a) (i) NaOH (50% aq soln), BnBr, nBu4NI, THF,
50–60 °C, 12 h (90%); (ii) 70% AcOH, 55 °C, 1.5 h (88%; 79% over two steps); (b) (i)
TBDMSCl, DMAP, imidazole, pyridine, 0 °C rt, 2 h, N2; (ii) MsCl, Et3N, CH2Cl2, 0 °C,
15 min, N2; (c) (i) HCl, MeOH, 0–20 °C, 2 h; (ii) KOH (20% aq soln) 0–20 °C, 3 h; (d)
33% w/v HBr in glacial AcOH, acetone, 0 °C, 30 min, N2 (57% over five steps from 6);
(e) Pd/C, HCOOH, MeOH, H2, rt, 2 h, (87%); (f) NaN3, DMF:H2O, 90–100 °C, 12 h,
(73%).
N
N
O
N N
HO
OH
HO
OH
16
15
Scheme 3. Reagents and conditions: (a) Ac2O, pyridine, rt, 3 h, N2 (90%); (b) alkyne,
CuSO4ꢀH2O, sodium ascorbate, iPrOH:H2O, 40–50 °C, 2 h; (c) NaOMe (1 M), MeOH,
rt, 15 min; (d) SO3ꢀpyridine complex, pyridine, 0–4 °C, 16 h.
Bhatt, Beenu
