Deprotection of α-imidazole/benzimidazole ribonucleosides by catalytic carbon tetrabromide initiated photolysis

Article abstract of DOI:10.1016/j.tetlet.2005.09.180

Several protected benzimidazole and imidazole α-ribonucleosides were deprotected in excellent yield at ambient temperature using CBr₄ initiated photolysis in methanol at ambient temperature. No selectivity was observed and both trityl and isopr

Full text of DOI:10.1016/j.tetlet.2005.09.180

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8617–8619
Deprotection of a-imidazole/benzimidazole ribonucleosides
by catalytic carbon tetrabromide initiated photolysis
Tilak Chandra and Kenneth L. Brown*
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701-3132, USA
Received 12 July 2005; revised 31 August 2005; accepted 1 September 2005
Available online 14 October 2005
Abstract—Several protected benzimidazole and imidazole a-ribonucleosides were deprotected in excellent yield at ambient temper-
ature using CBr4 initiated photolysis in methanol at ambient temperature. No selectivity was observed and both trityl and isoprop-
ylidene groups were deprotected under the reaction conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
5,6-Dimethyl-a-D-ribofuranosylbenzimidazole,1 the low-
er axial ligand in coenzyme B12 plays an as yet unknown
role in the enzymatic activation of coenzyme B12 for car-
bon–cobalt bond homolysis. We have consequently pur-
sued cobalamins with altered axial nucleosides in order
to investigate the role, if any, of the axial base. Although
some B12 analogues can be prepared by guided biosyn-
thesis,2 using fermentation of certain bacteria, many
important derivatives require semi-synthesis/partial syn-
thesis. Semi-synthesis of cobalamins3–5 with altered axial
nucleotide ligands is best achieved by coupling cobyric
acid6,7 with a suitable ribonucleoside phosphodiester.
The synthesis of such phosphodiesters requires several
steps, including selective glycosylation to make ribo-
nucleosides in the a-configuration,8–11 protection and
deprotection. We have recently reported the synthesis
of indoline and dimethylindoline ribonucleosides10 in
the a-configuration using 2-fluoro-1-methylpyridinium
tosylate as a condensing reagent.11 Deprotection of these
unstable a-nucleosides8–11 while retaining the a-configu-
ration is crucial. Trityl (Tr), dimethoxytrityl (DMTr) and
isopropylidene groups are commonly used for the pro-
tection of the 5-hydroxyl and 2,3-hydroxyl groups in
both carbohydrate and nucleoside chemistry.12 For a-
ribonucleosides, protection of the 20, 30, and 50 positions
is required for selectivity in the glycosylation reaction.
Strong acids such as formic acid13 and trifluoroacetic
acid (TFA)14 are typically used for the deprotection of
trityl and isopropylidene groups. Most of these methods
suffer from low yields and the use of strongly acidic con-
ditions, which can cause deglycosylation or decomposi-
tion of a-ribonucleosides.
While trityl and dimethoxytrityl ethers are selectively
deprotected to the corresponding alcohols by CBr4 in
methanol at reflux under neutral reaction conditions,15
at these temperatures imidazole ribonucleosides isomer-
ize from the a- to the b-anomer. In this letter, we report
a mild and highly efficient deprotection of trityl and
isopropylidene protecting groups without any deglycos-
ylation or anomerization, in high yield using sub-
stoichiometric amounts of carbon tetrabromide. Thus,
a-ribonucleosides of imidazole and benzimidazole were
readily deprotected by photoirradiation using catalytic
carbon tetrabromide (CBr4) in methanol at ambient
temperature. Although selective deprotection of trityl
versus isopropylidene groups of b-ribonucleosides and
sugars has been achieved using photolysis,16 the present
photolysis protocol shows no selectivity in trityl/isoprop-
ylidene deprotection for the a-ribonucleosides.
The photolysis reactions were carried out in glass vials
using a high pressure Xe–Hg photolysis lamp (254 nm
principal wavelength) for 30 min–1.0 h at ambient tem-
perature (Scheme 1). Complete conversion of the start-
ing material was confirmed by TLC (methanol/
methylene chloride 8:2) as well as 1H NMR. After com-
pletion, the methanol was removed under reduced pres-
sure, and water (10 mL) and methylene chloride (10 mL)
were added. After stirring for 10 min, the aqueous layer
was separated and evaporated under reduced pressure to
afford a viscous oil containing the desired compound in
*
Corresponding author. Tel.: +1 740 5931773; fax: +1 740 593
0148; e-mail: brownk3@ohio.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.180

8618
T. Chandra, K. L. Brown / Tetrahedron Letters 46 (2005) 8617–8619
B
O
H
O
TrO
O
TrO
TrO
(a)
OH
+
B
O
O
O
O
O
O
H3C
CH3
H3C
CH3
H3C
CH3
6, B = benzimidazole
2, B = benzimidazole
1
7, B = 5,6-dimethylbenzimidazole
8, B = 4-bromoimidazole
9, B = imidazole
3, B = 5,6-dimethylbenzimidazole
4, B = 4-bromoimidazole
5, B = imidazole
B
O
H
HO
O
HO
(b)
[2-4 or 6]
or
B
O
O
OH
HO
H3C
CH3
13, B = benzimidazole
10, B = benzimidazole
11, B = 5,6-dimethylbenzimidazole
12, B = 4-/5-bromoimidazole
Scheme 1. Preparation and deprotection of a-benzimidazole and imidazole ribonucleosides by photoirradiation. Reagents and conditions: (a) TMS-
protected benzimidazole/imidazole bases, 2-fluoromethyl pyridinium tosylate, DIEA, methylene chloride, ꢀ30 °C to 0 °C. (b) Methanol, carbon
tetrabromide, 20 °C, photolysis.
B
O
H
O
HO
HO
CBr4, methanol, reflux
+
B
[2-4 or 6]
OH
OH
HO
HO
10, B = benzimidazole
14, B = imidazole or
11, B = 5,6-dimethylbenzimidazole
12, B = 4-bromoimidazole
15, B = 4-bromoimidazole
Scheme 2. Deprotection of a/b-benzimidazole and imidazole ribonucleosides by carbon tetrabromide at reflux temperature.
Table 1. Photolysis reaction conditions and yields
excellent yield. Increasing the amount of carbon tetrabr-
omide from 0.05 to 0.5 equiv decreased the reaction time
H
H
O
O
TrO
HO
photolysis
but also decreased the observed yield (Table 1). b-Ribo-
nucleosides of benzimidazole, dimethylbenzimidazole
and 2,3-O-(1-methylethylidene)-5-O-(triphenylmethyl)-
a/b-D-ribofuranose17 were also deprotected under
similar conditions in yields of 80%, 85% and 80%,
respectively.
B
B
B = benzimidazole
O
OH
O
HO
B = dimethylbenzimidazole
B = 4-bromoimidazole
B = imidazole
H3C
CH3
CBr4 Reaction time Yield (%)b
a
S. No. Reactant (B)
1
2
3
4
5
6
7
8
a-Benzimidazole
a-Benzimidazole19
a-5,6-DMBzc
0.05
0.5
0.05
0.5
1.0 h
20 min
1.0 h
10–20 min
50 min
1.0 h
95
75–80
98
75
86
90
85
85
In contrast, deprotection of the a-ribonucleosides of
imidazole and 4-bromoimidazole with excess carbon
tetrabromide (1–3equiv) at reflux in methanol ( Scheme
2) produced mixtures of a- and b-anomers (Table 2).
These reactions take 5–6 h for complete removal of trityl
and isopropylidene groups. With less carbon tetrabro-
mide, the reaction is very sluggish and complete depro-
tection takes 10–12 h. However, in the case of the
benzimidazole and 5,6-dimethylbenzimidazole a-ribonu-
cleosides, we observed only 5% anomerization under
reflux conditions, possibly due to the more bulky bases
compared to the imidazole and 4-bromoimidazole
a-ribonucleosides.
a-5,6-DMBzc
a-Imidazole
a-4-Bromoimidazole 0.05
0.05
b-Benzimidazole
0.05
0.05
1.0 h
1.0 h
b-5,6-DMBzc
a Equiv of CBr4.
b Isolated yields.
c 5,6-DMBz = 5,6-dimethylbenzimidazole.
1-methylpyridinium tosylate as a condensing reagent.18
Both corresponding a- and b-ribonucleosides can be
easily separated by repeated flash silica gel chromato-
graphy and the structure and anomeric configurations
of these ribonucleosides were established by 2D NMR
spectroscopy (COSY, HMQC and NOESY).
a-Ribonucleosides of imidazole and benzimidazole can
be prepared by coupling their corresponding TMS pro-
tected bases with 2,3-O-(1-methylethyledene)-5-O-(tri-
phenylmethyl)-a/b-D-ribofuranose17 by using 2-fluoro-

T. Chandra, K. L. Brown / Tetrahedron Letters 46 (2005) 8617–8619
8619
Table 2. Reaction conditions and yields under reflux conditions in methanol and carbon tetrabromide
H
O
TrO
B
H
O
HO
O
HO
CBr4, methanol
reflux temp
+
B
B
O
O
OH
HO
OH
HO
H3C
CH3
a
S. No.
Reactant (B)
CBr4
Reaction time (h)
Yield a-anomer (%)b
Yield b-anomer (%)b
1
2
3
4
5
6
a-Benzimidazole
a-Benzimidazole
a-5,6-DMBzc
a-5,6-DMBzc
a-Imidazole
1–2
0.5
2
0.5
2
5–6
10–12
5–6
10–12
4–5
95
85
75
0
5
0
5
30
70–80
60–70
20
a-4-Bromoimidazole
34–5
80
a Equiv of CBr4.
b NMR yields.
c 5,6-DMBz = 5,6-dimethylbenzimidazole.
14. MacCoss, M.; Cameron, D. J. Carbohydr. Res. 1978, 60,
206–209.
Acknowledgements
15. Yadav, J. S.; Reddy, B. V. S. Carbohydr. Res. 2000, 329,
885–888.
16. Chen, M. Yi.; Patkar, L. N.; Jan, M.-D.; Lee, Adam S.-Y.;
Lin, Chun-C. Tetrahedron Lett. 2004, 45, 635–639.
17. Cousineau, T. J.; Secrist, J. A., III. J. Org. Chem. 1979, 44,
4351–4358.
This research was supported by the National Institute of
General Medical Sciences, Grant GM 48858.
References and notes
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19. (a-D-Ribofuranosyl)benzimidazole (10): A solution of
1-(5-O-triphenylmethyl-2,3-O-isopropylidene-a-D-ribofur-
anosyl)benzimidazole (60 mg, 0.107 mmol), and carbon
tetrabromide (0.05 equiv) in methanol (1 mL) was photo-
lysed using a high pressure Xe–Hg photolysis lamp
(254 nm principal wavelength) for 30 min–1.0 h with
completion of reaction being monitored by TLC. After
completion, the methanol was removed under reduced
pressure and the residue was dissolved in water (5 mL) and
washed thoroughly with methylene chloride to remove the
triphenylmethanol and carbon tetrabromide. The aqueous
layer was separated and concentrated under reduced
pressure afforded viscous oil in 90% yield. 1H NMR
(D2O): d 3.86 (dd, J = 4.7. 8.0 Hz, 1H, 50), 3.98 (dd,
J = 2.6, 10.0 Hz, 1H, 50), 4.49 (t, J = 4.7 Hz, 1H, 30), 4.55
(q, 1H, 40), 4.85 (t, J = 4.7 Hz, 1H, 20), 6.60 (d, J = 4.7 Hz,
1H, 10), 7.60–7.64 (m, 2H, Ar), 7.75 (dd, 1H, Ar), 7.81 (dd,
1H, Ar), 9.39 (s, 1H, imidazole); 1H NMR (CD3OD): d
3.72 (dd, J = 4.05. 8.5 Hz, 1H, 50), 3.81 (dd, J = 3.24,
9.39 Hz, 1H, 50), 4.34 (t, J = 4.5 Hz, 1H, 30), 4.44 (q, 1H,
40), 4.73(t, J = 5.27 Hz, 1H, 20), 6.55 (d, J = 5.2 Hz, 1H,
10), 7.59–7.62 (m, 2H, Ar), 7.79–7.81 (m, 1H, Ar), 7.91–
7.93(m, 1H, Ar), 9.52 (s, 1H, imidazole); 13C NMR
(D2O): d 63.78 (CH2, 50), 73.33 (30), 74.10 (20), 88.22 (40),
90.21 (10), 115.61 (CH), 117.15 (CH), 129.35 (CH), 129.62
(CH), 132.58 (Cquat), 132.83 (Cquat), 142.17 (CH);
HRMS: m/z: 251.1031 (calcd for C14H15N2O4; 251.1026)
(M+H); MS: (FAB) m/z 253, 251, 133, 120.