Preparation of nucleosides derived from 2-nitroimidazole and d -arabinose, d -ribose, and d -Galactose by the Vorbrueggen method and their conversion to potential precursors for tracers to image hypoxia

Article abstract of DOI:10.1021/jo200727k

2-Nitroimidazole was silylated using hexaethyldisilazane and then reacted with 1-O-acetyl derivatives of d-arabinose, d-ribose, and d-galactose in acetonitrile at mild temperatures (-20 °C to rt), catalyzed by triethylsilyl triflate (Vorbrueggen condition

Full text of DOI:10.1021/jo200727k

ARTICLE
pubs.acs.org/joc
Preparation of Nucleosides Derived from 2-Nitroimidazole and
€
D-Arabinose, D-Ribose, and D-Galactose by the Vorbruggen
Method and Their Conversion to Potential Precursors for
Tracers To Image Hypoxia
Anna Schweifer and Friedrich Hammerschmidt*
Institute of Organic Chemistry, University of Vienna, W€ahringerstrasse 38, A-1090 Vienna, Austria
S Supporting Information
b
ABSTRACT: 2-Nitroimidazole was silylated using hexaethyldisilazane and then
reacted with 1-O-acetyl derivatives of D-arabinose, D-ribose, and D-galactose in
acetonitrile at mild temperatures (ꢀ20 °C to rt), catalyzed by triethylsilyl triflate
(Vorbr€uggen conditions). The α-anomer was formed in the former case and the β-
anomers in the latter two cases (highly) selectively. When D-arabinose and D-ribose
were silylated with tert-butyldiphenylsilyl chloride in pyridine at the hydroxyl
groups at C-5 and acetylated at the other ones in a one-pot reaction, mixtures of
anomeric 1-O-acetyl derivatives were obtained. These were coupled by the Vorbr€uggen method and then deblocked at C-5 and
tosylated to give precursors for tracers to image hypoxia in four steps without using Hg(CN)2 necessary for other methods. The
Vorbr€uggen conditions enable a shorter route to azomycin nucleoside analogues than the previous coupling procedures.
’ INTRODUCTION
A large body of evidence indicates that tumor hypoxia has a
negative prognosis predictive value for solid tumor progression,
likeliness of metastasis and tumor prognosis, likeliness of metas-
tasis, and overall survival.1ꢀ3 In addition, tumor cell hypoxia has a
negative effect on anticancer treatment because of resistance to
radiation.4,5 Accordingly, it is important to identify and localize
tumor hypoxia in the management and treatment of cancer
patients. Contrary to invasive methods based on the oxygen
electrode system6 to determine the oxygenation distribution in
the tumor, noninvasive ones7,8 are based on imaging using
radiolabeled (123I, 124I, 125I, 18F, 60Cu, 62Cu, 64Cu) tracers
1ꢀ6 (Figure 1), preferably 18F-labeled 2-nitroimidazoles. The
tracer's primary cellular uptake results from diffusion and parti-
tion-based retention in lipophilic tissue.
The 2-nitroimidazole (azomycin)-based tracers are thought to
be reduced in hypoxic cells to reactive intermediates, which bind
to macromolecular components. Thus, they tend to be accumu-
lated in sites of hypoxia and can be used for imaging purposes
with single-photon-emission tomography (SPECT) and posi-
Figure 1. Radiolabeled tracers for imaging hypoxia.
More recently, the fluoroazomycin arabinoside α-[18F]FAZA
tron emission tomography (PET), the latter being the method of
choice. Indeed, a number of radiotracers for viable hypoxic cells
(5) has been studied extensively alone and relative to FMISO.15
in solid tumors are being evaluated clinically.9 The initial imaging
studies of tumor hypoxia used iodine-123-labeled iodoazomycin
arabinoside (α-IAZA, 4) with SPECT10 and fluorine-18-labeled
fluoromisonidazole (FMISO, 1) with PET.11,12 Recently,
[18F]fluoroerythronitroimidazole ([18F]FETNIM, 2) was stu-
died as a hypoxia imaging agent.13 The copper complex copper-
(II) diacetylbis(N4-methylthiosemicarbazone) (Cu-ATMS, 3)
labeled with the positron emitter 60Cu, 62Cu, or 64Cu is another
promising hypoxic imaging agent under evaluation.14
It was found that α-[18F]FAZA and [18F]FMISO are taken up
selelctively in vitro and in vivo in hypoxic cells.16 Machulla et al.
observed that α-[18F]FAZA shows biokinetics superior to
that of [18F]FMISO and is, thus, a promising PET tracer for
visualization of solid tumor hypoxia. The 125I- and 124I-labeled
Received: April 7, 2011
Published: September 09, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis of α-[18F]FAZA
Scheme 2. Synthesis of Hexaethyldisilazane and Its Use for
the Triethylsilylation of 2-Nitroimidazole
2-nitroimidazole β-D-galactosides 6 were used to image tumor
hypoxia in mice.17 As the uptake of α-[18F]FAZA is diffusion
controlled and its renal clearance is rapid, it is still attractive to
prepare other 2-nitroimidazole nucleosides and evaluate them as
precursors for tracers to image hypoxia. To improve the tumor/
background ratio of tracers, their active transport by cellular transport
systems such as nucleoside transporters could be exploited. Emami
et al. have established a yeast system for testing the transport of
fluoroazomycin nucleosides by four nucleoside transporters, which
might help to find better tracers than α-[18F]FAZA.18
Scheme 3. Preparation of D-Arabinofuranose Derivative 14
and Its Coupling with NI-TES by the Vorbru€ggen Method
Tracer 5 most favored at present for imaging hypoxia is
prepared from precursor α-7 by a substitution reaction (SN2)
with cyclotron-generated 18Fꢀ in combination with Kryptofix
2.2.2, followed by base-catalyzed removal of acetyl groups
and HPLC purification (Scheme 1). The 2-nitroimidazole
nucleosides underlying tracers 4, 5, and 6 are formed by a
K€onigsꢀKnorr reaction of 2-nitroimidazole or in some cases
its trimethylsilylated species in acetonitrile at 50ꢀ60 °C with a
benzoyl- or an acetyl-protected D-1-bromofuranose or D-1-bromo-
pyranose derivatives of D-arabinose or D-galactose, respec-
tively. Normally, excess Hg(CN)2 (2.2 equiv), sometimes in
combination with SnCl4, was used as a catalyst.19ꢀ21 This
method was used by Schneider et al. to prepare a number of
2-nitroimidazole nucleosides, two of which were converted to
radioiodinated tracers. When we started this project to prepare
known and new precursors for tracers to image hypoxia, we
decided to search for an alternative to the K€onigsꢀKnorr
procedure not involving metal salts, especially toxic Hg(CN)2.
Ideally, the method should use easily accessible starting materials
with an adequately silylated hydroxyl group at C-5 and acetyl
groups for the other hydroxyls of furanoses derived from D-
arabinose and D-ribose. The 2-nitroimidazole nucleosides then
formed would yield products which could be deprotected and
tosylated at C-5 to give the desired precursors. Additionally, the
desilylated products could be transformed to the fluorides and
deblocked to give the cold fluoro standards.
We accessed hexaethyldisilazane, a known23 but difficult to
prepare reagent, easily from (triethylsilyl)amine24 and chloro-
triethylsilane in the presence of a catalytic amount of triethylsilyl
triflate (TfOTES) in dry toluene in 79% yield (Scheme 2).
Initially, we refluxed a mixture of 2-nitroimidazole (NI) and
4ꢀ6 equiv of hexaethyldisilazane and a catalytic amount of
(NH4)2SO4 in pyridine until the reaction mixture was homo-
geneous. However, later we found that 2 equiv was sufficient for
silylation within 30 min and that the catalyst could be omitted.
Removal of volatile components left NI-TES (2-nitro-
1-(triethylsilyl)imidazole) as a crystalline product, which was
used directly. Surprisingly, (triethylsilyl)amine did not silylate NI
in refluxing pyridine.
In the first place, we wanted to couple NI-TES with a suitable
D-arabinofuranose derivative containing a silyl-proteced C-5
hydroxyl group. Thus, a mixture of D-arabinose and tert-butyldi-
phenylsilyl chloride (TBDPSCl) in pyridine was allowed to
warm in the cooling bath from ꢀ20 °C to rt for 18 h. Stirring
was continued for 6 h after the addition of acetic anhydride.
Aqueous workup and flash chromatography furnished a mixture
of anomeric acetates (α:β = 60:40) in an admixture with
impurities as a syrup in 71% yield (Scheme 3). The predominat-
ing α-anomer crystallized and was fully characterized. Recently,
Chatterjee et al. isolated the 5-O-TBDPS-protected D-arabinose
and then acetylated it in an overall yield of 46%.25 The coupling
experiments were performed with the anomeric mixture 14.
Under optimized conditions, a mixture of NI-TES and 14 in
CH3CN was cooled to ꢀ20 °C, and 1 equiv of a 1 M solution of
TfOTES in 1,2-C2H4Cl2 was added dropwise. Stirring was
continued while the reaction mixture was allowed to warm to
ꢀ8 °C within 3 h. Extractive workup and flash chromatography
furnished the α-nucleoside26 α-15 in 72% yield beside some
starting material and a trace of the β-anomer detected by TLC,
which was not isolated (Scheme 3). Anticipating later results,
α-15 was converted in two steps into precursor α-7. As the
’ RESULTS AND DISCUSSION
Preparation of Triethylsilylated 2-Nitroimidazole and
2-Nitroimidazole Nucleosides Derived from D-Arabinose.
We envisaged to test the Vorbr€uggen method for the coupling
first.22 It is based on the coupling of trimethylsilylated hetero-
cyclic bases with protected sugar derivatives with an acetoxy or
methoxy group at C-1 in CH3CN, CH2Cl2, or 1,2-C2H4Cl2,
catalyzed by trimethylsilyl triflate. Surprisingly, it has never been
used for the synthesis of azomycin nucleosides. The solubility of
2-nitroimidazole is very low in all common solvents, especially at
rt or below, and even trimethylsilylation with hexamethyldisila-
zane/(NH4)2SO4 in pyridine had only a marginal effect on its
solubility. Therefore, we decided to use triethylsilylation to
increase the solubility further, which proved to be critical for
our success.
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Scheme 4. Preparation and Coupling of Protected D-Riboses
17
Scheme 5. Coupling of 1-O-Acetyl-2,3,5-tri-O-benzoyl-α-D-
ribofuranose with NI-TES by the Vorbru€ggen Method
Scheme 6. Coupling of 1,2,3,4,6-Penta-O-acetyl-β-D-galacto-
pyranose with NI-TES by the Vorbru€ggen Method
β-nucleoside β-15 was also needed, CH3CN was replaced by 1,2-
C2H4Cl2, hoping to increase the amount of the β-anomer. When
NI-TMS and the mixture of α- and β-14 were coupled in 1,2-
C2H4Cl2 with 0.5 equiv of TfOTMS as a catalyst for 4 h at rt, the
yield for β-15 was 13% and that for α-15 16%. The yield of β-15
increased to 31%, when the coupling was modified (NI-TES,
50 °C, 1.2 equiv of TfOTES, 2 h). The low and irreproducible
yields in this halogenated solvent were attributed to the unsa-
tisfactory solubility of NI-TES. Although the β-nucleoside was
formed preferentially, the method was not suitable for the
preparation of relevant amounts of β-7. The preferred formation
of the α-anomer is attributed to the neighboring group effect by
the 2-acetoxy group, which is β-orientated.22 However, the
formation of the β-anomer results very likely from the inter-
mediacy of a nitronate ester as suggested by others.19
Preparation of 2-Nitroimidazole Nucleosides Derived
from D-Ribose. To broaden the scope of the method, we studied
the reaction of NI-TES with D-ribose and D-galactose derivatives
catalyzed by silyl triflates as well. First, D-ribose was silylated and
acetylated in a one-pot reaction in the same way as D-arabinose,
except that the acetylation was performed at 50 °C, to give a
mixture(54:46) ofα- and β-triacetate 17 which could beseparated
by flash chromatography (Scheme 4). Each anomer was reacted
with NI-TES in CH3CN catalyzed by 1 equiv of TfOTES. When
the reaction mixture was allowed to warm from ꢀ20 to ꢀ8 °C
within 2 h, triacetate β-17 furnished a 72% yield of β-nucleoside β-
18 and a trace of the α-nucleoside as detected by TLC. Similarly,
α-triacetate yielded 87% of the β- and a trace of the α-nucleoside
(20°C to rtwithin2 h). Asthe two anomers reacted similarly, their
separation was not worthwhile. In the latter case, the influence of
the temperature on the outcome was studied. Below ꢀ20 °C,
coupling did not take place; between ꢀ10 and ꢀ5 °C at a reaction
time of 4 h, a mixture of nucleosides resulted (β-18:α-18 = 2:1,
combined yield 60%). No nucleoside was formed in 1,2-C2H4Cl2
under a variety of conditions. An alternative for the preparation of
azomycin nucleosides derived from D-ribose is the coupling of
commercially available acetate 19 (Scheme 5). It was found
that TfOTMS was a better catalyst than TfOTES with this sub-
strate. When the Vorbr€uggen coupling was effected in CH3CN
(ꢀ20 to ꢀ10 °C, 1.2 equiv of TfOTMS), a 72% yield of nucleo-
side β-20 resulted. However, when the same reaction was per-
formed for 30 min at rt, a separable mixture (α-20, 42%; β-20,
31%) of nucleosides was obtained. These results underlined the
necessity to control the reaction temperature carefully and use
CH3CN as the solvent of choice for a good yield. For comparison,
Prisbe et al. found that NI and 19 gave a 61% yield of α-20, when
treated with 2 equiv of SnCl4 and Hg(CN)2 in CH3CN at 60 °C.19
To obtain β-20 in 68% yield, acetate 19 had to be first converted to
the corresponding bromide by bubbling HBr through a solution of
it and then reacting it analogously to before with 2 equiv of
Hg(CN)2 without SnCl4. The predominant formation of the
β-anomer here is again attributed to the neighboring group effect
(2-acyloxy group is α) and the α-anomer to the possible involve-
ment of a nitronate ester.
Preparation of 2-Nitroimidazole Nucleoside Derived from
D-Galactose. At last, commercially available β-D-galactopyranose
pentaacetate was converted to the 2-nitroimidazole nucleoside
β-22 in high yield (92%) in CH3CN under very mild conditions,
when the reaction mixture was stirred for 1 h at 0 °C and 1 h at rt
(Scheme 6). For comparison, the coupling of acetobromo-α-D-
galactose with 2-nitroimidazole catalyzed by 2.5 equiv of Hg-
(CN)2 for 23 h at 40 °C in a large volume of CH3CN yielded 88%
of the desired β-nucleoside.21
Conversion of 2-Nitroimidazole Nucleosides Derived
from α- and β-D-Arabinose and D-Ribose to (Putative) Pre-
cursors for Tracers To Image Hypoxia. The precursor α-7 for
the preparation of α-[18F]FAZA can be accessed easily from
silylated nucleoside α-15. It was deblocked with HF generated
in situ from KF/benzoic acid27 in refluxing CH3CN in 90% yield
and tosylated to give precursor α-728 in 94% yield, first prepared
by Wiebe et al. (Scheme 7). This sequence comprises only four
steps and is the shortest synthesis of precursor α-7, starting from
D-arabinose.
The synthesis of β-7 was first accomplished also by Wiebe
et al., starting from 1-β-(D-ribofuranosyl)-2-nitroimidazole
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Scheme 7. Transformation of Azomycin Nucleoside α-15
into Precursor α-7
Scheme 10. Conversion of Tribenzoate α-20 to the Silylated
Diacetate α-18
Scheme 8. Preparation of 3,5-O,O-(1,1,3,3-Tetra-
isopropyldisiloxanylidene)-Protected D-Riboses 24 and Their
Coupling with NI-TES by the Vorbru€ggen Method
impurities (47% yield) of α- and β-24 (74:19) was coupled with
NI-TES in CH3CN with 1 equiv of TfOTES at 0 °C for 45 min to
give separable nucleosides (β-25, 30%; α-25, 32%). Unfortu-
nately, lowering the reaction temperature to ꢀ10 °C favored the
α-anomer even more (β-25, 16%; α-25, 32%). However, the
yield of the desired β-anomer was too low to pursue this
approach any further. The putative precursor derived from β-
D-ribose was accessed from silyl-protected β-18 (Scheme 9). It
was selectively deblocked at C-50 and tosylated to furnish
precursor β-27. Analogously, the α-anomer was prepared from
α-18, which was either directly accessible by coupling by the
Vorbr€uggen method or accessible from tribenzoate α-20
(Scheme 10). Transesterification with MeOH/MeONa gave
triol nucleoside α-28 in an admixture with an unknown impurity,
possibly of structure 29, already reported19 by Prisbe et al. The
two compounds could not be separated by flash chromatography,
but easily after monosilylation with TBDPSCl. The silylated diol
α-30 formed was acetylated to give nucleoside α-18. The
seemingly obvious direct conversion of α-28 to the precursor
α-27 by monotosylation followed by acetylation did not work as
tosylation could not be conducted selectively, but produced a
ditosylate preferentially.
Scheme 9. Preparation of Putative Precursors α- and β-27
obtained by debenzoylation of D-ribose derivative β-20.21d,27
The hydroxyl groups at C-50 and C-30 were protected with the
30,50-O,O-(1,1,3,3-tetraisopropyldisiloxanylidene) group, and
the configuration of the free hydroxyl at C-20 was inverted by
substituting the triflate with tetrabutylammonium acetate.27
Then the disiloxanylidene group was removed, and the diol
was monotosylated and acetylated to give β-7. We thought that
we could shorten the lengthy synthesis by starting from a β-D-
ribose derivative already containing the disiloxanylidene group
(Scheme 8). Thus, D-ribose was silylated and acetylated in a one-
pot reaction in the same way as the TBDPS-protected analogue
17 was prepared. The crude anomeric mixture containing
’ CONCLUSIONS
Our results unambiguously establish that 1-O-acetyl-D-pen-
toses and D-galactose pentaacetate and triethylsilylated 2-nitro-
imidazole can be coupled in acetonitrile using TESOTf
(Vorbr€uggen method) to give 2-nitroimidazole nucleosides.
The anomeric ratio of the products is delicately influenced by
the substrate structure and the reaction temperature. This
approach is an attractive alternative to protocols based on excess
Hg(CN)2 alone or in combination with SnCl4 for coupling. 50-O-
TBDPS nucleosides can be desilylated and tosylated easily to
furnish precursors for tracers to image hypoxia.
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’ EXPERIMENTAL SECTION
reduced pressure. The crude product was purified by flash chromatog-
raphy (hexanes/EtOAc, 2:1, Rf 0.63) to give the mixture of anomeric
1H and 13C (J-modulated; additionally, non-J-modulated spectra were
recorded of compounds containing 2-nitroimidazole) NMR spectra
were measured at 300 K at 400.13 and 100.61 MHz, respectively. All
chemical shifts (δ) are given in parts per million. They were referenced
either to residual CHCl3 (δH 7.24)/toluene-d8 (CHD2, δH 2.09)/
CD3OD (CHD2, δH 3.31)/DMSO-d6 (CHD2, δH 2.50) or CDCl3 (δC
77.00)/toluene-d8 (CD3, δC 21.04)/CD3OD (CD3, δC 49.00)/DMSO-
d6 (CD3, δC 39.50). IR spectra of films on a silicon disk were recorded on
an FT-IR spectrometer.29 Optical rotations were measured at 20 °C on a
polarimeter in a 1 dm cell. Melting points are uncorrected.
acetates (1.83 g, 71%) as an oil,25 α:β = 60:40 (by H NMR), [α]2D0
1
+19.3 (c 3.0, acetone). After a few months crystals of the α-anomer
formed in the oil. They were collected after the oil was dissolved in
i-Pr2O/hexanes and recrystallized (i-Pr2O/hexanes) to give the homo-
geneous α-anomer: mp 92ꢀ93 °C; [α]2D0 +52.1 (c 1.1, acetone). Data
for α- and β-14: IR (Si) νmax 3072, 2933, 2859, 1750, 1428, 1371, 1221,
1113, 1065, 1008 cmꢀ1; 1H NMR (400.1 MHz, CDCl3) δ (α-14) 7.67
(m, 6H), 7.38 (m, 9H), 6.19 (s, 1H), 5.37 (dd, J = 4.8, 1.0 Hz, 1H), 5.20
(d, J = 1.0 Hz, 1H), 4.24 (td, J = 4.8, 4.0 Hz, 1H), 3.84 (AB system, JAB
=
11.1 Hz, JAX = JBX = 4.0 Hz, 2H), 2.10 (s, 3H), 2.09 (s, 3H), 2.03 (s, 3H),
1.06 (s, 9H); (β-14) 7.67 (m, 6H), 7.38 (m, 9H), 6.36 (d, J = 4.8 Hz,
1H), 5.62 (dd, J = 7.1, 6.0 Hz, 1H), 5.34 (dd, J = 7.1, 4.8 Hz, 1H), 4.12
(td, J = 6.0, 5.3 Hz, 1H), 3.81 (AB system, JAB = 11.0 Hz, JAX = JBX = 5.3
Hz, 2H), 2.06 (s, 3H), 2.05 (s, 3H), 1.88 (s, 3H), 1.06 (s, 9H); 13C NMR
(100.6 MHz, CDCl3) δ (α-14) 169.8, 169.6, 169.3, 135.61 (2C), 135.59
(2C), 133.1, 133.0, 129.7 (2C), 127.7 (4C), 99.6, 84.8, 81.4, 76.7, 62.7,
26.7 (3C), 21.0, 20.7, 20.6, 19.3; (β-14) 169.9, 169.8, 169.4, 135.6 (2C),
135.5 (2C), 133.2, 132.9, 129.8 (2C), 127.7 (4C), 93.6, 81.6, 75.6, 74.1,
64.3, 26.7 (3C), 20.9, 20.8, 20.4, 19.2. Anal. Calcd for C27H34O8Si: C,
63.01; H, 6.66. Found for crystalline α-14: C, 62.36; H, 6.84.
Flash (column) chromatography was performed with silica gel 60
(230ꢀ400 mesh) and monitored by TLC, carried out on 0.25 mm thick
plates, silica gel 60 F254. Spots were visualized by UV and/or by dipping
the plate into a solution of (NH4)6Mo7O24 4H2O (23.0 g) and
3
Ce(SO4)2 4H2O (1.0 g) in 10% aqueous H2SO4 (500 mL), followed
by heating with a heat gun.
3
General Procedure A: Triethylsilylation of 2-Nitroimida-
zole. A mixture of 2-nitroimidazole (0.113 g, 1 mmol), hexaethyldisi-
lazane (0.491 g, 2 mmol, 2 equiv), and dry pyridine (2 mL) was refluxed
for 30 min. The solution was cooled (silylated compound crystallized),
and volatile components were removed by bulb to bulb distillation
(70ꢀ75 °C, 0.4 mbar) to leave brown crystalline 1-(triethylsilyl)-
2-nitroimidazole, which was used immediately without further
purification.
General Procedure B: Desilylation of 2-Nitroimidazole
Nucleosides with a TBDPSO Group at C-50. A mixture of the
nucleoside (0.50 mmol), KF (0.407 g, 3.50 mmol, 7 equiv), and benzoic
acid (0.427 g, 3.50 mmol, 7 equiv) in dry CH3CN (11.5 mL) was heated
at 75 °C for 7 h (monitored by TLC).27 The mixture was then cooled,
filtered, and concentrated under reduced pressure.
General Procedure C: Tosylation of 2-Nitroimidazole Nu-
cleosides Derived from D-Pentoses with a Free 50-OH Group.
A solution of p-toluenesulfonyl chloride (0.521 g, 2.73 mmol, 3 equiv)
and nucleoside with a free 50-OH in dry pyridine (5 mL) was kept for 18
h at 4 °C (TLC, hexanes/EtOAc, 1:2). Then water (10 mL) and 2 M
HCl (10 mL) were added, and the mixture was extracted with EtOAc
(3 ꢁ 10 mL). The combined organic layers were washed with saturated
aq NaHCO3 (10 mL) and water (10 mL), dried (Na2SO4), and
concentrated under reduced pressure.
Hexaethyldisilazane (10). Triethylsilyl triflate (0.2 mL) was
added to a stirred solution of (triethylsilyl)amine (8)24 [9.66 g, 73.6
mmol, 3.2 equiv; 70ꢀ80 °C, 80 mmHg; 75% yield; n2D0 1.4250 (lit.24 bp
134 °C, n2D0 1.4267)] and chlorotriethylsilane (3.47 g, 3.86 mL, 23
mmol) in dry toluene (40 mL) at 0 °C. Precipitation of NH4Cl started
immediately. After being stirred for 2 h at rt, the mixture was filtered
through Celite. The filtrate was concentrated under reduced pressure,
and the residue was bulb to bulb distilled (70ꢀ75 °C, 0.5 mbar; lit.23b bp
100 °C, 1 mmHg) to give 10 (8.92 g, 79%) as a colorless liquid: nD27
1.4502; 1H NMR (400.1 MHz, toluene-d8) δ 0.98 (t, J = 8.0 Hz, 18H),
0.53 (q, J = 8.0 Hz, 12H), ꢀ0.29 (br s, 1H, NH); 13C NMR (100.6 MHz,
toluene-d8) δ 8.4, 8.0.
1-α-[20,30-Di-O-acetyl-50-O-(tert-butyldiphenylsilyl)-D-ara-
binofuranosyl]-2-nitroimidazole (α-15). A solution of α- and β-
14 (0.548 g, 1.06 mmol) in dry CH3CN (3 mL) was added to
2-nitroimidazole (0.113 g, 1 mmol) triethylsilylated according to general
procedure A under argon in dry CH3CN (5 mL). After the stirred
mixture was cooled to ꢀ20 °C, TfOTES (1 mL, 1 M in dry 1,2-
C2H4Cl2) was added, and stirring was continued for 3 h at ꢀ8 °C (TLC,
hexanes/EtOAc, 2:1). A saturated aq solution of NaHCO3 (10 mL) was
added, and the mixture was extracted with EtOAc (3 ꢁ 10 mL). The
combined organic layers were washed with water (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexanes/EtOAc, 2:1, Rf 0.21) to give
protected nucleoside α-15 (0.435 g, 72%) as a yellow oil (lit.25 mp
20
1
53 °C): [α]D +21.3 (c 1.1, acetone); the H NMR data agree with
those of the literature;25 IR (Si) νmax 2932, 2859, 1755, 1540, 1475,
1428, 1369, 1230, 1106 cmꢀ1 13C NMR (100.6 MHz, CDCl3) δ 169.2,
;
168.9, 144.2, 135.64 (2C), 135.56 (2C), 132.8, 132.7, 130.0 (2C), 128.5,
127.8 (2C), 127.5 (2C), 121.9, 92.6, 87.4, 81.8, 76.8, 63.6, 26.7 (3C),
20.6, 20.4, 19.2.
Preparation of α- and β-15 in 1,2-C2H4Cl2. A solution α- and
β-14 (0.680 g, 1.32 mmol) in dry 1,2-C2H4Cl2 (4 mL) was added under
argon at rt to 2-nitroimidazole (0.150 g, 1.32 mmol) trimethylsilylated
according to general procedure A, followed by TfOTMS (1.32 mL,
0.5 M in dry 1,2-C2H4Cl2). After the mixture was stirred for 4 h at rt,
CH2Cl2 (20 mL) and a saturated aq solution of NaHCO3 (20 mL) were
added. The organic phase was separated, and the aqueous one was
extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The residue
was purified by flash chromatography (hexanes/EtOAc, 3:1 and then
1:2; TLC, 2:1, Rf 0.21 for α-15 and 0.43 for β-15) to give recovered
starting material (0.306 g, 45%), β-15 (0.098 g, 13%), and α-15 (0.122 g,
16%).
1,2,3-Tri-O-acetyl-5-O-(tert-butyldiphenylsilyl)-α- and Tri-
O-acetyl-5-O-(tert-butyldiphenylsilyl)-β-D-ribofuranose (α-
and β-17). D-Ribose (0.751 g, 5 mmol) was silylated, acetylated, and
worked up in the same way as D-arabinose, except that the acetylation
was performed for 6 h at 60 °C. The crude product (α:β = 1:0.9) was
purified by flash chromatography (hexanes/EtOAc, 3:1, Rf 0.73 for β-
anomer and 0.58 for α-anomer, hexanes/EtOAc, 2:1) to give β-
triacetate β-17 (0.720 g, 28%; 10ꢀ15% of it was unknown compounds)
and α-triacetate α-17 (0.849 g, 33%; 6% of it was an impurity) as
colorless, very viscous oils. Data for β-17: [α]2D0 +2.17 (c 1.15, acetone);
1,2,3-Tri-O-acetyl-5-O-(tert-butyldiphenylsilyl)-α- and 1,2,
3-Tri-O-acetyl-5-O-(tert-butyldiphenylsilyl)-β-D-arabinofur-
anose (α- and β-14). A mixture of D-arabinose (0.751 g, 5 mmol) in
dry pyridine (10 mL) was cooled to ꢀ20 °C under argon, and TBDPSCl
(t-BuPhe2SiCl) (1.374 g, 1.30 mL, 5 mmol) was added. The reaction
mixture was allowed to slowly warm to rt in the cooling bath overnight
(TLC, hexanes/EtOAc, 2:1). After addition of Ac2O (4 mL) the solution
was stirred at rt for 6 h. Volatile components were removed under
reduced pressure and the residue taken up with water (10 mL) and 2 M
HCl (10 mL). The mixture was extracted with CH2Cl2 (3 ꢁ 10 mL).
The combined organic layers were washed with saturated aq NaHCO3
(10 mL) and water (10 mL), dried (Na2SO4), and concentrated under
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ARTICLE
IR (Si) νmax 3050, 2933, 2859, 1 754, 1429, 1371, 1221, 1113,
(100.6 MHz, CDCl3) δ 166.0, 165.2, 164.8, 144.4 (br), 133.9, 133.9,
133.7, 129.9 (2C), 129.8 (2C), 129.7 (2C), 129.1, 129.1, 128.8 (2C),
128.6 (2C), 128.6 (2C), 128.3, 128.3, 121.5, 89.6, 80.7, 76.1, 70.2, 63.0.
Data for α-20: [α]2D0 ꢀ56.8 (c 1.07, acetone); IR (Si) νmax 1732, 1539,
1479, 1452, 1365, 1267, 1095, 1070, 1026 cmꢀ1; 1H NMR (400.1 MHz,
CDCl3) δ 8.14ꢀ8.09 (m, 2H), 7.71ꢀ7.67 (m, 2H), 7.64ꢀ7.56 (m, 3H),
7.54ꢀ7.46 (m, 5H), 7.34ꢀ7.27 (m, 4H), 7.23 (d, J = 1.3 Hz, 1H), 7.16
(d, J = 5.6 Hz, 1H), 6.30 (t, J = 5.6 Hz, 1H), 5.92 (dd, J = 5.6, 3.2 Hz, 1H),
5.06 (ddd ≈ q, J = 3.4 Hz, 1H), 4.79 (dd, J = 12.4, 3.4 Hz, 1H), 4.63 (dd,
J = 12.4, 3.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 165.9, 165.0,
164.0, 144.6, 133.9, 133.8, 133.6, 129.7 (2C), 129.6 (2C), 129.4 (2C),
129.0, 128.7 (2C), 128.6 (2C), 128.5 (2C), 128.2, 128.2, 127.7, 122.5,
88.1, 82.7, 71.8, 71.3, 63.9.
1
1029 cmꢀ1; H NMR (400.1 MHz, CDCl3) δ 7.67ꢀ7.63 (m, 4H),
7.41ꢀ7.35 (m, 6H), 6.17 (d, J = 1.5 Hz, 1H), 5.55 (dd, J = 6.3, 4.8 Hz,
1H), 5.43 (dd, J = 4.8, 1.5 Hz, 1H), 4.24 (dt, J = 6.3, 3.5 Hz, 1H), 3.76
(AB system, JAX = JBX = 3.5 Hz, JAB = 11.3 Hz, 2H), 2.10 (s, 3H), 2.03 (s,
3H), 1.93 (s, 3H), 1.05 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 169.7,
169.48, 169.46, 135.60 (2C), 135.5 (2C), 133.0, 132.80, 129.84, 129.8,
127.8 (2C), 127.7 (2C), 98.2, 82.3, 74.5, 70.6, 63.2, 26.7 (3C), 20.9, 20.5,
20.5, 19.2. Anal. Calcd for C27H34O8Si: C, 63.01; H, 6.66. Found: C,
63.29; H, 6.78. Data for α-17: [α]2D0 +46.3 (c 1.2, acetone); IR (Si) νmax
3072, 2933, 2859, 1749, 1472, 1428, 1370, 1222, 1113, 1074, 1051,
1
1011 cmꢀ1; H NMR (400.1 MHz, CDCl3) δ 7.68ꢀ7.63 (m, 4H),
7.45ꢀ7.35 (m, 6H), 6.46 (d, J = 4.5 Hz, 1H), 5.50 (dd, J = 6.3, 2.0 Hz,
1H), 5.41 (dd, J = 6.3, 4.5 Hz, 1H), 4.29 (∼q, J ≈ 2.5 Hz, 1H), 3.79 (AB
system, J = 11.5, 3.0, 2.3 Hz, 2H), 2.11 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H),
1.05 (s, 9H); 13C NMR 100.6 MHz, CDCl3) δ 170.2, 169.9, 169.3, 135.6
(2C), 135.6 (2C), 132.8, 132.6, 130.3, 130.2, 127.8 (2C), 127.8 (2C),
94.5, 85.0, 70.6, 70.5, 63.4, 26.7 (3C), 21.1, 20.7, 20.3, 19.2.
1-β-(20,30,40,60-Tetra-O-acetyl-D-galactopyranosyl)-2-ni-
troimidazole (β-22). A solution of 1,2,3,4,6-penta-O-acetyl-β-D-
galactopyranose (1.171 g, 3 mmol) in dry CH3CN (20 mL) was added
to the mixture of 2-nitroimidazole (0.339 g, 3.0 mmol; triethylsilylated
according to general procedure A) in dry CH3CN (4 mL, sonicated for
2 min) under argon. After the stirred mixture was cooled to 0 °C,
TfOTES (3.6 mL, 1.2 equiv, 1 M in dry 1,2-C2H4Cl2) was added, and
stirring was continued for 1 h at 0 °C and 1 h at rt. A saturated aq solution
of NaHCO3 (20 mL) was added ,and the mixture was extracted with
EtOAc (3 ꢁ 15 mL). The combined organic layers were washed with
water (20 mL), dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(hexanes/EtOAc, 2:1; TLC, hexanes/EtOAc, 1:1, Rf 0.45) to give
nucleoside β-2221a (1.219 g, 92%) as a gum: [α]2D0 +62.50 (c 1.48,
1-β-[20,30-Di-O-acetyl-50-O-(tert-butyldiphenylsilyl)-D-
ribofuranosyl]-2-nitroimidazole (β-18). A solution of β-17
(0.395 g, 0.77 mmol) in dry CH3CN (3 mL) was added to 2-nitroimi-
dazole (0.087 g, 0.77 mmol) triethylsilylated according to general
procedure A in dry CH3CN (2 mL) under argon. After the stirred
mixture was cooled to ꢀ20 °C, TESOTf (0.77 mL, 1 M in dry 1,2-
C2H4Cl2) was added, and stirring was continued for 2 h while the
temperature of the reaction mixture was allowed to slowly rise to ꢀ8 °C
in the cooling bath (TLC, hexanes/EtOAc, 2:1). Saturated aq NaHCO3
(10 mL) was added, and the mixture was extracted with EtOAc (3 ꢁ
10 mL). The combined organic layers were washed with water (10 mL),
dried (Na2SO4), and concentrated under reduced pressure. The residue
was purified by flash chromatography (hexanes/EtOAc, 3:1, Rf 0.47 for
2:1) to give nucleoside β-1818 (0.315 g, 72%) as yellow crystals; a trace
of possibly α-anomer was detected by TLC: [α]2D0 +13.31 (c 1.3,
acetone); mp 130ꢀ131 °C (CHCl3/i-Pr2O) (lit.18 mp 52ꢀ53 °C).
Similarly, triacetate α-17 (0.395 g, 0.77 mmol) was reacted in the
same way, except that the temperature was allowed to warm to rt within
2 h, and yielded (0.381 g, 87%) β-18; a trace of possibly α-18 could be
detected in the crude product by TLC: IR (Si) νmax 2932, 1755, 1589,
1
acetone); IR (Si) νmax 1753, 1370, 1231,1094, 1064 cmꢀ1; H NMR
(400.1 MHz, CDCl3) δ 7.41 (d, J = 1.0 Hz, 1H), 7.16 (d, J = 1.0 Hz, 1H),
6.38 (d, J = 9.1 Hz, 1H), 5.51 (dd, J = 3.3, 1.0 Hz, 1H), 5.44 (dd, J = 10.1,
9.1 Hz, 1H), 5.33 (dd, J = 10.1, 3.3 Hz, 1H), 4.25 (ddd, J = 7.1, 5.8, 1.0
Hz, 1H), 4.14 (AB system, J = 11.4, 7.1, 5.8 Hz, 2H), 2.17 (s, 3H), 2.01
(s, 3H), 1.96 (s, 3H), 1.88 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ
170.3, 169.8, 169.6, 169.1, 144.5, 128.9, 122.1, 83.5, 74.2, 70.9, 68.7, 67.0,
61.1, 20.5 (2C), 20.4, 20.2.
1-α-(20,30-Di-O-acetyl-D-arabinofuranosyl)-2-nitroimida-
zole (α-23). Nucleoside α-15 (0.231 g, 0.407 mmol) was desilylated by
general procedure B. The crude product was purified by flash chroma-
tography (at first hexanes/EtOAc, 1:1, Rf 0.08, and then 1:5) to give α-
23 (0.113 g, 84%) as a crystalline solid: mp 115ꢀ116 °C (C2H4Cl2/i-
Pr2O) (lit.26 semisolid mass); [α]D20 ꢀ5.6 (c 1.1, acetone); IR (Si) νmax
1542, 1477, 1428, 1369, 1238, 1114, 1081, 1011 cmꢀ1; the 1H and 13
C
NMR data agree with those of the literature.18 Anal. Calcd for
C28H33N3O8Si: C, 59.24; H, 5.86; N, 7.40. Found: C, 58.98; H, 5.56;
N, 7.14.
3387, 2939, 1748, 1539, 1479, 1371, 1234, 1161, 1063 cmꢀ1; 1H and 13
NMR data agree with those of the literature.25
C
1-β- and 1-α-(20,30,5-Tri-O-benzoyl-D-ribofuranosyl)-2-ni-
troimidazole (β- and α-20). A solution of 1-O-acetyl-2,3,5-tri-O-
benzoyl-β-D-ribofuranose (0.605 g, 1.2 mmol, 1.2 equiv) in dry CH3CN
(4.6 mL) was added to the stirred mixture of 2-nitroimidazole (0.113 g,
1.0 mmol; triethylsilylated according to general procedure A) in dry
CH3CN (5.0 mL) under argon. TMSOTf (0.5 M, 2.4 mL, in dry
CH2Cl2) was added, and stirring was continued at rt (23 °C) for 1 h
(TLC, hexanes/EtOAc, 2:1). A saturated aq solution of NaHCO3
(10 mL) was added, and the mixture was extracted with EtOAc (3 ꢁ
10 mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by flash
chromatography (hexanes/EtOAc, 2:1; β-20, Rf 0.38; α-20, Rf 0.26) to
yield β-20 (0.173 g, 31%) as a yellow oil and α-20 (0.235 g, 42%) as
yellow crystals: mp 136ꢀ138 °C (CHCl3/i-Pr2O) [lit.19 mp 138.5ꢀ
140 °C (CH2Cl2/MeOH)]. Data for β-20: [α]2D0 +27.47 (c 0.91,
acetone); IR (Si) νmax 1733, 1541, 1479, 1452, 1366, 1268, 1118,
1094, 1071 cmꢀ1; 1H NMR (400.1 MHz, CDCl3) δ 8.09ꢀ8.05 (m, 2H),
7.99ꢀ7.95 (m, 2H), δ 7.91ꢀ7.87 (m, 2H), 7.64ꢀ7.51 (m, 3H), 7.57 (d,
J = 1.3 Hz, 1H), 7.50ꢀ7.44 (m, 2H), 7.43ꢀ7.38 (m, 2H), 7.37ꢀ7.32 (m,
2H), 7.12 (d, J = 1.3 Hz, 1H), 6.97 (d, J = 4.0 Hz, 1H), 5.86 (t, J = 5.6 Hz,
1H), 5.82 (dd, J = 5.6, 4.0 Hz, 1H), 4.86 (dd, J = 12.4, 2.7 Hz, 1H), 4.83
(∼td, J = 5.6, 3.5, 2.7 Hz, 1H), 4.70 (dd, J = 12.4, 3.5 Hz, 1H); 13C NMR
1-α-[20,30-Di-O-acetyl-50-O-(4-toluenesulfonyl)-D-ara-
binofuranosyl]-2-nitroimidazole (α-7). α-23 (0.300 g, 0.91
mmol) was tosylated by general procedure C. The crude product was
purified by flash chromatography (hexanes/EtOAc, 1:1, Rf 0.26) to give
tosylate α-7 (0.420 g, 95%) as colorless plates: mp 102ꢀ103 °C
(CHCl3/i-Pr2O); [α]D20 +39.3 (c 0.9, acetone);28 IR (Si) νmax 1750,
1540, 1477, 1368, 1232, 1191, 1178, 1096, 1052 cmꢀ1; the 1H and 13
C
NMR data agree with those of the literature, except that a signal in the
13C NMR spectrum at 20.4 is replaced by one at 17.3.28
1-β- and 1-α-[1,2-Di-O-acetyl-3,5-O,O-(1,1,3,3-tetra-
isopropyldisiloxanylidene)-D-ribofuranose (β- and α-24). D-
Ribose (0.45 g, 3 mmol) was dissolved in dry pyridine (15 mL) under
argon and cooled to ꢀ35 °C. 1,3-Dichloro-1,1,3,3-tetraisopropyldisi-
loxane (0.946, 0.96 mL) was added, and the mixture was stirred and
allowed to slowly warm in the cooling bath to rt (18 h). Ac2O (1.5 mL)
was added, and stirring was continued for another 6 h, before water
(2 mL) was added. After 10 min the mixture was concentrated under
reduced pressure. The residue was treated with water (20 mL) and
EtOAc (20 mL). The organic phase was separated, and the aq one was
extraceted with EtOAc (15 mL). The combined organic layers were
washed (20 mL each) with water, 2 N HCl, water, and a saturated aq
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The Journal of Organic Chemistry
ARTICLE
solution of NaHCO3, dried (Na2SO4), and concetrated under reduced
pressure. The residue was purified by flash column chromatography
(hexanes/EtOAc, 10:1; TLC, Rf 0.31 for 7:1) to yield a seemingly
homogeneous oily product [0.670 g, 47%; by 1H NMR a mixture of α-
anomer (δ 5.93, J = 7.9 Hz):β-anomer (δ 6.03, J = 0 Hz):unknown
compound (δ 6.09, J = 4.1 Hz) = 74:19:7], [α]2D0 ꢀ35.81 (c 1.55,
acetone), in which gradually crystals of the α-anomer formed. Hexanes
were added, and the mixture was stored at ꢀ18 °C. The colorless needles
were collected and recrystallized (hexanes, ꢀ18 °C). Data for α-24: mp
69ꢀ70 °C (hexanes, ꢀ18 °C); [α]2D0 ꢀ39.75 (c 1.2, acetone); IR (Si)
1H NMR (400.1 MHz, CDCl3) δ 5.93 (d, J = 7.9 Hz, 1H), 4.80 (dd, J =
7.9, 2.8 Hz, 1H), 4.57 (dd ≈ t, J = 2.8, 2.3 Hz, 1H), 4.10 (ddd, J = 9.6, 5.2,
2.3 Hz, 1H), 3.79 (AB part of ABX system, J = 11.0, 9.6, 5.2 Hz, 2H), 2.07
(s, 3H), 2.06 (s, 3H), 1.09ꢀ0.82 (m, 28H); 13C NMR (100.6 MHz,
CDCl3) δ 169.9, 169.4, 90.3, 71.1, 70.5, 70.5, 64.6, 21.0, 20.9, 17.4 (2C),
17.2 (2C), 17.2 (2C), 17.14, 17.09, 14.0, 13.6, 13.0, 12.6. Anal. Calcd for
C21H40O8Si2: C, 52.91; H, 8.46. Found: C, 52.64; H, 8.38.
1-β-[20,30-Di-O-acetyl-50-O-(4-toluenesulfonyl)-D-ribofu-
ranosyl]-2-nitroimidazole (β-27). A solution of 4-toluenesulfonyl
chloride (0.173 g, 0.91 mmol, 3 equiv) and alcohol β-26 (0.100 g, 0.304
mmol) in dry pyridine (2 mL) was kept for 18 h at 4 °C. When the
starting alcohol was consumed (TLC, hexanes/EtOAc, 1:1), water
(10 mL) and 2 M HCl (10 mL) were added. The mixture was extracted
with EtOAc (3 ꢁ 10 mL). The combined organic layers were washed
with saturated aq NaHCO3 (10 mL) and water (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexanes/EtOAc, 1:1, Rf = 0.41) to
give tosylate β-27 (0.102 g, 69%) as a yellow foam: [α]2D0 +44.2 (c 1.0,
acetone); IR (Si) νmax 1755, 1542, 1478, 1368, 1239, 1191, 1178,
1096 cmꢀ1; 1H NMR (400.1 MHz, CDCl3) δ 7.79 (m, 2H), 7.49 (d, J =
1.1 Hz, 1H), 7.36 (m, 2H), 7.12 (d, J = 1.1 Hz, 1H), 6.59 (d, J = 3.8 Hz,
1H), 5.38 (dd, J = 5.6, 3.8 Hz, 1H), 5.23 (dd ≈ t, J = 6.1, 5.6 Hz, 1H),
4.44 (dd, J = 11.4, 2.4 Hz, 1H), 4.38 (dt, J = 6.1, 2.3 Hz, 1H), 4.22 (dd, J =
11.4, 2.3 Hz, 1H), 2.44 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 169.2, 168.9, 145.7, 144.2, 132.0, 130.2 (2C),
129.1, 128.0 (2C), 121.7, 89.4, 79.6, 74.8, 68.7, 66.5, 21.7, 20.3, 20.2.
Anal. Calcd for C19H21N3O10S: C, 47.20; H, 4.38; N, 8.69. Found: C,
47.48; H, 4.48; N, 8.48.
νmax 2946, 2868, 1747, 1464, 1373, 1216, 1169, 1125, 1078, 1010 cmꢀ1
;
1-β- and 1-α-[20-O-Acetyl-30,50-O,O-(1,1,3,3-tetraisoprop-
yldisiloxanylidene)-D-ribofuranosyl]-2-nitroimidazole
(β- and α-25). A solution of α- and β-24 (0.634 g, 1.33 mmol) in dry
CH3CN (5 mL) was added to 2-nitroimidazole (0.107 g, 0.95 mmol)
triethylsilylated according to general procedure A in dry CH3CN (2 mL)
under argon. After the stirred mixture was cooled to 0 °C, TfOTES
(1.14 mL, 1 M solution in dry 1,2-C2H4Cl2) was added dropwise, and
stirring was continued for 45 min at that temperature. Then a saturated
aq solution of NaHCO3 (10 mL) was added, and the mixture was
extracted with EtOAc (3 ꢁ 15 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The residue
was flash chromatographed (hexanes/EtOAc, 5:1; β-25, Rf 0.36; α-25,
Rf 0.21) to yield nucleosides β-25 (0.152 g, 30%) and α-25 (0.158 g,
32%), both colorless needles. When the reaction mixture was allowed to
warm from ꢀ10 °C to rt, the β- and α-anomers were formed in yields of
16% and 32%, respectively. Data for β-25: mp 143ꢀ144 °C (i-Pr2O/
hexanes); [α]2D0 +4.06 (c 0.91, acetone); IR (Si) νmax 2946, 2868, 1764,
1543, 1474, 1370, 1231, 1116, 1073, 1040 cmꢀ1; 1H NMR (400.1 MHz,
CDCl3) δ 7.77 (d, J = 1.0 Hz, 1H), 7.14 (d, J = 1.0 Hz, 1H), 6.34 (s, 1H),
5.46 (d, J = 4.8 Hz, 1H), 4.43 (dd, J = 9.4, 4.8 Hz, 1H), 4.28 (d, J = 13.6
Hz, 1H), 4.10 (dd, J = 9.4, 2.5 Hz, 1H), 4.00 (dd, J = 13.6, 2.5 Hz, 1H),
2.17 (s, 3H), 1.11ꢀ0.83 (m, 28H); 13C NMR (100.6 MHz, CDCl3) δ
168.5, 143.7, 128.5, 122.3, 91.0, 82.6, 72.3, 66.8, 59.3, 20.5, 17.4, 17.3,
17.2, 17.2, 16.9, 16.8, 16.70, 16.66, 13.4, 12.9, 12.8, 12.6. Anal. Calcd for
C22H39N3O8Si2: C, 49.88; H, 7.42; N, 7.93. Found: C, 49.48; H, 7.61; N,
7.83. Data for α-25: mp 106ꢀ107 °C (i-Pr2O/hexanes); [α]2D0 +43.78 (c
0.95, acetone); IR (Si) νmax 2946, 2868, 1748, 1545, 1484, 1374, 1225,
1169, 1117, 1053, 1033, 1009 cmꢀ1; 1H NMR (400.1 MHz, CDCl3) δ
7.26 (d, J = 1.3 Hz, 1H), 7.11 (d, J = 1.3 Hz, 1H), 6.70 (d, J = 9.1 Hz, 1H),
4.86 (dd, J = 9.1, 2.3 Hz, 1H), 4.65 (t, J = 2.3 Hz, 1H), 4.22 (td, J = 8.3,
2.3 Hz, 1H), 3.92 (d, J = 8.3 Hz, 2H), 1.88 (s, 3H), 1.15ꢀ0.82 (m, 28H);
13C NMR (100.6 MHz, CDCl3) δ 169.5, 144.9, 128.7, 121.3, 80.7, 72.4,
71.2, 70.6, 66.5, 20.4, 17.41, 17.37, 17.22, 17.16, 17.1 (2C), 17.06, 17.02,
14.1, 13.7, 12.9, 12.8. Anal. Calcd for C22H39N3O8Si2: C, 49.88; H, 7.42;
N, 7.93. Found: C, 49.74; H, 7.40; N, 7.88.
1-α-[50-O-(tert-Butyldiphenylsilyl)-D-ribofuranosyl]-2-ni-
troimidazole (α-30). A mixture of tribenzoate α-20 (0.398 g, 0.714
mmol) and MeONa/MeOH (3.0 mL, 0.05 M) was stirred at 0 °C. When
the transesterification (TLC, hexanes/EtOAc, 1:2) was finished (2 h),
AcOH (3 drops) was added immediately, and the solvent was removed
under reduced pressure. The residue was purified by flash chromatog-
raphy (CHCl3/MeOH, 4:1, Rf 0.39) to yield an inseparable mixture of
α-28 and a side product (10ꢀ20%) with the tentatively assigned
1
structure 29 (0.132 g): H NMR (400.1 MHz, CD3OD) δ (α-28)
7.62 (s, 1H), 7.13 (s, 1H), 6.71 (d, J = 4.8 Hz, 1H), 4.61 (dd ≈ t, J = 5.3,
4.8 Hz, 1H), 4.31 (m, 1H), 3.84 (dd, J = 12.2, 2.8 Hz, 1H), 3.67 (dd, J =
12.2, 4.2 Hz, 1H); (29) 6.83 (s, 1H), 6.62 (s, 1H), 6.25 (d, J = 5.3 Hz,
1H), 5.56 (t, J = 5.3 Hz, 1H). TBDPSCl (0.412 g, 0.39 mL, 1.50 mmol)
was added to a solution of the mixture of α-28 and 29 (0.132 g) in dry
pyridine (2.5 mL), and the mixture was stirred at rt until the starting
material was consumed (2 h; TLC, CHCl3/MeOH, 4:1, for starting
material, hexanes/EtOAc, 1:1, for product α-30). The reaction was
quenched with water (10 mL) and 2 M HCl (10 mL), and the mixture
was extracted with EtOAc (3 ꢁ 10 mL). The combined organic layers
were washed with saturated aq NaHCO3 (10 mL) and water (10 mL),
dried (Na2SO4), and concentrated under reduced pressure. The crude
product was purified by flash chromatography (hexanes/EtOAc, 1:1, Rf
0.38) to give α-30 (0.179 g, 52%, starting from tribenzoate α-20): mp
150ꢀ151 °C (EtOAc); [α]2D0 ꢀ33.6 (c 1.22, EtOH); IR (ATR) νmax
3413, 3200, 2927, 1537, 1354, 1487, 1354, 1111, 1090, 1048,
1036 cmꢀ1; 1H NMR (400.1 MHz, DMSO-d6) δ 7.68ꢀ7.62 (m, 4H),
7.59 (s, 1H), 7.51ꢀ7.40 (m, 6H), 7.17 (s, 1H), 6.62 (d, J = 4.8 Hz, 1H),
5.49 (d, J = 5.8 Hz, 1H), 5.03 (d, J = 5.1 Hz, 1H), 4.55ꢀ4.49 (m, 1H),
4.34 (br s, 1H), 4.20ꢀ4.15 (m, 1H), 3.82 (AB system, J = 11.5, 3.7, 1.7
Hz, 2H), 1.03 (s, 9H); 13C NMR (100.61, DMSO-d6) δ 144.5, 135.1
(4C), 132.8, 132.7, 129.9 (2C), 128.0 (2C), 127.9 (2C), 127.1, 124.3,
89.9, 84.9, 71.0, 70.6, 63.8, 26.6 (3C), 18.8. Anal. Calcd for
C24H29N3O6Si: C, 59.61; H, 6.04; N, 8.69. Found: C, 59.62; H, 5.98;
N, 8.68.
1-β-[20,30-Di-O-acetyl-D-ribofuranosyl]-2-nitroimidazole
(β-26). Nucleoside β-18 (0.381 g, 0.67 mmol) was desilylated by
general procedure B. The crude product was purified by flash chroma-
tography (starting with hexanes/EtOAc, 1:1, Rf 0.18, and then hexanes/
EtOAc, 1:5) to give alcohol β-2618 (0.158 g, 71%) as yellow crystals: mp
125ꢀ126 °C (1,2-C2H4Cl2/i-Pr2O) (lit.18 mp 122ꢀ123 °C); [α]2D0
+29.82 (c 1.1, acetone); IR (Si) νmax 3374, 3121, 2937, 1750, 1541,
1-α-[20,30-Di-O-acetyl-50-O-(tert-butyldiphenylsilyl)-D-
ribofuranosyl]-2-nitroimidazole (α-18). Ac2O (0.3 mL) was
added to a solution of diol α-30 (0.070 g, 0.145 mmol) in dry pyridine
(0.3 mL) and dry CHCl3 (2 mL). The mixture was heated and stirred
for 30 min at 50 °C (TLC, hexanes/EtOAc, 1:1). After cooling, water
(5 mL) and 2 M HCl (5 mL) were added. The resulting mixture
was extracted with EtOAc (3 ꢁ 10 mL). The combined organic layers
were washed with saturated aq NaHCO3 (10 mL) and water (10 mL),
dried (Na2SO4), and concentrated under reduced pressure. The crude
1483, 1430, 1367, 1243, 1161, 1101, 1079, 1013 cmꢀ1; the 1H and 13
C
NMR data are identical to those of the literature.18 Anal. Calcd for
C12H15N3O8: C, 43.77; H, 4.59; N, 12.76. Found: C, 43.86; H, 4.42;
N, 12.73.
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The Journal of Organic Chemistry
ARTICLE
product was purified by flash chromatography (hexanes/EtOAc, 2:1,
Rf 0.56 for hexanes/EtOAc, 1:1) to give diacetate α-18 (0.074 g, 90%): mp
134ꢀ135 °C (CHCl3/i-Pr2O); [α]2D0 ꢀ41.49 (c 0.4, acetone); IR (Si)
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νmax 2932, 2859, 1753, 1539, 1478, 1367, 1233, 1105 cmꢀ1; H NMR
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’ AUTHOR INFORMATION
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Corresponding Author
*E-mail: friedrich.hammerschmidt@univie.ac.at.
’ ACKNOWLEDGMENT
This work was supported by Grant L420-N19 from Der
Wissenschaftsfonds (FWF). We are very much indebted to Prof.
Dr. H.-J. Machulla for bringing this topic to our attention. We
thank S. Felsinger for recording the NMR spectra.
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