Studies toward oxyacetamide-linked RNA analogues: Synthesis and conformation of a modified dinucleoside

Article abstract of DOI:10.1055/s-0031-1289783

A new oxyacetamide-modified dinucleoside with 5-(S) chirality, a hydrophobic 5-C-(2-methoxyethyl) group, and a 2-O-methyl group was synthesized from d-glucose. This dinucleoside showed a helical structure based on CD and NMR spectroscopy. The sugar puckering at the 5 and 3 ends were found to be S'- and N'-types, respectively. These results were substantiated by ab initio density functional theory. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1289783

PAPER
▌2277
paper
Studies toward Oxyacetamide-Linked RNA Analogues: Synthesis and
Conformation of a Modified Dinucleoside
Synthesis of Dinucleoside with Oxyacetamide Backbone
Amit M. Jabgunde,a Sachin D. Yeole,a,b Shrihari P. Sanap,a Shridhar R. Gadre,b Dilip D. Dhavale*a
a
Garware Research Center, Department of Chemistry, University of Pune, Pune 411 007, India
b
Department of Chemistry, I.I.T. Kanpur, Kanpur 208016, India
Fax +91(2025691728; E-mail: ddd@chem.unipune.ac.in
Received: 09.03.2012; Accepted after revision: 09.05.2012
Dedicated to Prof. M. S. Wadia on the occasion of his 75th birthday
modification with a four-atom amide2b or a five-atom
oxy/thioacetamide7,8 has found significant importance. In
this respect, Jones and co-workers7 developed thymidine
derivatives with an oxyacetamido linkage I, which was
Abstract: A new oxyacetamide-modified dinucleoside with 5′-(S)
chirality, a hydrophobic 5′-C-(2-methoxyethyl) group, and a 2′-O-
methyl group was synthesized from D-glucose. This dinucleoside
showed a helical structure based on CD and NMR spectroscopy.
The sugar puckering at the 5′ and 3′ ends were found to be ‘S’- and found to be water soluble and stable under physiologi-
‘N’-types, respectively. These results were substantiated by ab ini-
tio density functional theory.
cal/basic conditions. The molecular model study indicated
that the internucleoside distance in the oxyacetamido
Key words: modified dinucleoside, circular dichroism, oxyacet-
amide backbone, antisense agents, carbohydrates
backbone is close to that in polynucleotides. Egli and co-
workers reported that five-atom amide linkers, when com-
bined with appropriate sugar modifications, are compati-
ble with high-affinity RNA binding compared with that of
Over the last two decades, several modified antisense native DNA.2d Similarly, Kumar and co-workers reported
and/or antigene oligonucleotides (AONs) have been de- five-atom thioacetamide-linked oligonucleotides and
veloped to achieve an increased binding affinity towards demonstrated higher RNA binding selectivity as com-
complementary DNA/RNA with exonuclease stability pared to complementary DNA.8
and improved cellular uptake.1 These modifications in-
In addition, the chirality of the backbone was also found
volve: (i) replacement of the negatively charged phospho-
to play an important role in the hybridization properties of
diester with neutral phospho- and/or dephospho-
the modified AONs. In this respect, De Mesmaeker et al.3a
internucleoside linkages2 with C5′ chirality,3 (ii) estab-
synthesized chiral amide linked DNA and 2′-OMe RNA
with a methyl group at C5′ in both ‘R’ IIa and ‘S’ IIb con-
figurations and observed the improvement in thermal sta-
bility only when C5′ has the ‘S’ configuration (ΔTm
ranging from +3 to +4 °C/mod.). Similarly, Seth et al. re-
ported that the 5′-(S)-methyl group is compatible with the
lishment of a rigid sugar conformation by introduction of
2′-alkoxy, -thio, or -fluoro groups4 or by locking the con-
formation,5 and (iii) insertion of a hydrophobic group in
the vicinity of the phosphate to increase enzymatic stabil-
ity.3c,6 As far as the modification of phosphodiester with a
neutral backbone is concerned, a number of dephospho-
high affinity recognition of complementary nucleic acids
internucleoside linkages such as siloxane, carbonate, and
as compared to the 5′-(R)-methyl group.3c
carboxymethyl ester were introduced.1a Amongst these,
HO
HO
HO
T
B
T
O
O
O
HO
T
O
R1
O
O
P
O
OH
O
O
O–
H/OMe
T
O
NH
O
NH
O
HN
H
H
T
T
O
O
B
5'
O
O
R1
R2
5'
5'
5'
4'
MeO
1'
2'
1'
1'
1'
2'
2'
2'
3'
R2
HO
HO
H/OMe
HO
OMe
HO
III B = uracil, R1 = OH,
2 = OMe
IV B = thymine, R1 = OMe,
2 = OMe
IIa R1 = H, R2 = Me 5'-(R)
IIb R1 = Me, R2 = H 5'-(S)
I
14
R
R
Figure 1 Structure of modified dinucleosides
SYNTHESIS 2012, 44, 2277–2286
Advanced online publication: 19.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289783; Art ID: SS-2012-T0252-OP
© Georg Thieme Verlag Stuttgart · New York

2278
A. M. Jabgunde et al.
PAPER
The other parameter that influences the properties of OAc group.16 The 3-N of thymine residue in 5 was pro-
AONs is substitution at the C2′ carbon of the sugar fura- tected as its benzyloxymethyl derivative using benzyloxy-
nose such as 2′-O-methyl, 2′-thioalkyl, 2′-fluoro, and 2′- methyl chloride, which on deacetylation (K2CO3, MeOH)
O-(2-methoxyethyl) pyrimidine nucleotides. Amongst of the 2′-OAc group and desilylation of 7′-OTBDPS using
these, 2′-O-methylation was found to stabilize the C3′- tetrabutylammonium fluoride in tetrahydrofuran afforded
endo form (N-type) of the 3′-nucleotidyl unit of dinucleo- diol 6. Treatment of 6 with iodomethane in sodium hy-
side III resulting in a higher binding affinity.9 Inspired by dride gave the dimethylated product, which on reduction
these observations, and as a part of our continuous interest of the azide group (H2, 10% Pd/C) gave desired amine
in sugar and nucleoside chemistry,10 we have synthesized monomer 7a.
oxyacetamide-modified dinucleoside 14 with 5′-(S) con-
figuration, a hydrophobic 5′-C-2-methoxyethyl) group,
and a 2′-C-methoxy group (Figure 1). The helicity and the
For acid monomer 11a, D-glucose was converted into di-
acetone D-allose,17 which was reacted with ethyl bromo-
acetate in the presence of sodium hydride to give 818
N/S sugar conformations in dinucleoside 14 were deter-
(Scheme 2). Hydrolysis of the 5,6-acetonide group in 8,
mined by CD and NMR spectroscopy, respectively, and
oxidative cleavage of diol with sodium periodate, and re-
the observations were substantiated by ab initio calcula-
duction with sodium borohydride followed by silyl pro-
tection of the resulting C6 primary alcohol afforded 9.
tions. Our results in this direction are discussed herein.
The required nucleoside monomers 7a and 12 were syn- One-pot acetolysis and acetylation of the 2-OH afforded
thesized from D-glucose. Thus for amine monomer 7a, D- the glycosyl donor, which was glycosylated with silylated
glucose was converted into the diastereomeric inseparable thymine to give nucleoside 10. Benzyloxymethyl protec-
mixture of D-allo- and L-talo-configurated sugar β-hy- tion of 3-N of thymine residue in 10 followed by one-pot
droxy ester 1 in six steps with 87% yield as reported hydrolysis of the ethyl ester and 2′-OAc yielded nucleo-
earlier11 (Scheme 1). Reduction of 1 with lithium alumi- side acid monomer 11a.19 Having amine and acid nucleo-
num hydride, followed by regioselective protection of the side monomers in hand, we attempted the coupling
primary 7-OH with tert-butyldiphenylsilyl chloride and reaction. Thus, treatment of 7a and 11a with either N-[3-
conversion of the secondary 5-OH into its acetate afforded (dimethylamino)propyl]-N′-ethylcarbodiimide (EDCl) or
a separable diastereomeric mixture; column chromatogra- O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexa-
phy gave 2a and 2b in 4:1 ratio.12 Hydrolysis of the major fluorophosphate (HBTU) under a variety of reaction con-
acetate 2a gave 3 wherein; the stereochemical 5-(R) as- ditions (time and temperature) failed to give the
signment was established by desilylation in 3 and by dinucleoside. In fact, we isolated the lactone 12 in 52%
matching the spectral and analytical data with the reported yield due to intramolecular lactonization of the acid func-
compound.13 Mesylation of 3 using mesyl chloride and tionality with the 2′-OH group.
triethylamine in dichloromethane followed by sodium
Alternatively, we separately synthesized lactone 12 in
74% yield by treatment of 11a with EDCl and pentafluo-
rophenol (Scheme 2) and turned this lactone formation
into success by employing the aminolysis of lactone 12
azide treatment in N,N-dimethylformamide gave 5-(S)-az-
ido compound 4.14 One pot acetolysis of the 1,2-acetonide
and acetylation of the 2-OH afforded the glycosyl donor
which on modified Vorbruggen glycosylation15 with si-
with amine 7a using 1,2,4-triazole as an acyl-transfer
lylated thymine in the presence of trimethylsilyl triflate
gave β-nucleoside 5. The exclusive formation of β-nucle-
oside 5 could be due to the anchimeric assistance of the 2′-
catalyst20 affording dinucleoside 13 in 40% yield (Scheme
3).
O
7
6
OTBDPS
OEt
O
OTBDPS
R1
R2
R1
R2
H
H
4
H
5
O
O
HO
1
a
c
b
O
O
O
2
3
BnO
BnO
BnO
O
O
O
1
2a R1 = OAc, R2 = H
2b R1 = H, R2 = OAc
3 R1 = OH, R2 = H
d
f
4 R
1 = H, R2 = N3
OTBDPS
OH
H
OMe
O
H
H
O
T
O
R1
N3
BnO
T-BOM
N3
BnO
e
H2N
R2O
OAc
OH
OMe
5
6
7a R1 = T-BOM, R2 = Bn
7b R1 = T, R2 = H
T = thyminyl
g
Scheme 1 Synthesis of amine monomer 7a. Reagents and conditions: (a) 1. LiAlH4, THF, 91%; 2. TBDPSCl, imidazole, CH2Cl2, 96%; 3. Ac2O,
py, 80%; (b) K2CO3, MeOH, 96%; (c) 1. MsCl, Et3N; 2. NaN3, DMF, 71% (2 steps); (d) 1. Ac2O, AcOH, H2SO4, 75%; 2. thymine, BSA,
TMSOTf, MeCN, 73%; (e) 1. BOMCl, DBU, MeCN, CH2Cl2, 76%; 2. K2CO3, MeOH, 96%; 3. TBAF, THF, 75%; (f) 1. MeI, NaH, THF, 0
°C, 80%; 2. H2, 10% Pd/C, 88%; (g) H2, 10% Pd(OH)2/C, MeOH, 61%.
Synthesis 2012, 44, 2277–2286
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a Dinucleoside with an Oxyacetamide Backbone
2279
O
O
14 with the 5′-(S)-configuration, 2′-OMe group, and a 5′-
(2-methoxyethyl) side chain.
O
O
In order to confirm the helical conformation of dinucleo-
side 14, we performed circular dichroism (CD) studies.
Wherein the intensity of the CD signal of di- and oligonu-
cleotides is highly dependent on the proportion of mole-
cules that exist in a helical base-stacked conformation, as
opposed to a random conformation.3b,8b,21,22 The CD spec-
tra A (Figure 2) of dinucleoside 14 was recorded in the re-
gion 200–320 nm at 30 °C, which showed a strong
positive band at 275 nm, a strong negative band at 245 nm,
and a weak positive band at 220 nm. This data was found
to be similar to the reported CD profile of deoxyribose di-
nucleoside (TpT)21 and that of 2′-methoxy dinucleotide
(TmopTmo).22 This indicates that the oxyacetamide back-
bone of modified dinucleoside 14 with 5′-(S) configura-
tion adopts similar helical conformation as that of native
dinucleotide phosphate backbone as hypothesized by ear-
lier reports.21,22
O
a
b
O
D-glucose
O
OEt
8
OTBDPS
O
TBDPSO
T
O
O
O
d
c
O
O
O
OAc
O
OEt
9
OEt
10
OR1
TBDPSO
R2
O
T-BOM
O
e
O
O
OH
O
O
OH
O
12
11a R1 = TBDPS, R2 = T-BOM
f
11b R1 = H, R2 = thyminyl
Scheme 2 Synthesis of lactone monomer 12. Reagents and condi-
tions: (a) 1. ref. 17; 2. ref. 18; (b) 1. 30% HClO4, THF; 2. NaIO4,
acetone–H2O; 3. NaBH4 EtOH, 67% (3 steps); 4. TBDPSCl, imidaz-
ole, CH2Cl2, 94%; (c) 1. Ac2O, AcOH, H2SO4; 2. thymine, BSA,
TMSOTf, MeCN, 80%; (d) 1. BOMCl, DBU, MeCN, CH2Cl2, 73%;
2. LiOH·H2O, MeOH, H2O, 89%; (e) EDCl, pentafluorophenol,
CH2Cl2, 74%; (f) 1. TBAF, THF; 2. H2 (1.38 bar), 10% Pd(OH)2/C,
MeOH, 60% (2 steps).
O
Figure 2 CD profiles: A = dinucleoside 14, at concentration of 100
μM in water
NR2
R1O
N
O
O
a
Additionally, the CD spectra of 14 were recorded across a
range of temperatures 10–80 °C, wherein the major bands
at 275 and 245 nm showed a significant decrease in inten-
sity with an increase in temperature. This fact was sub-
stantiated by temperature dependent (30–80 °C) NMR
studies3b,21c of 14, wherein, the H6 proton of thymine
showed consistent upfield shift indicating an increase in
concentration of the unstacked conformation at higher
temperature (see Supporting Information, Figure S2). A
comparative study of corresponding monomers, 7a and 12
shows that, the chemical shift of H6 proton remains in-
variant with increase in temperature.
12
OH
O
O
N
NR2
O
NH
MeO
O
O
R3O
OMe
13 R1 = TBDPS,
b
R
2 = BOM, R3 = Bn
14 R1, R2, R3 = H
Scheme 3 Synthesis of dinucleoside 14. Reagents and conditions: (a)
7a, 1,2,4-triazole, DBU, CDCl3, 40%; (b) 1. TBAF, THF, 0 °C; 2. H2
(1.38 bar) 10% Pd(OH)2/C MeOH, (54% over 2 steps).
We further studied the sugar ring conformations of 14 in
1
deuterium oxide using H NMR spectroscopy. Assign-
ment of protons and coupling constant values were ob-
tained by decoupling experiments. In solution,
nucleosides and nucleotides exist in equilibrium between
north N-type (C3′-endo) and south S-type (C2′-endo) con-
Deprotection of C5′-O-silyl, 3-N-BOM, and C3′-O-ben-
zyl groups in 13 gave oxyacetamide linked dinucleoside
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2277–2286

2280
A. M. Jabgunde et al.
PAPER
formers and the percentage ratio of N/S conformer varies nucleoside due to perfect chirality in the backbone in or-
with respect to the presence of C2′ and C3′ substituents on der to achieve the minimum distance required for base
the sugar furanose ring. In general, the percentage N/S stacking conformation. The final B3LYP-optimized
conformation is determined by 1H NMR spectroscopy us- structure (Figure 3) of 14 showed a helical shape in accor-
ing the coupling constants between the sugar protons H1′– dance with CD spectra. However, theoretically calculated
H2′ and H3′–H4′ (J1′,2′ and J3′,4′). In 14, an accurate values lowest energy conformation (Figure 3) shows the position
for J1′,2′ is easily obtained with comparative ease, however of two bases perpendicular to each other. This fact result-
J3′,4′ is buried with complex multiplicity in the region δ = ed in an ambiguity in the base stacked conformation in 14.
4.20–4.40. Thus, using the J1′,2′ values we obtained the
population of C2′-endo (S%) of each sugar pucker using
the equation23 S% = 100 (J1′2′ – 1)6.9
and the results are given in Table 1.
The influence of monomethoxylation of dinucleoside
monophosphate [2′-O-methylcytidylyl-(3′→5′)-cytidine-
CmopC]24 as well as dimethoxylation of dinucleoside mo-
nophosphate (TmopTmo)22 on the sugar pucker of dinu-
cleoside is known. As shown in Table 1, in comparison to
native deoxyribose dinucleoside with a phosphodiester
backbone-TpT (5′-end sugar 30% N-type and 3′-end sugar
37% N-type),25 replacement of the phosphodiester back-
bone with an oxyacetamide linkage and the presence of
the 2′-OH group in 14 enforced the 5′-end sugar pucker
into the C2′-endo (S-type) conformation, while the 2′-
Figure 3 Lowest energy conformations of dinucleoside 14 and its
sugar units calculated in the solution phase
methoxylation of the 3′-end sugar of 14 significantly in-
creased the population of the N-type conformation analo-
gous to that observed in TmopTmo IV.
Furthermore, in the dinucleoside 14, the 5′-end sugar
adopts the S-type conformation while 3′-end sugar has the
Table 1 Sugar Furanose Conformation in Dinucleoside 14
N-type conformation (Figure 3). These observations were
TpTa
TmopTmob IV
N(%)
14
found to be in agreement with the conformations of sugar
rings found on the basis of 1H NMR spectrum of the dinu-
cleoside. Ab initio NMR calculations were also performed
for this B3LYP-optimized conformer of dinucleoside 14
using the same PCM model and water solvent. The chem-
ical shifts for hydrogen atoms were evaluated by compar-
ing with the reference viz. chemical shift of TMS
calculated at the same level of theory and with the same
SCRF model. The theoretically calculated 1H NMR chem-
ical shifts were also found to match quite well with their
experimental counterparts (Supporting Information,
Table S1).
furanose ring
5′-end
N(%)
J1′,2′ (Hz) N (%)
30
33
75
66
5.6
4.1
33
56
3′-end
a Ref. 21.
b Ref. 22.
The ability of density functional theory (DFT) to provide
reasonably accurate ab initio ground state geometries and
energies of molecules is well known and also the three-
parameter Becke–Lee–Yang–Parr (B3LYP) functional is
a popular one in contemporary DFT-based applications.
In general, the B3LYP functional26 is known to yield re-
sults that are reasonably close to experimental ones. In
view of this, the theoretical study of dinucleoside 14 was
carried out employing DFT with B3LYP functional and 6-
31+(d) basis set. Four different possible conformations of
dinucleoside 14 were generated based on the experimental
NMR. These structures were subjected for initial geome-
try optimization at HF/3-21G level of theory using
GAUSSIAN 4.1.27 These four conformers converged to
the same geometry after optimization. This minimum en-
ergy conformer of dinucleoside was again optimized at fi-
nal B3LYP/6-31+G(d) level applying Polarizable
Continuum Model (PCM) SCRF method available in
In conclusion, a convergent route has been developed for
the synthesis of 5-atom oxyacetamide internucleoside
linked dinucleoside 14 with 5′-(S) chirality, 5′-(2-meth-
oxyethyl) hydrophobic side chain, and 2′-OMe group. The
CD studies showed that the dinucleoside 14 exhibits heli-
cal structure with base stacking interactions. The NMR
studies showed 5′-end furanose ring adopting S-type and
3′-end preferring N-type conformation and these results
are substantiated by ab initio calculations. Our results thus
support the earlier reported fact that the chirality present
in the backbone could be responsible for the restricted ro-
tation of preorganized backbone resulting in to the base
stacked conformation of dinucleoside 14.
GAUSSIAN package with water as a solvent. Thus, in the Melting points were recorded with Thomas Hoover melting point
apparatus and are uncorrected. IR spectra were recorded with FT-IR
final optimized geometry of the dinucleoside 14 it was
found that the 5′-end sugar is rotated along the axis of di-
as a thin film or in Nujol mull or using KBr pellets. 1H NMR (300
Synthesis 2012, 44, 2277–2286
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of a Dinucleoside with an Oxyacetamide Backbone
2281
MHz) and 13C NMR (75 MHz) spectra were recorded using CDCl3
and/or D2O as solvent(s) with reference to TMS as an internal stan-
dard. Elemental analyses were carried out with a C,H-analyzer. Op-
tical rotations were measured using a polarimeter at 25 °C. TLC was
performed on pre-coated plates (0.25 mm, silica gel 60 F254). Col-
umn chromatography was carried out with silica gel (100–200
mesh). The reactions were carried out in oven-dried glassware un-
der a dry N2 atmosphere. MeOH, DMF, and THF were purified and
dried before use. Petroleum ether (PE) was the distillation fraction
bp 40–60 °C. LiAlH4, 10% Pd/C, and 10% Pd(OH)2/C were pur-
chased from Aldrich and/or Fluka.
[α]D26 +48 (c 1.30, CHCl3).
IR (neat): 3498, 1109, 1028 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.05 [s, 9 H, C(CH3)3], 1.37 (s, 3
H, CH3), 1.60 (s, 3 H, CH3), 1.62–1.83 (m, 2 H, H6), 2.97–3.32 (br
s, 1 H, exchangeable with D2O, OH), 3.76–3.94 (m, 2 H, H7), 4.00
(dd, J = 8.7, 4.4 Hz, 1 H, H3), 4.08 (dd, J = 8.7, 2.5 Hz, 1 H, H4),
4.20–4.28 (m, 1 H, H5), 4.56–4.60 (m, 2 H, H2, OCH2Ph), 4.77 (d,
J = 11.5 Hz, 1 H, OCH2Ph), 5.75 (d, J = 3.85, 1 H, H1), 7.20–7.43
(m, 11 H, HAr), 7.65–7.69 (m, 4 H, HAr).
13C NMR (75 MHz, CDCl3): δ = 19.1 [C(CH3)3], 26.6 (CH3), 26.8
[strong, C(CH3)3], 26.9 (CH3), 33.9 (C6), 62.3 (C7), 68.9 (C5), 72.0
(OCH2Ph), 76.8 (C2), 77.8 (C3), 81.1 (C4), 104.0 (C1), 112.8
(OCO), 127.7 (strong), 127.9, 128.1 (strong), 128.4 (strong), 129.7
(strong), 133.2, 133.3, 135.5 (strong), 137.5 (CAr).
5-O-Acetyl-3-O-benzyl-7-O-(tert-butyldiphenylsilyl)-6-deoxy-
1,2-O-isopropylidene-α-D-allo-hepto-1,4-furanose (2a)
D-Glucose was converted into a diastereometric mixture of 1 using
literature methods.11 A soln of 1 (6.76 g, 18.4 mmol) in THF (25
mL) was added over 10 min to a stirred soln of LiAlH4 (1.75 g, 46.1
mmol) in THF (20 mL) at 0 °C under a N2 atmosphere. The mixture
was stirred under N2 for 3 h at 25 °C, and quenched by careful ad-
dition of EtOAc and sat. aq NH4Cl, filtered, concentrated, and ex-
tracted with EtOAc (3 × 30 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The resi-
due was purified by column chromatography (PE–EtOAc, 1:1) to
afford an inseparable mixture of diastereomeric diols (5.44 g, 91%)
as a viscous oil.
Anal. Calcd for C33H42O6Si: C, 70.43; H, 7.52. Found: C, 70.31; H,
7.45.
5-Azido-3-O-benzyl-7-O-(tert-butyldiphenylsilyl)-5,6-dideoxy-
1,2-O-isopropylidene-β-L-talo-hepto-1,4-furanose (4)
A soln of 3 (3.49 g, 6.201 mmol), MsCl (0.72 mL, 9.302 mmol), and
Et3N (2.148 mL, 15.50 mmol) in anhyd CH2Cl2 (25 mL) was stirred
at 0 °C for 3 h. H2O (3 mL) was added to the mixture, which was
stirred for 15 min and then extracted with CH2Cl2 (3 × 30 mL). The
combined organic layers were dried (Na2SO4), and concentrated at
reduced pressure to afford 7 as a thick liquid. To the crude mesylate
in anhyd DMF (30 mL), NaN3 (0.523 g, 8.053 mmol) was added,
and the mixture was stirred at 120 °C for 6 h. EtOAc (90 mL) was
added to mixture, which was then washed with H2O (3 × 20 mL).
The organic layer was dried (Na2SO4), concentrated, and purified
by column chromatography (5% EtOAc–PE) to afford 4 as a vis-
cous oil (2.58 g, 71% over 2 steps); Rf = 0.6 (20% EtOAc–n-hex-
ane).
To an ice cooled soln of 5,7-diol (4.43g, 13.6 mmol) in anhyd
CH2Cl2 was added TBDPSCl (4.56 mL, 17.7 mmol) and imidazole
(1.11 g, 16.3 mmol) and the suspension was stirred at 25 °C. After
1 h, H2O (5 mL) and CHCl3 (20 mL) were added to the mixture, the
mixture was extracted with CHCl3 (3 × 25 mL), and the combined
organic layers were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by column chromatography
(15% EtOAc–PE) to give an inseparable mixture of monosilylated
alcohol (7.37 g, 96%) as a viscous oil; Rf = 0.23 (30% EtOAc–
n-hexane).
[α]D25 +43 (c 1.6, CHCl3).
IR (neat): 2930, 2108, 1261, 1109 cm–1.
To a soln of silylated alcohol (6.28 g, 11.1 mmol) in pyridine (20
mL, 20.0 mmol) at 25 °C was added Ac2O (40.7 mL, 40.1 mmol)
and the mixture was stirred for 3 h. The mixture was concentrated
and separated using column chromatography (4% EtOAc–PE) to af-
ford acetate 2a (5.39 g, 80%) as a viscous oil; Rf = 0.33 (20%
EtOAc–n-hexane).
[α]D27 +32 (c 1.92, CHCl3).
IR (neat): 1740, 1238, 1111, 1026 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.05 [s, 9 H, C(CH3)3], 1.35 (s, 3
H, CH3), 1.58 (s, 3 H, CH3), 2.01–1.82 (m, 2 H, H6), 1.87 (s, 3 H,
OCOCH3), 3.58–3.75 (m, 2 H, H7), 3.82 (dd, J = 8.8, 4.4 Hz, 1 H,
H4), 4.07 (dd, J = 8.8, 4.2 Hz, 1 H, H3), 4.50 (d, J = 11.2 Hz, 1 H,
OCH2Ph), 4.57 (t, J = 4.1 Hz, 1 H, H2), 4.72 (d, J = 11.2 Hz, 1 H,
OCH2Ph), 5.34–5.43 (m, 1 H, H5), 5.71 (d, J = 4.1 Hz, 1 H, H1),
7.20–7.50 (m, 11 H, HAr), 7.62–7.70 (m, 4 H, HAr).
13C NMR (75 MHz, CDCl3): δ = 19.1 [C(CH3)3], 20.9 (OCOCH3),
26.6 (CH3), 26.7 [strong, C(CH3)3], 26.8 (CH3), 33.5 (C6), 59.9
(C7), 69.8 (C5), 72.1 (OCH2Ph), 77.3 (C3), 78.9 (C4), 79.4 (C2),
103.9 (C1), 112.9 (OCO), 127.6 (strong), 127.9, 128.1, 128.3,
129.5, 133.6, 133.7, 135.5 (strong), 135.6 (strong), 137.4 (CAr),
170.3 (OCOCH3).
1H NMR (300 MHz, CDCl3): δ = 1.05 [s, 9 H, C(CH3)3], 1.37 (s, 3
H, CH3), 1.57 (s, 3 H, CH3), 1.95–2.21 (m, 2 H, H6), 3.72 (ddd, J =
11.4, 5.1, 2.6 Hz, 1 H, H5), 3.75–3.86 (m, 2 H, H7), 3.88 (dd, J =
8.8, 4.0 Hz, 1 H, H3), 4.10 (dd, J = 8.8, 2.6 Hz, 1 H, H4), 4.59 (d,
J = 11.8 Hz, 1 H, H5), 4.65 (t, J = 4.0 Hz, 1 H, H2), 4.80 (d, J = 11.8
Hz, 1 H, OCH2Ph), 5.76 (d, J = 4.0 Hz, 1 H, H1), 7.27–7.43 (m, 11
H, HAr), 7.64–7.70 (m, 4 H, HAr).
13C NMR (75 MHz, CDCl3): δ = 19.1, 26.5, 26.8, 26.9, 33.7, 57.3,
60.1, 72.2, 77.3, 78.2, 80.5, 104.0, 113.2, 127.7, 127.9, 128.1,
128.5, 129.7, 133.3, 133.4, 135.4, 135.4, 137.3.
Anal. Calcd for C33H41N3O5Si: C, 67.43; H, 7.03. Found: C, 67.31;
H, 7.12.
1-[2-O-Acetyl-5-azido-3-O-benzyl-5-C-[(S)-2-(tert-butyldiphe-
nylsiloxy)ethyl]-5,6-dideoxy-β-D-ribofuranosyl]thymine (5)
A soln of azide 4 (2 g, 3.403 mmol) in AcOH (6 mL), Ac2O (9 mL),
and H2SO4 (0.05 mL) was stirred at 0 °C for 2 h. Neutralization with
sat. K2CO3 soln, extraction with CH2Cl2, and column chromatogra-
phy (6% EtOAc–PE) gave an anomeric mixture (~8:2) of diacetates
(1.61 g, 75%) as thick liquid. To the well-stirred soln of thymine
(162 mg, 1.20 mmol) and BSA (0.81 mL, 3.316 mmol) in anhyd
MeCN was added soln of diacetate (635 mg, 1.005 mmol) in anhyd
MeCN at 25 °C. The mixture was cooled to 0 °C and TMSOTf
(0.182 mL, 1.005 mmol) was added dropwise and mixture was
stirred at 75 °C for 5 h. To the cooled (0 °C) mixture in CHCl3 (10
mL) was added sat. aq NaHCO3 soln (5 mL). The mixture was ex-
tracted with CHCl3 (3 × 20 mL), and the combined organic layers
were washed with brine and concentrated. Purification by column
chromatography (20% EtOAc–PE) gave nucleoside 5 (0.47 g, 73%)
as a white foam; Rf = 0.50 (35% EtOAc–PE).
Anal. Calcd for C35H44O7Si: C, 69.51; H, 7.52. Found: C, 69.66; H,
7.43.
3-O-Benzyl-7-O-(tert-butyldiphenylsilyl)-6-deoxy-1,2-O-isopro-
pylidene-α-D-allo-hepto-1,4-furanose (3)
To a stirred soln of 2a (3.77g, 0.624 mmol) in MeOH, K2CO3 (1.89
g, 1.373 mmol) was added and the mixture was stirred at 25 °C for
30 min. The mixture was neutralized with 1 M HCl and concentrat-
ed under reduced pressure. Purification by column chromatography
(15% EtOAc–PE) afforded 3 (3.4 g, 96%) as a viscous oil; Rf = 0.16
(20% EtOAc–n-hexane).
[α]D26 +42 (c 1.8, CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2277–2286

2282
A. M. Jabgunde et al.
PAPER
IR (neat): 2929, 2112, 1747, 1695, 1234, 1111 cm–1.
Anal. Calcd for C43H49N5O7Si: C, 66.56; H, 6.36. Found: C, 66.50;
H, 6.35.
1H NMR (300 MHz, CDCl3): δ = 1.07 [s, 9 H, C(CH3)3], 1.90–1.98
(m, 5 H, COCH3, H6′), 2.13 (s, 3 H, CH3), 3.76–3.88 (m, 3 H, H5′,
H7′), 4.06 (dd, J = 6.1, 2.2 Hz, 1 H, H4′), 4.25 (t, J = 6.1 Hz, 1 H,
H3′), 4.48 (d, J = 11.1 Hz, 1 H, H5′), 4.65 (d, J = 11.1 Hz, 1 H,
OCH2Ph), 5.35 (dd, J = 6.1, 3.6 Hz, 1 H, H2′), 5.94 (d, J = 3.6 Hz,
1 H, H1′), 7.31–7.45 (m, 12 H, H6, HAr), 7.63–7.68 (m, 4 H, HAr),
8.98 (s, 1 H, NH).
1H NMR (75 MHz, CDCl3): δ = 12.5, 19.1, 20.6, 26.7, 33.4, 58.5,
59.9, 73.5, 73.6, 76.1, 82.9, 88.2, 111.4, 127.7, 128.1, 128.2, 128.5,
129.7, 135.3, 135.4, 135.6, 136.8, 150.0, 163.5, 169.9.
5′-Azido-3′-O-benzyl-3-N-(benzyloxymethyl)-5′-deoxy-5′-C-
[(S)-2-hydroxyethyl]thymidine (6)
A 1 M soln of TBAF in THF (1.19 mL, 1.190 mmol) was added to
a soln of the monoalcohol (616 mg, 0.794 mmol) in THF (20 mL)
at 0 °C. The mixture was stirred for 1.5 h. Sat. aq NH4Cl soln was
added until neutrality and the mixture was extracted with EtOAc (3
× 20 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated in vacuo. The residue was purified by col-
umn chromatography (40% EtOAc–PE) to afford 6 (320 mg, 75%)
as a white foam; Rf = 0.24 (50% EtOAc–PE).
Anal. Calcd for C37H43N5O7Si: C, 63.68; H, 6.21. Found: C, 63.75;
H, 6.29.
[α]D21 +23 (c 1.7, CHCl3).
IR (neat): 3433, 2108, 1708, 1668 cm–1.
2′-O-Acetyl-5′-azido-3′-O-benzyl-3-N-(benzyloxymethyl)-5′-C-
[(S)-2-(tert-butyldiphenylsiloxy)ethyl]-5′-deoxythymidine
DBU (0.083 mL, 0.559 mmol) was added to a suspension of 5 (300
mg, 0.430 mmol) in MeCN (2 mL) and CH2Cl2 (2 mL) at r.t. At 10
°C, BOMCl (0.119 mL, 0.860 mmol) was added over 5 min. After
4 h at 16–18 °C, the mixture was diluted with EtOAc (15 mL) and
washed with H2O (2 × 5 mL) and sat. aq NaHCO3 (5 mL). The or-
ganic layer was dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by column chromatography (12% EtOAc–
PE) to afford BOM-protected thymidine (266 mg, 76%) as a white
foamy solid; Rf = 0.48 (30% EtOAc–PE).
1H NMR (300 MHz, CDCl3–D2O): δ = 1.70–2.20 (m, 5 H, CH3,
H6′), 3.62–3.72 (m, 1 H, H5′), 3.77 (t, J = 6.0 Hz, 2 H, H7′), 4.07
(dd, J = 5.8, 3.6 Hz, 1 H, H4′), 4.15 (t, J = 5.8 Hz, 1 H, H3′), 4.26
(dd, J = 5.8, 4.8 Hz, 1 H, H2′), 4.65 (AB q, J = 11.5 Hz, 2 H,
OCH2Ph), 4.70 (s, 2 H, OCH2Ph), 5.48 (AB q, J = 9.6 Hz, 2 H,
NCH2O), 5.77 (d, J = 4.8 Hz, 1 H, H1′), 7.20–7.44 (m, 11 H, H6,
HAr).
13C NMR (75 MHz, CDCl3–D2O): δ = 13.2, 33.2, 58.8, 59.3, 70.6,
72.2, 72.7, 73.3, 77.7, 83.1, 91.6, 110.6, 127.6, 127.7, 128.2, 128.6,
128.7, 134.9, 136.5, 137.8, 151.1, 163.1.
[α]D26 +33 (c 0.89, CHCl3).
IR (neat): 2926, 2112, 1745, 1674, 1462, 1089 cm–1.
Anal. Calcd for C27H31N5O7: C, 60.3; H, 5.81. Found: C, 66.40; H,
5.73.
1H NMR (300 MHz, CDCl3): δ = 1.05 [s, 9 H, (C(CH3)3], 1.82–2.00
(m, 5 H, COCH3, H6′), 2.06 (s, 3 H, CH3), 3.70–3.86 (m, 3 H, H5′,
H7′), 4.04 (dd, J = 7.5, 2.4 Hz, 1 H, H4′), 4.22 (dd, J = 7.5, 5.7 Hz,
1 H, H3′), 4.45 (d, J = 11.3 Hz, 1 H, OCH2Ph), 4.64 (d, J = 11.3 Hz,
1 H, OCH2Ph), 4.69 (s, 2 H, OCH2Ph), 5.36 (dd, J = 5.4, 3.0 Hz, 1
H, H2′), 5.47 (AB q, J = 9.6 Hz, 2 H, NCH2O), 5.89 (d, J = 3.0 Hz,
1 H, H1′), 7.20–7.48 (m, 17 H, H6, HAr), 7.60–7.70 (m, 4 H, HAr).
13C NMR (75 MHz, CDCl3): δ = 13.3, 19.2, 20.7, 26.8, 33.6, 58.5,
60.1, 70.6, 72.2, 73.6, 73.8, 76.2, 82.8, 89.4, 110.7, 127.6, 127.7,
127.8, 128.1, 128.2, 128.3, 128.6, 129.8, 133.1, 133.2, 134.4, 135.4,
135.5, 136.9, 137.9, 150.7, 163.2, 169.8.
5′-Azido-3′-O-benzyl-3-N-(benzyloxymethyl)-5′-deoxy-2′-O-
methyl-5′-C-[(S)-2-methoxyethyl]thymidine
A soln of nucleoside 6 (205 mg, 0.381 mmol) in anhyd THF (3 mL)
was added dropwise to a stirred suspension of 60% NaH (76 mg,
1.907 mmol) in anhyd THF (3 mL) at 0 °C followed by addition of
MeI (0.238 mL, 3.81 mmol). The mixture was stirred for 5 h and
neutralized with NH4Cl, EtOAc (60 mL) was added, and organic
phase was washed with brine and sat. aq NaHCO3 (3 × 20 mL), and
dried (Na2SO4). The solvent was removed under reduced pressure
and the residue was purified by column chromatography (silica gel,
20% EtOAc–PE) to afford dimethylated nucleoside (172 mg, 80%)
as a white foam; Rf = 0.7 (50% EtOAc–PE).
Anal. Calcd for C45H51N5O8Si: C, 66.07; H, 6.28. Found: C, 66.05;
H, 6.35.
[α]D21 +73 (c 0.55, CHCl3).
IR (neat): 2106, 1703, 1668, 2926 cm–1.
5′-Azido-3′-O-benzyl-3-N-(benzyloxymethyl)-5′-C-[(S)-2-(tert-
butyldiphenylsiloxy)ethyl]-5′-deoxythymidine
1H NMR (300 MHz, CDCl3): δ = 1.92 (s, 3 H, CH3), 1.98–2.04 (m,
2 H, H6′), 3.03–3.08 (m, 1 H, H5′), 3.37 (s, 3 H, OCH3), 3.50–3.62
(m, 5 H, H7′, OCH3), 3.76 (dd, J = 5.1, 1.5 Hz, 1 H, H4′), 3.94 (dd,
J = 8.1, 5.1 Hz, 1 H, H3′), 4.12 (dd, J = 8.1, 1.8 Hz, 1 H, H2′), 4.56
(d J = 11.7 Hz, 1 H, OCH2Ph), 4.68 (d J = 11.7 Hz, 1 H, OCH2Ph),
4.71 (s, 2 H, OCH2Ph), 5.48 (AB q, J = 9.9 Hz, 2 H, NCH2O), 5.89
(d, J = 1.8 Hz, 1 H, H1′), 7.20–7.44 (m, 10 H, HAr), 7.53 (br s, 1 H,
H6).
To a stirred soln of BOM-protected thymidine (266 mg, 0.325
mmol) in MeOH (5 mL) was added K2CO3 (67 mg, 0.487 mmol)
and the mixture was stirred at 25 °C for 30 min. The mixture was
neutralized with 1 M HCl, concentrated under reduced pressure, and
extracted with EtOAc (3 × 10 mL). The combined organic extracts
were dried (Na2SO4), filtered, and concentrated in vacuo. The resi-
due was purified by column chromatography (14% EtOAc–PE) to
afford the monoalcohol (0.242 mg, 96%) as a white foamy solid;
Rf = 0.55 (40% EtOAc–n-hexane).
13C NMR (75 MHz, CDCl3): δ = 13.4, 31.82, 58.4, 58.7, 59.9, 68.5,
70.5, 72.2, 72.7, 76.1, 81.7, 82.1, 88.7, 110.1, 127.7, 127.9, 128.2,
128.5, 134.1, 136.9, 137.9, 150.6, 163.3.
[α]D25 +11 (c 1.0, CHCl3).
IR (neat): 3444, 2928, 2112, 1712, 1668, 1464, 1091 cm–1.
Anal. Calcd for C29H35N5O7: C, 61.58; H, 6.24. Found: C, 61.51; H,
6.23.
1H NMR (300 MHz, CDCl3–D2O): δ = 1.07 [s, 9 H, C(CH3)3], 1.82–
2.02 (m, 5 H, CH3, H6′), 3.76–3.94 (m, 3 H, H5′, H7′), 4.12 (dd, J =
5.4, 2.7 Hz, 1 H, H4′), 4.21 (t, J = 5.4 Hz, 1 H, H3′), 4.29 (dd, J =
5.4, 4.0 Hz, 1 H, H2′), 4.70 (AB q, J = 11.5 Hz, 2 H, OCH2Ph), 4.75
(s, 2 H, OCH2Ph), 5.54 (AB q, J = 9.6 Hz, 2 H, NCH2O), 5.82 (d,
J = 4.0 Hz, 1 H, H1′), 7.20–7.55 (m, 17 H, H6, HAr), 7.62–7.80 (m,
4 H, HAr).
13C NMR (75 MHz, CDCl3–D2O): δ = 13.7, 19.5, 26.5, 33.8, 58.6,
60.1, 70.4, 72.2, 73.3, 73.6, 77.8, 83.5, 91.2, 110.2, 127.6, 127.7,
127.8, 128.1, 128.3, 128.6, 128.8, 129.9, 133.1, 133.2, 134.8, 135.4,
135.5, 136.5, 138, 150.1, 163.1.
5′-Amino-3′-O-benzyl-3-N-(benzyloxymethyl)-5′-deoxy-2′-O-
methyl-5′-C-[(S)-2-methoxyethyl]thymidine (7a)
The nucleoside (150 mg 0.265 mmol) was dissolved in MeOH and
hydrogenated at 1.38 bar using 10% Pd/C (15 mg) at 30 °C for 3 h.
The mixture was filtered through Celite, concentrated, and purified
using column chromatography (3% MeOH–CHCl3) to afford 7a
(126 mg, 88%) as a white foam.
IR (neat): 1708, 1626, 2926 cm–1.
Synthesis 2012, 44, 2277–2286
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a Dinucleoside with an Oxyacetamide Backbone
2283
1H NMR (300 MHz, CDCl3–D2O): δ = 1.60–2.07 (m, 5 H, CH3,
H6′), 3.07–3.20 (m, 1 H, H5′), 3.35 (s, 3 H, OCH3), 3.49–3.63 (m,
5 H, H7′, OCH3), 3.83 (dd, J = 5.4, 2.5 Hz, 1 H, H2′), 3.97 (dd, J =
7.2, 3.0 Hz, 1 H, H4′), 4.04 (dd, J = 7.2, 5.4 Hz, 1 H, H3′), 4.60 (d,
J = 11.7 Hz, 1 H, OCH2Ph), 4.72 (d, J = 11.7 Hz, 1 H, OCH2Ph),
4.75 (s, 2 H, OCH2Ph), 5.55 (AB q, J = 9.6 Hz, 2 H, NCH2O), 5.90
(d, J = 2.5 Hz, 1 H, H1′), 7.20–7.50 (m, 10 H, HAr), 7.80 (s, 1 H, H6).
13C NMR (75 MHz, CDCl3): δ = 13.1, 34.7, 49.1, 58.3, 58.6, 70.1,
70.4, 72.2, 72.4, 75.9, 81.7, 84.3, 89.2, 109.9, 127.5, 127.6, 127.9,
128.1, 128.2, 128.4, 128.5, 135.5, 137.4, 137.9, 150.6, 163.3.
13C NMR (75 MHz, CDCl3): δ = 14.1, 26.4, 26.6, 60.3, 61.3, 67.3,
78.1, 78.7, 103.8, 113.1, 170.7.
Anal. Calcd For C12H20O7: C, 52.17; H, 7.60. Found: C, 52.26; H,
7.63.
5-O-(tert-Butyldiphenylsilyl)-3-O-[(ethoxycarbonyl)methyl]-
1,2-isopropylidene-α-D-ribofuranose (9)
To an ice-cooled soln of the alcohol (1.649 g, 5.9 mmol) in anhyd
CH2Cl2 (20 mL) was added TBDPSCl (3.07 mL, 11.9 mmol) and
the mixture was stirred under a N2 atmosphere for 15 min. To the
mixture was added imidazole (0.812 mg, 11.9 mmol) and the sus-
pension was stirred at 25 °C for 1 h. H2O (5 mL) and CHCl3 (20 mL)
were added to the mixture, and it was extracted with CHCl3 (3 × 25
mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography (10% EtOAc–PE) to afford 9 (2.88 g, 94%) as
a viscous oil; Rf = 0.44 (20% EtOAc–PE).
Anal. Calcd for C29H37N3O7: C, 64.55, H, 6.9. Found: C, 64.49; H,
6.93.
5′-Amino-5′-deoxy-2′-O-methyl-5′-C-[(S)-methoxyethyl]thymi-
dine (7b)
To the solution of amine nucleoside 7a (120 mg, 0.222 mmol) in
MeOH was added Pd(OH)2 (6 mg, 5%) at 30 °C and stirred under
hydrogen pressure (1.38 bar) for 10 h. The reaction mixture was fil-
tered through Celite, concentrated and purified by column chroma-
tography (6% MeOH–CHCl3) to afford 7b (44 mg, 61%) as a white
foam; Rf = 0.1 (10% MeOH–CHCl3).
[α]D20 +21 (c 1.5, CHCl3).
IR (neat): 2929, 1748 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.04 [s, 9 H, C(CH3)3], 1.26 (t, J =
7.2 Hz, 3 H, CH3), 1.38 (s, 3 H, CH3), 1.57 (s, 3 H, CH3), 3.84 (dd,
J = 11.4, 2.1 Hz, 1 H, H5), 4.03 (br d, J = 11.4 Hz, 1 H, H5), 4.17
(AB q, J = 9.0 Hz, 2 H, OCH2CO), 4.16–4.27 (m, 4 H, H3, H4,
OCH2CH3), 4.78 (t, J = 3.3 Hz, 1 H, H2), 5.77 (d, J = 3.3 Hz, 1 H,
H1), 7.33–7.48 (m, 6 H, HAr), 7.64–7.76 (m, 4 H, HAr).
13C NMR (75 MHz, CDCl3): δ = 14.1, 19.3, 26.5, 26.7, 60.9, 61.7,
68.1, 78.3, 78.5, 79.1, 103.7, 113.0, 127.6, 127.7, 129.6, 129.7,
132.9, 133.4, 135.5, 135.6, 170.7.
[α]D31 +9 (c 0.2, MeOH).
IR (neat): 3360, 1668, 2926 cm–1.
1H NMR (300 MHz, D2O): δ = 1.90 (s, 3 H, CH3), 1.91–2.20 (m, 2
H, H6′), 3.40 (s, 3 H, OCH3), 3.49 (s, 3 H, OCH3), 3.60–3.80 (m, 3
H, H5′, H7′), 4.05 (dd, J = 8.7, 5.4 Hz, 1 H, H4′), 4.31 (dd, J = 5.7,
4.8 Hz, 1 H, H2′), 4.49 (t, J = 5.7 Hz, 1 H, H3′), 5.75 (d, J = 4.8 Hz,
1 H, H1′), 7.49 (s, 1 H, H6).
13C NMR (75 MHz, D2O): δ = 13.8, 30.8, 54.9, 60.7, 60.8, 71.3,
72.1, 83.5, 85.1, 93.3, 141.7, 153.9, 168.8.
Anal. Calcd for C28H38O7Si: C, 65.34. H, 7.44. Found: C, 65.39; H,
7.35.
Anal. Calcd for C14H23N3O6: C, 51.06; H, 7.04. Found: C, 51.13; H,
7.08.
2′-O-Acetyl-5′-O-(tert-butyldiphenylsilyl)-3′-O-[(ethoxycarbon-
yl)methyl]thymidine (10)
A soln of 9 (2.277 g, 4.43 mmol) in AcOH (6 mL), Ac2O (9 mL),
and H2SO4 (0.05 mL) was stirred at 0 °C for 1 h. Neutralization with
sat. aq K2CO3 soln, extraction with CH2Cl2 (25 mL), and column
chromatography (10% EtOAc–PE) gave an anomeric mixture
(~8:2) of the acetate (1.93 g, 78%) as a viscous oil. To the well-
stirred soln of thymine (0.732 g, 5.8 mmol) and BSA (3.54 mL, 14.5
mmol) in anhyd MeCN was added soln of the above acetate (2.7 g,
4.83 mmol) in anhyd MeCN at 25 °C. The mixture was cooled to 0
°C and TMSOTf (0.875 mL, 4.83 mmol) was added dropwise. The
mixture was stirred at 70 °C for 4 h and cooled to 0 °C. CHCl3 (25
mL) and subsequently sat. aq NaHCO3 soln (5 mL) were added. The
mixture was extracted with CHCl3 (3 × 60 mL), and the combined
organic layers were extracted with brine and concentrated. Purifica-
tion by column chromatography (20% EtOAc–PE) afforded nucle-
oside 10 (2.415 g, 80%) as a white solid; mp 125–127 °C; Rf = 0.43
(40% EtOAc–PE).
3-O-[(Ethoxycarbonyl)methyl]-1,2-isopropylidene-α-D-ribofu-
ranose
D-Glucose was converted into a alkylated allose 8 as reported earli-
er.17.18 To a soln of 8 (11.92 g 34.41 mmol) in THF (10 mL) at 0 °C
was added 30% HClO4 (10 mL) dropwise. The mixture was stirred
for 15 min at same temperature and neutralized using K2CO3, fil-
tered, and concentrated to afford the diol as a viscous oil.
To a soln of diol (8.942 g, 29.19 mmol) in acetone–H2O at 0 °C,
NaIO4 (9.366 g, 43.78 mmol) was added and mixture was stirred for
3 h. The excess of NaIO4 was decomposed using ethylene glycol (2
mL), and the mixture was concentrated and extracted with CHCl3 (3
× mL). Concentration of the combined organic layers afforded the
aldehyde as a thick oil.
To a soln of the aldehyde (7.44 g, 27.12 mmol) in EtOH (60 mL)
was added NaBH4 (1.003 g, 27.12 mmol) portionwise at –5 °C. The
mixture was stirred for 45 min and neutralized with 10% HCl (pH
7). Solvent was removed at reduced pressure and mixture was ex-
tracted with EtOAc (3 × 50 mL). The combined organic layers were
washed with H2O and brine, and dried (Na2SO4). Removal of sol-
vent at reduced pressure and column chromatography (silica gel,
25% EtOAc–PE) afforded the alcohol (6.36 g, 67% over 3 steps) as
a viscous oil; Rf = 0.48 (EtOAc).
[α]D28 +89 (c 2.6, CHCl3).
IR (neat): 3452, 1747, 2928 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.30 (t, J = 7.2 Hz, 3 H, CH3),
2.40–2.62 (br s, 1 H, exchangeable with D2O, OH), 1.37 (s, 3 H,
CH3), 1.59 (s, 3 H, CH3), 3.78–4.00 (m, 3 H, H3, H5), 4.12 (dt, J =
9.0, 3.0 Hz, 1 H, H4), 4.19 (d, J = 16.8 Hz, 1 H, OCH2CO), 4.24 (q,
J = 7.2 Hz, 2 H, OCH2CH3), 4.33 (d, J = 16.8 Hz, 1 H, OCH2CO),
4.71 (t, J = 3.6 Hz, 1 H, H2), 5.77 (d, J = 3.6 Hz, 1 H, H1).
[α]D21 +40 (c 0.77, CHCl3).
IR (neat): 1747, 1693, 1236, 1114 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.15 [s, 9 H, C(CH3)3], 1.30 (t, J =
7.2 Hz, 3 H, CH3), 1.61 (d, J = 1.1 Hz, 3 H, CH3), 2.21 (s, 3 H,
OCOCH3), 3.82 (dd, J = 11.4, 2.2 Hz, 1 H, H5a′), 4.11 (dd, J = 11.4,
2.2 Hz, 1 H, H5b′), 4.21 (q, J = 7.2 Hz, 2 H, OCH2CH3), 4.25 (d, J =
16.3 Hz, 1 H, OCH2CO), 4.29 (dd, J = 5.4, 3.3 Hz, 1 H, H3′), 4.32–
4.37 (m, 1 H, H4′), 4.42 (d, J = 16.3 Hz, 1 H, OCH2CO), 5.28 (dd,
J = 6.6, 5.4 Hz, 1 H, H2′), 6.29 (d, J = 6.6 Hz, 1 H, H1′), 7.36–7.54
(m, 7 H, HAr, H6), 7.66–7.80 (m, 4 H, HAr), 8.89–9.40 (br s, 1 H,
NH).
13C NMR (75 MHz, CDCl3): δ = 11.9, 14.1, 19.3, 20.6, 27.0, 61.0,
63.5, 68.5, 74.3, 77.8, 83.9, 85.5, 111.6, 127.9, 128.0, 130.0, 130.1,
132.3, 132.8, 134.9, 135.2, 135.6, 150.4, 169.6, 170.7.
Anal. Calcd for C32H40N2O9Si: C, 61.52; H 6.45. Found: C, 61.60;
H, 6.37.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2277–2286

2284
A. M. Jabgunde et al.
PAPER
2′-O-Acetyl-3-N-(benzyloxymethyl)-5′-O-(tert-butyldiphenylsi-
lyl)-3′-O-[(ethoxycarbonyl)methyl]thymidine
afford nucleoside 11b (0.016 g, 60% over two steps) as a white
foam; Rf = 0.33 (40% MeOH–CHCl3).
DBU (0.155 mL, 1.04 mmol) was added to a suspension of 10 (0.5
g, 0.8 mmol) in MeCN (2 mL) and CH2Cl2 (2 mL) at r.t. The mix-
ture was cooled to 10 °C and BOMCl (0.223 mL, 1.6 mmol) was
added. After 3.5 h at 20 °C, the mixture was diluted with EtOAc (15
mL) and washed with H2O (2 × 5 mL) and sat. aq NaHCO3 (5 mL).
The organic layer was dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was purified by column chromatography (17%
EtOAc–PE) to afford BOM-protected thymidine (440 mg, 73%) as
a white foamy solid; Rf = 0.61 (40% EtOAc–PE).
[α]D31 –17 (c 0.65, MeOH).
IR (neat): 3050, 1715 cm–1.
1H NMR (300 MHz, D2O): δ = 1.89 (s, 3 H, CH3), 3.82 (dd, J = 12.6,
4.1 Hz, 1 H, H5′a), 3.94 (dd, J = 12.6, 3.2 Hz, 1 H, H5′b), 4.04 (d,
J = 15.1 Hz, 1 H, OCH2CO), 4.05, 4.16 (t, J = 5.1 Hz, 1 H, H3′),
4.16 (d, J = 15.1 Hz, 1 H, OCH2CO), 4.18–4.26 (m, 1 H, H4′), 4.43
(t, J = 5.1 Hz, 1 H, H2′), 5.93 (d, J = 5.1 Hz, 1 H, H1′), 7.68 (s, 1 H,
H6).
[α]D23 +44 (c 1.32, CHCl3).
IR (neat): 1747, 2929, 1672, 1232 cm–1.
13C NMR (75 MHz, D2O): δ = 11.5, 60.7, 69.8, 72.5, 78.3, 82.4,
89.3, 111.4, 137.4, 151.6, 166.4, 177.8.
1H NMR (300 MHz, CDCl3): δ = 1.09 [s, 9 H, C(CH3)3], 1.24 (t, J =
7.2 Hz, 3 H, CH3), 1.59 (d, J = 0.8 Hz, 3 H, CH3), 2.15 (s, 3 H,
OCOCH3), 3.93 (dd, J = 12.0, 2.1 Hz, 1 H, H5a′), 3.99 (d, J = 16.5
Hz, 1 H, OCH2CO), 4.08 (dd, J = 12.0, 1.8 Hz, 1 H, H5b′), 4.16 (q,
J = 7.2 Hz, 2 H, OCH2CH3), 4.18 (d, J = 16.5 Hz, 1 H, OCH2CO),
4.22 (dd, J = 5.4, 4.0 Hz, 1 H, H3′), 4.25–4.30 (m, 1 H, H4′), 4.68
(s, 2 H, OCH2Ph), 5.21 (t, J = 5.6 Hz, 1 H, H2′), 5.46 (AB q, J = 9.6
Hz, 2 H, NCH2O), 6.22 (d, J = 5.6 Hz, 1 H, H1′), 7.20–7.48 (m, 12
H, HAr, H6), 7.60–7.74 (m, 4 H, HAr).
13C NMR (75 MHz, CDCl3): δ = 12.6, 14.1, 19.4, 20.7, 27.0, 61.0,
63.3, 68.5, 70.6, 72.2, 74.3, 77.5, 83.7, 86.7, 110.9, 127.6, 127.7,
127.9, 128, 128.2, 130.0, 130.1, 132.3, 132.8, 133.8, 135.3, 135.6,
137.9, 151.1, 163.3, 169.6, 170.2.
Anal. Calcd for C12H16N2O8: C, 45.57; H, 5.10. Found: C, 45.44; H,
5.03.
Thymidine Lactone 12
To a soln of sugar acid 11a in anhyd CH2Cl2 was added pentafluo-
rophenol (0.121 g, 0.658 mmol) followed by EDCl (0.126 g, 0.658
mmol) at 0 °C. The mixture was stirred for 4 h, diluted with CHCl3
and washed with 0.5 M HCl and brine. The organic layer was dried
(Na2SO4) and the solvent was removed under reduced pressure. Pu-
rification by column chromatography (20% EtOAc–PE) afforded
bicyclic lactone 12 (0.159 g, 74%) as a white foam; Rf = 0.53 (40%
EtOAc–PE).
IR (neat): 1745, 1693, 1230, 1112 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.12 [s, 9 H, C(CH3)3], 1.57 (d, J =
1.0 Hz, 3 H, CH3), 3.84 (dd, J = 12.0, 1.9 Hz, 1 H, H5′), 4.04 (dd,
J = 12.0, 2.3 Hz, 1 H, H5′), 4.10–4.26 (m, 3 H, H3′, H4′, OCH2CO),
4.50 (d, J = 17.2 Hz, 1 H, OCH2CO), 4.70 (s, 2 H, OCH2Ph), 4.90
(dd, J = 7.8, 4.8 Hz, 1 H, H2′), 5.50 (AB q, J = 9.6 Hz, 2 H, NCH2O),
6.47 (d, J = 7.8 Hz, 1 H, H1′), 7.20–7.50 (m, 12 H, HAr, H6), 7.60–
7.66 (m, 4 H, HAr).
13C NMR (75 MHz, CDCl3): δ = 12.5, 19.3, 27.1, 64.0, 64.5, 70.7,
72.2, 72.9, 78.6, 82.9, 86.5, 111.6, 127.6, 127.7, 128.0, 128.1,
128.2, 130.3, 130.4, 131.8, 133.2, 135.1, 135.2, 135.5, 137.8, 151.2,
163.0, 164.4.
Anal. Calcd for C40H48N2O10Si: C, 64.50; H, 6.49. Found: C, 64.59;
H, 6.55.
3-N-(Benzyloxymethyl)-5′-O-(tert-butyldiphenylsilyl)-3′-O-
(carboxymethyl)thymidine (11a)
To an ice cooled soln of the above nucleoside (0.4 g, 0.44 mmol) in
MeOH–H2O (4:1, 5 mL) was added LiOH·H2O (0.045 g, 1.08
mmol) at 0 °C. The mixture was brought up to 25 °C, stirred for 2.5
h and neutralized to pH 7 by addition of 1 M HCl. MeOH was evap-
orated and residue was extracted with CHCl3 (3 × 10 mL), the com-
bined CHCl3 layers were washed with H2O, dried (anhyd Na2SO4),
and the solvent removed under reduced pressure. Purification by
column chromatography (0.5% MeOH–CHCl3) afforded acid 11a
(0.321 g, 89%) as a white foam; Rf = 0.15 (10% MeOH–CHCl3).
Anal. Calcd for C36H40N2O8Si: C 65.83, H 6.14. Found: C, 65.85;
H, 6.19.
[α]D21 –4.88 (c 0.5, CHCl3).
Acetamido-Modified Dinucleoside 13
To a soln of nucleoside lactone 12 (0.048 g, 0.073 mmol) and nu-
cleoside amine 7a (0.047 g, 0.087 mmol) in CDCl3 was added 1,2,4-
triazole (0.005 g, 0.073 mmol) followed by addition of DBU (0.010
mL, 0.073 mmol). The mixture was stirred for 12 h at 25 °C, con-
centrated, and chromatographed (70% EtOAc–PE) to afford dimer
nucleoside 13 (0.035 g, 40%) as a white foam; Rf = 0.43 (60%
EtOAc–PE).
IR (neat): 3429, 1747 cm–1.
(NMR spectrum of this compound showed broadening of signals.)
1H NMR (300 MHz, CDCl3–D2O): δ = 1.06 [s, 9 H, C(CH3)3], 1.60
(s, 3 H, CH3), 3.76 (br d, J = 10.5 Hz, 1 H, H5′), 3.83–4.10 (m, 3 H,
H2′, H5′, OCH2CO), 4.10–4.36 (m, 3 H, H3′, H4′, OCH2CO), 4.52–
4.66 (br s, 2 H, OCH2Ph), 5.40 (br s, 2 H, NCH2O), 5.95 (br s, 1 H,
H1′), 7.18–7.65 (m, 12 H, HAr, H6), 7.65–7.75 (m, 4 H, HAr).
[α]D21 +1.8 (c 0.8, CHCl3).
13C NMR (75 MHz, CDCl3): δ = 12.5, 19.2, 27.1, 64.0, 70.7, 72.2,
72.9, 77.2, 78.7, 82.9, 86.4, 111.6, 127.6, 127.7, 127.9, 128.0,
128.1, 128.2, 128.3, 130.3, 130.4, 132.3, 132.3, 133.2, 135.1, 135.2,
135.5, 137.8, 151.2, 163.1, 164.4.
IR (neat): 1745, 1693, 1626, 2926 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.07 [s, 9 H, TA, C(CH3)3], 1.62
(s, 3 H, TA, CH3,), 1.62–2.05 (m, 5 H, TB, CH3, H6′), 3.29 (m, 4 H,
TB H5′, OCH3), 3.39–3.56 (m, 5 H, TB, OCH3, H7′), 3.77 (dd, J =
11.4, 2.7 Hz, 1 H, TA, H5′), 3.94 (t, J = 5.7 Hz, TB, 1 H, H4′), 3.98
(dd, J = 11.4, 3.8 Hz, 1 H, TA, H5′), 4.01–4.10 (m, 2 H, TA, H3′,
OCH2Ph), 4.14–4.24 (m, 3 H, TB-H2′, TA-H4′, OCH2Ph), 4.27 (t,
J = 5.5 Hz, 1 H, TA, H2′), 4.38–4.48 (m, 1 H, TB, H3′), 4.56–4.80
(m, 6 H, TA/TB, OCH2Ph, OCH2CO), 5.38 (d, J = 4.8 Hz, 1 H, TB,
H1′), 5.39–5.56 (m, 4 H, TA, TB, N-CH2O, N-CH2O), 5.92 (d, J =
5.5 Hz, 1 H, TA, H1′), 7.08 (br s, 1 H, NHCO), 7.24–7.44 (m, 22 H,
TA, TB, HAr, H6), 7.61–7.65 (m, 4 H, TA, HAr); TA: 5′-end thymidine,
TB: 3′-end thymidine.
Anal. Calcd for C36H42N2O9Si: C, 64.07, H, 6.27. Found: C, 64.01;
H, 6.26.
3′-O-(Carboxymethyl)thymidine (11b)
A 1 M soln of TBAF in THF (0.216 mL, 0.0261 mmol) was added
to a soln of nucleoside 11a (0.080 g, 0.0144 mmol) in THF (3 mL)
at 0 °C. The reaction mixture was stirred for 1.5 h. A sat. aq soln of
NH4Cl was added until neutrality and the mixture was extracted
with EtOAc (3 × 5 mL). The combined organic layer was dried
(Na2SO4), filtered and concentrated in vacuo. The crude compound
was subjected to hydrogenation using 10% Pd(OH)2/C (0.03 g) in
MeOH under hydrogen pressure (1.38 bar) for 3 h. The reaction
mixture was filtered through Celite, concentrated and purified by
column chromatography (6% MeOH–CHCl3 and 0.5% NH4OH) to
13C NMR (75 MHz, CDCl3): δ = 12.7, 12.9, 19.3, 26.9, 31.7, 48.3,
58.5, 58.8, 63.4, 69.3, 70.1, 70.4, 70.5, 73.1, 74.0, 77.2, 79.4, 80.1,
83.7, 90.4, 93.7, 110.5, 110.7, 127.6, 127.7, 127.8, 127.9, 128.0,
Synthesis 2012, 44, 2277–2286
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a Dinucleoside with an Oxyacetamide Backbone
2285
128.1, 128.2, 128.5, 130.0, 130.1, 132.3, 132.7, 134.2, 135.2, 135.5,
137.1, 137.6, 137.7, 137.8, 151.0, 151.4, 163.3, 169.4.
(2) (a) Ts’O, P. O. P.; Miller, P. S.; Aurelian, L.; Murakami, A.;
Agris, C.; Blake, K. R.; Lin, S. B.; Lee, B. L.; Smith, C. C.
Ann. N. Y. Acad. Sci. 1988, 507, 220. (b) De Mesmaeker, A.;
Lesueur, C.; Btvikrre, M. O.; Waldner, A.; Fritsch, V.; Wolf,
R. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2790.
(c) Crooke, S. T. Antisense Nucleic Acid Drug Dev. 1998, 8,
115. (d) Pallan, P. S.; von Matt, P.; Wilds, C. J.; Altmann,
K.-H.; Egli, M. Biochemistry 2006, 45, 8048.
Anal. Calcd for C65H77N5O15Si: C, 65.52, H, 6.71. Found: C, 65.29;
H, 6.41.
Deprotected Dinucleoside 14
A 1 M soln of TBAF in THF (0.019 mL, 0.0439 mmol) was added
to a soln of protected dinucleoside 13 (0.035 g, 0.0293 mmol) in
THF (2 mL) at 0 °C. The mixture was stirred for 1.5 h. Sat. aq
NH4Cl soln was added until neutrality and the mixture was extract-
ed with EtOAc (3 × 5 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated in vacuo. The crude compound
was subjected to hydrogenation using 10% Pd(OH)2/C (0.03 g) in
MeOH under H2 pressure (1.38 bar) for 5 h. The mixture was fil-
tered through Celite, concentrated, and purified by column chroma-
(3) (a) De Mesmaeker, A.; Leberton, J.; Jouanno, C.; Fritsch,
V.; Wolf, R. M.; Wendeborn, S. Synlett 1997, 1287.
(b) Bagmare, S.; D’Costa, M.; Kumar, V. A. Chem.
Commun. 2009, 6646. (c) Seth, P. P.; Allerson, C. R.;
Siwkowski, A.; Vasquez, G.; Berdeja, A.; Migawa, M. T.;
Gaus, H.; Prakash, T. P.; Bhat, B.; Swayze, E. E. J. Med.
Chem. 2010, 53, 8309. (d) Trafelet, H.; Parel, S. P.;
Leumann, C. J. Helv. Chim. Acta 2003, 86, 3671.
(4) (a) Martin, P. Helv. Chim. Acta 1995, 78, 486. (b) Shohda,
K.; Okamoto, I.; Wada, T.; Seio, K.; Sekine, M. Bioorg.
Med. Chem. Lett. 2000, 10, 1795. (c) Rajeev, K. G.; Prakash,
T. P.; Manoharan, M. Org. Lett. 2003, 5, 3005.
(d) Saneyoshi, H.; Seio, K.; Sekine, M. J. Org. Chem. 2005,
70, 10453.
(5) Lauritsen, A.; Wengel, J. Chem. Commun. 2002, 530.
(6) (a) Saha, A. K.; Caulfield, T. J.; Hobbs, C.; Upson, D. A.;
Waychunas, C.; Yawman, A. M. J. Org. Chem. 1995, 60,
788. (b) Wang, G.; Middleton, P. J. Tetrahedron Lett. 1996,
37, 2739.
(7) Gait, M. J.; Jones, A. S.; Walker, R. T. J. Chem. Soc., Perkin
Trans. 1 1974, 1684.
(8) (a) Gogoi, K.; Gunjal, A. D.; Phalgune, U. D.; Kumar, V. A.
Org. Lett. 2007, 9, 2697. (b) Gokhale, S. S.; Gogoi, K.;
Kumar, V. A. J. Org. Chem. 2010, 75, 7431.
(9) Kawai, G.; Yamamoto, Y.; Kamimura, T.; Masegi, T.;
Sekine, M.; Hata, T.; Iimori, T.; Watanabe, T.; Miyazawa,
T.; Yokoyama, S. Biochemistry 1992, 31, 1040.
(10) (a) Mane, R. S.; Ghosh, S.; Chopade, B. A.; Reiser, O.;
Dhavale, D. D. J. Org. Chem. 2011, 76, 2892. (b) Karche, N.
P.; Jachak, S. M.; Dhavale, D. D. J. Org. Chem. 2003, 68,
4531. (c) Sanap, S. P.; Ghosh, S.; Jabgunde, A. M.; Pinjari,
R. V.; Gejji, S. P.; Singh, S.; Chopade, B. A.; Dhavale, D. D.
Org. Biomol. Chem. 2010, 8, 3307. (d) Jabgunde, A. M.;
Kalamkar, N. B.; Chavan, S. T.; Sabharwal, S. G.; Dhavale,
D. D. Bioorg. Med. Chem. 2011, 19, 5912.
tography (5% MeOH–CHCl3
+ 0.5% NH4OH) to afford
dinucleoside 14 (0.01 g, 54% over 2 steps) as a white foam; Rf =
0.53 (20% MeOH–CHCl3).
[α]D22 –6.37 (c 0.27, MeOH).
IR (neat): 1708, 1626, 2926 cm–1.
1H NMR (300 MHz, D2O, recorded after 24 h): δ = 1.74–2.11 (m, 8
H, TA/TB CH3, H6′), 3.16–3.18 (m, 1 H, TB H5′), 3.34 (s, 3 H, TB
OCH3), 3.44–3.63 (m, 5 H, TB H7′, OCH3), 3.78 (dd, J = 12.6, 4.1
Hz, 1 H, TA H5′), 3.87 (dd, J = 12.6, 3.5 Hz, 1 H, TA H5′), 3.99 (t,
J = 5.9 Hz, 1 H, TB H4′), 4.06 (t, J = 5.3 Hz, 1 H, TA H3′), 4.12 [dd,
J = 5.6, 4.4 Hz, (apparent triplet) 1 H, TB H2′], 4.20–4.40 (m, 4 H,
TA H4′, TB H3′, OCH2CO), 4.47 (t, J = 5.6 Hz, 1 H, TA H2′), 5.78
(d, J = 4.4 Hz, 1 H, TB H1′), 5.95 (d, J = 5.6 Hz, 1 H, TA H1′), 7.48
(s, 1 H, TA H6), 7.65 (s, 1 H, TB H6); TA: 5′-end nucleoside, TB: 3′-
end nucleoside.
13C NMR (75 MHz, D2O): δ = 14.03, 33.1, 45.3, 60.5, 60.7, 63.4,
71.2, 71.7, 72.1, 74.9, 81.1, 84.2, 85.0, 87.1, 91.3, 91.8, 114.1,
139.6, 140.9, 154.1, 169.4, 174.6.
Anal. Calcd for C26H37N5O13: C, 49.76, H, 5.94. Found: C, 49.95;
H, 5.99.
CD Analysis
Samples of nucleosides 7b and 11b and dinucleoside 14 were pre-
pared in deionized H2O. CD analysis of compounds was carried out
at 100 μM concentration at varying temperature using 1-cm path
length cell. The CD spectrum was scanned from 320–200 nm wave-
length range for all the compounds. The data were processed using
OriginPro 8. The solvent baseline at each temperature was subtract-
ed from the sample data, and the resulting spectrum smoothed.
(11) Rauter, A. P.; Figueiredo, J. A.; Ismael, M. I.; Justino, J.
J. Carbohydr. Chem. 2004, 23, 513.
(12) Our attempts to separate the diastereomeric mixture of 5-C-
hydroxy derivatives, namely mesyl, tosyl, and benzoyl, were
unsuccessful.
Acknowledgment
(13) Bouc, G. L.; Thomassigny, C.; Greck, C. Tetrahedron:
Asymmetry 2006, 17, 2006.
We are thankful to Dr (Mrs) V. A. Kumar, Dr V. Madhuri for their
valuable discussions and Dr (Mrs) Moneesha D’Costa for CD spec-
troscopy study. We gratefully acknowledge financial support from
DST, New Delhi (Project No. SR/OC-20/2010) and UGC (New
Delhi) for a Senior Research Fellowship to A.M.J. S.D.Y. is thank-
ful to C-DAC, Pune for financial and computational support. S.P.S.
is thankful to CSIR, New Delhi for Senior Research fellowship
S.R.G. is grateful to DST for the award of J. C. Bose national fel-
lowship.
(14) We attempted the synthesis of 1,3-aminol at C5 of sugar
furanose by the Wittig reaction of D-ribopentodialdose
followed by azide/benzylamine conjugate addition,
reduction of ester group and glycosylation. However, these
attempts were unsuccessful at one stage or another.
(15) Vorbrüggen, H.; Krolikewicz, K.; Bennua, B. Chem. Ber.
1981, 114, 1234.
(16) Wilson, L. J.; Hager, M. W.; El-Kattan, Y. A.; Liotta, D. C.
Synthesis 1995, 1465.
(17) Dhavale, D. D.; Tagliavini, E.; Trombini, C.; Umani-
Ronchi, A. J. Org. Chem. 1989, 54, 4100.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(18) Anzai, K.; Saita, T. J. Chem. Soc., Chem. Commun. 1976,
681.
(19) Our attempts to selectively hydrolyze the 2′-OAc group in 10
were unsuccessful. This could be due to equal reactivity of
acetate and ester group towards hydrolysis.
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© Georg Thieme Verlag Stuttgart · New York
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PAPER
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