Stereoselective synthesis of 2′-deoxynucleoside analogues as building blocks for deoxynucleoside chemistry

Article abstract of DOI:10.1016/j.tetasy.2011.06.009

Three pairs of enantiomeric 2′-deoxynucleoside analogues 4a, 4b, 4c, 4e and 4d, 4f, respectively, have been synthesized from enantiomerically pure highly functionalized furanoid glycals 2a-d by involving a similar synthetic strategy. These analogues have

Full text of DOI:10.1016/j.tetasy.2011.06.009

Tetrahedron: Asymmetry 22 (2011) 992–999
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of 20-deoxynucleoside analogues as building blocks
for deoxynucleoside chemistry
Pinki Pal a, Pragya Singh b, Brijesh Kumar b, Harsh Mohan Guniyal b, Arun K. Shaw a,
⇑
a Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
b Division of Sophisticated Analytical Instrumentation Facility, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Three pairs of enantiomeric 20-deoxynucleoside analogues 4a, 4b, 4c, 4e and 4d, 4f, respectively, have
been synthesized from enantiomerically pure highly functionalized furanoid glycals 2a–d by involving
a similar synthetic strategy. These analogues have various well defined stereogenic centres and are useful
building blocks for deoxynucleoside chemistry.
Article history:
Received 19 April 2011
Accepted 7 June 2011
Available online 19 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
been reported by various groups. Robles et al. described the NIS
mediated glycosidation between differently protected threo-fura-
The occurrence of carbohydrates as biological scaffolds and
energy reservoirs in the living cell makes them an important class
of natural products. They are also significant from a pharmaceuti-
cal point of view due to their involvement in cell–cell recognition
processes and signal transduction.1a–c Chemists from all over the
world utilize carbohydrates as ‘chiral pool’ materials or building
blocks for the synthesis of biologically important natural products,
and natural product like molecules and drugs. The chiral building
blocks (CBBs) derived from sugars containing one or more stereo-
genic centres have played significant roles in the synthesis of
biologically and pharmacologically active important molecules,
such as natural products, natural product like molecules and
nucleosides.1a–h
noid glycals and silylated pyrimidine bases followed by hydride
reduction of the resulting 20-iodonucleosides with nBu3SnH in
the presence of AIBN as a radical initiator to furnish 20-deoxynucle-
osides in good yields.6d Castillón et al. have reported a ‘one pot’
stereoselective conversion of differently protected threo- and ery-
thro-furanoid glycals to 20-deoxy-20-phenylselenenylnucleosides,
which were ultimately converted into 20-deoxynucleosides in good
yields.7b,7e Recently, Haraguchi et al. reported the exclusive forma-
tion of differently protected b-anomers of 20-deoxynucleosides
from differently protected erythro-furanoid glycals by adopting
the methodology developed by Kim and Misco.6e
Over the last few years, our group has been working on the syn-
thesis of commercially available sugar derived enantiomerically
pure chiral building blocks (CBBs)1e and their utilization towards
the total synthesis of natural products9a,9c and natural product like
molecules.9b,9d,9e,9g We have already reported the synthesis of four
stereochemically different enantiomerically pure, furanoid glycal
building blocks 2a–d (Fig. 2)9f and also very recently shown their
synthetic utility to obtain some natural products such as the aggre-
gation pheromones brevicomins and styryllactones (+)-cardiobut-
anolide, (ꢀ)-cardiobutanolide and (+)-goniofufurone.9h It is
evident from the stereo-structures of these building blocks that
natural as well as unnatural 20,30-dideoxy nucleosides and 20-
deoxynucleosides can be derived from them. Recently, Ferrero
and Gotor et al. reported the synthesis of 30-O-acetyl-protected
20-deoxynucleosides as building blocks for nucleic acid chemistry.1f
Thus, inspired by literature reports on the interesting and impor-
tant biological activities of 20-deoxynucleosides we decided to
undertake the synthesis of six 20-deoxynucleoside analogue build-
ing blocks from the stereochemically different furanoid glycals 2a–
d by adopting a methodology reported earlier by Kim and Misco
(Fig. 3).6a
The synthesis of nucleoside analogues having modified sugar
and/or nucleobases moieties has received much attention because
of their general biological activities2 and potential use as antivi-
ral3,4 and antineoplastic5 therapeutic agents.6d Over the last few
decades, deoxynucleosides have attracted the attention of many
research groups due to their antiviral and antitumor activities.
They are also important components of antisense oligonucleotides.
The 20-deoxynucleosides such as 30-azido-20,30-dideoxythymidine
(AZT), 20,30-dideoxyinosine (ddI), 20,30-didehydro-20,30-dideoxyt-
hymidine (d4T) and related analogues have shown potent antiviral
activity, particularly against human immunodeficiency virus (HIV)
(Fig. 1), which is the causative agent for acquired immunodefi-
ciency syndrome (AIDS).1g
The syntheses of 20,30-dideoxy nucleosides and 20-deoxynucleo-
sides by NIS,6 PhSeCl,7 PhSCl8-mediated electrophilic glycosidation
between the corresponding furanoid glycals and nucleobases have
⇑
Corresponding author. Tel.: +91 923 530 3775.
E-mail address: akshaw55@yahoo.com (A.K. Shaw).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.009

P. Pal et al. / Tetrahedron: Asymmetry 22 (2011) 992–999
993
O
N
O
O
N
NH
NH
NH
HO
HO
N
H
HO
O
O
O
N
N
O
O
H
H
H
H
H
N3
d4T
AZT
O
ddI
O
NH2
NH2
N
NH
N
O
N
O
O
HO
HO
O
O
N
H
N
N
OH
H
H
H
H
HO
H2N
OH
telbivudine
decitabin
3'-amino-2',3'-dideoxycytidine
Figure 1. Some representative deoxynucleosides.
O
(S)
O
(S)
O
O
H
H
(R)
O
(R)
O
O
(R)
O
(R)
O
O
O
(S)
O
(S)
H
H
(S)
(R)
(S)
(R)
OBn
OBn
OBn
OBn
2a
2b
2c
2d
Figure 2. Structures of furanoid glycals 2a–d.
O
O
H
N
O
NH
NH
O
O
O
O
O
(S)
H
N
N
O
(R)
O (R)
(S)
N
H
O (R)
(S)
O
O
(S)
H
(S)
(R)
O
O
H
H
H
O
(S)
(R)
(R)
OBn
OBn
OBn
4a
4c
4b
O
H
N
O
H
O
NH
N
O
O
O
H
H
N
N
H
O
(R)
O
O
(S)
N
O
(R)
(R)
(S)
(S)
(R)
(R)
(S)
O
O
H
H
H
(S)
O
(S)
O
(R)
OBn
OBn
OBn
4e
4d
4f
Figure 3. Structures of 20-deoxynucleoside analogues 4a–f.
intermediates 3a–f to obtain the corresponding 20-deoxynucleo-
side analogues 4a–f were carried out (Scheme 1) and the results
are summarized in Table 1.
2. Results and discussion
Our general synthetic approach to obtain a family of 20-deoxy-
nucleoside analogues 4a–f with well defined stereogenic centres
at the 10-, 30-, 40- and 50-positions from glycals 2a–d is outlined
in Scheme 1. These were synthesized from pyranoid glycals de-
rived allylic alcohol 1 by adopting our previously published
procedures.9f
The NIS-mediated electrophilic glycosylation of silylated thy-
mine with furanoid glycals 2a–d followed by the removal of the
iodo group at the 20-position of the resulting 20-iodonucleoside
As shown in entry 1 of Table 1, 2a treatment with bis-(trimeth-
ylsilyl)thymine (2.0 equiv) in the presence of NIS (2.5 equiv) in dry
DCM at ꢀ30 °C?rt overnight afforded glycosylated product 3a,
which, without purification, was directly converted into 20-deoxy-
nucleoside analogue 4a in 26% yield (over two steps) in the pres-
ence of nBu3SnH and
a
radical initiator ABCN [1,10-azobis-
(cyclohexanecarbonitrile)] (Scheme 2). The stereochemistry of
compound 4a was determined on the basis of its NOE spectrum.

994
P. Pal et al. / Tetrahedron: Asymmetry 22 (2011) 992–999
O
OH
O
O
ref [9f]
NIS, bis(TMS)thymine,
dry DCM, - 30 οC-rt,
overnight
BnO
OH
OBn
OBn
2a-d
1
H
H
N
O
O
N
O
O
O
5'
O
5'
nBu3SnH, ABCN
N
O
N
O
1'
4'
4'
1'
O
O
dry toluene, reflux
2 h
3'
2' 3'
OBn
I
OBn
4a-f
3a-f
Scheme 1. General strategy for the synthesis of 20-deoxynucleoside analogues 4a–f.
Table 1
Synthesis of 20-deoxynucleoside analogues 4a–f prepared via Scheme 1
Entry
Furanoid glycals 2a–d
20-Deoxynucleoside analogues 4a–f, yield% (for two steps)
Diastereomeric ratio (a-anomer/b-anomer)
O
H
N
O
H
O
O
O
H
N
O
1
—
H
OBn
O
O
2a
OBn
4a (26%)
O
NH
N
O
O
O
O
O
O
O
H
2
—
H
H
OBn
OBn
2b
4b (27%)
O
O
NH
NH
O
O
O
O
O
O
O
O
O
N
H
N
H
O
O
H
3
4:1
H
H
OBn
2c
OBn
OBn
4d
separable diastereomers, overall yield 40%
4c
O
O
H
H
N
O
H
O
N
O
O
O
H
H
N
O
O
N
OBn
4
1:3
O
H
O
H
2d
O
O
OBn
OBn
4f
separable diastereomers, overall yield 36%
The 10-H showed an NOE correlation with one of the two 20-H con-
firming the syn relationship between them and this 20-H was la-
belled as 2b0-H, which again showed NOE correlations with 30-H,
40-H. Both 10-H and 30-H showed NOE correlation with 40-H. Thus,
all of these correlations supported the syn relationship between
10-H, 2b0-H, 30-H and 40-H [2b0-H/10-H (11.4%), 2b0-H/30-H (6.6%),

P. Pal et al. / Tetrahedron: Asymmetry 22 (2011) 992–999
995
H
N
H
N
O
O
O
O
O
H
H
H
N
O
O
N
O
a
b
O
H
H
O
O
O
O
I
OBn
OBn
OBn
2a
3a
4a
Scheme 2. Synthesis of 20-deoxynucleoside analogue 4a. Reagents and conditions: (a) NIS, bis-(trimethylsilyl)thymine, dry DCM, ꢀ30 °C?rt, overnight; (b) nBu3SnH, ABCN,
dry toluene, reflux, 2 h.
a similar mechanistic pathway as was shown in the case of 4a.
The -face approach of NIS to the -bond in 2b generated a cyclic
H
3
O
N
a
p
O
4
2
iodonium intermediate which was regioselectively opened by bis-
(trimethylsilyl)thymine to furnish the 20-deoxy-20-iodo-b-nucleo-
side analogue 3b followed by nBu3SnH mediated dehydroiodin-
ation in the presence of the radical initiator ABCN to give the
desired 20-deoxy-b-nucleoside analogue 4b in 27% yield over two
steps (Table 1, Scheme 4). The 1H NMR spectroscopy data of 4b
are superimposable with the 1H NMR spectroscopy of 4a but the
N 1
H
5'
5
O
6'
6
1'
4'
H
Hb
O
2' 3'
O
Ha
OBn
H
[a
]
D
of 4b {½a 2D5
¼ þ17:7 (c 0.27, MeOH)} was opposite to that of
ꢁ
4a
4a {½a 2D5
¼ ꢀ23:4 (c 1.67, MeOH)}.
ꢁ
Figure 4. NOE correlations of 20-deoxynucleoside analogue 4a.
We next studied erythro-furanoid glycal 2c, which under the
identical reaction conditions furnished a mixture of two com-
pounds. Column chromatographic purification of the mixture led
to the isolation of 4c and 4d in 8% and 32% yields, respectively
(over two steps, Table 1, Scheme 5). The NOE experiment was also
carried out for the complete characterization of 4c. The irradiation
of the signal of one of the two protons at C-20 labelled as 2b0-H led
to an enhancement of the signal of 30-Hb [2b0-H/30-Hb (3.1%)],
whereas no enhancement was seen for the signal of 10-H. On the
other hand, irradiation of the signal of 10-H showed only an
enhancement for the signal 2a0-H [10-H/2a0-H (4.6%)], which con-
firms the syn relationship between them. Thus, the 10-H should
40-H/10-H (2.7%), 40-H/2b0-H (1.6%), 40-H/30-H (5.8%)] and, therefore,
10-H should be b. On the basis of the above correlations between
the protons, we were able to identify 4a as the 20-deoxy-
a-nucleo-
side analogue (Fig. 4).
The formation and the stereochemistry of the 20-deoxy-
a-
nucleoside analogue 4a were further supported by the mechanism
proposed by Kim and Misco. Accordingly, NIS preferentially ap-
proached from the b-face of 2a carrying two syn
a-bulky groups
at C-30 and C-40 to form cyclic iodonium intermediate A followed
by its regio and stereospecific openings with bis-(trimethyl-
be
a
and hence 4c was identified as the 20-deoxy-b-nucleoside ana-
silyl)thymine to furnish the 20-deoxy-20-iodo-
a
-nucleoside ana-
logue 3a, which upon reductive dehalogenation with nBu3SnH
gave the 20-deoxy-
-nucleoside analogue 4a (Scheme 3).
logue (Fig. 5).
In the case of 20-deoxynucleoside analogue 4d, the signal for
2b0-H upon irradiation in the NOE experiment led to the enhance-
ments of signals 10-H and 30-H [2b0-H/10-H (10.4%), 2b0-H/30-H
(6.9%)], whereas irradiation of the signal of 2a0-H did not show
a
With these results in hand, we further extended our study on
furanoid glycal 2b, which was an optical antipode of 2a. Thus,
the 20-deoxynucleoside analogue 4b (obtained from 2b) followed
I
β−face
O
O
H
O
O
H
O
OTMS
+
O
N
I
N
I+
O
TMSO
:
N
OBn
O
A
OBn
2a
H
N
H
N
O
O
O
O
H
H
N
N
O
O
nBu3SnH, ABCN
H
H
O
O
O
O
I
OBn
OBn
4a
3a
Scheme 3. Kim and Misco’s proposed mechanism for synthesis of 20-deoxynucleoside analogue 4a.

996
P. Pal et al. / Tetrahedron: Asymmetry 22 (2011) 992–999
O
O
NH
N
NH
N
O
O
O
O
O
O
O
O
O
O
O
a
b
H
H
H
H
H
OBn
OBn
I
OBn
2b
3b
4b
Scheme 4. Synthesis of 20-deoxynucleoside analogue 4b. Reagents and conditions: (a) NIS, bis-(trimethylsilyl)thymine, dry DCM, ꢀ30 °C?rt, overnight; (b) nBu3SnH, ABCN,
dry toluene, reflux, 2 h.
O
O
NH
NH
O
O
O
O
O
O
O
O
N
H
N
H
O
O
O
a
b
+
H
H
H
I
I
OBn
OBn
OBn
3c
3d
2c
O
O
NH
NH
O
O
O
O
O
O
N
H
N
H
O
O
+
H
H
OBn
OBn
4d
4c
Scheme 5. Synthesis of 20-deoxynucleoside analogues 4c and 4d. Reagents and conditions: (a) NIS, bis-(trimethylsilyl)thymine, dry DCM, ꢀ30 °C?rt, overnight; (b) nBu3SnH,
ABCN, dry toluene, reflux, 2 h.
Under identical reaction conditions, the formation of a mixture
O
O
of nucleosides was obvious from erythro-furanoid glycal 2d having
two anti bulky groups at C-30 and C-40 which were enantiomeric to
2c. The chromatographic purification of the mixture containing the
isomeric nucleoside analogues led to the isolation of 20-deoxynu-
NH
2
NH
2
4
4
3
3
O
O
O
5'
O
5'
5
5
N1
O
N1
H
Hb
O
6
O
6
O
1'
1'
4'
4'
cleoside analogues 4f {½a D26
¼ þ12:1 (c 0.57, MeOH)} as the major
ꢁ
6'
6'
H
2' 3'
2' 3'
H
H
product in 27% yield (over two steps) and 4e {½a D25
¼ þ1:4 (c
ꢁ
Hb
Ha
OBn
OBn
H
0.37, MeOH)} as the minor product in 9% yield (over two steps) (Ta-
ble 1, Scheme 7), whose 1H NMR data are identical with those of 4d
and 4c, respectively. However, their specific rotations were oppo-
site to that of 4d and 4c, respectively, as shown above.
Ha
H
4c
4d
Figure 5. NOE correlations of 20-deoxynucleoside analogues 4c and 4d.
3. Conclusion
any enhancement in signals for 10-H and 30-H and, therefore, 4d
In conclusion, we have synthesized three pairs of enantiomeric
20-deoxynucleoside analogues 4a, 4b, 4c, 4e and 4d, 4f, respec-
tively, as building blocks from furanoid glycals 2a–d, by involving
a similar synthetic strategy. The synthesis of 20-deoxynucleoside
analogues 4a and 4b from their respective threo-furanoid glycals
2a,b carrying two bulky syn-groups at the 30- and 40-positions
was highly stereoselective, whereas moderate selectivity was ob-
served in the synthesis of 20-deoxynucleoside analogues 4c–f from
their respective erythro-furanoid glycals 2c,d where the substitu-
ents at the 30- and 40-positions are the same as in 2a,b but with
an anti disposition. The identification of all of these compounds
was done by NOE experiments and NOESY correlation study. These
molecules have different scopes for diversification, which can be
utilized for the synthesis of other natural and unnatural 20-deoxy-
nucleosides of various biological interests (Fig. 6). Therefore,
was identified as the 20-deoxy-
a-nucleoside analogue (Fig. 5).
The formation of the 20-deoxynucleoside analogues 4c and 4d in
a ratio of 1:4 from erythro-furanoid glycal 2c with two anti bulky
groups at C-30 and C-40 could be explained on the basis that NIS
can approach from both the
a- and the b-face of p-bond in 2c to
form the corresponding cyclic iodonium intermediates B and C,
which were opened regioselectively by bis-(trimethylsilyl)thymine
to furnish 20-deoxy-20-iodo-b-nucleoside analogue 3c and 20-
deoxy-20-iodo-
a-nucleoside analogue 3d, respectively. The mix-
ture without further purification, upon treatment with nBu3SnH,
and ABCN in refluxing toluene afforded 20-deoxy-b-nucleoside ana-
logue 4c {½a 2D5
ꢁ
¼ ꢀ1:9 (c 0.10, MeOH)} and 20-deoxy-
a
-nucleoside
analogue 4d {½a 2D6
ꢁ
¼ ꢀ10:2 (c 0.40, MeOH)} in
a 1:4 ratio
(Scheme 6).

P. Pal et al. / Tetrahedron: Asymmetry 22 (2011) 992–999
997
OTMS
N
TMSO
:
N
I
β-face
α-face
O
O
O
O
O
O
O
+
O
O
O
+
N
I
H
H
H
+
OBn
OBn
OBn
I
O
B
OTMS
N:
2c
C
N
TMSO
O
O
NH
NH
O
O
O
O
O
O
N
N
H
O
O
+
H
H
H
I
I
OBn
OBn
3c
3d
nBu3SnH, ABCN
O
O
NH
NH
O
O
O
O
O
O
N
H
N
H
O
O
+
H
H
OBn
OBn
4c
4d
Scheme 6. Plausible mechanism for synthesis of 20-deoxy-b-nucleoside analogue 4c and 20-deoxy-
a-nucleoside analogue 4d.
further applications of this method involving reactions between
furanoid glycals 2a–d and other nucleobases and chemical
transformations of the resulting analogues to obtain new modified
20-deoxynucleosides for evaluation of their various biological activ-
ities are currently underway in our laboratory.
recorded on Perkin–Elmer 881 and FTIR-8210 PC Shimadzu Spec-
trophotometers. Mass spectra were recorded on a JEOL JMS-600H
high resolution spectrometer using EI mode at 70 eV. DART-HRMS
were recorded on a JEOL-AccuTOF, JMS-T100LC spectrometer.
Optical rotations were determined on an Autopol III polarimeter
using a 1 dm cell at 25–32 °C in methanol as the solvent; concen-
trations mentioned are in g/100 mL.
4. Experimental
4.1. General
4.2. General procedure for the synthesis of compounds 4a–f
To a DCM (15 mL) solution of N-iodosuccinimide (NIS) (509 mg,
2.26 mmol) at ꢀ30 °C, were added a DCM (5 ml) solution of bis-
(trimethylsilyl)thymine (490 mg, 1.81 mmol) and DCM (5 mL)
solution of furanoid glycal 2a (250 mg, 0.91 mmol) under an Ar
atmosphere and the mixture was stirred for 1 h at the same tem-
perature. After 1 h, the temperature was increased from ꢀ30 °C
to room temperature and the stirring was continued for a further
18–19 h. After 18–19 h, a saturated aqueous solution of Na2S2O7
(15 mL) was added and the resulting solution was extracted with
DCM (3 ꢂ 10 mL). The combined organic phases were dried over
Na2SO4 and the solvent was removed under reduced pressure to
obtain the crude 20-deoxy-20-iodo-nucleoside analogue 3a, which
was used as such for next step without further purification.
To the crude compound 3a in toluene (25 ml), nBu3SnH (0.7 ml,
2.70 mmol) and ABCN (1,10-azobis-(cyclohexanecarbonitrile))
(50 mg) were added under an Ar atmosphere and the reaction
Organic solvents were dried by standard methods. All the prod-
ucts were characterized by 1H, 13C, two-dimensional homonuclear
COSY (correlation spectroscopy), heteronuclear single quantum
coherence (HSQC), heteronuclear multiple bond correlation spec-
troscopy (HMBC), IR, DART-HRMS, and EI-HRMS (C, H, O). Analyti-
cal TLC was performed using 2.5 ꢂ 5 cm plates coated with a
0.25 mm thickness of silica gel (60F-254), visualization was accom-
plished with CeSO4 and subsequent charring over hot plate. Col-
umn chromatography was performed using silica gel (60–
120 mesh) and silica gel (230–400 mesh). NMR spectra were re-
corded on Bruker Avance 300 MHz spectrometer at 300 MHz (1H)
and 75 MHz (13C), 400 MHz spectrometer at 400 MHz (1H) and
100 MHz (13C) Experiments were recorded in CDCl3 at 25 °C.
Chemical shifts are given on the d scale and are referenced to the
TMS at 0.00 ppm for proton and 0.00 ppm for carbon. For 13C
NMR reference CDCl3 appeared at 77.00 ppm. For IR spectra were

998
P. Pal et al. / Tetrahedron: Asymmetry 22 (2011) 992–999
H
N
O
H
N
O
O
O
O
H
H
H
O
N
H
O
O
N
O
a
H
O
b
O
+
O
O
I
I
OBn
OBn
OBn
3f
3e
2d
O
H
N
H
O
N
O
O
O
H
H
N
O
N
O
O
H
+
H
O
O
OBn
OBn
4e
4f
Scheme 7. Synthesis of 20-deoxynucleoside analogues 4e and 4f. Reagents and conditions: (a) NIS, bis-(trimethylsilyl)thymine, dry DCM, ꢀ30 °C?rt, overnight; (b) nBu3SnH,
ABCN, dry toluene, reflux, 2 h.
(dd, J = 2.9, 8.2 Hz, 1H, 40-H), 4.00 (dd, J = 5.5, 8.6 Hz, 1H, 6a0-H),
4.15–4.24 (m, 2H, 30-H, 6b0-H), 4.49–4.71 (m, 3H, 50-H, 2CH2Ph),
6.34 (dd, J = 2.0, 8.5 Hz, 1H, 10-H), 7.28–7.37 (m, 5H, ArH), 7.612–
7.614 (m, 1H, 6-H), 8.55 (s, 1H, –NH); 13C (75 MHz, CDCl3): d
12.3 (CH3), 25.5 (CH3), 26.9 (CH3), 38.5 (CH2), 67.5 (CH2), 72.0
(CH2), 72.5 (CH), 76.9 (CH), 83.8 (CH), 84.6 (CH), 109.4 (qC),
110.9 (qC), 127.6, 128.1, 128.6 (ArC), 136.8 (CH), 137.4 (ArqC),
150.5 (C@O), 163.6 (C@O); DART-HRMS calcd for C21H27N2O6
[M+H]+ 403.1869, found 403.1853.
H
N
O
O
O
*
O
O
N
*
*
*
OBn
Figure 6. Sites of diversification of 20-dexynucleoside analogues 4a–f.
4.2.3. 1-[(10S,30R,40R,50S)-30-O-Benzyl-20-deoxy-50,60-O-isopropyl-
idene-L-ribofuranosyl]thymine 4c
White solid; yield: 8% (for two steps, 29 mg); mp 78–80 °C; elu-
ent for column chromatography: EtOAc/hexane (23:77, v/v);
mixture was stirred for 2 h under refluxing condition. The solvent
was removed under vacuum after completion of the reaction (TLC).
The crude product was purified by column chromatography (230–
400 mesh silica gel) to obtain 20-deoxynucleoside analogue 4a in
26% yield (95 mg) over two steps. A similar reaction protocol was
adopted for synthesis of 4b–f.
½
a 2D5
ꢁ
¼ ꢀ1:9 (c 0.10, MeOH); Rf 0.35 (1:1 EtOAc/hexane); IR (neat,
cmꢀ1): 769, 1068, 1217, 1464, 1654, 2364, 2855, 2923, 3403; 1H
(300 MHz, CDCl3): d 1.38 (s, 3H), 1.43 (s, 3H), 1.91 (s, 3H), 2.03–
2.12 (m, 1H, 2b0-H), 2.46–2.52 (m, 1H, 2a0-H), 3.75 (dd, J = 6.2,
8.5 Hz, 1H, 6a0-H), 4.09–4.15 (m, 2H, 40-H, 6b0-H), 4.22–4.24 (m,
1H, 30-H), 4.33–4.38 (m, 1H, 50-H), 4.50 (d, J = 11.8 Hz, 1H, CH2Ph),
4.58 (d, J = 11.6 Hz, 1H, CH2Ph), 6.35 (dd, J = 6.0, 7.8 Hz, 1H, 10-H),
7.29–7.39 (m, 5H, ArH), 7.50 (s, 1H, 6-H), 8.28 (s, 1H, –NH); 13C
(75 MHz, CDCl3): d 12.7 (CH3), 24.8 (CH3), 26.3 (CH3), 37.6 (CH2),
65.9 (CH2), 71.4 (CH2), 75.6 (CH), 77.9 (CH), 85.2 (2CH), 109.9
(qC), 111.0 (qC), 127.8, 128.0, 128.5 (ArC), 135.8 (CH), 137.3 (ArqC),
150.1 (C@O), 163.5 (C@O); DART-HRMS calcd for C21H27N2O6
[M+H]+ 403.1869, found 403.1881.
4.2.1. 1-[(10R,30R,40S,50R)-30-O-Benzyl-20-deoxy-50,60-O-isopropyl-
idene-D-arabinofuranosyl]thymine 4a
White solid; yield: 26% (for two steps, 95 mg); mp 88–92 °C;
eluent for column chromatography: EtOAc/hexane (1:2, v/v);
½
a 2D5
ꢁ
¼ ꢀ23:4 (c 1.67, MeOH); Rf 0.45 (1:1 EtOAc/hexane); IR (neat,
cmꢀ1): 769, 1067, 1219, 1466, 1694, 2366, 2856, 2926, 3427; 1H
(300 MHz, CDCl3): d 1.42 (s, 3H), 1.45 (s, 3H), 1.70 (s, 3H), 2.18
(d, J = 15.2 Hz, 1H, 2a0-H), 2.53–2.63 (m, 1H, 2b0-H), 3.81 (dd,
J = 2.8, 8.2 Hz, 1H, 40-H), 4.00 (dd, J = 5.5, 8.5 Hz, 1H, 6a0-H), 4.15–
4.24 (m, 2H, 30-H, 6b0-H), 4.48–4.71 (m, 3H, 50-H, 2CH2Ph), 6.34
(d, J = 6.8 Hz, 1H, 10-H), 7.35 (br s, 5H, ArH), 7.61 (s, 1H, 6-H),
8.75 (s, 1H, –NH); 13C (75 MHz, CDCl3): d 12.3 (CH3), 25.4 (CH3),
26.8 (CH3), 38.5 (CH2), 67.4 (CH2), 72.0 (CH2), 72.5 (CH), 76.9
(CH), 83.8 (CH), 84.6 (CH), 109.3 (qC), 110.8 (qC), 127.6, 128.0,
128.5 (ArC), 136.8 (CH), 137.4 (ArqC), 150.6 (C@O), 163.7 (C@O);
4.2.4. 1-[(10R,30R,40R,50S)-30-O-Benzyl-20-deoxy-50,60-O-isopropyl-
idene-L-ribofuranosyl]thymine 4d
White solid; yield: 32% (for two steps, 117 mg); mp 130–
134 °C; eluent for column chromatography: EtOAc/hexane (6:19,
DART-HRMS calcd for
403.1853.
C
21H27N2O6 [M+H]+ 403.1869, found
v/v); ½a 2D6
ꢁ
¼ ꢀ10:2 (c 0.40, MeOH); Rf 0.32 (1:1 EtOAc/hexane); IR
(KBr, cmꢀ1): 769, 1066, 1217, 1467, 1684, 2365, 2928, 3022,
3452; 1H (300 MHz, CDCl3): d 1.35 (s, 3H), 1.47 (s, 3H), 1.76 (s,
3H), 2.23 (d, J = 15.1 Hz, 1H, 2a0-H), 2.59–2.69 (m, 1H, 2b0-H),
3.85–3.94 (m, 2H, 40-H, 6a0-H), 4.08–4.14 (m, 1H, 6b0-H), 4.28 (d,
J = 5.9 Hz, 1H, 30-H), 4.35 (d, J = 7.4 Hz, 1H, 50-H), 4.49 (d,
J = 11.3 Hz, 1H, CH2Ph), 4.55 (d, J = 11.3 Hz, 1H, CH2Ph), 6.31 (dd,
J = 1.6, 7.7 Hz, 1H, 10-H), 7.28–7.37 (m, 5H, ArH), 7.55 (s, 1H, 6-
H), 8.71 (s, 1H, –NH); 13C (75 MHz, CDCl3): d 12.4 (CH3), 24.9
(CH3), 26.8 (CH3), 37.8 (CH2), 66.9 (CH2), 71.3 (CH2), 74.9 (CH),
78.9 (CH), 85.9 (CH), 87.3 (CH), 110.1 (qC), 110.3 (qC), 127.7,
4.2.2. 1-[(10S,30S,40R,50S)-30-O-Benzyl-20-deoxy-50,60-O-isopropyl-
idene- -arabinofuranosyl]thymine 4b
L
White solid; yield: 27% (for two steps, 98 mg); mp 78–80 °C;
eluent for column chromatography: EtOAc/hexane (1:2, v/v);
½
a 2D5
ꢁ
¼ þ17:7 (c 0.27, MeOH); Rf 0.45 (1:1 EtOAc/hexane); IR (neat,
cmꢀ1): 769, 1066, 1219, 1464, 1690, 2364, 2854, 2923, 3427; 1H
(300 MHz, CDCl3): d 1.42 (s, 3H), 1.45 (s, 3H), 1.71 (s, 3H), 2.18
(dd, J = 2.0, 15.2 Hz, 1H, 2b0-H), 2.53–2.63 (m, 1H, 2a0-H), 3.81

P. Pal et al. / Tetrahedron: Asymmetry 22 (2011) 992–999
999
128.1, 128.6 (ArC), 136.6 (CH), 137.1 (ArqC), 150.5 (C@O), 163.7
(C@O); DART-HRMS calcd for C21H27N2O6 [M+H]+ 403.1869, found
403.1852.
for financial support and Mr. A.K. Pandey for technical assistance.
P. Pal thanks CSIR New Delhi for awarding Senior Research Fellow-
ship. CDRI communication No. 8080.
4.2.5. 1-[(10R,30S,40S,50R)-30-O-Benzyl-20-deoxy-50,60-O-isopropyl-
References
idene-D-ribofuranosyl]thymine 4e
White solid; yield: 9% (for two steps, 33 mg); mp 78–80 °C; elu-
ent for column chromatography: EtOAc/hexane (23:77, v/v);
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½
a 2D5
ꢁ
¼ þ1:4 (c 0.37, MeOH); Rf 0.35 (1:1 EtOAc/hexane); IR (KBr,
cmꢀ1): 769, 1068, 1217, 1464, 1654, 2364, 2855, 2923, 3403; 1H
(300 MHz, CDCl3): d 1.38 (s, 3H), 1.43 (s, 3H), 1.92 (s, 3H), 2.05–
2.12 (m, 1H, 2a0-H), 2.46–2.53 (m, 1H, 2b0-H), 3.75 (dd, J = 6.3,
8.6 Hz, 1H, 6a0-H), 4.09–4.15 (m, 2H, 40-H, 6b0-H), 4.22–4.24 (m,
1H, 30-H), 4.31–4.38 (m, 1H, 50-H), 4.50 (d, J = 11.6 Hz, 1H, CH2Ph),
4.58 (d, J = 11.6 Hz, 1H, CH2Ph), 6.36 (dd, J = 6.0, 8.0 Hz, 1H, 10-H),
7.31–7.39 (m, 5H, ArH), 7.51 (s, 1H, 6-H), 8.43 (s, 1H, –NH); 13C
(75 MHz, CDCl3): d 12.6 (CH3), 24.8 (CH3), 26.3 (CH3), 37.7 (CH2),
65.9 (CH2), 71.4 (CH2), 75.7 (CH), 77.9 (CH), 85.3 (2CH), 109.9
(qC), 111.0 (qC), 127.8, 128.0, 128.5 (ArC), 135.8 (CH), 137.3 (ArqC),
150.1 (C@O), 163.5 (C@O); DART-HRMS calcd for C21H27N2O6
[M+H]+ 403.1869, found 403.1862.
4. Herdewijn, P.; Balzarini, J.; De Clercq, E.; Pauwels, R.; Baba, M.; Broder, S.;
Vanderhaeghe, H. J. Med. Chem. 1987, 30, 1270–1278.
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4.2.6. 1-[(10S,30S,40S,50R)-30-O-Benzyl-20-deoxy-50,60-O-isopropyl-
idene-D-ribofuranosyl]thymine 4f
White solid; yield: 27% (for two steps, 98 mg); mp 128–130 °C;
eluent for column chromatography: EtOAc/hexane (6:19, v/v);
½
a 2D6
ꢁ
¼ þ12:1 (c 0.57, MeOH); Rf 0.33 (1:1 EtOAc/hexane); IR (neat,
cmꢀ1): 768, 1066, 1219, 1462, 1689, 2363, 2856, 2924, 3447; 1H
(300 MHz, CDCl3): d 1.34 (s, 3H), 1.46 (s, 3H), 1.76 (s, 3H), 2.23
(d, J = 15.3 Hz, 1H, 2b0-H), 2.59–2.68 (m, 1H, 2a0-H), 3.84–3.94 (m,
2H, 40-H, 6a0-H), 4.08–4.14 (m, 1H, 6b0-H), 4.28 (d, J = 5.9 Hz, 1H,
30-H), 4.35 (d, J = 7.4 Hz, 1H, 50-H), 4.49 (d, J = 11.3 Hz, 1H, CH2Ph),
4.55 (d, J = 11.3 Hz, 1H, CH2Ph), 6.31 (dd, J = 1.7, 7.8 Hz, 1H, 10-H),
7.28–7.37 (m, 5H, ArH), 7.545–7.549 (m, 1H, 6-H), 8.92 (s, 1H, –
NH); 13C (75 MHz, CDCl3): d 12.4 (CH3), 24.8 (CH3), 26.7 (CH3),
37.7 (CH2), 66.8 (CH2), 71.3 (CH2), 74.8 (CH), 78.9 (CH), 85.9 (CH),
87.3 (CH), 110.1 (qC), 110.3 (qC), 127.6, 128.0, 128.5 (ArC), 136.6
(CH), 137.1 (ArqC), 150.6 (C@O), 163.9 (C@O); DART-HRMS calcd
for C21H27N2O6 [M+H]+ 403.1869, found 403.1890.
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Acknowledgements
We are thankful to Sophisticated Analytical Instrument Facility,
CDRI for providing spectral data, DST (project SR/SI/OC-17/2010)