Diastereoselective addition of planar N-heterocycles to vinyl sulfone-modified carbohydrates: a new route to isonucleosides

Article abstract of DOI:10.1016/j.tet.2008.08.050

Michael-type addition reactions of planar N-heterocycles at the C-2 positions of vinyl sulfone-modified carbohydrates provide an efficient and general route for the carbon-N-heterocycle bond formation. Therefore, the addition pattern of planar heterocycles, such as imidazole, triazole, thymine, and adenine to 3-C-phenylsulfonyl-hex-2-enopyranosides (1α/1β) and 3-C-p-toluenesulfonyl-pent-2-enofuranosides (2α/2β) was studied for developing a general methodology for the synthesis of new classes of isonucleosides possessing a carbon-N-heterocycle linkage at C-2 positions of furanosyl and pyranosyl sugars. To a great extent, the anomeric configurations of the starting vinyl sulfones play crucial roles in deciding the diastereoselectivity of addition of heterocycles. However, the trityl protected 3-C-p-toluenesulfonyl-hex-2-enopyranosides (33α/33β) were judged to be more practical starting materials for desulfonylation and deprotection for the synthesis of a new class of thymine and adenine deoxyisonucleosides.

Full text of DOI:10.1016/j.tet.2008.08.050

Tetrahedron 64 (2008) 10406–10416
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective addition of planar N-heterocycles to vinyl sulfone-modified
carbohydrates: a new route to isonucleosides
,
Aditya K. Sanki a y, Rahul Bhattacharya b, Ananta Kumar Atta b, Cheravakkattu G. Suresh c,
,
Tanmaya Pathak b
*
a Organic Chemistry Division (Synthesis), National Chemical Laboratory, Pune 411 008, India
b Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
c Division of Biochemical Sciences, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 May 2008
Received in revised form 16 August 2008
Accepted 19 August 2008
Available online 23 August 2008
Michael-type addition reactions of planar N-heterocycles at the C-2 positions of vinyl sulfone-modified
carbohydrates provide an efficient and general route for the carbon–N-heterocycle bond formation.
Therefore, the addition pattern of planar heterocycles, such as imidazole, triazole, thymine, and adenine
to 3-C-phenylsulfonyl-hex-2-enopyranosides (1a/1b) and 3-C-p-toluenesulfonyl-pent-2-enofuranosides
(2 /2 ) was studied for developing a general methodology for the synthesis of new classes of iso-
a
b
nucleosides possessing a carbon–N-heterocycle linkage at C-2 positions of furanosyl and pyranosyl
sugars. To a great extent, the anomeric configurations of the starting vinyl sulfones play crucial roles in
deciding the diastereoselectivity of addition of heterocycles. However, the trityl protected 3-C-p-tolu-
enesulfonyl-hex-2-enopyranosides (33a/33b) were judged to be more practical starting materials for
desulfonylation and deprotection for the synthesis of
deoxyisonucleosides.
a
new class of thymine and adenine
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Interestingly, oligonucleotides comprising of O-methylated deoxy-
anhydrohexitol nucleosides such as 1,5-anhydro-3-O-methyl-2-
In order to broaden the scope of nucleoside-based therapeutics,1
a novel class of modified nucleosides in which nucleobases are
linked to the non-anomeric carbons of carbohydrates has been
designed. These ‘isonucleosides’ are promising therapeutic agents
of apparently very low toxicity and some of them show strong and
selective anti-cancer and anti-viral activities. The bond connecting
the nucleobase and carbohydrate in isonucleosides has higher de-
gree of stability toward acids and enzymatic deamination when
compared to that of naturally occurring nucleosides.2–4 Over the
last few years many isonucleoside derivatives, such as exo-methyl-
ene-, branched-, 40-thio-, pyranosyl, etc. have been reported to be
promising therapeutic agents.4 Although methyl 2-deoxy-2-(purin-
9-yl) arabinofuranosides and methyl 3-deoxy-3-(purin-9-yl) xylo-
furanosides were the first isonucleosides to be synthesized2 and
biologically tested, there are only two other reports on isonucleo-
sides comprising of O-methyl group at the anomeric center.3a
(uracil-1-yl)-2-deoxy-
D-altro-hexitol and methyl-2-(thymin-1-yl)-
2,3-dideoxy- -arabino-hexopyranoside have been noted for their
D
unique hybridization properties.3b In a related development, a sig-
nificant number of imidazole5 and triazole6 nucleosides have been
shown to exhibit a broad spectrum of activity against a range of
viral and other diseases. However, there are only a few reports on
imidazole5g,l–n and triazole6b,f nucleoside analogues possessing
a carbon–N-heterocycle linkage at C-2 positions of the sugars.
The most common methods reported for the synthesis of iso-
nucleosides are (a) regioselective ring opening of epoxides by
nucleobases,2,3,4a,d,e,k,q (b) nucleophilic substitution of sulfonates
derived from 1,4-anhydropentitols by nucleobases,4h (c) sub-
stitution of an alcohol with a base under Mitsunobu conditions,4d,r
(d) coupling of nucleobases directly with cyclic sulfates derived
from carbohydrates,4j,n and (e) preparation of nucleosides from
aminoaldetols.4o
In addition to the above methods, reactions of nucleobases with
activated olefins such as 2,3-dideoxy-3-nitro-hex-2-enopyr-
anosides4f,7 and 2,3-dideoxy-hex-2-enopyranosid-4-uloses8 were
also used as a strategy for the synthesis of isonucleosides. However,
the usefulness of nitro-alkene sugars4f,7 and hexenopyranoside
uloses6,8 as precursors for the synthesis of isonucleosides is
* Corresponding author. Tel.: þ91 3222 283342; fax: þ91 3222 282252.
E-mail address: tpathak@chem.iitkgp.ernet.in (T. Pathak).
Present address: Department of Chemistry, The University of Toledo, 2801 W.
y
Bancroft Street, Toledo, OH 43606, USA.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.050

A.K. Sanki et al. / Tetrahedron 64 (2008) 10406–10416
10407
BnO
O
O
O
O
O
X
Ph
O
Ph
XH, TMG
DMF, rt
O
OMe
O
1
PhO2S
OMe
PhO2S
OMe
OMe
1
p-
TolO2S
BnO
2
7-10
X =
O
N
NH2
O
O
Ph
OMe
Me
O
N
N
N
HN
N
N
PhO2S
N
p-
TolO2S
1
O
N
N
N
2
9
10
8
7
Figure 1.
(1.5 h, 90%)
(1 h, 65%)
(1 h, 58%)
(1.5 h, 70%)
Scheme 2.
reportedly limited only to pyranose systems and therefore cannot
be considered as of general utility. We, on the other hand have
established over the years that vinyl sulfone-modified hex-2-eno-
ambient temperature to afford single isomers 7–10, respectively, in
moderate to good yields (Scheme 2).
The structures of 4, 5, 8, and 9 were unambiguously established
by X-ray crystallography. However, it was necessary to analyze the
NMR data of compounds 3, 6, 7, 10 and compare the data with those
of 4, 5, 8, 9. We have observed that for methyl 4,6-O-(phenyl-
methylene)-a-D-hexopyranosides with D-allo- and D-gluco-config-
urations, a coupling constant (J1,2) value of 3.3–3.8 Hz implies
a characteristic arrangement of equatorial H-1/axial H-2. For
-altro- and D-manno-configurations a coupling constant (J1,2) value
of 0.6–1.7 Hz is the characteristic of equatorial H-1/equatorial H-2
arrangement.7,15g,11a,16 Hence, by comparing J1,2 values of com-
pounds 3 (1.0 Hz) and 4 (0 Hz) with those of the known compounds
12 (1.2 Hz) and 13 (1.2 Hz) obtained from 11
concluded that compound 3 was possessing
pyranosides 1
sides 2 /2
(Fig. 1) are efficient chiral building blocks.9 Amines9–11
and carbon nucleophiles9,12 added to these highly reactive Michael
acceptors 1 /1 and 2 /2 in diastereoselective fashion and the
a/1b and vinyl sulfone-modified pent-2-enofurano-
a
b
a
b
a b
products were obtained in excellent yields. We therefore opined
that vinyl sulfone-modified carbohydrates would be useful chiral
building blocks for generating new isonucleosides and biologically
relevant new chemical entities when treated with imidazole and
triazole. However, the directive effect of the anomeric configura-
D
tions of 1
reactions was not obvious.9 It was, therefore, necessary to study the
diastereoselective addition of planar heterocycles to 1 /1 and 2
and to establish the structures of the products unambiguously.14
a/1b and 2a/2b on the stereochemical outcome of these
a
b
a/
2
b
a
(Scheme 3),7a it was
-manno-configura-
It should also be noted that the success of the proposed synthetic
strategy would also depend crucially on the desulfonylation of
these products at the final step.
D
tion. On the contrary, J1,2 values of 5 (3.4 Hz) and 6 (major isomer;
3.4 Hz) were in agreement with those of the reported compounds
having D-allo- or D-gluco-configuration. Since the structure of 5 is
confirmed by X-ray, the major isomer 6 was identified as a gluco-
derivative. In the case of compounds 7–10, H-1 signals appeared as
doublets with relatively large coupling constant (J1,2) values rang-
ing between 7.3 and 7.9 Hz. Having compared J1,2 values of the
2. Results and discussion
2.1. Reactions of 1
a
and 1
b
with planar heterocycles
a on treatment with imidazole, 1,2,4-
known compounds 14 (7.5 Hz) and 15 (8.0 Hz) obtained from 11
b
a
-Methoxy vinyl sulfone 1
(Scheme 4)7b,c with those of 7–10, it was concluded that H-1 and H-
triazole and thymine in the presence of tetramethyl guanidine
(TMG) in anhydrous DMF at ambient temperature, generated single
isomers 3, 4, and 5, respectively, in excellent yields (Scheme 1).
Adenine, on the other hand, under similar reaction conditions
afforded an inseparable mixture of two compounds in a ratio of
2.2:1. However, by comparing the spectra of the small amount of
compound that crystallized out from the mixture of adenine ad-
ducts with that of 5, the major isomer present in the reaction
2 of 7–10 were diaxially oriented and all isomers in b-series were
assigned gluco-configuration. 13C NMR spectra of trans-fused hexo-
pyranoside derivatives have also been studied thoroughly. As per
the report, on changing a substituent from equatorial to axial po-
sition at C-2, a large shielding would be expected at C-4.17 This fact
holds true in the case of 3, 4, and 5. C-4 peaks of 3 and 4 (
73.9, respectively) are more shielded than that of 5 ( 76.3). Simi-
larly, for -series 7–10, C-4 peaks appeared between 75.4 and 76.6
indicating equatorial orientations of the substituents at C-2.
In a partially rigid bicyclic system like 1 or 1 , sterically de-
d 74.3 and
d
b
d
mixture has been assigned the structure 6 (Scheme 1). Similarly,
b-
vinyl sulfone 1 was treated with imidazole, 1,2,4-triazole, thy-
b
a
b
mine, and adenine in the presence of TMG in anhydrous DMF at
manding bulky phenylsulfonyl group should occupy the equatorial
position after the nucleophilic addition. Interestingly though, the
X
O
O
Ph
XH, TMG
DMF, rt
R
O
1
O
O
O
PhO2S
O
Ph
ref 7a
OMe
Ph
O
O
Y
O2N
OMe
O2N
OMe
3 X = Imidazolyl; Y = H
11
12 R = theophyllinyl
4 X = 1,2,4-Triazolyl; Y = H
5 X = H; Y = Thyminyl
6 X = H; Y = Adeninyl
13 R = 2,6-dichloropurinyl
Scheme 3.
O
X =
NH2
Me
HN
N
N
N
N
N
O
O
O
N
O
R
Ph
Ph
OMe
O
N
O
OMe
O
N
N
N
O2N
ref 7b,c
O2N
11
5
6
4
14 R = theophyllinyl
15 R = 2,6-dichloropurinyl
3
(4 h, 58%)
[60 h, 60%(2.2:1)]
(5 h, 95%)
(2 h, 98%)
Scheme 1.
Scheme 4.

10408
A.K. Sanki et al. / Tetrahedron 64 (2008) 10406–10416
addition of p-toluenethiol to 1-p-toluenesulfonyl-cyclohexene
generated the thermodynamically less stable cis-2-p-tol-
ylmercapto-1-p-toluenesulfonyl-cyclohexane and not the thermo-
dynamically more stable trans-product.18 On the basis of reactions
BnO
OMe
O
Y
X
of 11
ophiles, a generalization can be made that the axial attack pre-
dominates over equatorial attack for 11 and the converse is true
for However, the stereochemical
-vinyl compounds 11b 7,15,16
course of addition of planar heterocycles to 1 did not fully abide by
this generalization. Although the addition of imidazole and 1,2,4-
triazole to 1 generated products 3 and 4, respectively, with
a/11b (structurally comparable to 1a/1b) with several nucle-
20 Y = p-TolO2S; X = imidazolyl
22 Y = p-TolO2S; X = adeninyl
24 Y = p-TolO2S; X = triazolyl
a
XH, DMF
DMF, rt
b
.
2
+
a
BnO
OMe
O
Y
a
manno-configuration, the configurations at C-2 positions of thy-
mine analogue 5 and the adenine analogue 6 (major isomer), on the
contrary were surprisingly different (gluco-configuration) from
those reported for purine adducts 12 and 13 (Scheme 3).7a On the
X
21 Y = p-TolO2S; X = thyminyl
23 Y = p-TolO2S X = triazolyl
X =
basis of the reported reaction patterns of 1a and 1b, we propose
O
N
NH2
Me
that two factors, namely (a) stereoelectronic repulsions between
incoming nucleophiles and OMe group/C1–O1 bond/C1–O5 bond
and (b) stability of diequatorial (C-2, C-3) over equatorial/axial or
axial/axial products would broadly decide the outcome of a re-
action. In the case of manno-isomers 3 and 4, we presume that the
stereoelectronic repulsion caused by C1–O1 (OMe group) from the
N
HN
N
N
N
N
N
O
N
N
N
20
(4 h, 82%)
22
23, 24 (1:1)
21
(12 h, 60%)
(28 h, 75%)
(8 h, 82%)
a
-face of the sugar ring to imidazole and triazole was more im-
Scheme 6.
portant. In the case of 5 and 6, sterically bulky thymine and adenine
residues naturally preferred the equatorial dispositions. The ste-
attack the C-2 position from the
the intermediate carbanion after the addition of a nucleophile
would be protonated from the -side of the furanose ring to push
a bulky –SO2Tol(p) group to the -side of the ring. The X-ray
analysis of a single crystal of 17 (J1,2¼2.0 Hz) unambiguously
established the -arabino-configuration. It is clearly evident from
the available data that the J1,2 values of authentic methyl -ara-
binofuranosides19a,d,10b,13 range between 0 and 3.0 Hz. The J1,2
values for authentic methyl
-ribofuranosides17,18,10d range be-
tween 4.0 and 4.9 Hz and the same for methyl -xylofuranosides
b-face of the furanose ring and (b)
reochemical course of the reactions of planar heterocycles with 1
a/
1
b
was further investigated using MM2 calculations. Compound 3
b
was found to be less stable than its C2 epimer by 0.16 kcal/mol and
therefore it may be considered as a kinetic product. The kinetic
product 4 was also found to be less stable than its C2 epimer by
0.48 kcal/mol. However, MM2 calculations revealed that com-
pounds 5 and 6 were the most stable products. All other di-
astereomers of 3–6 were found to be energetically less stable. On
a
D
a-D
a-D
the other hand, in the case of 1
b, the stability of triequatorial
a-D
products 7–10 outweighed all other factors.
are always ranging between 4.0 and 4.7 Hz.19a,c,d,20b,c,10b Excluding
the possibility of any lyxo-derivative formation for steric reasons,
the J1,2 values of 16–19, which ranged between 0 and 2.4 Hz, surely
indicated the presence of arabino-configuration in these molecules.
Using the similar arguments, we expected to obtain xylo-de-
2.2. Reactions of 2
Reactions of 2
a
and 2
b with planar heterocycles
a
with imidazole, 1,2,4-triazole, thymine, and
adenine in the presence of TMG in anhydrous DMF at ambient
rivatives from the reactions between 2b and the planar heterocy-
temperature yielded single isomers 16, 17, 18, and 19, respectively,
cles. It has also been reported earlier that Michael addition of
various nucleophiles to 30-ene-sulfone derivatives of uridine and
adenosine produced mainly the xylo-derivatives although in limited
number of cases ribo-derivatives were also obtained.21 The X-ray
in excellent yields (Scheme 5). Reactions of 2
b with imidazole,
thymine, and adenine under similar conditions, afforded single
isomers 20, 21, and 22, respectively, in excellent to moderate yields.
However, 1,2,4-triazole on reaction with 2
of two diastereomers 23 and 24 approximately in a 1:1 ratio
(Scheme 6).
b
, generated a mixture
diffraction experiments unambiguously established 23 as a
xylo-derivative and 24 as a -ribo-analogue. It is reported that the
J1,2 values of authentic methyl
-xylofuranosides19a,e,20b,c,10b
range between 0 and 2.3 Hz and those of methyl -ribofur-
anosides19a,20a,10b are close to 0 Hz. The J1,2 values of 5-O-benzyl
protected methyl
-arabino-derivatives,19a–c,e however, range
between 3.0 and 4.0 Hz. Excluding the possibility of any -arabino-
derivative formation on the basis of steric consideration, we have
assigned
D-
D
b-D
The products from the reactions of 2
were expected to have arabino-configuration for two reasons: (a)
methoxy group at C-1 would direct all four bulky nucleophiles to
a
with planar heterocycles
b-D
a
-
b-D
D
XH, TMG
DMF, rt
BnO
2
O
D
-ribo-configuration to 20, 21, and 22 (J1,2¼0 Hz for all
X
three). Although the J1,2 values of 21 (4.4 Hz) and 23 (3.9 Hz) were
OMe
higher than those of related compounds mentioned above, it
should be mentioned here that the J1,2 values of C-branched
furanosyl derivatives (obtained from 2 ), whose structures have
been assigned unambiguously are 3.5 Hz and 3.9 Hz.13 We, there-
fore, assigned -xylo-configuration to 21 as well.
Diastereoselectivity of addition of nucleophiles to 2,3-dideoxy-
3-C-nitro-pent-2-enofuranosides22 has not been studied but there
are reports on the regioselective opening of epoxides directed by
the configurations at the anomeric center.23 It has also been
reported that the addition of p-toluenethiol to 1-p-toluenesulfonyl
cyclopentene system generated thermodynamically more stable
D-xylo-
SO2Ar
16-19
Ar = p-Tol
b
X =
O
NH2
Me
D
HN
N
N
N
N
N
N
N
N
O
N
N
19
18
16
17
(1 h, 96%)
(1 h, 82%)
(12 h, 90%)
(1 h, 82%)
Scheme 5.

A.K. Sanki et al. / Tetrahedron 64 (2008) 10406–10416
10409
trans-2-p-tolylmercapto-1-p-toluenesulfonyl cyclopentane.24 Mo-
6, 10
reover, it has already been mentioned that the addition of various
nucleophiles to 30-ene-sulfone derivatives of nucleosides produced
mainly the xylo-derivatives.21 Thus, in the light of above observa-
tions it may be concluded that addition of imidazole, 1,2,4-triazole,
(a) Na-Hg (6%), MeOH, Na2HPO4, 4 h, rt
(c) AcCl, py, DMAP, 20 h, 0 °C to rt
O
O
B
Ph
X
thymine, and adenine to
a-vinyl sulfone 2a should generate
O
products with arabino-configurations, which indeed was the case.
On the other hand, addition of the same set of nucleophiles to
Y
27 X = H; Y = OMe; B = AAc (56% from 6)
b
-vinyl sulfone 2b produced two different sets of products, namely
28 X = OMe; Y = H; B = AAc
ribo-derivatives 20, 22, and 24, and xylo-derivatives 21 and 23.
According to MM2 energy minimization calculations, the ribo-
analogue 20 obtained from the reaction of 2b with imidazole was
(58% in 2 steps from 10)
29 X = H; Y = OMe, B = A (64% from 6)
NH2
NHAc
found to be the most favorable diastereomer, whereas the triazole
derivatives 23 and 24 formed in 1:1 ratio were found to be ener-
getically almost equally favorable. Accordingly compounds 21 and
22 were found to be the most stable products. All other di-
astereomers of 20–24 were energetically less stable. The approach
of all nucleophiles to C-2 was most probably directed by the ster-
eoelectronic effect of the anomeric methoxy group. For 16–19, 21,
and 23, the trans-relationship of groups at C-2 and C-3 was also
expected to follow the literature precedence discussed above.
N
N
N
N
N
AAc
=
A =
N
N
N
Scheme 8.
the phenylmethylene group of compounds 27–29 under acidic or
reductive conditions afforded inseparable mixture of compounds.
Since we were unable to remove the phenylmethylene group from
compounds 27–29, we designed an alternative strategy for the
synthesis of adenine isonucleosides. We presumed that trityl pro-
tected vinyl sulfone-modified carbohydrates would be more useful
for the synthesis of these compounds. We, therefore, converted
2.3. Desulfonylation leading to the synthesis of
isonucleosides
Since the success of a scheme for the synthesis of deoxy-
nucleosides using vinyl sulfone-modified carbohydrates would
depend crucially on the desulfonylation step, we experimented
with the most common desulfonylating agents known in the lit-
erature.12a The Na–Hg-mediated reduction is the most widely used
radical-based method for the desulfonylation of organic molecules
the known15 vinyl sulfone 33
two steps in excellent overall yield (Scheme 9). The
a
into the tritylated analogue 34
a in
-anomer
b
was synthesized as follows. The known epoxide10 30 was treated
with thiocresol in the presence of TMG to obtain the sulfide 31.
MMPP mediated oxidation of 31 afforded the sulfone 32. The crude
sulfone was mesylated and an in situ elimination of the methane-
and has been used extensively for the desulfonylation of
b-amino
sulfonate group produced 33b in 89% overall yield. Compound 33b
sulfones and
g
-amino sulfone derivatives.12 Another electron-
was converted to the tritylated derivative 34b in the usual way
transfer method that uses Mg metal in MeOH has also been
reported with there being at least one report where Mg in MeOH
was successfully used for the desulfonylation of a b-amino sulfone
(Scheme 9).
Tritylated a-methoxy vinyl sulfone 34a on treatment with ad-
enine in the presence of TMG in anhydrous DMF at ambient tem-
perature, afforded an inseparable mixture of compounds 35 in 1:1
ratio. The mixture was subjected to Na–Hg mediated desulfonyla-
tion to afford a single compound 36 proving that the sulfonylated
derivatives 35 were a mixture of C-3 epimers. The trityl group of 36
was removed easily under acidic condition and the deprotected
compound. However, attempted desulfonylation of furanosides
16–24 using Na–Hg, MeOH–Mg or even with our reagent12 MeOH–
Mg–NiBr2 used successfully in the synthesis of furanosyl deoxy-
aminosugars led to extensive degradation of the starting materials.
Only the pyranosides were found to be stable toward Na–Hg (6%)
mediated desulfonylation reactions. Thus, the thymine derivatives
5 and 9 on treatment with Na–Hg (6%) in a buffered system un-
derwent efficient desulfonylation. The product of the desulfonyla-
tion reaction was directly deprotected under reductive conditions
and finally acetylation produced the desired isonucleosides 25 and
26 in 72% and 64% overall yields, respectively (Scheme 7). In the
adenine series compound 6, which was a mixture of epimers at C-3
and the pure compound 10 were also desulfonylated successfully
with Na–Hg (6%) and the products were isolated as the acetyl de-
rivatives 27 and 28, respectively (Scheme 8). Since it was necessary
to establish the stereochemistry at C-3 of 6 (or its desulfonylated
product) we also isolated crystalline 29 because of its utility in
X-ray analysis of its single crystal. However, attempted removal of
O
O
Ph
Ph
p-TolSH, TMG, DMF
OMe
O
O
30
OH
MsCl, py,
+4 °C, 16 h
O
O
OMe
O
X
31: X=p-TolS
32: X=p-TolO2S
MMPP
MeOH
(i) MeOH, AcCl,
0 ºC to rt, 2 h
O
O
Ph
p-TolO2S
33α X= H, Y= OMe
X
Y
O
(ii) TrCl, py, rt, 48 h
5, 9
(a) Na-Hg (6%), MeOH, Na2HPO4, 4 h, rt
(b) H2, Pd-C, MeOH, 16 h, rt
(c) Ac2O, py, DMAP, 20 h, 0 °C to rt
33β X= OMe, Y= H (89% in 4 steps from 30)
TrO
HO
O
X
AcO
AcO
O
X
Y
p-TolO2S
T
Y
34 X= H, Y= OMe (80% in 2 steps from 33 )
α
α
25 X = H; Y = OMe (72% in 3 steps from 5)
26 X = OMe; Y = H (64% in 3 steps from 9)
34β X= OMe, Y= H (61% in 2 steps from 33β)
Scheme 7.
Scheme 9.

10410
A.K. Sanki et al. / Tetrahedron 64 (2008) 10406–10416
product was isolated as the peracetylated derivative 37 in 88% yield
in two steps (Scheme 10). Since the structure of compound 29 was
established by X-ray analysis, the trityl derivative 36 was depro-
tected and converted to 29 to establish the C-20 configuration of the
pronounced in the case of pentofuranosyl systems. It, however,
remains undecided at this stage, whether the carbohydrate ring
puckering caused by the stereoelectronic properties of thymine,
adenine or triazole and their probable interactions with ArSO2
group are in any way responsible for the formation of gluco-de-
Michael adduct 35. The b-methoxy vinyl sulfone 34b (Scheme 11)
under similar reaction conditions reacted with adenine to afford
a single isomer 38. Compound 38 was desulfonylated by Na–Hg to
39 in good yield. Compound 39 was detritylated under acidic
condition and the product was isolated as the peracetylated de-
rivative 40 in 49% yield in two steps (Scheme 11).25
rivatives from 1a . Although the
or ribo-derivatives from 2b 24
pentofuranosyl isonucleosides underwent extensive degradation
under desulfonylation conditions, the hexopyranosyl thymines
were easily desulfonylated. Desulfonylated and deprotected hexo-
pyranosyl adenines were obtained using a modified route. As a
result of the present study, it was possible to synthesize several
new C1-O-methylated 20,30-dideoxyhexopyranosyl nucleosides.
The biological properties of this new group of isonucleosides as
monomers and as oligomers will be reported elsewhere.
adenine
TMG
TrO
HO
O
A
Na-Hg (6%)
MeOH. 4 h,
34
DMF, rt
TolO S
p-
2
68 h, 63%
OMe rt, 70%
4. Experimental
35
(i) MeOH,
AcCl,
4.1. General methods
TrO
HO
AcO
AcO
O
A
O
B
0 °C, 4 h
(ii) AcCl, py,
24 h, 88%
All reactions were conducted under nitrogen atmosphere at
ambient temperature. Melting points were determined in open-
end capillary tubes and are uncorrected. Carbohydrates and other
fine chemicals were obtained from commercial suppliers and are
used without purification. Solvents were dried and distilled fol-
lowing the standard procedures. TLC was carried out on pre-coated
silica gel plates (F254) and the spots were visualized with UV light or
by charring the plate dipped in 5% H2SO4–MeOH solution. Column
chromatography was performed on silica gel (230–400 mesh).
Most of the 1H NMR spectra were recorded at 200 MHz in CDCl3
using residual CHCl3 as internal reference and a few were recorded
at 300 MHz, 400 MHz and 500 MHz in appropriate deuterated
solvent. Most of the 13C NMR was recorded at 50.0 MHz in CDCl3
OMe
OMe
36
37 B = AAc
(i) MeOH, AcCl, 0 °C, 4 h
29
(i) benzaldehydedimethyl acetal
p-TSA, DMF, 100 °C, 2.5 h, 39%
NH2
NHAc
N
N
N
N
N
AAc
=
A =
N
N
N
Scheme 10.
using triplet centered at
d 77.27 as internal reference and a few
were recorded at 75 MHz and 100 MHz in CDCl3. DEPT experiments
were carried out to identify the methylene carbons using above
mentioned spectrometer. Optical rotations were recorded at
589 nm. Micro analytical data were obtained from Carlo-Erba
CHNS-0 EA 1108 elemental analyzer located at the National
Chemical Laboratory, Pune, India.
TrO
HO
O
A
OMe
adenine, TMG
34
p- TolSO2
DMF, rt
4 h, 80%
38
TrO
O
Na-Hg (6%)
MeOH. 4 h, rt, 53%
OMe
HO
4.2. General procedure for the synthesis of 3, 4, 7, 8, 16, 17, 20,
23, and 24
A
39
To a well-stirred solution of imidazole or 1,2,4-triazole and TMG
in anhydrous DMF (10 mL/mmol) was added appropriate vinyl
sulfone-modified carbohydrate (1 equiv) and the mixture was
stirred at ambient temperature. After completion of the reaction
(TLC), water (1 mL) was added and the excess solvent was evapo-
rated under reduced pressure to obtain a solid residue. The solid
residue was dissolved in EtOAc and saturated NaHCO3 solution was
added. The aqueous layer was extracted with EtOAc (3ꢀ40 mL). The
combined organic layers were dried over Na2SO4, filtered, and
the filtrate was concentrated to dryness under reduced pressure.
The crude material was purified over silica gel to obtain the title
compounds.
(i) MeOH, AcCl
0 °C, 4 h
AcO
AcO
O
OMe
(ii) AcCl, py
24 h, 49%
B
40 B = AAc
NH2
NHAc
N
N
N
N
N
AAc
=
A =
N
N
N
Scheme 11.
3. Conclusion
4.3. General procedure for the synthesis of 5, 6, 9, 10, 18, 19, 21,
and 22
We have developed a general methodology for the synthesis of
several biologically relevant intermediates where planar hetero-
cycles imidazole, triazole, thymine, and adenine are attached to the
C-2 positions of both hexose and pentose systems. Since this
methodology has rendered a direct access to new isonucleosides,
we anticipate that other nucleobases can also be condensed readily
with vinyl sulfone-modified carbohydrates. In most of the cases
studied the diastereoselectivity of addition was directed by the
configuration at the anomeric position but this effect was more
To a well-stirred solution of the appropriate nucleobase and
TMG in anhydrous DMF (10 mL/mmol) was added appropriate vinyl
sulfone-modified carbohydrate (1 equiv) and the resulting mixture
was stirred at ambient temperature. After completion of the re-
action (TLC), the reaction mixture was diluted with EtOAc (80 mL)
and undissolved solid was filtered off. The filtrate was washed with
saturated NaHCO3 solution and the aqueous phase was extracted

A.K. Sanki et al. / Tetrahedron 64 (2008) 10406–10416
10411
with EtOAc (3ꢀ30 mL). The combined organic extracts were dried
4.7. Methyl 2-C-adenin-9-yl-2,3-dideoxy-4,6-O-
over Na2SO4, filtered, and the filtrate was concentrated under re-
duced pressure. The crude material was purified over silica gel to
obtain the title compounds.
(phenylmethylene)-3-C-phenylsulfonyl-
glucopyranosides 6
a-D-
Compound 1
a (0.2 g, 0.515 mmol) was reacted with adenine
(0.626 g, 4.63 mmol) in the presence of TMG (0.45 mL, 3.6 mmol) to
generate a mixture of isomers in 60 h (0.16 g, 60%). Eluent: MeOH/
CHCl3 (1:19). A small amount of the major isomer contaminated
with a small amount of minor isomer was isolated by crystallization
[EtOAc/petroleum ether (1:3)]. 1H NMR (200 MHz, CDCl3; only
4.4. Methyl 2,3-dideoxy-2-C-imidazolyl-4,6-O-
(phenylmethylene)-3-C-phenylsulfonyl-
a-D-
mannopyranoside 3
Compound 1a (0.25 g, 0.644 mmol) was reacted with imidazole
(0.131 g, 1.93 mmol) in the presence of TMG (0.16 mL, 1.28 mmol) to
afford a fluffy material 3 in 2 h following the general procedure
major peaks reported):
d
3.36 (s, 3H), 3.80 (t, 1H, J¼7.9 Hz), 4.10–
3.98 (m, 2H), 4.30 (dd, 1H, J¼3.9, 10.3 Hz), 4.50 (t, 1H, J¼9.2 Hz),
4.79 (d, 1H, J¼3.4 Hz), 5.41 (s, 1H), 5.47 (dd, 1H, J¼4.0, 12.3 Hz), 5.83
(br s, 2H), 7.39–7.17 (m, 8H), 7.64 (d, 2H, J¼7.3 Hz), 8.01 (s, 1H), and
8.42 (s, 1H).
described above (0.29 g, 98%). Eluent: EtOAc/petroleum ether (7:3).
27
Decomposition point: 185 ꢁC; [
a
]
ꢂ18.4 (c 1.00, CHCl3); IR (Nujol):
D
1379 and 1461 cmꢂ1 1H NMR (200 MHz, CDCl3):
; d 3.45 (s, 3H),
4.07–3.92 (m, 3H), 4.32 (m, 2H), 4.87 (d, 1H, J¼1.0 Hz), 5.25 (d, 1H,
4.8. Methyl 2,3-dideoxy-2-C-imidazolyl-4,6-O-(phenyl-
J¼3.4 Hz), 5.50 (s, 1H), 7.50–7.09 (m, 10H), 7.61 (d, 2H, J¼7.4 Hz),
methylene)-3-C-phenylsulfonyl-
b-D-glucopyranoside 7
and 7.94 (s, 1H); 13C NMR (50 MHz, CDCl3):
d 55.2, 61.9, 64.6, 68.9
(CH2), 74.3 (CH2), 100.4, 102.3, 120.3, 126.3, 128.1, 128.6, 128.7, 129.3,
133.5, 136.1, 139.1, and 140.4; MS m/z (EI): 77 (18), 91 (24), 105 (27),
121 (100), 149 (41), 157 (23), 247 (45), and 456 (<1 Mþ). Anal. Calcd
for C23H24N2O6S: C, 60.51; H, 5.29; N, 6.13; S, 7.02. Found: C, 60.22;
H, 5.59; N, 6.09; S, 7.29.
Compound 1 (0.37 g, 0.945 mmol) was reacted with imidazole
(0.193 g, 2.83 mmol) in the presence of TMG (0.23 mL, 1.89 mmol)
to yield a fluffy material 7 in 1.5 h following the general procedure
b
described above (0.3 g, 70%). Eluent: EtOAc/petroleum ether (3:1);
26
mp: 82–83 ꢁC; [
a
]
D
ꢂ24.7 (c 1.01, CHCl3); IR (Nujol): 1448, 1498,
2848, 2873, 2939, 2974, and 4214 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
3.35 (s, 3H), 3.66 (m, 1H), 3.86 (t, 1H, J¼10.3 Hz), 4.02 (t, 1H,
4.5. Methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-
J¼10.2 Hz), 4.22 (t, 1H, J¼10.3 Hz), 4.38 (dd, 1H, J¼4.8, 10.7 Hz), 4.54
(d, 1H, J¼7.3 Hz), 4.64 (dd, 1H, J¼7.5, 10.6 Hz), 5.51 (s, 1H), 6.93 (s,
1H), 7.03 (s, 1H), 7.45–7.25 (m, 8H), and 7.60 (m, 3H); 13C NMR
phenylsulfonyl-2-C-(1H-1,2,4-triazol-1-yl)-
mannopyranoside 4
a-D-
(50 MHz, CDCl3):
d 56.7, 57.5, 66.3, 67.5, 68.6 (CH2), 75.4, 101.5,
Compound 1
a (0.2 g, 0.515 mmol) was reacted with 1,2,4-tri-
103.1, 117.3, 126.1, 128.0, 128.6, 128.9, 129.1, 129.4, 133.6, 136.4, 137.7,
and 140.1; MS m/z (EI): 77 (13), 91 (9), 105 (23), 149 (100), 209 (19),
239 (16), 247 (7), and 456 (<1 Mþ). Anal. Calcd for C23H24N2O6S: C,
60.51; H, 5.29; N, 6.13; S, 7.02. Found: C, 60.43; H, 5.58; N, 6.02; S,
7.50.
azole (0.177 g, 2.57 mmol) in the presence of TMG (0.19 mL,
1.54 mmol) to furnish needle shaped crystal 4 in 5 h following the
general procedure described above (0.22 g, 95%). Eluent: EtOAc/
petroleum ether (3:7). Recrystallized from EtOAc/petroleum ether
26
(1:3); mp: 157–158 ꢁC; [
a
]
ꢂ35.9 (c 1.01, CHCl3); IR (CHCl3): 1448,
D
1510, 1583, 1780, 2225, 2339, and 2360 cmꢂ1
;
1H NMR (200 MHz,
4.9. Methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-
phenylsulfonyl-2-C-(1H-1,2,4-triazol-1-yl)-
glucopyranoside 8
CDCl3):
d
3.45 (s, 3H), 4.11–3.87 (m, 3H), 4.30 (dd, 1H, J¼3.9, 9.7 Hz),
b-D-
4.83 (s, 1H), 4.98 (dd, 1H, J¼8.8, 11.3 Hz), 5.42 (d, 1H, J¼4.4 Hz), 5.60
(s, 1H), 7.35–7.12 (m, 7H), 7.48 (t, 1H, J¼7.8 Hz), 7.63 (d, 2H,
J¼7.3 Hz), 8.04 (s, 1H), and 8.42 (s, 1H); 13C NMR (50 MHz, CDCl3):
Compound 1b (0.097 g, 0.25 mmol) was reacted with 1,2,4-tri-
d
55.1, 56.9, 62.1, 65.0, 69.0 (CH2), 73.9, 99.9, 102.2, 126.3, 128.2,
azole (0.086 g, 1.25 mmol) in the presence of TMG (0.1 mL,
0.75 mmol) to furnish a needle shaped crystalline compound 8 in
1 h following the general procedure described above (0.07 g, 58%).
Eluent: EtOAc/petroleum ether (3:7). Recrystallized from EtOAc/
petroleum ether (1:3); mp: 128–129 ꢁC; [
128.8, 129.3, 133.7, 136.5, 140.2, 147.0, and 152.6; MS m/z (EI): 308
(47), 316 (68), 317 (34), 334 (7), 436 (35), 386 (7), 455 (7), 456 (6),
and 457 (6 Mþ). Anal. Calcd for C22H23O6N3S$2H2O: C, 53.54; H,
4.69; N, 8.51; S, 6.49. Found: C, 53.59; H, 4.66; N, 8.04; S, 6.88.
26
a
]
ꢂ70.2 (c 1.12, CHCl3);
D
IR (CHCl3): 1448, 1506, 2337, 2360, 2401, 2879, 2941, and
4.6. Methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-
3134 cmꢂ1 1H NMR (500 MHz, C6D6):
;
d
2.90 (s, 3H), 3.17 (dt, 1H,
phenylsulfonyl-2-C-(thymin-1-yl)-
a
-
D
-glucopyranoside 5
J¼4.83, 14.45 Hz), 3.41 (t, 1H, J¼10.2 Hz), 3.95 (dd, 1H, J¼4.87,
10.38 Hz), 4.12 (dd, 1H, J¼9.55, 10.23 Hz), 4.48 (d,1H, J¼7.54 Hz),
4.62 (t, 1H, J¼10.76 Hz), 4.72 (q, 1H), 5.16 (s, 1H), 6.69 (t, 2H,
J¼7.64 Hz), 6.78 (m, 1H), 7.22–7.09 (m, 5H), 7.59 (d, 2H, J¼7.6 Hz),
Compound 1 (0.2 g, 0.515 mmol) was reacted with thymine
a
(0.454 g, 3.6 mmol) in the presence of TMG (0.32 mL, 2.57 mmol)
to produce a plate shaped crystalline compound 5 in 4 h following
the general procedure described above (0.15 g, 58%). Eluent:
7.92 (s, 1H), and 7.95 (s, 1H); 13C NMR (50 MHz, CDCl3):
d 57.8, 58.0,
64.5, 67.6, 68.7 (CH2), 75.7, 101.7, 102.7, 126.2, 128.1, 128.2, 128.8,
129.2, 133.7, 136.3, 140.3, 145.8, and 152.0; MS m/z (EI): 77 (44), 81
(100), 91 (22), 150 (49), 210 (28), 316 (6), and 457 (<1 Mþ). Anal.
Calcd for C22H23O6N3S$1H2O: C, 55.57; H, 4.87; N, 8.83; S, 6.74.
Found: C, 55.45; H, 5.06; N, 8.78; S, 7.32.
CHCl3/MeOH (19:1). Recrystallized from CHCl3/petroleum ether
26
(1:3); mp: 169–170 ꢁC; [
a
]
ꢂ34.0 (c 1.12, CHCl3); IR (CHCl3):
D
1689, 2401, and 4214 cmꢂ1 1H NMR (200 MHz, CDCl3):
; d 1.93 (s,
3H), 3.40 (s, 3H), 4.07–3.68 (m, 4H), 4.25 (dd, 1H, J¼3.9, 10.3 Hz),
4.72 (d, 1H, J¼3.4 Hz), 5.34 (s, 1H), 5.50 (dd, 1H, J¼3.9, 11.7 Hz),
7.53–7.23 (m, 9H), 7.80 (d, 2H, J¼7.3 Hz), and 8.87 (br s, 1H); 13C
4.10. Methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-
NMR (50 MHz, CDCl3):
d
12.8, 51.2, 55.7, 61.6, 62.7, 69.1 (CH2), 76.6
phenylsulfonyl-2-C-(thymin-1-yl)-
b-D-glucopyranoside 9
(C-4), 98.1, 101.9, 110.6, 126.3, 128.3, 128.9, 129.2, 129.4, 134.2,
136.5, 138.1, 139.3, 151.7, and 163.7; MS m/z (EI): 164 (41), 207
(100), 221 (32), 267 (41), 313 (20), and 514 (<1 Mþ). Anal. Calcd for
Compound 1 (0.2 g, 0.515 mmol) was reacted with thymine
b
(0.454 g, 3.6 mmol) in the presence of TMG (0.32 mL, 2.57 mmol) to
generate a needle shaped crystalline compound 9 in 1.5 h following
the general procedure described above (0.24 g, 90%). Eluent: CHCl3/
C
25H26N2O8S$1.5H2O: C, 55.55; H, 5.21; N, 5.18; S, 5.93. Found: C,
55.48; H, 5.25; N, 5.05; S, 5.61.

10412
A.K. Sanki et al. / Tetrahedron 64 (2008) 10406–10416
MeOH (49:1). Recrystallized from EtOAc/petroleum ether (1:3);
1H NMR (200 MHz, CDCl3):
d 2.40 (s, 3H), 3.36 (s, 3H), 3.58 (dd, 1H,
26
mp: 234–235 ꢁC; [
a
]
ꢂ38.0 (c 1.10, CHCl3); IR (CHCl3): 1693, 2401,
J¼2.0, 11.2 Hz), 3.84 (dd, 1H, J¼2.0, 11.2 Hz), 4.41 (dd, 1H, J¼6.8,
13.2 Hz), 4.65 (d, 1H, J¼11.7 Hz), 4.51 (d, 1H, J¼12.2 Hz), 4.77 (m,
1H), 5.12 (d, 1H, J¼2.0 Hz), 5.19 (dd, 1H, J¼2.0, 6.4 Hz), 7.24 (d, 2H,
J¼8.3 Hz), 7.33 (s, 5H), 7.62 (d, 2H, J¼8.3 Hz), and 7.85 (d, 2H,
D
2931, 3394, and 4214 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d 1.96 (s,
3H, thymine Me), 3.51 (s, 3H), 3.68 (q, 1H), 3.77 (t, 1H, J¼10.2 Hz),
3.96 (t, 2H, J¼9.5 Hz), 4.31 (dd, 1H, J¼4.8, 10.2 Hz), 5.13 (d, 1H,
J¼10.2 Hz), 5.21 (d, 1H, J¼7.3 Hz), 5.31 (s, 1H), 7.01 (d, 3H, J¼7.3 Hz),
7.34–7.21 (m, 6H), 7.72 (d, 2H, J¼7.7 Hz), and 9.50 (br s, 1H); 13C
J¼10.7 Hz); 13C NMR (50 MHz, CDCl3):
d 21.3, 55.3, 66.4, 67.0, 69.0
(CH2), 73.3 (CH2), 77.3, 106.6, 127.4, 128.0, 128.1, 129.8, 134.5, 137.5,
143.4, 145.5, and 152.2; MS m/z (EI): 91 (100), 122 (26), 160 (6), 228
(8), 253 (3), 337 (3), 413 (2), and 443 (2 Mþ). Anal. Calcd for
NMR (50 MHz, CDCl3): d 12.4, 57.8, 61.7, 63.2, 67.3, 68.8 (CH2), 76.2,
100.2, 101.7, 110.8, 126.3, 128.1, 128.3, 129.0, 129.3, 133.8, 136.3,
140.4, 143.9, 151.1, and 164.6; MS m/z (EI): 77 (29), 91 (22), 81 (100),
207 (43), 247 (8), 313 (4), 374 (1), and 514 (<1 Mþ). Anal. Calcd for
C22H25N3O5S: C, 59.58; H, 5.67; N, 9.47; S, 7.22. Found: C, 59.77; H,
5.96; N, 9.33; S, 7.71.
C
25H26N2O8S$0.5H2O: C, 57.45; H, 5.20; N, 5.36; S, 6.13. Found: C,
57.36; H, 5.34; N, 5.10; S, 6.27.
4.14. Methyl 5-O-benzyl-2,3-dideoxy-2-C-thymin-1-yl-3-C-p-
toluenesulfonyl- -arabinofuranoside 18
a
-D
4.11. Methyl 2-C-adenin-9-yl-2,3-dideoxy-4,6-O-
(phenylmethylene)-3-C-phenylsulfonyl-
glucopyranoside 10
b-D
-
Compound 2a (0.35 g, 0.935 mmol) was reacted with thymine
(0.824 g, 6.54 mmol) in the presence of TMG (0.58 mL, 4.67 mmol)
to generate a fluffy mass 18 in 1 h following the general procedure
Compound 1
b
(0.12 g, 0.317 mmol) was reacted with adenine
described above (0.38 g, 82%). Eluent: MeOH/acetone/CHCl3
25
(0.385 g, 2.85 mmol) in the presence of TMG (0.27 mL, 2.21 mmol)
to generate an amorphous solid 10 in 1 h following the general
(1:1:18); mp: 65–67 ꢁC; [
a
]
þ21.0 (c 1.09, CHCl3); IR (CHCl3): 1377,
D
1458, 1596, 1689, 2401, 2871, 2929, 3218, 3392, and 4214 cmꢂ1; 1H
NMR (200 MHz, CDCl3): 1.51 (s, 3H), 2.43 (s, 3H), 3.26 (s, 3H), 3.74
procedure described above (0.11 g, 65%). Eluent: CHCl3/MeOH
d
27
(19:1); mp: 235–236 ꢁC; [
a
]
ꢂ38.0 (c 0.970, CHCl3); IR (Nujol):
(dd, 1H, J¼2.9, 11.2 Hz), 3.97 (dd, 1H, J¼2.0, 10.8 Hz), 4.16 (q, 1H),
4.59 (m, 3H), 4.90 (s, 1H), 5.39 (d, 1H, J¼6.8 Hz), 7.13 (s, 1H), 7.32 (m,
7H), 7.80 (d, 2H, J¼8.3 Hz), and 9.13 (s, 1H); 13C NMR (50 MHz,
D
1608, 1676, 2678, 2754, 3284, 3350, 3564, 3616, and 3666 cmꢂ1; 1H
NMR (200 MHz, CDCl3): 3.34 (s, 3H), 3.88 (m, 2H), 3.91 (dd, 1H,
d
J¼8.8, 10.2 Hz), 4.41 (dd, 1H, J¼9.8, 15.6 Hz), 4.74 (dd, 1H, J¼8.3,
11.2 Hz), 5.14 (d, 1H, J¼7.9 Hz), 5.46 (t, 1H, J¼11.2 Hz), 5.53 (s, 1H),
6.02 (br s, 2H), 7.21 (m, 4H), 7.32 (m, 4H), 7.46 (d, 2H, J¼6.9 Hz), 7.83
CDCl3): d 12.0, 21.7, 55.1, 63.4, 67.0, 69.6 (CH2), 74.0 (CH2), 77.6,
106.9, 112.3, 128.0,128.7, 129.1, 130.2,134.7, 137.4, 137.7, 145.8, 150.3,
and 163.6; MS m/z (EI): 91 (100), 65 with <1%, 79, 217, 285, 379,
468, and 500 (Mþ). Anal. Calcd for C25H28N2O7S: C, 59.97; H, 5.63;
N, 5.59; S, 6.40. Found: C, 59.54; H, 5.29; N, 5.20; S, 7.06.
(s, 1H), and 8.22 (s, 1H); 13C NMR (50 MHz, CDCl3):
d 56.9, 57.9, 62.2,
67.9, 69.0 (CH2), 76.2, 101.1, 101.8, 120.3, 126.4, 127.9, 128.3, 128.8,
129.4, 133.6, 136.5, 140.4, 143.0, 149.7, 152.6, and 155.8; MS m/z (EI):
77 (64), 81 (100), 91 (46), 105 (58), 136 (86), 216 (76), 247 (31), 276
(11), 322 (27), 382 (120), and 523 (4 Mþ). Anal. Calcd for
4.15. Methyl 2-C-adenin-9-yl-5-O-benzyl-2,3-dideoxy-3-C-
p-toluenesulfonyl-a-D-arabinofuranoside 19
C
25H25N5O6S$1.5H2O: C, 54.54; H, 5.12; N, 12.77; S, 5.82. Found: C,
54.61; H, 5.16; N, 12.67; S, 5.98.
Compound 2 (0.31 g, 0.82 mmol) was reacted with adenine
a
(0.997 g, 7.38 mmol) in the presence of TMG (0.72 mL, 5.74 mmol)
4.12. Methyl 5-O-benzyl-2,3-dideoxy-2-C-imidazolyl-3-C-
to yield to an amorphous solid 19 in 1 h following the general
p-toluenesulfonyl-
a
-
D
-arabinofuranoside 16
procedure described above (0.4 g, 96%). Eluent: MeOH/acetone/
25
CHCl3 (1:2:97); mp: 61–63 ꢁC; [
a
]
þ45.0 (c 1.09, CHCl3); IR
D
Compound 2 (0.23 g, 0.622 mmol) was reacted with imidazole
a
(CHCl3): 1473, 1596, 1639, 2401, 2869, 2927, 3176, 3355, 3409, 3481,
(0.126 g,1.86 mmol) in the presence of TMG (0.15 mL,1.24 mmol) to
and 4214 cmꢂ1 1H NMR (200 MHz, CDCl3):
;
d
2.31 (s, 3H), 3.34 (s,
afford a needle shaped crystalline compound 16 in 12 h following
3H), 3.75 (dd, 1H, J¼2.4, 11.3 Hz), 3.98 (dd, 1H, J¼1.5, 11.3 Hz), 4.64
(dd, 2H, J¼11.4, 28.3 Hz), 4.85–4.72 (m, 2H), 5.12 (d, 1H, J¼2.4 Hz),
5.37 (dd, 1H, J¼2.5, 6.4 Hz), 5.98 (br s, 2H), 7.11 (d, 2H, J¼7.9 Hz),
the general procedure described above (0.24 g, 90%). Eluent: ace-
26
tone/CHCl3/petroleum ether (1:1:3); mp: 158–159 ꢁC; [
a
]
þ42.2
D
(c 1.07, CHCl3); IR (CHCl3): 1498, 3111, 3622, 3724, and 3757 cmꢂ1
;
7.37 (m, 5H), 7.60 (d, 2H, J¼8.3 Hz), 7.82 (s, 1H), and 8.23 (s, 1H); 13
C
1H NMR (200 MHz, CDCl3):
d
2.43 (s, 3H), 3.34 (s, 3H), 3.45 (dd, 1H,
NMR (50 MHz, CDCl3): d 21.5, 55.7, 62.4, 66.1, 69.6 (CH2), 73.8 (CH2),
J¼2.9, 11.2 Hz), 3.88 (dd, 1H, J¼1.5, 11.2 Hz), 4.03 (q, 1H), 4.55 (dd,
2H, J¼12.2, 25.9 Hz), 4.72 (dt, 1H, J¼2.0, 8.3 Hz), 4.94 (d, 1H,
J¼4.4 Hz), 4.98 (s, 1H), 6.91 (s, 2H), 7.08 (s, 1H), 7.30 (m, 7H), and
77.3, 106.8, 119.5, 127.7, 127.9, 128.3, 128.5, 129.7, 134.6, 137.8, 139.3,
145.4, 149.3, 152.9, and 155.8; MS m/z (EI): 91 (100), 136 (14), 188
(21), 219 (14), 294 (18), 354 (1.6), 403 (1.3), 418 (1.8), 478 (1), and
509 (<1 Mþ). Anal. Calcd for C25H27N5O5S: C, 58.92; H, 5.33; N,
13.74; S, 6.29. Found: C, 59.06; H, 5.39; N, 13.77; S, 7.10.
7.66 (d, 2H, J¼7.8 Hz); 13C NMR (50 MHz, CDCl3):
d 21.5, 54.9, 64.7,
68.9 (CH2), 69.5, 73.7 (CH2), 77.6, 107.9, 116.9, 127.7, 128.3, 128.4,
130.2, 135.0, 136.3, 137.4, and 145.7; MS m/z (EI): 91 (100), 121 (6),
159 (36), 227 (52), 411 (6), and 442 (1.3 Mþ). Anal. Calcd for
4.16. Methyl 5-O-benzyl-2,3-dideoxy-2-C-imidazolyl-3-C-
C
23H26N2O5S: C, 62.42; H, 5.91; N, 6.33; S, 7.24. Found: C, 62.37; H,
p-toluenesulfonyl-b-D-ribofuranoside 20
5.91; N, 6.07; S, 7.30.
Compound 2 (0.39 g, 1.04 mmol) was reacted with imidazole
b
4.13. Methyl 5-O-benzyl-2,3-dideoxy-3-C-p-toluenesulfonyl-
(0.212 g, 3.12 mmol) in the presence of TMG (0.26 mL, 2.08 mmol)
to afford a cotton like crystalline 20 in 4 h following the general
procedure described above (0.38 g, 82%). Eluent: acetone/CHCl3/
2-C-(1H-1,2,4-triazol-1-yl)-a-D-arabinofuranoside 17
Compound 2 (0.27 g, 0.732 mmol) was reacted with 1,2,4-tri-
a
petroleum ether (1:1:3). Recrystallized from CHCl3/petroleum
26
azole (0.252 g, 3.66 mmol) in the presence of TMG (0.27 mL,
2.19 mmol) to produce a needle shaped crystalline compound 17 in
1 h following the general procedure described above (0.26 g, 82%).
ether (1:3); mp: 128–129 ꢁC; [
a
]
D
ꢂ1.3 (c 1.12, CHCl3); IR (CHCl3):
1596, 2341, 2360, 2401, 2866, 2933, 2966, and 4214 cmꢂ1; 1H NMR
(200 MHz, CDCl3): 2.08 (br hump, 1H), 2.42 (s, 3H), 3.30 (s, 3H),
d
Eluent: EtOAc/petroleum ether (3:7). Recrystallized from EtOAc/
3.34 (m, 1H), 3.59 (dd, 1H, J¼2.0, 10.7 Hz), 4.26 (q, 1H), 4.46 (dd, 2H,
J¼12.2, 14.6 Hz), 4.79 (m, 1H), 4.88 (d, 1H, J¼5.9 Hz), 4.96 (s, 1H),
7.00 (d, 2H, J¼11.2 Hz), and 7.33 (m, 9H); 13C NMR (50 MHz, CDCl3):
26
petroleum ether (1:3); mp: 106–107 ꢁC; [
a
]
D
þ53.3 (c 1.01, CHCl3);
IR (CHCl3): 1305, 1315, 1361, 1454, 1506, 1596, 1720, and 2401 cmꢂ1
;

A.K. Sanki et al. / Tetrahedron 64 (2008) 10406–10416
10413
d
21.7, 54.6, 62.7, 65.0, 71.6 (CH2), 73.3 (CH2), 78.3, 106.9 (C-1), 127.6,
C22H25N3O5S: C, 59.58; H, 5.67; N, 9.47; S, 7.22. Found: C, 59.92; H,
127.8, 128.1, 128.4, 130.0, 135.2, 137.6, and 145.5; MS m/z (EI): 91
5.29; N, 9.36; S, 7.45. Compound 24: isolated yield: 0.02 g (sepa-
(100), 121 (6), 159 (10), 227 (18), and 442 (3 Mþ). Anal. Calcd for
rated by recrystallization). Recrystallized from EtOAc/petroleum
26
C
23H26N2O5S: C, 62.42; H, 5.91; N, 6.33; S, 7.24. Found: C, 62.49; H,
ether (1:4); mp: 82–83 ꢁC; [
a]
þ13.7 (c 1.00, CHCl3); IR (CHCl3):
D
6.12; N, 6.34; S, 7.56.
1425, 1502, 1527, 1598, 2360, 2399, 2432, 3629, 3681, and
4214 cmꢂ1 1H NMR (200 MHz, CDCl3):
;
d
2.44 (s, 3H), 3.34 (s, 3H),
4.17. Methyl 5-O-benzyl-2,3-dideoxy-2-C-(thymin-1-yl)-
3.38–3.26 (m, 1H), 3.72 (dd, 1H, J¼1.5, 11.3 Hz), 4.42 (dd, 3H, J¼12.2,
22.4 Hz), 4.75 (m, 1H), 5.08 (s, 1H), 5.14 (d, 1H, J¼5.9 Hz), 7.36–7.25
(m, 7H), 7.54 (d, 2H, J¼8.3 Hz), 7.92 (s, 1H), and 8.25 (s, 1H); 13C
3-C-p-toluenesulfonyl-
b-D-xylofuranoside 21
Compound 2 (0.24 g, 0.641 mmol) was reacted with thymine
b
NMR (125 MHz, CDCl3): d 21.9, 54.9, 64.1, 65.4, 70.8 (CH2), 73.6
(0.565 g, 4.48 mmol) in the presence of TMG (0.4 mL, 3.205 mmol)
to generate an amorphous solid 21 in 8 h following the general
(CH2), 78.9, 106.2, 127.7, 128.0, 128.6, 130.2, 135.9, 138.1, 145.8, and
152.2; MS m/z (EI): 91 (100), 122 (10), 228 (25), 253 (12), 337 (7),
and 443 (10, Mþ). Anal. Calcd for C22H25N3O5S: C, 59.58; H, 5.67; N,
9.47; S, 7.22. Found: C, 59.48; H, 5.64; N, 9.66; S, 7.69.
procedure described above (0.26 g, 82%). Eluent: CHCl3/MeOH
25
(99:1); mp: 80–81 ꢁC; [
a
]
D
ꢂ44.0 (c 1.12, CHCl3); IR (CHCl3): 1465,
1596, 1691, 2343, 2360, 2401, 2931, 3392, 3629, 3678, and
4214 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
1.63 (s, 3H), 2.41 (s, 3H),
4.20. Methyl 2,3-dideoxy-4,6-di-O-acetyl-2-C-(thymin-1-yl)-
3.31 (s, 3H), 3.74 (dd, 1H, J¼4.4, 10.3 Hz), 3.87 (dd, 1H, J¼2.2,
10.3 Hz), 4.04 (q, 1H), 4.66 (dd, 2H, J¼12.1, 18.7 Hz), 4.77 (m, 1H),
4.91 (d, 1H, J¼4.4 Hz), 5.56 (dd, 1H, J¼4.7, 10.6 Hz), 6.83 (s, 1H), 7.38
(m, 7H), 7.69 (d, 2H, J¼8.1 Hz), and 8.81 (br s, 1H); 13C NMR
a
-
D
-glucopyranoside 25
To a well-stirred solution of 5 (0.25 g, 0.49 mmol) and Na2HPO4
(0.55 g, 4 mmol) in anhydrous MeOH (10 mL) was added Na–Hg
(w6%, 15.8 g) and the resulting mixture was stirred at ambient
temperature under N2 atmosphere. After 4 h (TLC) the reaction
mixture was diluted with EtOAc (40 mL) and undissolved solid was
filtered off by passing through a Celite bed. The filtrate was evap-
orated under reduced pressure. The crude residue was triturated in
EtOAc and the organic layer was washed with saturated NaHCO3
solution (3ꢀ30 mL). The organic layer was separated, dried over
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. The crude material was purified over silica gel to afford
a white solid. The solid thus obtained was dissolved in anhydrous
MeOH containing AcOH (MeOH/AcOH¼80:1) and N2 gas was
bubbled for 15 min to remove dissolved oxygen. Pd–C (10%, 0.02 g)
was added to this solution and debenzyledination was complete in
12 h at ambient temperature under H2 atmosphere. The reaction
mixture was filtered through Celite and the Celite bed was thor-
oughly washed with warm MeOH. The filtrate was evaporated
under reduced pressure to obtain a jelly material, which was dis-
solved in anhydrous pyridine (10 mL). The resulting solution was
cooled to 0 ꢁC. Acetic anhydride (0.2 mL, 2.11 mmol) was added
dropwise to this solution with stirring and the reaction mixture was
allowed to attain room temperature. Stirring was continued over-
night until TLC showed completion of the reaction. The solvent was
then co-evaporated three times with a mixture of methanol and
toluene (1:3). The residue thus obtained was triturated in EtOAc
(50 mL) and the organic layer was washed with saturated NaHCO3
solution (3ꢀ30 mL). The organic layer was separated, dried over
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. The crude material was purified over silica gel to furnish
(75 MHz, CDCl3): d 12.3, 21.7, 55.3, 57.2, 63.2, 71.9 (CH2), 73.6 (CH2),
76.3, 101.4, 110.2, 127.7, 127.9, 128.6, 128.7, 130.2, 134.3, 137.2, 138.0,
146.2, 151.2, and 163.4; MS m/z (EI): 91 (100), 217 (12), 285 (6), 333
(3), 379 (2), 468 (6), and 500 (6 Mþ). Anal. Calcd for
C
25H28N2O7S$1H2O: C, 57.89; H, 5.82; N, 5.40; S, 6.18. Found: C,
57.74; H, 5.52; N, 5.38; S, 6.86.
4.18. Methyl 2-C-adenin-9-yl-5-O-benzyl-2,3-dideoxy-
3-C-p-toluenesulfonyl-
b-D-ribofuranoside 22
Compound 2 (0.38 g, 1.01 mmol) was reacted with adenine
b
(1.22 g, 9.09 mmol) in the presence of TMG (0.88 mL, 7.07 mmol) to
generate an amorphous solid 22 in 12 h following the general
procedure described above (0.31 g, 60%). Eluent: MeOH/acetone/
25
CHCl3 (1:2:97); mp: 196–198 ꢁC; [
a
]
D
þ27.0 (c 1.01, CHCl3); IR
(Nujol): 1579, 1598, 1658, 3159, 3274, 3338, and 3390 cmꢂ1
;
1H
NMR (200 MHz, CDCl3): 2.36 (s, 3H), 3.35 (s, 3H), 3.56 (dd, 1H,
d
J¼6.3, 10.7 Hz), 3.69 (dd, 1H, J¼2.9, 10.8 Hz), 4.35 (t, 1H, J¼7.3 Hz),
4.58 (dd, 2H, J¼12.3, 17.6 Hz), 5.14 (s, 1H), 5.18 (m, 1H), 5.40 (d, 1H,
J¼5.4 Hz), 5.95 (br s, 2H), 7.08 (d, 2H, J¼8.3 Hz), 7.37 (m, 7H), 7.99 (s,
1H), and 8.20 (s, 1H); 13C NMR (50 MHz, CDCl3):
d 21.8, 55.4, 58.7,
64.5, 72.7 (CH2), 73.7 (CH2), 78.2, 107.4 (C-1), 119.5, 128.0, 128.7,
130.0, 135.2, 137.9, 140.0, 145.7, 150.6, 153.1, and 155.7; MS m/z (EI):
91 (100), 136 (22), 154 (3), 188 (4), 219 (6), and 354 (4). Anal. Calcd
for C25H27N5O5S: C, 58.92; H, 5.33; N,13.74; S, 6.29. Found: C, 59.44;
H, 5.19; N, 13.13; S, 6.58.
4.19. Methyl 5-O-benzyl-2,3-dideoxy-3-C-p-toluenesulfonyl-
2-C-(1H-1,2,4-triazol-1-yl)-
5-O-benzyl-2,3-dideoxy-3-C-p-toluenesulfonyl-2-C-(1H-1,2,4-
triazol-1-yl)- -ribofuranoside 24
b
-
D
-xylofuranoside 23 and methyl
a glassy solid 25 (0.13 g, 72%). Eluent: EtOAc/petroleum ether (7:3);
27
Rf (2% MeOH/DCM) 0.33; [
a
]
þ122.9 (c 0.676, CHCl3); IR (KBr):
D
b
-D
1372, 1468, 1650, 1681, 1696 and 1736 cmꢂ1
.
1H NMR (200 MHz,
CDCl3): 1.89 (s, 3H), 2.04 (s, 3H), 2.09 (s, 3H), 2.15–2.20 (m, 2H),
d
Compound 2
b
(0.27 g, 0.732 mmol) was reacted with 1,2,4-tri-
3.38 (s, 3H), 3.86–3.93 (m, 1H), 4.13–4.23 (m, 2H), 4.71 (d, 1H,
azole (0.252 g, 3.66 mmol) in the presence of TMG (0.27 mL,
2.19 mmol) to produce the mixture of 23 and 24 in 28 h following
the general procedure described above (0.22 g, 75%). Eluent: EtOAc/
J¼3.1 Hz), 4.86–4.96 (m, 2H), 7.17 (d, 1H, J¼0.6 Hz), 9.53 (br s, 1H);
13C NMR (50 MHz, CDCl3):
d 12.4, 20.6, 20.7, 28.5 (CH2), 50.8, 55.1,
62.2 (CH2), 66.6, 67.8, 96.5, 110.1, 137.5, 151.3, 163.8, 169.4, 170.7;
HRMS (ESþ), m/z calcd for (MþH)þ C16H23N2O8: 371.1454. Found:
371.1449.
petroleum ether (3:7). Compound 23: isolated yield: 0.08 g; mp:
26
179–180 ꢁC; [
a
]
D
ꢂ5.0 (c 1.06, CHCl3); IR (CHCl3): 1452, 1504, 1596,
1753, 2341, 2360, 2399, 3620, 3681, 3786, and 4214 cmꢂ1; 1H NMR
(200 MHz, CDCl3): 2.37 (s, 3H), 3.40 (s, 3H), 4.11 (m, 2H), 4.68 (s,
d
4.21. Methyl 2,3-dideoxy-4,6-di-O-acetyl-2-C-(thymin-1-yl)-
-glucopyranoside 26
b-
3H), 4.92 (dt, 1H, J¼3.4, 8.05 Hz), 5.05 (d, 1H, J¼3.9 Hz), 5.17 (dd, 1H,
J¼3.6, 9.0 Hz), 7.16 (d, 2H, J¼8.3 Hz), 7.36 (m, 5H), 7.49 (d, 2H,
J¼8.3 Hz), 7.65 (s, 1H), and 7.76 (s, 1H); 13C NMR (50 MHz, CDCl3):
D
Compound 9 (0.25 g, 0.49 mmol) was converted to a hygro-
scopic solid 26 (0.116 g, 64%) following the procedure described for
d
21.7, 56.7, 66.3, 67.4, 69.8 (CH2), 73.7 (CH2), 78.9,108.1,127.7,128.0,
128.5, 130.1, 135.7, 138.1, 144.2, 145.7, and 152.8; MS m/z (EI): 91
the preparation of 25. Eluent: EtOAc/petroleum ether (7:3); Rf (2%
27
(100), 228 (6), 255 (11), 412 (9), and 443 (6 Mþ). Anal. Calcd for
MeOH/DCM) 0.4. [
a
]
ꢂ28.4 (c 0.676, CHCl3); IR (KBr): 1375, 1466,
D

10414
A.K. Sanki et al. / Tetrahedron 64 (2008) 10406–10416
1656, 1688, 1701, and 1743 cmꢂ1. 1H NMR (200 MHz, CDCl3):
d
1.89
4.25. Methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-p-
toluenesulfonyl- -erythro-hex-2-enopyranoside 33
(s, 3H), 2.04 (s, 3H), 2.08 (s, 3H), 2.34–2.53 (m, 2H), 3.47 (s, 3H),
3.75–3.83 (m, 2H), 4.21–4.25 (m, 2H), 4.74–4.79 (m,1H), 5.07 (d,1H,
J¼7.95 Hz), 6.87 (d, 1H, J¼1.14 Hz), 8.99 (br s, 1H); 13C NMR
b-D
b
To a well-stirred solution of 30 (3.2 g, 12.1 mmol) in anhydrous
DMF (15 mL) were added thiocresol (7.51 g, 60.6 mmol) and TMG
(4.56 g, 36.36 mmol) under N2 atmosphere. The resulting reaction
mixture was heated at 80–90 ꢁC for 3 h and allowed to attain room
temperature. Brine solution (80 mL) was added into it. The mixture
was extracted with EtOAc (3ꢀ30 mL). Combined organic layers
were washed with saturated NaHCO3 (2ꢀ25 mL), dried over
Na2SO4, and filtered. The filtrate was evaporated under reduced
pressure to furnish a syrupy material. The crude syrup was purified
over silica gel using petroleum ether/EtOAc (3:1) as the eluent to
yield 31 (4.42 g, 94%). To a solution of 31 (4.20 g, 10.82 mmol) in
MeOH (30 mL) was added MMPP (16.88 g, 34.17 mmol). The re-
action mixture was stirred for 6 h at ambient temperature and fil-
tered. The filtrate was evaporated under reduced pressure to afford
a crude residue. The crude material was neutralized with saturated
NaHCO3 (70 mL). The mixture was extracted with EtOAc (3ꢀ30 mL).
Combined organic layers were dried over Na2SO4, filtered, and the
filtrate was concentrated to dryness under reduced pressure to
yield 32 quantitatively. To a solution of 32 in anhydrous pyridine
(25 mL) was added a solution of methanesulfonyl chloride (2.8 mL,
36.45 mmol) in anhydrous pyridine (15 mL) at 0 ꢁC. The reaction
mixture was left overnight at 4 ꢁC. The reaction mixture was
poured into saturated NaHCO3 (70 mL) and filtered through a Celite
bed. The filtrate was extracted with dichloromethane (3ꢀ30 mL)
and the organic extracts were collected together, dried over
Na2SO4, and filtered. DBU (3.4 mL, 22.78 mmol) was added to the
filtrate and after 5 min the solvent was evaporated under reduced
pressure. The resulting residue was purified over silica gel to yield
(50 MHz, CDCl3): d 12.3, 20.7, 20.8, 31.1 (CH2), 56.8, 60.8, 62.5 (CH2),
66.7, 74.9, 100.8, 110.8, 140.7, 150.8, 164.2, 169.8, 170.8; HRMS (ESþ),
m/z calcd for (MþH)þ C16H23N2O8: 371.1454. Found: 371.1446.
4.22. Methyl 2-C-(N-acetyl-adenin-9-yl)-2,3-dideoxy-4,6-O-
(phenylmethylene)-a-D-glucopyranoside 27
Compound 6 (0.24 g, 0.46 mmol) was desulfonylated with Na–
Hg (w6%, 15 g) as described above, in anhydrous MeOH (20 mL) in
the presence of Na2HPO4 (0.6 g, 4.2 mmol) in 4 h at ambient tem-
perature to obtain a white solid. To a well-stirred solution of the
crude solid in anhydrous pyridine (20 mL) was added a catalytic
amount of DMAP (10 mg). Acetyl chloride (0.1 mL, 1.40 mmol) was
added into the reaction mixture at 0 ꢁC under N2 atmosphere. The
reaction mixture was slowly allowed to attain room temperature
and stirring was continued overnight until TLC showed completion
of the reaction. The excess solvent was evaporated under reduced
pressure and the crude residue was co-evaporated with a mixture
of methanol and toluene (1:3) to remove residual pyridine com-
pletely. Crude material thus obtained was dissolved in EtOAc
(40 mL) and the organic layer was washed with saturated NaHCO3
solution (3ꢀ30 mL), dried over Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure to afford a residue. The res-
idue was purified over silica gel to obtain a hygroscopic solid 27
27
(0.11 g, 56%). Eluent: EtOAc/petroleum ether (7:3); [
a]
þ45.4 (c
D
0.71, CHCl3); 1H NMR (200 MHz, CDCl3):
d
2.17–2.41 (m, 2H), 2.62 (s,
3H), 3.38 (s, 3H), 3.79–4.04 (m, 3H), 4.31–4.38 (m, 1H), 4.83 (d, 1H,
J¼3.28 Hz), 5.04–5.14 (m,1H), 5.61 (s,1H), 7.37–7.52 (m, 5H), 8.18 (s,
a colorless jelly 33b (4.03 g, 88%; four steps from epoxide 30). El-
1H), 8.60 (br s, 1H), 8.67 (s, 1H); 13C NMR (50 MHz, CDCl3):
d
25.6,
uent: with EtOAc/petroleum ether (2:3); Rf (40% EtOAc/petroleum
28
30.4 (CH2), 51.9, 55.2, 64.2, 69.2 (CH2), 76.4, 97.1, 102.0, 121.2, 126.2,
128.4, 129.3, 137.1, 142.4, 149.3, 151.3, 152.3, 170.7; HRMS (ESþ), m/z
calcd for (MþNa)þ C21H23N5O5Na: 448.1597. Found: 448.1596.
ether) 0.33; [
d
a
]
D
ꢂ8.2 (c 0.75, CHCl3); 1H NMR (400 MHz, CDCl3):
2.34 (s, 3H), 3.50 (s, 3H), 3.67–3.73 (m, 1H), 3.78–3.89 (m, 1H),
4.24–4.28 (m, 1H), 4.56–4.59 (m, 1H), 5.41 (d, 1H, J¼1.2 Hz), 5.53 (s,
1H), 6.89 (s, 1H), 7.11 (d, 2H, J¼8.0 Hz), 7.22–7.38 (m, 5H), and 7.68
4.23. Methyl 2-C-(N-acetyl-adenin-9-yl)-2,3-dideoxy-4,6-O-
(d, 2H, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3):
d 21.7, 55.8, 68.6
(phenylmethylene)-
b-D
-glucopyranoside 28
(CH2), 69.8, 73.72, 98.8, 102.1, 126.3, 128.1, 128.9, 129.2, 129.4, 136.5,
136.7, 136.8, 143.1, and 144.6; HRMS (ESþ), m/z calcd for (MþH)þ
C21H23O6S: 403.1215. Found: 403.1214.
Compound 10 (0.30 g, 0.57 mmol) was converted to a hygro-
scopic solid material 28 (0.14 g, 58%) in 48 h following the pro-
cedure described above for the preparation of 27. Eluent: EtOAc/
4.26. Methyl 2,3-dideoxy-3-C-p-toluenesulfonyl-6-O-
27
petroleum ether (4:1);
(200 MHz, CDCl3):
[
a
]
D
ꢂ2.1 (c 0.55, CHCl3); 1H NMR
trityl-
a-
D
-erythro-hex-2-enopyranoside 34
a
d
2.41–2.52 (m, 1H), 2.61 (s, 3H), 2.92–3.14 (m,
1H), 3.34 (s, 3H), 3.72–3.89 (m, 3H), 4.39–4.47 (m, 2H), 5.14 (d, 1H,
To a well-stirred solution of compound 33
a
(0.5 g, 1.24 mmol) in
J¼8.17 Hz), 5.59 (s, 1H), 7.35–7.52 (m, 5H), 7.96 (s, 1H), 8.66 (s, 1H),
anhydrous MeOH (20 mL) was added acetyl chloride (0.2 mL,
2.82 mmol) dropwise at 0 ꢁC under N2 atmosphere over a period of
0.5 h. The resulting solution was stirred at room temperature. After
2.5 h (TLC) the solution was evaporated to dryness under reduced
pressure and the residual liquid was co-evaporated twice with
pyridine to obtain a syrupy compound. The compound thus
obtained was dissolved in EtOAc, washed thoroughly with satu-
rated NaHCO3 solution, dried over Na2SO4, and filtered. The filtrate
was evaporated under reduced pressure to obtain a crude mass. The
crude mass was purified over silica gel with petroleum ether/EtOAc
mixture (3:1) as eluent to generate a colorless jelly compound. To
a solution of this compound (1.8 g, 5.73 mmol) in anhydrous pyri-
dine (40 mL) was added trityl chloride (3.5 g, 12.55 mmol) and the
resulting solution was stirred at ambient temperature under N2
atmosphere. After 48 h (TLC), excess pyridine was evaporated to
half of its original volume. The solution was poured into an ice-cold
saturated NaHCO3 solution and the mixture was stirred for 30 min.
The mixture was extracted with EtOAc (3ꢀ30 mL). The combined
organic layers were dried over Na2SO4 and filtered. The filtrate was
evaporated to dryness under reduced pressure. The crude material
9.28 (br s, 1H); 13C NMR (50 MHz, CDCl3):
d 25.7, 32.8 (CH2), 56.8,
57.1, 68.9 (CH2), 70.4, 76.2, 101.7, 101.8, 122.2, 126.1, 128.3, 129.2,
137.0, 142.9, 149.4, 151.3 (C), 152.0, 170.8; HRMS (ESþ), m/z calcd for
(MþH)þ C21H24N5O5: 426.1777. Found: 426.1778.
4.24. Methyl 2-C-(adenin-9-yl)-2,3-dideoxy-4,6-O-
(phenylmethylene)-a-D-glucopyranoside 29
Compound 6 (0.24 g, 0.46 mmol) was desulfonylated with Na–
Hg (w6%, 15 g) in anhydrous MeOH (20 mL) in the presence of
Na2HPO4 (0.6 g, 4.2 mmol) in 4 h at ambient temperature to pro-
28
duce a white solid 29 (0.11 g, 64%). Mp: 103–104 ꢁC; [
a
]
D
þ32.6 (c
0.71, CDCl3); 1H NMR (200 MHz, CDCl3):
d 2.30–2.60 (m, 2H), 3.36
(s, 3H), 3.75–3.96 (m, 3H), 4.29–4.35 (m, 1H), 4.81 (d, 1H, J¼3.3 Hz),
4.96–5.07 (m, 1H), 5.59 (s, 1H), 5.70 (br s, 2H), 7.32–7.51 (m, 5H),
8.00 (s, 1H), and 8.33 (s, 1H); 13C NMR (50 MHz, CDCl3):
d 30.4
(CH2), 51.7, 55.2, 64.2, 69.2 (CH2), 76.7, 97.2, 101.9, 118.9, 126.1, 128.3,
129.2, 137.1, 139.8, 149.8, 153.0, 155.5; HRMS (ESþ), m/z calcd for
(MþH)þ C19H22N5O4: 384.1672. Found: 384.1679.

A.K. Sanki et al. / Tetrahedron 64 (2008) 10406–10416
10415
thus obtained was purified over silica gel to furnish a white solid
34 (2.5 g, 80%). Eluent: with EtOAc/petroleum ether (1:3); Rf (25%
EtOAc/petroleum ether) 0.32; mp: 109–111 ꢁC; [
CHCl3); 1H NMR (200 MHz, CDCl3):
2.42 (s, 3H), 2.93 (d, 1H,
heated at 100–110 ꢁC under vacuum. After 2.5 h (TLC), the reaction
mixture was cooled to room temperature and poured into an ice-
cold, saturated NaHCO3 solution. The aqueous layer was extracted
with EtOAc (3ꢀ25 mL). Organic layers were pooled together, dried
over anhydrous Na2SO4, filtered, and the filtrate was evaporated to
dryness. The residue was purified over silica gel to obtain com-
pound 29 (0.07 g, 39% in two steps).
a
28
a]
ꢂ18.6 (c 0.315,
D
d
J¼4.68 Hz), 3.25–3.42 (m, 2H), 3.51 (s, 3H), 3.93 (m, 1H), 4.34–4.36
(m, 1H), 5.11 (d, 1H, J¼3.05 Hz), 6.83 (d, 1H, J¼2.9 Hz), 7.19–7.45 (m,
17H), and 7.78 (d, 2H, J¼8.2 Hz); 13C NMR (50 MHz, CDCl3):
d 21.6,
56.1, 63.2 (CH2), 63.4, 71.1, 86.8, 94.6,127.0,127.2,128.2,128.6,129.8,
135.2, 136.6, 143.7, 144.4, and 144.5; HRMS (ESþ), m/z calcd for
(MþNa)þ C33H32O6SNa: 579.1817. Found: 579.1813.
4.30. Methyl 2,3-dideoxy-4,6-di-O-acetyl-2-C-(N-acetyl-
adenin-9-yl)-a-D-glucopyranoside 37
4.27. Methyl 2,3-dideoxy-3-C-p-toluenesulfonyl-6-O-trityl-
b
-
To a solution of 36 (0.11 g, 0.2 mmol) in anhydrous MeOH
(10 mL) was added acetyl chloride (0.15 mL, 1.9 mmol) at 0 ꢁC and
the solution was stirred under N2 atmosphere. After 4 h (TLC), an-
hydrous pyridine (2 mL) was added to this solution and the
resulting solution was evaporated under reduced pressure. Re-
sidual pyridine was co-evaporated with toluene to obtain a residue.
The residue was acetylated with acetyl chloride (0.7 mL, 9 mmol) in
anhydrous pyridine (10 mL) in the presence of catalytic amount of
DMAP (10 mg) in 20 h at ambient temperature. Usual work-up and
purification over silica gel afforded 37 (0.76 g, 88%) as a hygroscopic
D
-erythro-hex-2-enopyranoside 34
b
Compound 34b (colorless jelly, 1.02 g, 61%) was synthesized
from 33 (1.2 g, 2.98 mmol) following the procedure described for
b
28
the preparation of 34a. Rf (33% EtOAc/petroleum ether) 0.36; [a]
D
ꢂ119.8 (c 0.60, CHCl3); 1H NMR (200 MHz, CDCl3):
d 2.37 (s, 3H),
2.43–3.33 (m, 3H), 3.37 (s, 3H), 3.95–4.01 (m, 1H), 4.45–4.47 (m,
1H), 5.10 (br s, 1H), 6.84 (d, 1H, J¼2 Hz), 7.19–7.41 (m, 17H), and 7.76
(d, 2H, J¼8.3 Hz); 13C NMR (50 MHz, CDCl3):
d 21.5, 55.9, 61.6, 62.9
(CH2), 76.4, 86.8, 95.4, 127.0, 127.7, 128.3, 128.5, 129.9, 135.4, 135.6,
142.5, 143.6, and 145.0. Anal. Calcd for C33H32O6S$1.5H2O: C, 67.91;
H, 6.04. Found: C, 67.84; H, 5.91.
solid. Eluent: EtOAc/petroleum ether (7:3); Rf (2% MeOH/DCM)
27
0.28; [
a]
þ48.8 (c 0.676, CHCl3); 1H NMR (200 MHz, CDCl3):
d 2.04
D
(s, 3H), 2.09 (s, 3H), 2.16–2.57 (m, 2H), 2.63 (s, 3H), 3.36 (s, 3H),
4.04–4.27 (m, 3H), 4.81 (d, 1H, J¼3.0 Hz), 4.89–5.07 (m, 2H), 8.14 (s,
1H), 8.64 (s, 1H), and 8.82 (br s, 1H); 13C NMR (50 MHz, CDCl3):
4.28. Methyl 2,3-dideoxy-6-O-trityl-2-C-(adenin-9-yl)-
a
-
D
-glucopyranoside 36
d 20.7, 20.8, 25.6, 30.0 (CH2), 51.1, 55.3, 62.2 (CH2), 66.2, 68.0, 77.2,
96.6, 121.1, 141.8, 149.1, 151.2, 152.3, 169.7, 170.5, 170.8; HRMS (ESþ),
To a well-stirred solution of adenine (0.44 g, 3.27 mmol) and
TMG (0.3 mL, 2.35 mmol) in anhydrous DMF (20 mL) was added
34 (0.26 g, 0.47 mmol) and the mixture was stirred at room
m/z calcd for (MþH)þ C18H24N5O7: 422.1676. Found: 422.1681.
a
4.31. Methyl 2,3-dideoxy-6-O-trityl-2-C-(adenin-9-yl)-
temperature. After 3 days (TLC), the reaction mixture was diluted
with EtOAc (40 mL) and filtered. The filtrate was washed with
saturated NaHCO3 solution. Organic layers were separated, dried
over Na2SO4, and filtered. The filtrate was concentrated under re-
duced pressure. The crude material was purified over silica gel to
obtain an inseparable mixture 35. To a solution of 35 in anhydrous
MeOH (20 mL) were added Na2HPO4 (0.6 g, 4.2 mmol) and (w6%)
Na–Hg (15 g). The resulting mixture was stirred at room tempera-
ture under N2 atmosphere. After 4 h (TLC) the reaction mixture was
diluted with EtOAc (50 mL) and filtered through a Celite bed. The
filtrate was evaporated under reduced pressure. The residue was
triturated with EtOAc (30 mL) and the organic layer was washed
with saturated NaHCO3 solution. The organic layers were separated,
dried over Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure to obtain a residue. The residue was purified over
b-D-glucopyranoside 39
Compound 39 (0.12 g, 43%) was obtained as a glassy solid from
b (0.3 g , 0.54 mmol) following the procedure described for the
34
synthesis of compound 36. [
1374, 1458, 1637, 1647, 1735, and 3448 cmꢂ1
CDCl3): 2.35–2.43 (m, 1H), 2.56–2.72 (m, 1H), 3.35 (s, 3H), 3.39–
28
a]
ꢂ101.9 (c 0.71, CHCl3); IR (KBr):
D
;
1H NMR (200 MHz,
d
3.57 (m, 2H), 3.72–3.86 (m, 2H), 4.13–4.41 (m, 1H), 5.05 (d, 1H,
J¼8.16 Hz), 5.85 (br s, 2H), 7.12–7.52 (m, 15H), 7.71 (s, 1H), 8.31 (s,
1H); 13C NMR (50 MHz, CDCl3):
d 35.8 (CH2), 56.0, 56.6, 64.9 (CH2),
68.0, 77.1, 87.4, 101.6, 119.2, 127.3, 128.0, 128.6, 140.2, 143.4, 150.0,
152.6, 155.5; HRMS (ESþ), m/z calcd for (MþH)þ C31H32N5O4:
538.2454. Found: 538.2451.
4.32. Methyl 2,3-dideoxy-4,6-di-O-acetyl-2-C-(N-acetyl-
silica gel to provide a hygroscopic solid 36 (0.11 g, 44% from 34
a
).
adenin-9-yl)-b-D-glucopyranoside 40
28
Eluent: CHCl3/MeOH (49:1); [
a
]
þ29.9 (c 0.710, CHCl3); 1H NMR
D
(200 MHz, CDCl3):
d
2.20–2.43 (m, 2H), 3.25 (s, 3H), 3.32–3.48 (m,
Compound 40 (0.15 g, 88%) was obtained from 39 (0.22 g,
2H), 3.68–3.77 (m, 1H), 3.83–3.93 (m, 1H), 4.77 (d, 1H, J¼3.1 Hz),
0.4 mmol) following the procedure described for the synthesis of
4.84–4.94 (m, 1H), 6.01 (br s, 2H), 7.11–7.36 (m, 9H), 7.45–7.49 (m,
compound 37. Eluent: EtOAc/petroleum ether (7:3); Rf (2% MeOH/
27
6H), 7.98 (s, 1H), and 8.31 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
32.6
DCM) 0.39; colorless, hygroscopic solid; [
a
]
ꢂ17. 2 (c 0.676,
D
(CH2), 51.4, 54.9 (CH2), 64.7 (CH2), 67.7, 70.5, 87.4, 96.4, 118.7, 127.2,
128.0, 128.5, 139.8, 143.5, 149.7, 152.8, and 155.3; HRMS (ESþ), m/z
calcd for (MþH)þ C31H32N5O4: 538.2454. Found: 538.2452.
CHCl3); IR (KBr): 1375, 1459, 1585, 1611, 1638, 1736, and 3430 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
2.08 (s, 3H), 2.11 (s, 3H), 2.58–2.62 (m,
4H), 2.89–2.93 (m, 1H), 3.35 (s, 3H), 3.98–4.09 (m, 1H), 4.26–4.35
(m, 3H), 4.86–4.98 (m, 1H), 5.18 (d, 1H, J¼8.0 Hz), 7.87 (s, 1H), 8.61
4.29. Conversion of 36 to 29
(br s, 1H), 8.65 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 20.8, 25.6, 32.1
(CH2), 56.3, 56.9, 62.5 (CH2), 66.3, 75.0, 101.0, 122.3, 143.2, 149.4,
151.9, 152.3, 169.8, 170.8. HRMS (ESþ), m/z calcd for (MþH)þ
C18H24N5O7: 422.1676. Found: 422.1670.
To a solution of 36 (0.21 g, 0.39 mmol) in dry MeOH (20 mL) was
added acetyl chloride (0.35 mL) at 0 ꢁC and the solution was stirred
for 4 h. To this solution was added dry pyridine (5 mL) and the
resulting solution was evaporated under reduced pressure. Re-
sidual pyridine was co-evaporated with dry toluene (2ꢀ5 mL) and
the residue was dissolved in dry DMF (5 mL). To this solution were
added benzaldehyde dimethylacetal (0.65 mL, 4.48 mmol), p-TSA
(36.1 mg, 0.19 mmol) and the resulting reaction mixture was
Acknowledgements
T.P. thanks Indo-French Centre for the Promotion of Advance
Research, New Delhi, for funding (Project No. 3405-1). A.K.S., R.B.,
and A.A. thank the Council of Scientific and Industrial Research,

10416
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New Delhi, India for fellowships. The Department of Science and
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facility in the Department of Chemistry, Indian Institute of Tech-
nology, Kharagpur, India.
Supplementary data
Crystallographic data (excluding structure factors) for the
structures of compounds 4, 5, 8, 9, 17, 23, 24, 29 have been de-
posited with the Cambridge Crystallographic Data Centre as sup-
plementary publication nos. CCDC 687457–687464. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk). 1H and 13C NMR spectra of all new
compounds are provided. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
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25. Desulfonylated nucleosides were isolated as peracetylated derivatives 25, 26,
37, and 40 for their easy isolation and characterization. For further modifi-
cations these compounds may be deacetylated and reprotected. Alterna-
tively, compounds
5
and 9, immediately after desulfonylation and
debenzyledination (Scheme 7) may be protected with other masking groups
and isolated. For adenine analogues, the tritylated compounds 39 (Scheme
10) and 36 (Scheme 11) may be functionalized directly depending on the
requirement.
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