Studies on the synthesis and unusual behavior of vinyl sulfone-modified hexenopyranosylthymines

Article abstract of DOI:10.1016/j.carres.2008.02.016

Although vinyl sulfone-modified- (VSM) pent-2′-enofuranosyl nucleosides 2 and hex-2-enopyranosyl glycoside 4 are easily synthesized from the corresponding mesylated sulfones 1c and 3c, respectively, via an oxidation-mesylation-elimination route, the 3′-C-sulfonyl-hex-2′-enopyranosylthymine 11 is not obtained from 10 and a glycal derivative 12 is formed instead. On the other hand, 3′-C-sulfonyl-hex-3′-enopyranosylthymine 20 is easily synthesized from the mesylated sulfone 19. Again unlike the reaction patterns of VSM-pent-2′-enofuranosyl nucleosides 2 and hex-2-enopyranosyl glycosides 4 as Michael acceptors, the reactions of nucleophiles with 3′-C-sulfonyl-hex-3′-enopyranosylthymine 20 yielded a rearranged product 21 instead of Michael adducts.

Full text of DOI:10.1016/j.carres.2008.02.016

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 1163–1170
Studies on the synthesis and unusual behavior of vinyl
sulfone-modified hexenopyranosylthymines
Sachin G. Deshpande,a Cheravakkattu G. Sureshb and Tanmaya Pathakc,*
aOrganic Chemistry Division (Synthesis), National Chemical Laboratory, Pune 411 008, India
bDivision of Biochemical Sciences, National Chemical Laboratory, Pune 411 008, India
cDepartment of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 14 January 2008; received in revised form 12 February 2008; accepted 14 February 2008
Available online 21 February 2008
Abstract—Although vinyl sulfone-modified- (VSM) pent-20-enofuranosyl nucleosides 2 and hex-2-enopyranosyl glycoside 4 are
easily synthesized from the corresponding mesylated sulfones 1c and 3c, respectively, via an oxidation–mesylation–elimination route,
the 30-C-sulfonyl-hex-20-enopyranosylthymine 11 is not obtained from 10 and a glycal derivative 12 is formed instead. On the other
hand, 30-C-sulfonyl-hex-30-enopyranosylthymine 20 is easily synthesized from the mesylated sulfone 19. Again unlike the reaction
patterns of VSM-pent-20-enofuranosyl nucleosides 2 and hex-2-enopyranosyl glycosides 4 as Michael acceptors, the reactions of
nucleophiles with 30-C-sulfonyl-hex-30-enopyranosylthymine 20 yielded a rearranged product 21 instead of Michael adducts.
Ó 2008 Published by Elsevier Ltd.
Keywords: Hexopyranosyl nucleosides; Vinyl sulfone-modified nucleosides; Unsaturated nucleosides; Michael addition; Glycal
1. Introduction
with the enzymes.9 In fact a wide range of vinyl
sulfone-modified (VSM) organic molecules have been
subjected to extensive biological studies.9 Surprisingly,
no biological data on any VSM carbohydrates and
nucleosides are available in the literature to date.9
Our interest in developing methodologies for the func-
tionalization of hexopyranosyl nucleosides8 at the 20, 30,
or 40 positions for the generation of new six-membered
nucleosides prompted us to initiate a study for the
designing of VSM pyranosyl nucleosides. As VSM-
pent-20-enofuranosyl nucleosides 2 synthesized from 1a
via 1b and 1c (Scheme 1) were used as efficient Michael
The selective reverse transcriptase inhibitory properties
of the unsaturated nucleoside, 20,30-didehydro-20,30-di-
deoxythymidine (d4T, stavudine), have triggered the
designing of a plethora of unsaturated furanosyl nucle-
osides having variations at either or both of the 20-
and 30-positions.1 Attempts are also currently underway
to synthesize and study the biological properties of a
wide range of unsaturated pyranosyl nucleosides.2–4
As part of a program on the synthesis of modified
nucleosides,5–8 we functionalized furanosyl nucleosides
with electron-rich double bonds such as those of enam-
ines6 as well as with electron-deficient double bonds
such as those of vinyl sulfones.7 Although the vinyl sul-
fone moiety was identified as a biologically important
functional group long ago, in recent times vinyl sulfone-
containing dipeptides are shown to be efficient cysteine
protease inhibitors through covalent bond formation
OR
B
RO
RO
B
O
O
p-TolO2S
X
2
1a X =
1b X =
1c X =
p
-TolS; R = H
-TolSO2; R = H
p-TolSO2; R = OMs B = nucleobases
p
Scheme 1. Reported10 synthesis of vinyl sulfone-modified nucleo-
sides 2.
*
Corresponding author. Tel.: +91 03222 283342/282251; fax: +91
03222 282252; e-mail: tpathak@chem.iitkgp.ernet.in
0008-6215/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.carres.2008.02.016

1164
S. G. Deshpande et al. / Carbohydrate Research 343 (2008) 1163–1170
acceptors for the generation of a range of amino- and
branched-chain nucleosides,10 we presumed that VSM
hexopyranosyl nucleosides, in addition to their potential
biological properties,9 would also act as useful interme-
diates for the functionalization of the sugar moiety of
pyranosyl nucleosides.
AcO
RO
RO
O
O
(ic)
O
(ia)
T
T
AcO
TsO
OAc
OR'
5
SAr
6 R = R' = Ac
7 R = R' = H
(ib)
O
Ph
(ii)
O
O
Ph
(iiia)
T
OR
O
T
O
OMs
SO2Ar
SO2Ar
2. Results and discussion
8 R = SAr; R' = H
10
9 R = SO2Ar; R' = H
2.1. Attempted synthesis of 30-C-sulfonyl-hex-20-enopyr-
anosylthymine (11)
Ph
O
O
T
O
O
N
ArO2S
In connection with VSM carbohydrates, we have
demonstrated that the b-anomeric derivative 4 was
easily accessible from 3a via 3b and 3c (Scheme 2).11
We therefore decided to apply a similar strategy to syn-
thesize VSM pyranosyl nucleosides. Our synthesis
started from 1-(2,4,6-tri-O-acetyl-3-O-tosyl-b-D-gluco-
pyranosyl)thymine (5), which was converted to a mix-
ture of 6 and partially deacetylated compounds earlier
reported by us (Scheme 3).8 Complete deacetylation of
the mixture was achieved by NaOMe in methanol. Triol
7 thus obtained was benzylidenated yielding the partially
protected alcohol 8. Compound 8 was oxidized with
magnesium monoperoxypthalate (MMPP) in MeOH
to produce the sulfonylated nucleoside 9. Crude 9 was
mesylated using the standard conditions, and product
10 was subsequently treated with 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU). Although oxidation–mesylation–
base treatment is a standard route that was used earlier
for the synthesis of VSM-nucleosides (Scheme 1) and
carbohydrates (Scheme 2), to our surprise in this case
Me
T =
(iiib)
11
NH
O
Ph
O
O
O
T
ArO2S
12
Ar = p-Tol
Scheme 3. Reagents and conditions: (i) (a) p-TolSH, NaOMe, DMF,
90 °C, 10 h; (b) NaOMe, MeOH, rt, 6 h; (c) PhCH(OCH3)2, TsOH,
DMF, 100 °C, 1 h, 66% (from 5); (ii) MMPP, MeOH, rt, 3–3.5 h; (iii)
(a) MsCl, pyridine, 0–4 °C, overnight; (b) DBU, DCM, rt, 5 h, 52%
(from 8).
ternary C-10 was established to be d 149.0 on the basis of
its correlations with two b protons, H-30 (d 4.20) and H-
6 (d 7.13) in the heteronuclear multiple bond correlation
(HMBC) spectrum. The identification of C-10 as a qua-
ternary carbon and the presence of the olefinic proton at
a higher field (d 5.40 as opposed to >d 6.50) established
the position of the double bond between C-10 and C-20.
Since the hex-1-enopyranosyl nucleoside 12 was not the
desired product, no attempt was made further to unam-
biguously establish the configuration of the C-30 center
of this compound (Scheme 3).
Although VSM-nucleoside 2 and the carbohydrate 4
were easily synthesized from the mesylates 1c (Scheme
1) and 3c (Scheme 2), respectively,the failure of the same
reaction sequence to afford the VSM hexopyranosyl
nucleosides 11 was a surprising result. The unexpected
result may be partially explained by considering the fact
that the presence of a better electron-withdrawing and
sterically bulkier nucleobase at the anomeric position
of the mesylate 10 as opposed to the methoxy group
of 3c tripped the balance in favor of the C-10–C-20 elim-
ination product 12 instead of desired 11. However, as
mentioned above, the VSM-nucleoside 2 was easily syn-
thesized following a similar route. Therefore, to settle
the anomaly, we argued that for the trans-elimination
required for the bond formation between C-20 and
C-30, the H-30 and C-40-OMs should be antiperiplanar
(diaxial). In that case the mesylated compound 10
needed to flip to a twist-boat conformation 10a, which
1
the desired compound 11 was not produced. In the H
NMR spectrum, the H-20 proton of nucleoside 2
(B = U) appeared10 at d 6.56, and the H-2 olefinic pro-
ton of the carbohydrate 4 appeared11 at d 6.94 (1H,
m). The absence of any such peak around this region
and the unusual chemical shift values of the other pro-
1
tons in the H NMR spectrum of the product of mesy-
late 10 indicated the absence of a vinyl sulfone group.
The isolated product was identified as 1-[2,3-deoxy-
(4,6-O-benzylidene)-(3-C-p-toluenesulfonyl)-erythro-b-D-
hex-1-eno-pyranosyl]- thymine 12 as follows: The signal
of the H-20 alkene proton for 12 appeared (1H–1H
COSY) as a doublet at d 5.40. The peak position of qua-
O
Ph
O
Ph
p-TolO2S
O
O
OMe
OR
OMe
O
O
X
3a X =
3b X =
3c X =
p
-TolS; R = H
-TolSO2; R = H
p-TolSO2; R = OMs
4
p
Scheme 2. Reported11 synthesis of vinyl sulfone-modified carbohy-
drate 4.

S. G. Deshpande et al. / Carbohydrate Research 343 (2008) 1163–1170
1165
O
N
Me
O
O
Me
NH
NBz
O
O
Ph
N
(i)
(iii)
DBU
p-TolO2S
H
O
O
8
O
11
OR
SAr
H
H
13 R = H
(ii)
OSO2Me
14 R = Bn
10a
RO
R'O
Ph
O
O
O
(iv)
T
O
T
OBn
OBn
SAr
SAr
15
Me
16 R = R' = H
(v)
O
17 R = Tr; R' = H
NH
O
Ph
O
N
RO
TrO
O
O
T
O
12
R'O
T
O
(vi)
O
DBU
H
OBn
SO2Ar
p-TolSO2
ArO2S
OBn
SO2Me
20
18 R = Tr; R' = H
19 R = Tr; R' = OMs
(vii)
10
O
Scheme 4. Probable mechanism of formation of the undesired
glycal 12.
Me
NH
Ar = p-TolO2S
T =
N
O
would have created severe 1,3-diaxial interaction
between the bulky nucleobase and H-30 proton (Scheme
4).12a Under the circumstances, the acidity of H-10 as
well as the stability of C-10–C-20 olefin via conjugation
of the ring oxygen would favor the formation of com-
pound 12. It should be noted that the steric hindrance
mentioned in Scheme 4 would be minimal in the case
of the carbohydrate-derived mesylate 3c because of the
much smaller bulk of OMe and also because of the fact
that the methyl group attached to oxygen was ‘removed
somewhat’12b from the ring. It is noteworthy that the
synthesis of the vinyl nitro analogue 1-(4,6-O-benzyl-
idene-2,3-didehydro-2,3-dideoxy-3-nitro-b-D-hexopyran-
osyl)uracil was also difficult because the compound was
‘too unstable’.13 However, it was possible to generate
this compound in situ, and the Michael addition product
was isolated although the authors suggested the involve-
ment of a ‘boat-like aci-nitro intermediate’ in the prod-
uct formation process.13 It is probable that the different
structural as well as electronic features of the –NO2 and
the –SO2Ar groups also contributed significantly to the
stability of one vinyl derivative over the other. However,
it is also probable that the vinyl sulfone derivative 11
formed first via the elimination and then underwent
rearrangement to yield glycal 12.
Scheme 5. Reagents and conditions: (i) (a) TMSCl, pyridine, 1 h;
BzCl, pyridine, rt, 1 h; (b) 0.25% TFA, CH2Cl2, MeOH, 20 min; (ii)
BnBr, NaH, DMF, rt, overnight; (iii) NaOMe, MeOH, rt, 3–5 h; (iv)
aq TFA (80%), rt, 30–45 min; (v) TrCl, pyridine, reflux, 3 h; (vi)
MMPP, MeOH, rt, 3–3.5 h; (vii) MsCl, pyridine, 0–4 °C, overnight.
functionalization of the C-40 position. Because of its
easy accessibility, we started our synthesis from thionu-
cleoside 8. Our intention was to deprotect 15, protect the
primary alcohol selectively, and then mesylate the C-40
hydroxyl group. However, for this strategy it was neces-
sary to mask the C-20 hydroxyl group. The instability of
ester groups under nucleophilic reaction conditions to
be used later prompted us to benzylate the C-20 hydroxyl
group. It was therefore necessary to protect the nucleo-
base prior to the protection of the C-20 hydroxyl group
to avoid any alkylation of the nucleobase. Thus, alcohol
8 was treated with chlorotrimethylsilane in pyridine at
0 °C, followed by benzoyl chloride in a one-pot fashion.
The product, after usual work-up, was treated with
0.25% TFA in 1:1 MeOH–CH2Cl2 for a few minutes
to produce the N3-benzoylated derivative 13. Com-
pound 13 was benzylated using excess of benzyl bromide
and NaH in anhydrous DMF. After purification, com-
pound 14 was treated with NaOMe in MeOH to afford
nucleoside 15. Compound 15 was treated with 4:1 TFA–
water for a brief period to remove the benzylidene
protecting group. The primary C-60 hydroxyl group of
16, thus obtained, was protected with trityl group to
produce 17. Compound 17 was oxidized to sulfone
nucleoside 18. Sulfone 18 was mesylated in pyridine,
and the reaction condition was basic enough to initi-
ate an elimination reaction to afford the desired
2.2. Synthesis of 30-C-sulfonyl-hex-30-enopyranosyl-
thymine (20)
With the non-availability of one required VSM-nucleo-
side 11, we decided to explore the possibility of synthe-
sizing 30-C-sulfonyl-hex-30-enopyranosylthymine 20
(Scheme 5), which was expected to be useful for the

1166
S. G. Deshpande et al. / Carbohydrate Research 343 (2008) 1163–1170
TrO
T
O
(i) or (ii)
20
p-TolO2S
OBn
21
O+
T
H
-
p-TolO2S
OBn
21a
Scheme 6. Reagents and conditions: (i) benzylamine, EDC, rt, 48 h,
55%; (ii) piperadine, EDC, rt, 5 h, 50%.
H-60, H-600 (d 3.50) in the HMBC spectrum. Identifica-
tion of C-50 as a quaternary carbon and the presence
of the olefinic proton H-40 at a higher field (d 5.10 as
opposed to >d 6.50 for vinyl sulfones 2 and 4) devoid
of any coupling with H-50, established the position of
the double bond between C-40 and C-50. Almost all the
other reactions produced inseparable mixtures of
products (Table 1). In this case also no attempt was
made to establish the configuration at the C-30 position.
The formation of compound 21 may be considered as
a simple migration of a double bond that was facilitated
by the abstraction of the C-50 proton, followed by the
stability imparted by the delocalization of the lone pairs
of the ring oxygen. Although 20 did not react as a
Michael acceptor, there are several reports on the
addition of nucleophiles at the C-4 position of pyranosyl
Michael acceptors, such as the addition of azide to
methyl 6-O-benzoyl-3,4-dideoxy-a-D-glycero-hex-3-eno-
pyranosid-2-ulose,14 functionalization of C-4 of methyl
3,4-dideoxy-6-O-(l-ethoxyethyl)-a-D-glycero-hex-3-eno-
pyranosid-2-ulose with a methyl group,15 and most
notably, the reaction of benzylamine with phenyl 4,6-
di-O-acetyl-2-O-benzyl-3-deoxy-3-nitro-b-D-glucopyran-
oside to afford the corresponding Michael adduct in
77% yield via the in situ generated vinyl nitro
derivative.16
Figure 1. ORTEP of compound 20.
1-[2-O-benzyl-3,4-deoxy-(3-C-p-toluenesulfonyl)-6-O-tri-
tyl-erythro-b-D-hex-3-eno-pyranosyl]thymine 20. The
characteristic peak of the vinyl proton of the vinyl sul-
fone group was identified at d 7.10–7.43. However, the
structure of 20 was established unambiguously with
the 0help of X-ray crystallography (Fig. 1); notably the
0
˚
C-3 –C-4 bond length was 1.31 A, which was less than
the average C–C single bond length.
Compound 20 was easily synthesized from 19 because,
in this case the six-membered ring could easily flip to the
required conformation to place the H-30 and the C-40-
OMs in the antiperiplanar positions. It is important to
note that even a strong base like DBU could not facili-
tate the formation of vinyl sulfone 11 from 10 (Scheme
3), whereas under the conditions employed for mesyla-
tion, 19 was transformed to 20 by pyridine at +4 °C.
2.3. Reactions of 30-C-sulfonyl-hex-30-enopyranosyl-
thymine (20)
Michael acceptor 20 was treated with several amines and
carbon nucleophiles generated from nitromethane or
dimethyl malonate. Only benzylamine and piperidine in
a nonpolar solvent like 1,2-dichloroethane (EDC) affor-
ded an isomerized single product 21, which was identi-
fied as having a C-40–C-50 double bond to give the
more stable product, namely, 1-[2-O-benzyl-3,4-dide-
oxy-(3-C-p-toluenesulfonyl)-6-O-trityl-erythro-b-D-hex-
4-eno-pyranosyl]thymine (21) in 50–55% yield (Scheme
6). The peak at d 5.84 (1H NMR) for compound 21
was identified as the H-10 proton, and the rest of the pro-
tons were assigned using the correlation spectrum.
Notably the absence of H-50-proton, simplified the
splitting patterns of H-60 and H-600 protons that
appeared at d 3.44–3.55. The peak position of quater-
nary C-50 was established at d 156.1 on the basis of its
correlations with two a protons, H-40 (d 5.10) and
Table 1. Reactions of 20 under various conditionsa
Sl.
Reaction conditions
Products
no.
1
2
3
Benzylamine (5 equiv) in EDC; 48 h
Piperidine (5 equiv) in EDC; 5 h
Isobutylamine (neat); 8–10 h
55% 21
50% 21
Inseparable
mixture
4
5
6
7
EtNH2 aq (70%, excess) in dioxane;
1 h
NH3 aq (excess) in dioxane; rt; 1 h
Inseparable
mixture
Inseparable
mixture
Inseparable
mixture
Inseparable
mixture
Nitromethane–NaOMe in MeOH; rt;
10–12 h
Dimethyl malonate–NaH in THF; rt;
24 h
a All reactions were carried out at room temperature.

S. G. Deshpande et al. / Carbohydrate Research 343 (2008) 1163–1170
1167
In summary, on one hand the presence of a nucleo-
base at the anomeric position of a VSM hexopyaran-
oside drastically altered its properties, which led to the
formation of glycal derivative 12 instead of 30-C-sulf-
onyl-hex-20-enopyranosylthymine 11; this is an unex-
pected deviation from the known pattern of reactions
of mesylated sulfones, such as 1c and 3c under basic
conditions. On the other hand, in spite of the reported
reactions of vinylnitro-modified hex-3-enopyranosides
and related Michael acceptors with nucleophiles, 30-C-
sulfonyl-hex-30-enopyranosylthymine (20) uncharacter-
istically underwent isomerization instead of the expected
Michael addition reactions.
pressure. The residue was diluted with EtOAc (50 mL),
and the solution was washed with satd aq NaHCO3
(2 ꢀ 25 mL). The organic layer was dried over anhyd
Na2SO4, and filtered, and the filtrate was concentrated.
The crude product was purified over a silica gel column
to afford 8. (Eluent: 3:2 EtOAc–petroleum ether.) The
compound was crystallized from a CHCl3–petroleum
ether mixture to give 8 as white crystals: 0.32 g, (66%)
25
from 5. Mp: 220 °C. ½aꢁD ꢂ73.0 (c 1.20, CHCl3). IR
(Nujol): 1686 cmꢂ1 1H NMR (200 MHz, CDCl3): d
.
1.94 (s, 3H), 2.29 (s, 3H), 3.71–4.10 (m, 5H), 4.37 (dd,
J = 4.8, 10.2 Hz, 1H), 5.62 (s, 1H), 5.69 (d, J = 8.8 Hz,
1H), 7.03 (d, J = 7.9 Hz, 2H), 7.12 (s, 1H), 7.37–7.51
(m, 7H, aromatic), 9.26 (s, 1H). 13C NMR (50.3 MHz,
CDCl3):d 12.3, 20.8, 59.0, 67.6, 68.5 (CH2), 69.0, 78.0,
82.3, 101.4, 111.5, 126.2, 128.1, 129.0, 129.7, 131.2,
133.3, 135.0, 136.9, 137.8, 151.0, and 163.5. Anal. Calcd
for C25H26N2O6Sꢃ0.5H2O: C, 61.09; H, 5.54. Found: C,
61.35; H, 5.44.
3. Experimental
3.1. General methods
Melting points were determined in open-end capillary
tubes and are uncorrected. Carbohydrates and other fine
chemicals were obtained from commercial suppliers and
were used without purification. Solvents were dried and
distilled following the standard procedures. TLC was
carried out on precoated plates (E. Merck Silica Gel
60, F254), and the zones were visualized with UV light
or by charring the plates dipped in 5% H2SO4–MeOH
or 5% H2SO4–vanillin–EtOH. Column chromatography
was performed on silica gel (60–120 or 230–400 mesh).
1H and 13C NMR spectra for most of the compounds
were recorded at 200 and 50.3 MHz, respectively, in
CDCl3 unless stated otherwise. Optical rotations were
recorded at 589 nm.
3.3. 1-[4,6-O-Benzylidene-2,3-deoxy-(3-C-p-toluenesulf-
onyl)-erythro-b-D-hex-1-eno-pyranosyl]thymine (12)
A mixture of compound 8 (0.96 g, 2 mmol) and MMPP
(4.94 g, 10 mmol) in MeOH (150 mL) was stirred vigor-
ously at rt for 3–3.5 h. The reaction mixture was passed
through a basic alumina column, and the filtrate was
evaporated under reduced pressure. A pyridine solution
(25 mL) of the resulting product 9 (1.0 g, 1.94 mmol)
was cooled to 0 °C in an ice bath. Methanesulfonyl chlo-
ride (0.9 mL, 10 mmol) was added dropwise to the reac-
tion mixture. The reaction mixture was kept at +4 °C
overnight. The reaction mixture was quenched with ice.
Pyridine was evaporated under reduced pressure, and
co-evaporated with toluene. The residue was diluted with
DCM (75 mL). The organic layer was washed with satd
aq NaHCO3 (2 ꢀ 10 mL), water (5 mL), and brine
(5 mL). The organic layer was dried over anhyd Na2SO4,
and filtered. The filtrate was evaporated under reduced
pressure. A solution of the crude mesylated sulfone nucle-
oside 10 in DCM (40 mL) was cooled to 0 °C in an ice
bath. To the reaction mixture was added DBU (0.61 g,
4 mmol), dropwise with constant stirring. The mixture
was stirred at rt for 5 h. The volume of the reaction mix-
ture was reduced to one-fifth by evaporation. The solu-
tion thus obtained was loaded directly on a silica gel
column. (Eluent: 3:2 EtOAc–petroleum ether) Purifica-
tion afforded compound 12. The product was crystallized
from an EtOAc–petroleum ether mixture to afford 12 as
white crystals: 0.46 g, (52% overall from 8). Mp: 204 °C
3.2. 1-(4,6-O-Phenylmethylene-3-deoxy-3-S-tolyl-b-D-
allopyranosyl)thymine (8)
To a solution of 4-methylbenzenethiol (p-toluenethiol,
0.87 g, 7 mmol) in DMF (5 mL), NaOMe (0.27 g,
5 mmol) was added. The reaction mixture was stirred
at rt for 0.5 h. Compound 5 (0.57 g, 1.0 mmol) was
added, and the reaction mixture was heated at 90 °C
for 10 h. The reaction mixture was allowed to cool to
rt, and DMF was evaporated under reduced pressure.
To a methanolic solution (10 mL) of the reaction mix-
ture, NaOMe (0.17 g, 3 mmol) was added. After 6 h at
rt, the reaction mixture was neutralized with Dowex
H+ (50 ꢀ 8) and filtered. All volatiles were removed
under reduced pressure, and the crude residue was
purified over silica gel to get 7. To a mixture of the
unprotected thio nucleoside 7 (0.32 g, 0.81 mmol) and
benzaldehyde dimethyl acetal (0.18 g, 1.21 mmol) in
DMF (25 mL), a catalytic amount of p-toluenesulfonic
acid (p-TsOH) was added. The reaction mixture was
heated at 100 °C under vacuum for 1 h. After cooling
the mixture at rt, DMF was evaporated under reduced
27:7
(dec.); ½aꢁD +14.6 (c 1.60, CHCl3). IR (CHCl3): 1732,
1
1697.2. H NMR (400 MHz, CDCl3) (1H–1H COSY): d
1.95 (s, 3H, CH3 thymine), 2.36 (s, 3H, CH3), 3.84 (t,
J = 10.3 Hz, 1H, H600), 4.09 (m, 1H, H50), 4.20 (m, 2H,
H30, H40), 4.48 (dd, J = 5.0, 10.3 Hz, 1H, H60), 5.37 (s,
1H, PhCH), 5.40 (d, 1H, H20), 6.98 (m, 2H, aromatic),

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S. G. Deshpande et al. / Carbohydrate Research 343 (2008) 1163–1170
7.13 (s, 1H, H6), 7.24–7.32 (m, 5H, aromatic), 7.82 (d,
J = 8.3 Hz, 2H, aromatic), 9.00 (s, 1H, NH). 13C NMR
(100.6 MHz, CDCl3) (1H–13C COSY; HSQC): d 12.0
(C-methyl thymine), 21.5 (C-methyl), 63.1 (C-30), 67.6
(CH2, C-60), 69.4 (C-50), 73.4 (C-40), 90.3 (C-20), 100.9
(PhC), 111.2, 125.6, 127.8, 128.7, 129.0, 129.8, 135.3,
135.8, 138.7 (C-6 thymine), 145.3, 149.0, 149.7, 164.0.
Anal. Calcd for C25H24N2O7S: C, 60.47; H, 4.87. Found:
C, 60.38; H, 4.49.
12.3, 20.9, 53.1, 67.0, 68.4 (CH2), 69.4 (CH2), 73.5,
77.8, 79.5, 101.3, 110.9, 126.1, 128.0, 128.2, 128.4,
128.9, 129.4, 131.5, 133.8, 136.0, 136.7, 137.5, 150.5,
163.6. Anal. Calcd for C32H32N2O6Sꢃ0.25H2O: C,
66.59; H, 5.65. Found: C, 66.74; H, 5.54.
3.5. 1-[2-O-Benzyl-3,4-deoxy-(3-C-p-toluenesulfonyl)-6-
O-trityl-erythro-b-D-hex-3-eno-pyranosyl]thymine (20)
3.4. 1-[2-O-Benzyl-(4,6-O-phenylmethylene)-3-deoxy-3-
S-(p)-tolyl-b-D-allopyranosyl]thymine (15)
Compound 15 (2.84 g, 5 mmol) was treated with 4:1
TFA–water (3 mL) at rt for 30–45 min. All the volatiles
were evaporated under reduced pressure to afford 16. A
solution of crude 16 (2.34 g, 5 mmol) in dry pyridine
(20 mL) was reacted with trityl chloride (1.68 g,
6 mmol). The reaction mixture was heated under reflux
for 3 h. The reaction mixture was cooled to rt. Pyridine
was evaporated under reduced pressure. The reaction
mixture was diluted with EtOAc (150 mL), washed with
water (10 mL), and brine (5 mL), and the organic layer
was dried over Na2SO4, and filtered. The filtrate was
concentrated, and the crude product was purified over
a neutral alumina column (Eluent: 1:6 EtOAc:Hexane)
to afford 17 (3.2 g, 90%). A mixture of 17 (3.47 g,
4.78 mmol) and MMPP (11.82 g, 23.9 mmol) in MeOH
(150 mL) was stirred vigorously at rt for 3–3.5 h. The
solvent was concentrated to a small volume, and filtered
over a column of basic alumina affording a polar com-
pound 18. A solution of the trityl-protected sulfone
nucleoside 18 (3.28 g, 4.42 mmol) in dry pyridine
(30 mL) was cooled to 0 °C in ice bath. Methanesulfonyl
chloride (1.8 mL, 22.1 mmol) was added dropwise to the
reaction mixture. The reaction mixture was kept at
+4 °C overnight. The reaction mixture was quenched
with ice. Pyridine was evaporated under reduced pres-
sure and co-evaporated with toluene. The residue was
diluted with CH2Cl2 (75 mL), the organic layer was
washed with satd aq NaHCO3 (2 ꢀ 10 mL), water
(5 mL), and brine (5 mL). The organic layer was dried
over Na2SO4, and filtered. The filtrate was concentrated,
and the product was purified over a neutral alumina col-
umn (Eluent: 1:3 EtOAc–petroleum ether) to yield com-
pound 18. The product was crystallized from a mixture
of CHCl3 and petroleum ether to yield 18 as colorless
To a solution of 8 (0.96 g, 2 mmol) in dry pyridine
(10 mL) were added Et3N (1.01 mL, 10 mmol) and
chlorotrimethylsilane (0.4 mL, 3 mmol) under cold con-
ditions. After stirring the reaction mixture for 1 h, it was
cooled using an ice bath. Benzoyl chloride (0.35 mL,
3 mmol) was added dropwise and the reaction mixture
was stirred at rt for an additional 1 h. The reaction
mixture was quenched with a few drops of satd aq
NaHCO3. Pyridine was evaporated under reduced pres-
sure, and co-evaporated with toluene. The residue was
diluted with EtOAc (50 mL), and the organic layer was
washed with satd aq NaHCO3 (3 ꢀ 10 mL), water
(5 mL), and brine (5 mL). The organic layer was dried
over Na2SO4 and filtered. The filtrate was evaporated
under reduced pressure. TFA (0.05 mL) was added to
a solution of the crude product in a 1:1 mixture of
CH2Cl2 and MeOH (20 mL), and the solution was left
at rt for 20 min. All volatiles were removed under
reduced pressure, and the crude product was purified
over a silica gel column (Eluent: 1:1 EtOAc:Hexane)
to afford 13 (0.82 g; 70%). A mixture of 13 (1.23 g,
2.1 mmol) and benzyl bromide (2.5 mL, 21 mmol) in
DMF (10 mL) was cooled to 0 °C in an ice bath. To
the reaction mixture was added NaH (0.092 g, 2.25 mmol,
60% dispersion in oil) in portions with constant stirring.
The reaction mixture was stirred overnight at rt. The
reaction mixture was diluted with EtOAc (250 mL).
The organic layer was washed with brine (3 ꢀ 15 mL).
The volatiles were evaporated under reduced pressure.
Purification over silica gel column (Eluent: 1:3
EtOAc:Hexane) gave benzyl bromide-free compound
14. A solution of 14 in MeOH (40 mL), and NaOMe
(0.33 g, 6 mmol) was stirred at rt for 3–5 h. Dowex H+
(50 ꢀ 8) resin was used to neutralize the solution. Silica
gel column purification (Eluent: 1:1 EtOAc–petroleum
ether) gave the desired compound 15 as a foamy solid:
crystals: 2 g, (61% from 15). Mp: 225–229 °C (dec.).
28
½aꢁD ꢂ87.8 (c 1.98, CHCl3). IR (CHCl3): 1695 cmꢂ1
.
1H NMR (400 MHz, CDCl3) (1H–1H COSY): d 1.69
(s, 3H, CH3 thymine), 2.37 (s, 3H, CH3), 3.28 (dd, 1H,
H60), 3.36 (dd, 1H, H600), 4.54–4.63 (m, 3H, H20, ben-
27:1
zylic CH2), 4.73 (m, 1H, H50), 5.83 (d, J1 ,2 = 7.4 Hz,
1H, H10), 6.85 (s, 1H, H6), 7.10–7.43 (m, 23H, aromatic,
H40), 7.69 (d, J = 8.3 Hz, 2H, aromatic), 8.49 (s, 1H,
NH). 13C NMR (50.3 MHz, CDCl3): d 12.4, 21.5,
64.7 (CH2), 71.2, 74.2, 74.8 (CH2), 81.2, 87.0, 111.5,
127.3, 127.9, 128.6, 129.5, 134.1, 136.4, 137.3, 140.6,
141.3, 143.1, 144.4, 150.3, 163.1. Anal. Calcd for
0
0
0.80 g, (66% from 13). Mp: 108–110 °C; ½aꢁD ꢂ92.9 (c
1.40, CHCl3). IR (CHCl3): 1718.5, 1685.7 cmꢂ1 1H
.
NMR (200 MHz, CDCl3): d 1.78 (s, 3H), 2.31 (s, 2H),
3.62–3.80 (m, 3H), 4.17 (m, 3H), 4.30–4.35 (m, 1H),
4.50 (d, J = 12.6 Hz, 1H), 5.55 (s, 1H), 6.09 (bs, 1H),
6.64 (br s, 1H), 7.03–7.56 (m, 14H, aromatic), 8.38 (d,
J = 8.6 Hz, 1H). 13C NMR (50.3 MHz, CDCl3): d

S. G. Deshpande et al. / Carbohydrate Research 343 (2008) 1163–1170
1169
1
C44H40N2O7Sꢃ0.25H2O: C, 70.90; H, 5.47. Found: C,
www.ccdc.cam.ac.uk), and H and 13C NMR spectra
of compounds 5, 8, 12, 15, 20, and 21. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.carres.2008.02.016.
70.89; H, 5.37.
3.6. 1-[2-O-Benzyl-3,4-deoxy-(3-C-p-toluenesulfonyl)-6-
O-trityl-erythro-b-D-hex-4-eno-pyranosyl]thymine (21)
3.6.1. Reaction A. A mixture of 20 (0.20 g, 0.27 mmol)
and benzylamine (0.14 g, 1.35 mmol) in EDC (5 mL)
was stirred at rt for 48 h. The reaction mixture was
directly loaded onto a silica gel column. (Eluent:
1:3 EtOAc–petroleum ether) The column purification
afforded the amine free compound 21.
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ether), to afford 21 as a white solid: 0.14 g, (55%). Mp:
28
118–120 °C (dec.). ½aꢁD +22.1 (c 1.40, CHCl3). IR
(CHCl3): 1765, 1716.5 cmꢂ1
.
1H NMR (400 MHz,
CDCl3) (1H–1H COSY): d 1.73 (s, 3H, CH3, thymine),
2.46 (s, 3H, CH3), 3.44–3.55 (m, 2H, H60, H600), 4.22
(m, 1H, H30), 4.34 (m, 1H, H20), 4.63 (d, J = 11.7 Hz,
1H, benzylic CH2), 4.81 (d, J = 11.7 Hz, 1H, benzylic
CH), 5.10 (bs, 1H, H40), 5.84 (d, J1 ,2 = 9.0 Hz, 1H,
H10), 6.66 (s, 1H, H6), 7.23–7.35 (m, 22H, aromatic),
7.87 (d, J = 8.1 Hz, 2H, aromatic), 8.35 (s, 1H, NH).
13C NMR (100.6 MHz, CDCl3) (1H–13C COSY;
HSQC): d 12.4 (C-methyl thymine), 21.7 (C-methyl),
61.7 (CH2, C-60), 66.9 (C-30), 71.0 (C-20), 73.2 (benzylic
C), 81.0 (C-10), 87.2 (Trityl C), 91.2 (C-40), 111.7,
127.2, 127.9, 128.1, 128.3, 128.4, 128.5, 129.0, 129.9,
133.9, 134.1, 136.4 (C-6), 143.2, 145.3, 150.5, 156.1,
163.2. Anal. Calcd for C44H40N2O7SꢃH2O: C, 69.63;
H, 5.58. Found: C, 69.25; H, 5.70.
0
0
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Acknowledgment
T.P. thanks Indo-French Centre for the Promotion of
Advance Research, New Delhi, for funding (Project
No. 3405-1). S.G.D. and T.P. thank Dr. M. S. Shashi-
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Supplementary data
Complete crystallographic data for the structural analy-
sis have been deposited with the Cambridge Crystallo-
graphic Data Centre, CCDC No. 673335. Copies of
this information may be obtained free of charge from
the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB21EZ, UK. (fax: +44-
1223-336033, e-mail: deposit@ccdc.cam.ac.uk or via:

1170
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