A general and efficient route to 3′-deoxy-3′-N-, S-, and C-substituted altropyranosyl thymines from 2′,3′-O-anhydro-mannopyranosylthymine

Article abstract of DOI:10.1016/j.tet.2006.11.025

An efficient route to 1-(2,3-O-anhydro-4,6-O-phenylmethylene-β-d-mannopyranosyl) thymine from 1,2,4,6-tetra-O-acetyl-3-O-tosyl-β-d-glucopyranose has been devised. This newly synthesized epoxide is opened up regioselectively at the C-3′-position by N-, S-,

Full text of DOI:10.1016/j.tet.2006.11.025

Tetrahedron 63 (2007) 602–608
A general and efficient route to 30-deoxy-30-N-, S-, and
C-substituted altropyranosyl thymines from 20,30-
O-anhydro-mannopyranosylthymine
Sachin G. Deshpandea and Tanmaya Pathakb,
*
aOrganic Chemistry Division (Synthesis), National Chemical Laboratory, Pune 411 008, India
bDepartment of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 3 May 2006; revised 23 October 2006; accepted 9 November 2006
Available online 29 November 2006
Abstract—An efficient route to 1-(2,3-O-anhydro-4,6-O-phenylmethylene-b-D-mannopyranosyl) thymine from 1,2,4,6-tetra-O-acetyl-3-O-
tosyl-b-D-glucopyranose has been devised. This newly synthesized epoxide is opened up regioselectively at the C-30-position by N-, S-, and
C-nucleophiles to afford a wide range of new 30-deoxy-30-substituted altropyranosyl thymines.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
Nucleophilic ring-opening of 20,30-O-anhydro-uridine/lyxo-
uridine and ribo-/lyxo-thymidine 1 and 2 in general is one
of the most important strategies for the synthesis of sugar-
modified nucleosides (Fig. 1).1,7 The methodology has
been used extensively for the synthesis of 20/30-amino-
30-deoxy-,1,8 20/30-thio-30-deoxy-,9 and 20/30-branched-
30-deoxy-10 pentofuranosyl nucleosides. Considering the
importance of hexopyranosyl nucleosides as ‘new chemical
entities’ and in our quest for new methodologies for the syn-
thesis of modified nucleosides,8c,h,11 we envisaged that
a functionalized compound like 20,30-O-anydro hexopyrano-
syl pyrimidine would have the potential to act as a versatile
and general intermediate for the synthesis of modified
hexopyranosyl pyrimidines. The selection of an epoxy
nucleoside was also important because of the fact that
1-(2,4,6-tri-O-acetyl-3-O-tosyl-b-D-glucopyranosyl) thymine
(compound 11, Scheme 2) although useful in producing var-
ious 30-deoxy-30-substituted allopyranosyl nucleosides,11h
was incapable of reacting with a number of nucleophiles
including amines and carbon nucleophiles because of the
sluggish reactivity of C-30 position on steric grounds.
The chemotherapeutic properties of dideoxynucleosides
have triggered significant levels of interest in the synthesis
and biological properties of pentofuranosyl nucleosides
over the years.1 However, the biological properties of several
unnatural hexopyranosyl nucleosides were also recognized
quite early. For example, 1-(2-deoxy-b-D-arabinohexopyra-
nosyl) thymine,2a,b hexopyranosyl nucleosides derived from
allose, altrose, gulose, talose, and mannose,2c 1-(2-deoxy-6-
O-phosphono-b-D-ribohexopyranosyl)-2,4-pyrimidinedione,2d
etc. have demonstrated interesting and varied biological
properties. Synthetic studies on the pyranosyl nucleoside-
based naturally occurring antibiotics have also been docu-
mented.3 Furthermore, the syntheses and biological
properties of a large number of pyranosyl azidonucleosides
have been reviewed.1 More recently, the syntheses and
biological properties of a new class of sugar-modified
nucleosides derived from 1,5-anhydrohexitols have been
reported.4 The syntheses of pyranose nucleosides and other
nucleosides carrying tetrahydropyran structures have been
reviewed.5 However, all these reported methodologies are
narrowly focused only to prepare special classes of com-
pounds.2–6 Surprisingly, no serious effort has been made so
far to develop general methodologies for the synthesis of
modified hexopyranosyl nucleosides from common interme-
diates as was the case for the pentofuranosyl nucleosides.1,7
A full evaluation of the biological activity of differently
substituted pyranose nucleosides will be possible only
when they are easily accessible.
O
R'
NH
N
O
RO
O
O
1 R = H; 2 R = Me
* Corresponding author. Tel.: +91 3222 283342; fax: +91 3222 282252;
e-mail: tpathak@chem.iitkgp.ernet.in
Figure 1.
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.11.025

S. G. Deshpande, T. Pathak / Tetrahedron 63 (2007) 602–608
603
2. Results and discussion
2.1. Synthesis of manno-epoxide 3
using a procedure reported for the coupling of nucleobases
with pentaacetyl glucose (Scheme 2).18 A large coupling
constant for H10–H20 (J1,2¼9.5 Hz) indicated the b-configu-
ration at C-10 of 11.18 At this stage we were looking for an
efficient method for the deacetylation of 40- and 60-O-acetyl
groups retaining the 20-O-acetyl protection. This was neces-
sary because we did not want the deacetylated 20-OH to
attack intramolecularly the C-30 position. Attempted depro-
tection using MeOH–NH3 or MeOH–NaOMe produced an
inseparable mixture of compounds. After several experi-
ments, we identified MeOH–iPrNH2 as the best combination
for the selective deacetylation of 40- and 60-O-acetyl groups
to afford the diol 12. Although the exact reason for this
selective deacetylation was not clear to us, we argued that
the presence of a controlled amount of amine (11:iso-
propylamine¼1:10) instead of a large excess of amine (for
example, in saturated MeOH–NH3) in the reaction mixture
might have contributed to the selectivity. To establish the
sites of deacetylation unambiguously, we directly converted
crude 12 to the benzylidene-protected nucleoside 6 in an
overall 70% yield over the two steps. This protecting group
blocked the 40- and 60-hydroxyl groups and established the
absence of any acetyl group on those two sites. Moreover,
analytical and spectral data unambiguously established the
structure of 6 and in turn that of 12 (Scheme 2).
Although the epoxide ring-opening of nucleosides may
appear to be an obvious strategy for the synthesis of modified
hexopyranosyl nucleosides we were surprised to note that
such compounds have not been exploited for the modifica-
tion of sugar residues of these nucleosides. We planned
to synthesize the benzylidene-protected manno-epoxide 3
(Scheme 1) because such compounds were known to
undergo trans-diaxial type of attack of nucleophiles at C-30
affording only altropyranosyl derivatives.12 For the synthe-
sis of manno-epoxide it would be necessary to selectively
tosylate the C-20 position of the partially protected diol 4
to get compound 5. However, the reported selectivity of
tosylation of the glucopyranosyl moiety of various nucleo-
sides was confusing,13–15 and the known report on the
selective 30-O-tosylation of methyl 4,6-O-benzylidene-b-D-
glucopyranoside made use of equivalent amounts of dibutyl-
tin oxide.16 We wanted to avoid the use of highly toxic
dibutyltin oxide in our large scale preparations and consid-
ered using pre-tosylated carbohydrates instead (see later)
for coupling with the pyrimidine base to access directly 30-
O-tosylated nucleosides, such as 6. Basic hydrolysis of 6
would produce allo-epoxide 7 but in the case of pyrimidine
nucleosides, an intramolecular attack by the C-2 of the nu-
cleobase at the C-20 of the carbohydrate would open up the
epoxide ring of 7 to produce the 2,20-O-anhydro-derivative
8. Compound 9, easily produced from 8 would afford, under
basic conditions manno-epoxide 3 (Scheme 1). The pattern
of reaction sequences described here was well established
in the case of epoxides derived from uridine.7
RO
AcO
AcO
TsO
O
O
RO
i)
T
OAc
TsO
OAc
OAc
10
11 R = OAc
12 R = OH
ii)
iii)
6 R, R = CHPh
O
O
N
N
O
iv)
Ph
O
R'O
O
O
R'O
R"O
AcO
O
T
T
R"O
OR
8 R = H
HO
OH
OTs
4
5
v)
T
vi)
8a R = 4-nitrobenzoyl
9 R = OMs
O
O
vii)
R'O
R"O
TsO
O
O
O
Ph
T
O
T
O
3
R'O
R"O
OAc
6
3
Scheme 2. Reagents and conditions: (i) 2,4-di-O-trimethylsilylthymine,
SnCl4, 1,2-dichloroethane, 50 ꢀC, 75%; (ii) iso-propylamine, MeOH, rt,
5 h; (iii) PhCH(OCH3)2, TsOH, DMF, 100 ꢀC, 1.5 h, 70% (from 11); (iv)
NaOMe, MeOH, rt, 30 h; (v) 4-nitrobenzoyl chloride, Py, rt, overnight;
(vi) MsCl, Py, +4 ꢀC, overnight; and (vii) 2 M NaOH, dioxane, rt, 0.5 h,
30–34% (from 6 to 3).
T
O
R'O
R"O
O
7
O
Reaction of 6 with NaOMe/MeOH produced the highly
hygroscopic material 8, which was identified as its p-nitro-
benzoyl derivative 8a (see Section 4). Mesylation of 8
with mesyl chloride in pyridine at 0 ꢀC afforded 9. The crude
mesylated product 9 was converted directly to 20,30-O-anhy-
dro-mannopyranosyl nucleoside 3 by aqueous NaOH treat-
ment in 30% overall yield over the three steps (Scheme 2).
O
N
N
R'O
R"O
O
OR
8 R = H
9 R = OMs
R',R" = HCPh
Scheme 1.
Our synthesis started with the easy conversion of 1,2:5,6-di-
O-isopropylidene-3-O-p-toluenesulfonyl-a-D-glucofuranose17
to 1,2,4,6-tetra-O-acetyl-3-O-tosyl-b-D-glucopyranose 10 on
large scale. Compound 10 was coupled with bistrimethyl-
silylated thymine to get the nucleoside 11 in good yield
2.2. Reactions of manno-epoxide 3
To establish the synthetic utility of epoxide 3, a range of nu-
cleophiles was selected for opening the epoxide ring. Thus,

604
S. G. Deshpande, T. Pathak / Tetrahedron 63 (2007) 602–608
keeping in mind the importance of azido nucleosides,1 3 was
reacted with a mixture of LiN3 and NH4Cl at elevated tem-
perature in anhydrous ethanol to afford a single product 13a
containing the azido group. The product after purification
was treated with TFA/water mixture (4:1) for a brief period
to remove the phenylmethylene protecting group. However,
for the convenience of isolation and purification the depro-
tected compound was acetylated to obtain 14a in 65%
(Scheme 3). This strategy of acetylation after deprotection
was followed in all subsequent reactions with other nucleo-
philes. Since 20-amino-20-deoxythymidine was identified for
its anti-HIV property in certain cell-lines,1 and some of the
30-N-alkylamino-30-deoxy-ara-uridines8c were identified as
potential inhibitors of ribonuclease A and angiogenin,8h we
reacted 3 with a series of amines. Thus, iso-butylamine
(70 ꢀC for 24 h), pyrrolidine (90 ꢀC for 24 h), morpholine
(90 ꢀC for 25 h), and 1-acetylpiperazine (90 ꢀC for 30 h)
opened the epoxide ring of 3 in DMSO to generate aminonu-
cleosides 13b–e, respectively. Imidazole also reacted with 3
at an elevated temperature to afford 13f. The methodology
was equally useful for the formation of a C–S bond at the
C-30 position. Thus, two thio-nucleophiles such as p-tolyl-
thiol and NH4SCN also opened the epoxide ring of 3 to gen-
erate thionucleosides 13g and 13h, respectively. To expand
the scope of the methodology further, an important transfor-
mation was achieved by opening the epoxide ring of 3 with
NaCN in DMF at elevated temperature to get 13i (Scheme
3).19 Compounds 13b–i were converted to their triacetylated
derivatives 14b–i, respectively. As expected,12 all epoxide
opening reactions reported here generated single products.
All products were identified as their triacetylated derivatives
14a–i.
3. Conclusion
The strategy of coupling directly 1,2,4,6-tetra-O-acetyl-
3-O-tosyl-b-D-glucopyranose 10 with thymine, selective
deacetylation of the product 11 and subsequent synthetic
manipulations of 12 provided easy access to a versatile
intermediate 1-(2,3-O-anhydro-4,6-O-phenylmethylene-b-
D-mannopyranosyl) thymine 3. This epoxy nucleoside
reacted with azide, amines, sulfur nucleophiles as well as a
carbon nucleophile paving theway for the synthesis of a great
number and wide variety of hitherto unknown 30-deoxy-30-
substituted-altropyranosyl thymines. It should be noted
that these altropyranosyl nucleosides could not have been
accessed by any other synthetic strategy. The biological
properties of some of these compounds will be reported at
a later date.
4. Experimental
4.1. General methods
All fine chemicals were obtained from commercial-suppliers
and were used without purification. Solvents were dried and
distilled following standard procedures. Melting points were
€
determined in open-end capillary tubes using a Buchi B-540
electro-thermal melting point apparatus and are uncorrected.
Analytical TLC was carried out on pre-coated aluminum
plates (E-Merck silica gel 60, F254) and spots were visual-
ized with UV light or by charring the plate dipped in either
5% H2SO4–MeOH solution or ninhydrin solution in EtOH.
Column chromatography was performed on silica gel
(60–120 or 230–400 mesh). IR spectra were recorded as
Nujol mull, or in solution (cond 1 mM) on a Shimadzu
1
FTIR-8400 spectrophotometer. H NMR was recorded at
200 MHz using AC 200 MHz, at 300 MHz using MSL
300 MHz, or 500 MHz using DRX 500 MHz in CDCl3 using
trimethylsilane as an internal standard. Special experiments
OH
O
O
Ph
3
T
O
1
such as H–1H COSY were carried out on 400 MHz at AV
X
400 MHz. 13C-spectra and DEPT were recorded at 50.3,
75.5 or 125.8 MHz using the triplet centered at d 77.0 as
the standard. Specific rotations were determined using
Bellingham ADP220 polarimeter or a JASCO P-1030 polari-
meter at 589 nm. Mass spectral data were obtained using VG
Analytical 70-250 AC normal geometry double focussing
mass spectrometer, or Waters LCT mass spectrometer.
Microanalytical data were obtained using a Carlo-Erba
CHNS-0 EA 1108 Elemental analyzer.
13a LiN3, NH4Cl, EtOH, reflux, 10 h (83%)
13b isobutylamine, DMSO 70 °C, 22 h (79%)
13c pyrrolidine, DMSO, 90 °C, 24 h (84%)
13d morpholine, DMSO, 90 °C, 25 h (80%)
13e 1-acetylpiperazine, 90 °C, 30 h (56%)
13f imidazole, TMG, DMSO, 70 °C, 20 h (86%)
13g TolSH, NaOMe, DMF, 70 °C, 10 h (66%)
13h NH4SCN, DMF, 70 °C, 10 h (71%)
13i NaCN, DMF, 70 °C, 10 h (68%)
OAc
O
i) TFA, water, rt,
10-20 min
ii) Ac2O, pyridine,
rt, overnight.
AcO
AcO
T
4.1.1. 1-(2,4,6-Tri-O-acetyl-3-O-tosyl-b-D-glucopyrano-
syl) thymine 11. A mixture of thymine (2.52 g, 20 mmol),
hexamethyldisilazane (15 mL), a few drops of trimethylsilyl
chloride and a few crystals of NH4(SO4)2 was heated
under reflux for 3–5 h to get a clear solution. After cooling
the moisture-sensitive reaction mixture to rt, volatiles were
evaporated under reduced pressure. A solution of 10 (5.02 g,
10 mmol) in anhydrous 1,2-dichloroethane (60 mL) was
added to the flask. Tin(IV) chloride (1.64 mL, 14 mmol)
was injected in the flask with care. The reaction was allowed
to stir at 50 ꢀC. After 18 h the reaction mixture was cooled to
rt. The reaction mixture was carefully poured into saturated
NaHCO3 solution (150 mL) and the products were extracted
with chloroform (3ꢁ75 mL). Any emulsion formed was
X
14a (65%); 14b (70%); 14c (85%)
14d (75%); 14e (75%); 14f (65%)
14g (55%); 14h (56%); 14i (65%)
X =
a) N3 b) HNCH2CH(CH3)2 c)
N
N
f)
N
e)
N
NAc
d)
N
O
g) p-TolS h) SCN i) CN
Scheme 3.

S. G. Deshpande, T. Pathak / Tetrahedron 63 (2007) 602–608
605
filtered over a Celite bed and the bed was washed with chlo-
roform (5ꢁ20 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered and the filtrate was concen-
trated under reduced pressure. The crude product was puri-
fied over silica gel column to afford 11 (4.25 g, 75%).
Eluent: EtOAc/petroleum ether (2:3). White solid. Mp:
123–125 ꢀC. [a]D27 +16.7 (c 1.0, CHCl3). IR (Nujol): 1749,
4.1.4. 2,20-O-Anhydro-1-(3-O-4-nitrobenzoyl-4,6-O-phe-
nylmethylene-b-D-altropyranosyl) thymine 8a. To a solu-
tion of compound 8 (0.13 g, 0.36 mmol) in pyridine (7 mL)
was added 4-nitrobenzoyl chloride (0.34 g, 1.85 mmol) at rt.
The reaction mixture was stirred overnight. The reaction
mixture was diluted with CH2Cl2 (75 mL) and washed
with saturated NaHCO3 solution (2ꢁ15 mL). The organic
layer was separated, dried over anhydrous Na2SO4, filtered,
and the filtrate was concentrated to obtain a residue. The
crude product was purified on flash silica gel column to get
the desired 4-nitrobenzoyl derivative 8a (0.11 g, 62%; over-
all yield from 6). Eluent: EtOAc/petroleum ether (4:1). Pale
yellow solid. Mp: >300 ꢀC. [a]2D6 ꢂ32.6 (c 0.35, DMF). IR
1
1693 cmꢂ1. H NMR (1H–1H COSY) (CDCl3): d 1.87 (s,
3H, CH3), 1.94 (s, 3H, thymine CH3), 2.01 (s, 3H, CH3),
2.08 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.90–3.93 (m, 1H,
H50), 4.11 (dd, J¼2.0, 12.8 Hz, 1H, H600), 4.27 (dd, J¼5.0,
12.8 Hz, 1H, H60), 5.08 (apparent t, J¼9.3 Hz, 1H, H30),
5.18–5.24 (m, 2H, H20, H40), 5.88 (d, J1,2¼9.5 Hz, 1H,
1
H1 ), 7.11 (s, 1H, H-6), 7.33 (d, J¼8.3 Hz, 2H, aromatic),
(Nujol): 1742, 1676 cmꢂ1. H NMR (CD2Cl2): d 1.91 (s,
0
7.71 (d, J¼8.3 Hz, 2H, aromatic), 8.84 (br s, 1H, NH). 13C
NMR (CDCl3): d 12.2, 20.0, 20.3, 20.4, 21.3, 61.6 (CH2),
67.2, 68.8, 74.3, 79.4, 79.8, 112.0, 127.3, 129.7, 133.7,
134.4, 145.0, 150.5, 163.3, 169.2, and 170.2. Anal. Calcd
for C24H28N2O12S$1/2H2O: C, 49.91; H, 5.06. Found: C,
50.00; H, 5.28. MS: EI m/z 568 [4M+], 443 [100M+ꢂ
thymine], 396 [29M+ꢂO-tosyl].
3H), 3.69 (t, J¼10.3 Hz, 1H), 4.08–4.19 (m, 2H), 4.36 (dd,
J¼3.7, 9.5 Hz, 1H), 4.83 (s, 1H), 5.58 (s, 1H), 5.83 (d,
J¼3.6 Hz, 1H), 6.08 (s, 1H), 7.23–7.31 (m, 6H, aromatic),
8.23 (d, J¼8.8 Hz, 2H), 8.30 (d, J¼8.8 Hz, 2H). 13C NMR
(CD2Cl2): d 14.2, 62.7, 66.6, 69.0 (CH2), 74.0, 78.2, 82.8,
102.7, 120.5, 124.4, 126.6, 128.8, 129.8, 131.1, 131.6,
134.8, 137.3, 151.8, 160.3, 180.6. Anal. Calcd for
C25H21N3O9: C, 59.17; H, 4.17. Found: C, 58.95; H, 4.09.
MS: EI m/z 507 [100M+].
4.1.2. 1-(2-O-Acetyl-4,6-O-(phenylmethylene)-3-O-tosyl-
b-D-glucopyranosyl) thymine 6. To a solution of compound
11 (4.0 g, 7.04 mmol) in anhydrous methanol (75 mL), was
added iso-propylamine (4.15 g, 70.4 mmol). The reaction
mixture was stirred at rt for 5 h and then evaporated to dry-
ness to provide product 12, which was used in the next
step without further purification. To a solution of crude 12
in anhydrous DMF (35 mL), benzaldehyde dimethyl acetal
(1.42 mL, 10 mmol) and p-toluenesulfonic acid (10–12 mg)
were added. The reaction mixturewas heated at 100 ꢀC under
vacuum for 1 h. DMF was evaporated to dryness. The resid-
ual reaction mixture was re-dissolved in EtOAc (150 mL)
and washed with aqueous saturated NaHCO3 solution
(2ꢁ25 mL). The organic layer was evaporated and the resi-
due was dried. The crude product was purified over silica
gel column to get the desired product 6 (3.0 g, 70% from
11). Eluent: EtOAc/petroleum ether (1:1). White needles.
Mp: 168–170 ꢀC. [a]D26 ꢂ42.2 (c 1.52, CHCl3). IR (Nujol):
1755, 1711, 1697 cmꢂ1. 1H NMR (1H–1H COSY) (CDCl3):
d 1.94 (s, 3H), 2.05 (s, 3H), 2.31 (s, 3H), 3.69–3.76 (m, 3H,
H40, H50, H60), 4.35–4.40 (m, 1H, H600), 5.06–5.15 (m, 1H,
H30), 5.26 (apparent t, J¼9.3 Hz, 1H, H20), 5.40 (s, 1H),
5.93 (d, J¼9.5 Hz, 1H, H10), 7.00 (d, J¼8.3 Hz, 2H), 7.11
(s, 1H), 7.31–7.40 (m, 5H, aromatic), 7.67 (d, J¼8.3 Hz, 2H),
8.61 (s, 1H). 13C NMR (DMSO-d6): d 12.3, 20.2, 21.3, 67.3,
67.6 (CH2), 69.9, 76.8, 79.8, 100.6, 110.3, 126.2, 127.6,
128.1, 129.1, 129.9, 133.9, 136.5, 137.0, 144.9, 150.6, 154.7,
163.7, 169.2. Anal. Calcd for C27H28N2O10S$1/4H2O: C,
56.19; H, 4.98. Found: C, 56.20; H, 5.25. HRMS (ES+):
m/z calculated for C27H29N2O10S [M+H]+: 573.1543; found:
573.1517.
4.1.5. 1-(2,3-O-Anhydro-4,6-O-phenylmethylene-b-D-
mannopyranosyl) thymine 3. To a solution of 8 (obtained
from 1.9 g/3.32 mmol of 6 as described above) in anhydrous
pyridine (60 mL) was added methanesulfonyl chloride
(1.70 mL, 21 mmol) at 0 ꢀC. The reaction mixture was kept
overnight at +4 ꢀC. The solution was partitioned between
saturated NaHCO3 solution (30 mL) and CHCl3 (30 mL).
The aqueous phase was washed with CHCl3 (3ꢁ30 mL).
The combined organic layers were dried over anhydrous
Na2SO4, filtered, and the filtrate was concentrated to dryness
under reduced pressure to obtain 9. An aqueous solution of
NaOH (2 M, 4.1 mL) was added drop-wise to a solution of
crude 9 in dioxane (20 mL). The reaction mixture was stirred
for 0.5 h at rt. EtOAc (50 mL) was added and the mixture was
washed with saturated NaHCO3 solution (2ꢁ15 mL). The
organic layer was dried over anhydrous Na2SO4, filtered,
and the filtrate was concentrated to dryness. The residue
was purified over silica gel to afford 3 (0.4 g, 34% from 6).
Eluent: EtOAc/petroleum ether (2:3). White needles. Mp:
255–257 ꢀC. [a]D29 +43.9 (c 1.1, CHCl3). IR (Nujol): 1714,
1682 cmꢂ1 1H NMR (1H–1H COSY) (CDCl3): d 1.96
.
(s, 3H), 3.42 (d, J¼3.8 Hz, 1H, H20), 3.51–3.57 (m, 1H,
H50), 3.63 (d, J¼3.7 Hz, 1H, H30), 3.76–3.81 (m, 2H,
H40, H60), 4.32 (dd, J¼4.6, 10.5 Hz, 1H, H600), 5.60 (s, 1H),
6.32 (s, 1H, H10), 7.39–7.41 (m, 3H), 7.44 (s, 1H), 7.50–
7.52 (m, 2H), 8.79 (s, 1H). 13C NMR (CDCl3): d 12.4,
50.5, 55.0, 68.8 (CH2), 70.3, 74.1, 78.1, 102.6, 111.5,
126.1, 128.3, 129.3, 136.6, 150.6, 163.5. Anal. Calcd for
C18H18N2O6$1CHCl3: C, 47.77; H, 4.01. Found: C, 47.91;
H, 4.18. MS: EI m/z 358 [26M+], 233 [4M+ꢂthymine].
4.1.3. 2,20-O-Anhydro-1-(4,6-O-phenylmethylene-b-D-
altropyranosyl) thymine 8. A solution of compound 6
(1.9 g, 3.32 mmol) in anhydrous methanol (60 mL) was
treated with sodium methoxide (0.91 g, 16.5 mmol) at rt.
After 30 h the solution was neutralized with Dowex
(50ꢁ8) H+ resin. The reaction mixture was filtered and the
filtrate was concentrated to dryness under reduced pressure.
Hygroscopic 8 was dried by coevaporation with pyridine and
taken on directly for next reactions.
4.2. General method for the reaction of epoxide
3 with various nucleophiles
A mixture of epoxide 3 and the nucleophile in an appropriate
solvent was heated until the epoxide disappeared (TLC). The
mixture was cooled to rt and the volatiles were removed
under reduced pressure. For 14a–e and 14g–i, the residue
was diluted with EtOAc (50–75 mL) and for 14f CH2Cl2

606
S. G. Deshpande, T. Pathak / Tetrahedron 63 (2007) 602–608
(50 mL) was used. The solution was successively washed
with saturated NaHCO3 solution (2ꢁ15 mL), water (10 mL),
and brine (5 mL). The organic layer was dried over anhy-
drous Na2SO4 and filtered. The filtrate was evaporated
to dryness and the solid residue was purified over silica
gel to obtain a single compound 13a–i. The product was
treated with TFA/water mixture (4:1, 1 mL) at rt for up to
20 min (TLC). Solvents were evaporated and the residue
was dried under reduced pressure. The residue was acety-
lated with acetic anhydride in dry pyridine at rt. Pyridine
was evaporated under reduced pressure and the residue
was dissolved in EtOAc (150 mL). The organic layer was
washed with saturated NaHCO3 solution (3ꢁ20 mL). The
organic layer was separated, dried over anhydrous
Na2SO4, and filtered. The filtrate was evaporated to dryness.
The residue thus obtained was purified over silica gel to
afford compounds 14a–i.
5.45–5.46 (m, 1H), 6.25 (s, 1H), 7.31 (s, 1H), 8.38 (s, 1H).
13C NMR (CDCl3): d 12.5, 20.7, 21.1, 23.4 (CH2), 52.7
(CH2), 62.2, 63.1 (CH2), 68.3, 69.6, 72.6, 78.2, 109.8,
136.0, 149.7, 163.5, 169.2, 169.5, 170.7. Anal. Calcd for
C21H29N3O9$1/2H2O: C, 52.94; H, 6.35. Found: C, 53.22;
H, 6.48. MS: ESI m/z 468.2 [100(M+H)+], 214.1
[32(M+H)+ꢂ(thymine+3ꢁCH3CO)+H+].
4.2.4. 1-(2,4,6-Tri-O-acetyl-3-N-morphino-b-D-altropyr-
anosyl) thymine 14d. A mixture of 3 (0.36 g, 1 mmol)
and morpholine (0.43 g, 5 mmol) in DMSO (4 mL) was
heated at 90 ꢀC for 25 h; 13d (0.36 g, 80%), 14d (0.29 g,
75%). Eluent: EtOAc/petroleum ether (3:2). White foam.
Mp: 97–99 ꢀC. [a]D29 +37.1 (c 1.30, CHCl3). IR (CHCl3):
1
1745.5, 1689.5 cmꢂ1. H NMR (CDCl3): d 1.94 (s, 3H),
2.06 (s, 3H), 2.13 (s, 6H), 2.67–2.78 (m, 4H), 2.98 (br s,
1H), 3.73 (br s, 4H), 4.25–4.34 (m, 2H), 4.38–4.41 (m,
1H), 5.33 (br d, 1H), 5.46 (br s, 1H), 6.23 (s, 1H), 7.27 (s,
1H), 8.80 (br s, 1H). 13C NMR (CDCl3): d 12.4, 20.7,
21.1, 51.6 (CH2), 62.0, 63.0 (CH2), 67.1 (CH2), 67.7, 74.9,
78.6, 109.9, 136.0, 149.7, 163.5, 169.2, 169.5, 170.6. Anal.
Calcd for C21H29N3O10$1/2H2O: C, 51.21; H, 6.14. Found:
C, 51.09; H, 5.83. MS: ESI m/z 484.2 [100(M+H)+], 358.1
[8(M+H)+ꢂthymine], 274.1 [31(M+H)+ꢂ(thymine+2ꢁ
CH3CO)+2H+].
4.2.1. 1-(2,4,6-Tri-O-acetyl-3-azido-b-D-altropyranosyl)
thymine 14a. A mixture of epoxide 3 (0.36 g, 1.0 mmol),
LiN3 (0.490 g, 10.0 mmol), and NH4Cl (0.27 g, 5.0 mmol)
was heated under reflux in anhydrous EtOH (10 mL) for
10 h; 13a (0.33 g, 83%), white solid; 14a (0.25 g, 65%).
Eluent: EtOAc/petroleum ether (2:3). White solid. Mp:
85–87 ꢀC. [a]D29 +55.1 (c 1.0, CHCl3). IR (CHCl3):
1
2115.8 cmꢂ1. H NMR (CDCl3): d 1.93 (s, 3H), 2.09 (s,
3H), 2.12 (s, 3H), 2.17 (s, 3H), 4.23–4.37 (m, 4H), 5.14–
5.17 (m, 2H), 6.02 (s, 1H), 7.23 (s, 1H), 9.27 (s, 1H). 13C
NMR (CDCl3): d 12.5, 20.5, 20.6, 20.7, 59.0, 62.6 (CH2),
66.0, 68.8, 73.0, 77.9, 110.3, 135.5, 149.5, 163.4, 168.8,
169.6, 170.6. Anal. Calcd for C17H21N5O9: C, 46.47; H,
4.82. Found: C, 46.34; H, 5.30. MS: ESI m/z 440.1
[100(M+H)+], 314.1 [28(M+H)+ꢂthymine].
4.2.5. 1-(2,4,6-Tri-O-acetyl-3-N-(1-acetylpiperazino)-b-
D-altropyranosyl) thymine 14e. A mixture of epoxide 3
(0.36 g, 1 mmol) and 1-acetylpiperazine (0.64 g, 5 mmol)
in DMSO (5 mL) was heated at 90 ꢀC for 30 h; 13e
(0.28 g, 56%), 14e (0.22 g, 75%). Eluent: EtOAc/petroleum
ether (3:2). White foam. Mp: 105–107 ꢀC. [a]D29 +38.2 (c
0.60, CHCl3). IR (CHCl3): 1745.5, 1689.5, 1637.5 cmꢂ1
.
1H NMR (1H–1H COSY) (CDCl3): d 1.94 (s, 3H, thymine
CH3), 2.05 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.13 (s, 6H, 2ꢁ
CH3), 2.52–2.55 (m, 1H, piperazine), 2.68–2.83 (m, 3H, pi-
perazine), 3.02 (dd, J¼3.3, 4.1 Hz, 1H, H30), 3.45–3.47 (m,
3H, piperazine), 3.74–3.78 (m, 1H, piperazine), 4.26–4.33
(m, 3H, H50, H60, H600), 5.30 (dd, J¼3.3, 5.5 Hz, 1H, H40),
4.2.2. 1-(2,4,6-Tri-O-acetyl-3-N-isobutylamino-b-D-altro-
pyranosyl) thymine 14b. A mixture of 3 (0.36 g, 1 mmol)
and iso-butylamine (0.51 g, 7 mmol) in DMSO (5 mL) was
heated at 70 ꢀC for 24 h; 13b (0.35 g, 79%), 14b (0.26 g,
70%). Eluent: EtOAc/petroleum ether (3:2). White foam.
Mp: 76–78 ꢀC. [a]D29 +78.9 (c 1.10, CHCl3). IR (CHCl3):
5.44 (dd, J¼2.2, 5.1 Hz, 1H, H20), 6.22 (d, J1 ,2 ¼2.3 Hz,
1H, H10), 7.27 (s, 1H, H-6), 9.28 (br s, 1H, NH). 13C NMR
(CDCl3): d 12.4, 20.6, 20.7, 21.1, 41.6 (CH2), 46.5 (CH2),
50.9 (CH2), 61.8, 63.0 (CH2), 67.6, 67.8, 75.6, 78.7, 110.0,
135.9, 149.8, 163.5, 168.9, 169.2, 169.4, 170.5. Anal. Calcd
for C23H32N4O10$1H2O: C, 50.92; H, 6.35. Found: C, 50.76;
H, 6.55. MS: ESI m/z 525.2 [100(M+H)+].
0
0
1
2958.6, 1745.5, 1691.5 cmꢂ1. H NMR (CDCl3): d 0.93
(d, J¼6.8 Hz, 3H), 0.97 (d, J¼6.8 Hz, 3H), 1.73–1.75 (m,
1H), 1.93 (s, 3H), 2.07 (s, 3H), 2.11 (s, 3H), 2.12 (s, 3H),
2.50–2.53 (m, 2H), 3.26 (br s, 1H), 4.18–4.26 (m, 2H),
4.43–4.45 (m, 1H), 5.18 (br d, 1H), 5.23 (s, 1H), 6.35 (s,
1H), 7.30 (s, 1H), 8.32 (br s, 1H). 13C NMR (CDCl3):
d 12.4, 20.3, 20.4, 20.6, 20.7, 20.8, 28.5, 55.5 (CH2), 56.7,
63.2 (CH2), 66.5, 68.4, 72.8, 78.2, 109.8, 136.1, 149.5,
163.3, 169.2, 170.6. Anal. Calcd for C21H31N3O9$1H2O:
C, 51.74; H, 6.82. Found: C, 51.94; H, 6.41. MS: ESI m/z
470.2 [100(M+H)+], 344.1 [22(M+H)+ꢂthymine].
4.2.6. 1-(2,4,6-Tri-O-acetyl-3-N-imidazoline-b-D-altro-
pyranosyl) thymine 14f. 1,1,3,3-Tetramethylguanidine
(0.17 g, 1.5 mmol) was added to a solution of imidazole
(0.17 g, 2.5 mmol) in DMSO (2 mL). After 15 min at rt,
the epoxide 3 (0.18 g, 0.5 mmol) was added to the solution.
The reaction mixture was heated at 70 ꢀC for 20 h; 13f
(0.18 g, 86%), 14f (0.12, 65%). Eluent: EtOAc/petroleum
ether (4:1). White solid. Mp: 108–110 ꢀC. [a]D27 +20.4 (c
4.2.3. 1-(2,4,6-Tri-O-acetyl-3-N-pyrrolidino-b-D-altro-
pyranosyl) thymine 14c. A mixture of 3 (0.36 g, 1 mmol)
and pyrrolidine (0.35 g, 5 mmol) in DMSO (3 mL) was
heated at 90 ꢀC for 24 h; 13b (0.36 g, 84%), 14c (0.33 g,
85%). Eluent: EtOAc/petroleum ether (3:2). White foam.
Mp: 89–92 ꢀC. [a]D27 +68.3 (c 1.18, CHCl3). IR (CHCl3):
1
1.47, CHCl3). IR (CHCl3): 1753.2, 1691.5 cmꢂ1. H NMR
(CDCl3): d 1.95 (s, 3H), 2.00 (s, 3H), 2.13 (s, 3H), 2.16 (s,
3H), 4.22–4.47 (m, 3H), 4.76 (dd, J¼4.3, 5.8 Hz, 1H),
5.22 (dd, J¼4.3, 5.9 Hz, 1H), 5.64 (dd, J¼3.1, 5.5 Hz,
1H), 6.25 (d, J¼3.2 Hz, 1H), 7.15 (br s, 2H), 7.23 (s, 1H),
7.70 (s, 1H). 13C NMR (CDCl3): d 12.4, 20.3, 20.7, 55.8,
62.9 (CH2), 68.0, 69.1, 76.1, 78.8, 110.5, 118.5, 130.2,
135.2, 137.3, 149.7, 163.4, 168.7, 169.6, 170.4. Anal. Calcd
1
1743.5, 1687.6 cmꢂ1. H NMR (CDCl3): d 1.76–1.79 (m,
4H), 1.93 (s, 3H), 2.07 (s, 3H), 2.09 (s, 3H), 2.11 (s, 3H),
2.72–2.73 (m, 2H), 2.79–2.80 (m, 2H), 2.92–2.93 (m, 1H),
4.25 (dd, J¼2.0, 12.3 Hz, 1H), 4.32 (dd, J¼5.9, 12.3 Hz,
1H), 4.59–4.61 (m, 1H), 5.27 (dd, J¼2.8, 10.3 Hz, 1H),

S. G. Deshpande, T. Pathak / Tetrahedron 63 (2007) 602–608
607
for C20H24N4O9$1/4H2O: C, 51.23; H, 5.27. Found: C,
51.31; H, 5.46. MS: ESI m/z 465.2 [100(M+H)+].
Both the authors thank Dr. M.S. Shashidhar for his support
and interest in this work.
4.2.7. 1-(2,4,6-Tri-O-acetyl-3-S-thio-(p)tolyl-b-D-altro-
pyranosyl) thymine 14g. NaOMe (0.14 g, 2.5 mmol) was
added to a solution of p-thiocresol (0.44 g, 3.5 mmol) in
DMF (5 mL). After 15 min at rt, epoxide 3 (0.18 g,
0.5 mmol) was added to the solution. The reaction mixture
was heated at 70 ꢀC for 10 h; 13g (0.16 g, 66%), 14g
(0.12 g, 55%). Eluent: EtOAc/petroleum ether (3:2). White
needles. Mp: 77–82 ꢀC. [a]D25 +99.1 (c 1.29, CHCl3). IR
References and notes
1. Pathak, T. Chem. Rev. 2002, 102, 1623 and references cited
therein.
2. (a) Zorbach, W.; Durr, G. J., Jr. J. Org. Chem. 1962, 27, 1474;
(b) Langen, P.; Etzold, G. Biochem. Z. 1963, 339, 190; (c)
Lerner, L. M.; Kohn, P. J. Med. Chem. 1964, 7, 655; (d)
Nord, L. D.; Dalley, N. K.; McKernan, P. A.; Robins, R. K.
J. Med. Chem. 1987, 30, 1044.
1
(CHCl3): 1745.5, 1689.5 cmꢂ1. H NMR (CDCl3): d 1.93
(s, 3H), 2.01 (s, 3H), 2.03 (s, 3H), 2.13 (s, 3H), 2.33 (s, 3H),
4.00–4.04 (m, 1H), 4.29–4.44 (m, 3H), 5.11–5.18 (m, 2H),
6.49 (d, J¼1.6 Hz, 1H), 7.15 (d, 2H), 7.27 (s, 1H), 7.44 (d,
2H), 8.72 (s, 1H). 13C NMR (CDCl3): d 12.5, 20.7, 20.8,
21.1, 49.5, 62.9 (CH2), 65.9, 70.1, 73.8, 78.0, 110.0, 127.5,
130.2, 134.0, 135.9, 138.9, 149.5, 163.5, 168.9, 169.7,
170.7. Anal. Calcd for C24H28N2O9S$1/4H2O: C, 54.90; H,
5.47. Found: C, 54.77; H, 5.40. MS: ESI m/z 521.1 [100(M+
H)+], 461.1 [43(M+H)+ꢂCH3CO2H], 395.1 [28(M+H)+ꢂ
thymine], 275.1 [25(M+H)+ꢂ(thymine+2ꢁCH3CO2H)].
3. Knapp, S. Chem. Rev. 1995, 95, 1859.
4. (a) Ostrowski, T.; Wroblowski, B.; Busson, R.; Rozenski, J.; De
Clercq, E.; Bennett, M. S.; Champness, J. N.; Summers, W. C.;
Sanderson, M. R.; Herdewijn, P. J. Med. Chem. 1998, 41, 4343;
(b) Wouters, J.; Herdewijn, P. Bioorg. Med. Chem. Lett. 1999, 9,
1563.
5. Herdewijn, P. Synthesis of Pyranose Nucleosides and
Related Nucleosides with a Six-membered Carbohydrate
Mimic. In Recent Advances in Nucleosides: Chemistry and
Chemotherapy; Chu, C. K., Ed.; Elsevier Science B.V.:
Amsterdam, Netherlands, 2002; pp 239–290.
6. (a) Tatsumi, Y.; Kazuo, M.; Hiroshi, S.; Shuichi, S.; Naotaka, Y.
J. Chem. Soc., Perkin Trans. 1 1977, 1654; (b) Augustyns, K.;
Rozenski, J.; Van Aerschot, A.; Janssen, G.; Herdewijn, P.
J. Org. Chem. 1993, 58, 2977; (c) Bjoersne, M.; Classon, B.;
Kvarnstroem, I.; Samuelsson, B. Tetrahedron 1993, 49, 8637;
(d) Hanessian, S.; Conde, J. J.; Khai, H. H.; Lou, B.
Tetrahedron 1996, 52, 10827; (e) Sugimura, H.; Sujino, K.
Nucleosides Nucleotides 1998, 17, 53; (f) Vanheusden, V.;
Busson, R.; Herdewijn, P.; Van Calenbergh, S. J. Org. Chem.
2004, 69, 4446.
7. Moffatt, J. G. Nucleoside Analogues: Chemistry, Biology, and
Medical Applications; Plenum: London, 1979; p 71.
8. Selected references on the opening of pentofuranosyl nucleo-
side epoxides by nitrogen nucleophiles: (a) Vial, J. M.;
Johansson, N. G.; Vrang, L.; Chattopadhyaya, J. Antiviral
Chem. Chemother. 1990, 1, 183; (b) Huang, J.-T.; Chen, L.-C.;
Wang, L.; Kim, M.-H.; Warshaw, J. A.; Armstrong, D.; Zhu,
Q.-Y.; Chou, T.-C.; Watanabe, K. A.; Matulic-Adamic, J.;
SU, T.-L.; Fox, J. J.; Polsky, B.; Baron, P. A.; Gold, J. W. M.;
Hardy, W. D.; Zuckermanf, E. J. Med. Chem. 1991, 34, 1640;
(c) Bera, S.; Pathak, T.; Langley, G. J. Tetrahedron 1995,
51, 1459; (d) Maruyama, T.; Utsumi, K.; Tomioka, H.;
Kasamoto, M.; Sato, Y.; Anne, T.; de Clercq, E. Chem.
4.2.8. 1-(2,4,6-Tri-O-acetyl-3-S-thionitrilo-b-D-altropyr-
anosyl) thymine 14h. A mixture of epoxide 3 (0.36 g,
1 mmol) and NH4SCN (0.36 g, 5 mmol) in DMF (3 mL)
was heated at 70 ꢀC for 5 h; 13h (0.3 g, 71%), 14h (0.18 g,
56%). Eluent: EtOAc/petroleum ether (1:1). White foam.
Mp: 89–90 ꢀC. [a]D25 +65.0 (c 1.40, CHCl3). IR (CHCl3):
2164 cmꢂ1. 1H NMR (CDCl3): d 1.94 (s, 3H), 2.12 (s, 3H),
2.14 (s, 3H), 2.20 (s, 3H), 4.23–4.42 (m, 4H), 5.30 (dd, 1H),
5.43–5.45 (m, 1H), 6.01 (d, J¼1.5 Hz, 1H), 7.21 (s,
1H), 8.93 (s, 1H). 13CNMR (CDCl3): d 12.4, 20.3, 20.4,
20.6, 48.5, 62.2 (CH2), 64.5, 68.8, 73.9, 77.8, 108.8, 110.5,
135.0, 149.6, 163.5, 168.5, 169.3, 170.4. Anal. Calcd for
C18H21N3O9S: C, 47.47; H, 4.65. Found: C, 47.77; H,
4.64. MS: ESI m/z 456.1 [100(M+H)+], 414.1 [22(M+H)+ꢂ
CH3CO+H+], 330.1 [38(M+H)+ꢂthymine].
4.2.9. 1-(2,4,6-Tri-O-acetyl-3-cyano-b-D-altropyranosyl)
thymine 14i. A mixture of epoxide 3 (0.18 g, 0.5 mmol)
and NaCN (0.12 g, 2.5 mmol) in DMSO (2 mL) was heated
at 70 ꢀC for 10 h; 13i (0.14 g, 68%), 14i (0.10 g, 65%). Elu-
ent: EtOAc/petroleum ether (2:3). White solid. Mp: 99 ꢀC.
1
[a]D25 +64.5 (c 0.78, CHCl3). IR (CHCl3): 2254.6 cmꢂ1. H
NMR (1H–1H COSY) (CDCl3): d 1.93 (s, 3H, thymine
CH3), 2.12 (s, 3H, CH3), 2.14 (s, 3H, CH3), 2.19 (s, 3H,
CH3), 3.56 (dd, J¼2.8, 11.1 Hz, 1H, H30), 3.96ꢂ3.98 (m,
1H, H50), 4.19 (dd, J¼2.5, 12.5 Hz, 1H, H60), 4.32 (dd,
J¼6.0, 12.5 Hz, 1H, H600), 5.39 (apparent t, J¼10.1 Hz,
1H, H40), 5.70 (m, 1H, H20), 5.87 (d, J¼1.3 Hz, 1H, H10),
7.19 (s, 1H, H-6), 9.77 (br s, 1H, NH). 13C NMR (CDCl3):
d 12.5, 20.3, 20.5, 20.7, 36.6, 62.1 (CH2), 63.5, 66.1, 77.3,
80.5, 111.0, 115.0, 134.4, 149.9, 163.3, 168.9, 169.2,
170.5. Anal. Calcd for C18H21N3O9$1/2H2O: C, 50.00; H,
5.13. Found: C, 50.23; H, 5.20. MS: ESI m/z 424.1 [100(M+
H)+], 382.1 [35(M+H)+ꢂCH3CO+H+], 298.1 [51(M+H)+ꢂ
thymine].
ꢀ
Pharm. Bull. 1995, 43, 955; (e) Garcıa-Alles, L. F.;
Magdalena, J.; Gotor, V. J. Org. Chem. 1996, 61, 6980; (f)
Von Calenbergh, S.; von Frijtag Drabbe Kunzel, J. K.;
Blaton, N. M.; Peeters, O. M.; Rozenski, J.; Van Aerschot,
A.; De Bruyn, A.; De Keukeleire, D.; Von Calenbergh, S.;
Herdewijn, P. J. Med. Chem. 1997, 40, 3765; (g) Van
Calenbergh, S.; Von Calenbergh, S.; Herdewijn, P.
Nucleosides Nucleotides 1998, 17, 1571; (h) Maiti, T. K.; De,
S.; Dasgupta, S.; Pathak, T. Bioorg. Med. Chem. 2006, 14,
1221.
9. Selected references on the opening of pentofuranosyl nucleo-
side epoxides by sulfur nucleophiles: (a) Mengel, R.;
Griesser, H. Tetrahedron Lett. 1977, 18, 1177; (b) Mundill,
P. H. C.; Fries, R. W.; Woenckhaus, C.; Plapp, B. V. J. Med.
Chem. 1981, 24, 474; (c) Wu, J.-C.; Pathak, T.; Tong, W.;
Vial, J.-M.; Remaud, G.; Chattopadhyaya, J. Tetrahedron
Acknowledgements
S.G.D. thanks the Council of Scientific and Industrial Re-
search, New Delhi, India for a Senior Research Fellowship.

608
S. G. Deshpande, T. Pathak / Tetrahedron 63 (2007) 602–608
1988, 44, 6705; (d) Onuma, S.; Kumamoto, H.; Kawato, M.;
Tanaka, H. Tetrahedron 2002, 58, 2497.
13. p-Toluenesulfonylation of 7-(4,6-benzylidene-b-D-glucopyra-
nosyl) theophylline produced the 30-O-tosylated isomer
(like 4 in Scheme 1) in significant amount. This compound
would generate the allo-epoxide (like 3 in Scheme 1). See:
Harvey, W. E.; Michalski, J. J.; Todd, A. R. J. Chem. Soc.
1951, 2271.
14. An unidentified ‘monotosyl monoacetate’ obtained from 1-
(4,6-O-benzylidene-b-D-glucopyranosyl)-4-ethoxy-2(lH) pyri-
midone was converted to the manno-epoxide (like 6 in Scheme
1); however, in this case it was necessary to protect the O-4 of
the pyrimidine base with ethyl group. The initial tosylation was
claimed to have taken place at O-2 of the gluco-nucleoside
(like 5 in Scheme 1) to generate 2-O-tosyl derivative (like 9
in Scheme 1). See: Ref. 12a.
15. Similar selectivity14 of tosylation was also necessary for
the formation of cytosine manno-epoxide. See: Watanabe,
K. A.; Wempen, I.; Fox, J. J. Chem. Pharm. Bull. 1970, 18,
2368.
16. Tsuda, Y.; Nishimura, M.; Kobayashi, T.; Sato, Y.; Kanemitsu,
K. Chem. Pharm. Bull. 1991, 39, 2883.
10. Selected references on the opening of pentofuranosyl nucleo-
side epoxides by carbon nucleophiles: (a) Amin, M. A.;
Stoeckli-Evans, H.; Gossauer, A. Helv. Chim. Acta 1995, 78,
1879; (b) Faul, M. M.; Huff, B. E.; Dunlap, S. E.; Frank,
S. A.; Fritz, J. E.; Kaldor, S. W.; LeToumeau, M. E.; Staszak,
M. A.; Ward, M. A.; Werner, J. A.; Winneroski, L. L.
Tetrahedron 1997, 53, 8085; (c) Hirota, K.; Takasu, H.;
Sajiki, H. Heterocycles 2000, 52, 1329; (d) Peoc’h, D.;
Swayze, E. E.; Bhat, B.; Sanghvi, Y. S. Nucleosides
Nucleotides Nucleic Acid 2004, 23, 411.
11. (a) Sakthivel, K.; Kumar, R. K.; Pathak, T. Tetrahedron 1993,
49, 4365; (b) Sakthivel, K.; Bera, S.; Pathak, T. Tetrahedron
1993, 49, 10387; (c) Sakthivel, K.; Pathak, T.; Suresh, C. G.
Tetrahedron 1994, 50, 13251; (d) Bera, S.; Sakthivel, K.;
Langley, G. J.; Pathak, T. Tetrahedron 1995, 51, 7857; (e)
Sakthivel, K.; Pathak, T. Tetrahedron 1996, 52, 4877; (f)
Bera, S.; Pathak, T. Tetrahedron 1999, 55, 13051; (g) Bera,
S.; Langley, G. J.; Pathak, T. J. Org. Chem. 1998, 63, 1754;
(h) Deshpande, S. G.; Pathak, T. Tetrahedron Lett. 2004, 45,
2255; (i) Bera, S.; Pathak, T. Synlett 2004, 2147.
17. Whistler, R. L.; Doner, L. W. Methods Carbohydr. Chem. 1972,
6, 215.
12. For the regioselectivity of opening of manno-epoxides, see: (a)
Stevens, C. L.; Nielsen, N. A.; Blumbergs, P. J. Am. Chem. Soc.
1964, 86, 1894; (b) Willams, N. R. Adv. Carbohydr. Chem.
Biochem. 1970, 25, 109; (c) Collins, P. M.; Ferrier, R. J.
Monosaccharides their Chemistry and their Roles in Natural
18. Niedballa, U.; Vorbruggen, H. J. Org. Chem. 1976, 41, 2084.
19. There are only a few reports on the synthesis of 30-carbon
branched pyranosyl nucleosides but all these methods either
coupled the branched chain sugars with nucleobases19a or
functionalized naturally occurring uridine by treatment with
metaperiodate and subsequent base-catalyzed cyclization with
nitroethane.19b See: (a) Rosenthal, A.; Ratcliffe, M. Carbohydr.
Res. 1975, 39, 79; (b) Lichtenthaler, F. W.; Zinke, H. J. Org.
Chem. 1972, 37, 1612.
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p 204; (d)
Ravindran, B.; Pathak, T. J. Org. Chem. 1999, 64, 9715; (e)
Ravindran, B.; Sakthivel, K.; Suresh, C. G.; Pathak, T.
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