A short synthesis of bicyclic sugar pyrimidine nucleosides from C-glycosides

Article abstract of DOI:10.1016/S0040-4039(01)00889-9

The C-glycosides were prepared from dichloroketene cycloaddition reaction to glycals and converted to bicyclic sugar nucleosides in good yields.

Full text of DOI:10.1016/S0040-4039(01)00889-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4879–4881
A short synthesis of bicyclic sugar pyrimidine nucleosides from
C-glycosides
Jonghoon Oh,a,* Chung Ryul Leea and Keun Ho Chunb
aDepartment of Chemistry and Research Institute for Basic Science, Chonnam National University,
Kwangju 500-757, South Korea
bSchool of Basic Science, Soongsil University, Seoul 156-743, South Korea
Received 3 May 2001; revised 24 May 2001; accepted 25 May 2001
Abstract—The C-glycosides were prepared from dichloroketene cycloaddition reaction to glycals and converted to bicyclic sugar
nucleosides in good yields. © 2001 Elsevier Science Ltd. All rights reserved.
Over recent decades much attention has been focused
on the synthesis of nucleoside derivatives. Among them
are C-branched sugar nucleosides,1 bicyclic sugar
nucleosides,2 acyclic sugar nucleosides3 and carbocyclic
sugar nucleosides.4 Many structural modifications on
the ribose ring3 of the nucleoside have been made to
find molecules showing enhanced biological activities
such as anti-HIV and anti-HBV. In this paper, we wish
to present a synthesis of new nucleosides bearing a
bicyclic sugar ring.
of dichloroketene took place from the a face of glucal
presumably due to the C-3 stereochemistry. Oxidation
of 2 with mCPBA–NaHCO3 in CH2Cl2 gave lactone,
which was then reduced and acetylated to give lactol
acetates 3 in 64%. The intermediates 3 were then sub-
jected to N-glycosylation conditions6 (uridine, potas-
sium nonafluoro-1-butanesulfonate, 1,1,1,3,3,3-hexa-
methyldisilazane, chlorotrimethylsilane in acetonitrile)
to afford a and b nucleosides in 34 and 57% yield,
respectively. The total isolated yield of glycosylation is
excellent, however, the bicyclic ring system and bulky
tribenzyl groups did not play an important role in the
stereoselectivity during N-glycosylation. The two iso-
mers were separated by careful preparative TLC
(CH2Cl2–ether, 3:1), and the fast moving isomer was
found to be the b isomer by NOE. Irradiation of H-2%b
(2.07 ppm) gave NOE on H-6 (7.95 ppm) and irradia-
tion of H-2%a (2.59 ppm) did not show NOE on H-6.
The stereochemistry was confirmed by irradiation of
H-6 to give strong NOE on H-2%b and no NOE H-2%a.
The conformational analysis, by NMR and X-ray tech-
nology, of ribose and deoxyribose ring of nucleosides
has been a subtle subject in nucleoside synthesis.2d–g,7
Based on relatively small coupling constants between
H-1% and H-2%b (2.1 and 3.1 Hz, respectively), furanose
part of our bicyclic sugar in 5 and 6 are unlikely to
have S-conformation. However, more systematic study
is necessary to figure out the major conformation of
our bicyclic sugar to understand the relationship
between the conformations and activities of 5 and 6.
In the course of the synthesis of C-glycoside, we found
that [2+2] cycloaddition of dichloroketene to glycal and
subsequent chemical modification of the cyclobutanone
intermediate would provide a very powerful and
efficient protocol for the stereo- and regioselective
introduction of functionalized alkyl chain on C-1 of
glycoside.5 With respect to the application of this pro-
tocol, it was envisioned that the C-branched glycoside
from dichloroketene cycloaddition could provide a use-
ful moiety of bicyclic sugar ring of nucleoside.
Our synthesis, as outlined in Scheme 1, begins with the
preparation of lactol acetates 3. Tri-O-benzyl-D-glucal
(1) was treated with dichloroketene, generated in situ
from a zinc–copper couple and trichloroacetyl chloride
in ether, to give a labile dichlorocyclobutanone interme-
diate. The latter was further treated with zinc in acetic
acid to afford dechlorinated cyclobutanone containing
C-glycoside 2 in 90% for two steps. The cycloaddition
The synthesis of bicyclic nucleoside was completed by
deblocking (H2, Pd/C, 1N HCl, MeOH) of three
hydroxyl groups to give 6 in 80% yield.8 Nucleoside 6
Keywords: C-glycoside; dichloroketene cycloaddition; glycal; bicyclic
sugar nucleoside.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00889-9

4880
J. Oh et al. / Tetrahedron Letters 42 (2001) 4879–4881
BnO
BnO
BnO
O
BnO
BnO
O
O
b
a
OAc
BnO
O
O
OBn
2
OBn
OBn
3
1
O
N
O
OBn
NH
O
NH
OBn
BnO
BnO
O
(4a)
+ α isomer
BnO
OAc
O
N
H
O
O
O
BnO
3
c
5
O
NH
OH
d
N
O
β isomer
5
HO
HO
O
O
6
Scheme 1. Reagents and conditions: (a) trichloroacetylchloride, Zn(Cu), ether, 0°C, 30 min; Zn, AcOH, 5 h, 90%; (b) mCPBA,
NaHCO3, 0°C, N2, CH2Cl2, 1 h; DIBALH, CH2Cl2, −78°C, N2, 15 min; Ac2O, −78°C to rt, 8 h, 64%; (c) uracil, potassium
nonafluoro-1-butanesulfonate, 1,1,1,3,3,3-hexamethyldisilazane, TMSCl, acetonitrile, rt, 30 min; (d) H2, Pd/C (3%). 1N HCl,
MeOH, 6 h, 80%.
Table 1. Summary of N-glycosylation yield
O
O
O
H3C
F
4c
NH
O
NH
NH
4a
4b
N
H
N
H
O
N
H
O
OBn
BnO
BnO
O
98%
71%
β isomer: 57%
α isomer: 34%
3
OAc
OAc
mixture of α and β
mixture of α and β
O
OBn
BnO
BnO
β isomer: 23%
α isomer: 27%
O
β isomer: 57%
α isomer: 31%
β isomer: 44%
α isomer: 42%
7
O
has a unique structure, i.e. a deoxyribose unit bearing a
glucose subunit.
In conclusion, we successfully demonstrated the synthe-
sis of novel bicyclic sugar nucleosides bearing glucose
and galactose moieties on the deoxy ribose ring in good
yields from C-glycosides, which were prepared from
dichloroketene cycloaddition to glycals.
As outlined in Table 1, thymine (4b) and 5-fluorouracil
(4c), however, gave an inseparable mixture of two
isomers in 98 and 71% yield, respectively. Lactol
acetates 7, prepared from tri-O-benzyl-D-galactal fol-
lowing the same procedure for compounds 3 in com-
parable yields, were also subjected under glycosylation
conditions with three bases (4a, 4b, 4c) to afford
bicyclic sugar ring nucleosides bearing galactose stereo-
chemistry on the bicyclic sugar ring moiety in moderate
yields and stereoselectivity.
Acknowledgements
This work was financially supported by Korea
Research foundation Grant (KRF-1999-015-DP0222).

J. Oh et al. / Tetrahedron Letters 42 (2001) 4879–4881
5. Oh, J. Tetrahedron Lett. 1997, 38, 3249–3250.
4881
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