Synthesis of anhydro psicofuranosyl nucleosides

Article abstract of DOI:10.1016/S0040-4039(02)01472-7

Methyl 1-O-mesyl-5-O-toluoyl-β-D-psicofuranoside (5) was synthesised from the known 1,3;4,5-di-O-isopropylidene-β-D-psicofuranose (1) as a key carbohydrate precursor for the preparation of anhydro psicofuranosyl nucleosides. Transformation of 5 into aceta

Full text of DOI:10.1016/S0040-4039(02)01472-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6553–6555
Synthesis of anhydro psicofuranosyl nucleosides
Jarkko Roivainen,a Jouko Vepsa¨la¨inen,b Alex Azhayeva,* and Igor A. Mikhailopuloc,*
aDepartment of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland
bDepartment of Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland
cInstitute of Bioorganic Chemistry, National Academy of Sciences, Acad. Kuprevicha 5, 220141 Minsk, Belarus
Received 18 May 2002; revised 1 July 2002; accepted 16 July 2002
Abstract—Methyl 1-O-mesyl-5-O-toluoyl-b- -psicofuranoside (5) was synthesised from the known 1,3;4,5-di-O-isopropylidene-b-
D
D
-psicofuranose (1) as a key carbohydrate precursor for the preparation of anhydro psicofuranosyl nucleosides. Transformation
of 5 into acetate 7 or bromide 10 followed by (i) coupling with persilylated N6-benzoyladenine in the presence of SnCl4, and (ii)
treatment with MeONa/MeOH gave 1%,3%-anhydro nucleoside 9. Employment of silylated thymine in a similar sequence of
reactions afforded the 1%,4%-anhydro nucleoside 12. Reaction of blocked 11 with NH3/MeOH gave O2,1%-anhydro nucleoside 13,
which was rearranged into 12 upon MeONa/MeOH treatment. Condensation of the 1%,3%-anhydro sugar 15 with silylated thymine
gave, after deprotection, the 1%,3%-anhydro nucleoside 16. © 2002 Elsevier Science Ltd. All rights reserved.
During recent years, rigid nucleosides have attracted
much attention as constituents of oligonucleotides.1–3
Oligonucleotides containing rigid nucleosides display a
number of exciting biological properties, which are of
importance for possible biomedical applications.
Application of acetate 7 or bromide 10 in a coupling
reaction with silylated bases was found to be advanta-
geous over that of 6. Thus, the reaction of 7 with
persilylated N6-benzoyladenine in the presence of SnCl4
under reflux for 35 min in acetonitrile (MeCN) gave,
after standard workup, the desired 8 in 95% yield.
Condensation of bromide 10 with the same base
resulted in the formation of 8 (95%). Bromide 10, in
turn, was prepared in quantitative yield either from
acetate 7, or directly from methyl glycoside 6. Treat-
ment of the protected nucleoside 8 with MeONa/
MeOH under very mild conditions resulted in
deprotection, accompanied by the 1%,3%-anhydro ring
closure giving rise to nucleoside 9.6
In the present communication, we describe the synthesis
of new rigid nucleosides (9 and 16, 12 and 13), which
contain different kinds of anhydro bridges. The first
part of this approach was to prepare the aforemen-
tioned rigid nucleosides by the synthesis of methyl
1-O-mesyl-5-O-toluoyl-b- -psicofuranoside (5) as a key
D
carbohydrate precursor (Scheme 1). This was obtained
in four steps, in high combined yield, by conventional
procedures from the known 1,3;4,5-di-O-isopropyli-
dene-b-
-psicofuranose (1).4 Acetylation of 5 gave
D
The coupling of bromide 10 with silylated thymine,
followed by treatment of intermediate 11 with MeONa/
MeOH, afforded the 1%,4%-anhydro nucleoside 12 (23%,
combined).7 Under more mild conditions, upon treat-
ment of 11 with methanolic ammonia, we have moni-
tored (RP HPLC) the gradual deacetylation of 11 to
tentative 14, followed by an intramolecular attack of
the C2 carbonyl group at the base on the C1% carbon
atom, leading to the O2,1%-anhydro nucleoside 138 in
26% combined yield.9 The latter rearranged to the
1%,4%-anhydro nucleoside 12 upon treatment with
MeONa/MeOH.
methyl glycoside 6, which was used in a reaction with
persilylated bases, similar to the procedure, reported
earlier.5 It was, however, found that 6 reacts very
slowly with persilylated N6-benzoyladenine in the pres-
ence of SnCl4 under reflux for 8 h in 1,2-dicloroethane
(DCE) to furnish the protected b- -nucleoside 8 in 33%
D
yield.
In order to prepare 1%,3%-anhydro thymine nucleoside 16,
an alternative procedure was developed (Scheme 2).
* Corresponding authors. Tel.: +358-17-162204; fax: +358-17-162456;
e-mail: alex.azhayev@uku.fi
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01472-7

6554
J. Roi6ainen et al. / Tetrahedron Letters 43 (2002) 6553–6555
RO
O
TolO
OMe
TolO
OMe
OMs
O
O
O
O
OR
b
d
f
O
O
O
O
RO
OR
1, R = H
3, R = H
4, R = Ms
5, R = H
c
e
a
2, R = Tol
6, R = Ac
TolO
OAc
OMs
TolO
AdeBz
OMs
HO
Ade
O
O
8
O
g
h
AcO
OAc
AcO
OAc
HO
O
7
9
j
TolO
Br
TolO
Thy
O
O
i
k
OMs
OMs
6 or 7
AcO
OAc
AcO
OAc
10
11
Me
N
O
N
HO
Thy
OH
HO
Thy
HO
O
O
O
OMs
O
O
HO
OH
HO
OH
14
13
12
Tol = p-toluoyl
Scheme 1. (a) Tol-Cl/Py/toluene, −78°C, −20°C, 24 h (78–94%); (b) 0.4 M HCl/MeOH, 20°C, 2–3 h (91%); (c) MsCl/NEt3/tolu-
ene, 20°C, 18 h (95%); (d) 1.0 M HCl/MeOH, 20°C, 48 h (87% based on the conversion of 4, 28% of which was recovered); (e)
Ac2O/Py, 20°C, 18 h (73%); (f) (i) CF3COOH/H2O (95:5, vol), 20°C, 19–20 h; (ii) Ac2O/Py, −4°C, 20 h (S50%); (g) 7/persilylated
N6-benzoyladenine/SnCl4 (molar ratio=1.0:1.5:3.4), MeCN, reflux, 35 min (95%); (h) 8/MeONa/MeOH, 20°C, 18 h (87%); (i) 6
or 7/HBr/AcOH, 20°C, 1–3 h; (j) 10/persilylated N6-benzoyladenine/SnCl4 (molar ratio=1.0:1.5:2.0), MeCN, 60°C, 3 h; (k) (i)
10/persilylated thymine/SnCl4 (molar ratio=1.0:1.5:2.0), MeCN, 60°C, 1.5 h; (ii) 0.4 M MeONa/MeOH, 50°C, 18 h (12, 23%
combined)
Glycoside 5 was transformed in two steps to the 1,3-
anhydro derivative 15 in high yield. Its condensation
with silylated thymine, in the presence of SnCl4 under
reflux, followed by deprotection resulted in the forma-
tion of the desired 16 in 50% overall yield.10
Acknowledgements
The authors are indebted to Dr. Seppo Auriola for the
electrospray ionisation mass spectra. We thank Dr.
James Callaway (University of Kuopio) for reading the
manuscript. Financial support from the Technology
Development Center of Finland is gratefully
acknowledged.
In conclusion, we have developed two alternative path-
ways for the preparation of 1%,3%-anhydro psicofuranosyl
nucleosides. The synthesis of 1%,4%- and O2,1-anhydro
psicofuranosyl thymine nucleosides was also achieved.

J. Roi6ainen et al. / Tetrahedron Letters 43 (2002) 6553–6555
6555
absent due to the long relaxation time.
7. 1-(1,4-Anhydro-b- -psicofuranosyl)thymine (12): glassy
TolO
OMe
OMs
O
D
product; UV (MeOH): umax nm (m) 261.0 (10 000), umin
232.0 nm (2800); CD (MeOH) u, nm ([U]×10−3): 264.0
(−4.8), 293.0 (+2.75), 248 and 278 (0). HPLC [(column:
Waters XTerra RP18, 5 mm, 4.6×150 mm; linear gradient
(0“4%) of CH3CN in water; flow rate of 1.0 mL/min
HO
OH
a,b
5
TolO
OMe
1
O
(time of analysis 20 min)]: retention time (tR) 7.5 min; H
NMR (D2O), lTMS, ppm; J, Hz: 7.49 (br.s, 1H, H-6), 4.64
(d, 1H, J1%,1%%=8.85, H-1%), 4.27 (d, 1H, H-1%%), 4.96 (br.s,
1H, J3%,4%<1.0, H-3%), 4.31 (br.s, 1H, J4%,5%<1.0, H-4%), 4.21
(dt, 1H, J5%,6%=J5%,6%%=5.02, H-5%), 3.62 (d, 2H, H-6% and
TolO
O
15
c,d
H-6%%), 1.85 (d, 3H, JCH3,H6=1.16, 5-CH6 3.
13C NMR
(DMSO-d6), lTMS, ppm: 167.14 (C-4), 152.82 (C-2),
140.20 (C-6), 113.11 (C-5), 96.51 (C-2%), 83.67 (C-5%),
78.34 (C-4%), 71.39 (C-1%), 71.45 (C-3%), 61.06 (C-6%), 12.33
HO
Thy
O
(5-C
6 H3).
8. O2,1%-Anhydro-1-(b-
D
-psicofuranosyl)thymine
(13):
HO
O
started to darken at 195°C and melted at 208°C (from
EtOH); UV (MeOH): umax nm (m) 229.0 (9200) and 254.0
(11 300), umin 215.5 nm (7180) and 236.5 (8650); CD
(MeOH) u, nm ([U]×10−3): 242.0 (−14.45), 265.0 (+10.4),
275.0 (−4.0), 224, 255 and 300 (0). HPLC [(column:
Waters XTerra RP18, 5 mm, 4.6×150 mm; linear gradient
(0“4%) of CH3CN in water; flow rate of 1.0 mL/min
16
Scheme 2. (a) 0.4 M MeONa/MeOH, 20°C, 24 h; (b) Tol-Cl/
NEt3/toluene, 20°C, 18 h (the yield of 15 from 5 was 72%); (c)
15/persilylated thymine/SnCl4 (molar ratio=1.0:1.5:2.0),
MeCN, reflux, 18 h (79%); (d) saturated NH3 in MeOH 20°C,
72 h (the yield of 16 from 15 was 64%).
1
(time of analysis 20 min)]: retention time (tR) 6.5 min; H
NMR (CD3OD/H2O), lTMS, ppm; J, Hz: 7.77 (q, 1H,
References
J
H6,CH3=1.16, H-6), 5.14 (d, 1H, J1%,1%%=10.64, H-1%), 4.67
(d, 1H, H-1%%), 4.72 (d, 1H, J3%,4%=4.73, H-3%), 4.35 (dd,
1H, J4%,5%=2.08, H-4%), 4.17 (m, 1H, J5%,6%=3.48, J5%,6%%
4.00, H-5%), 3.78 (dd, 1H, J6%,6%%=12.66, H-6%), 3.77 (dd,
1H, H-6%%), 1.96 (d, 3H, JCH3,H6=1.16, 5-CH3
). 13C NMR
1. Leumann, C. J. Bioorg. Med. Chem. 2002, 10, 841–854.
2. Orum, H.; Wengel, J. Curr. Opin. Mol. Ther. 2001, 3,
239–243.
3. Rajwanshi, V. K.; Hakansson, A. E.; Sorensen, M. D.;
Pitsch, S.; Singh, S. K.; Kumar, R.; Nielsen, P.; Wengel,
J. Angew. Chem., Int. Ed. Engl. 2000, 39, 1656–1659.
4. Prisbe, E. J.; Smejkal, J.; Verheyden, J. P. H.; Moffatt, J.
G. J. Org. Chem. 1976, 41, 1836–1846.
=
6
(CD3OD/H2O), lTMS, ppm: 178.3 (C-4), 163.61 (C-2),
134.38 (C-6), 121.64 (C-5), 101.84 (C-2%), 88.56 (C-5%),
76.36 (C-4%), 75.25 (C-1%), 73.75 (C-3%), 64.04 (C-6%), 15.92
(5-C6 H3).
9. A similar cyclisation was recently observed in the case of
a related 3%-deoxynucleoside: Kvaerno, L.; Wightman, R.
H.; Wengel, J. J. Org. Chem. 2001, 66, 5106–5112.
5. Azhayev, A.; Guzaev, A.; Hovinen, J.; Mattinen, J.;
Sillanpa¨a¨, R.; Lo¨nnberg, H. Synthesis 1994, 396–400%.
6. 9-(1,3-Anhydro-b-D-psicofuranosyl)adenine (9): mp 226–
10. 1-(1,3-Anhydro-b-D-psicofuranosyl)thymine (16): mp
230°C (from MeOH); UV (MeOH): umax nm (m) 259.0
(13 900), umin 226.0 nm (1900); CD (MeOH) u, nm ([U]×
10−3): 215.0 (−8.8), 254.0 (+5.6), 275.0 (−4.0), 230, 265
and 291.0 (0). HPLC [(column: Waters XTerra RP18, 5
mm, 4.6×150 mm; linear gradient (0“4%) of CH3CN in
195°C (from EtOH); UV (MeOH): umax nm (m) 269
(8300), umin 233 nm (70); CD (MeOH) u, nm ([U]×10−3):
−221 (0), 243 (+2.14), 256 (0), 272 (−3.21) and 295 (0).
HPLC [(column: Waters XTerra RP18, 5 mm, 4.6×150
mm; linear gradient (0“4%) of CH3CN in water; flow
rate of 1.0 mL/min (time of analysis 30 min)]: retention
time (tR) 12.0 min; 1H NMR (CD3OD), lTMS, ppm; J,
water; flow rate of 1.0 mL/min (time of analysis 30 min)]:
1
retention time (tR) 10.5 min; H NMR (CD3OD), lTMS
,
ppm; J, Hz: 8.22 and 8.21 (2s, 2H, H-2 and H-8), 5.55 (d,
1H, J1%,1%%=8.3, H-1%), 5.09 (d, 1H, H-1%%), 5.76 (d, 1H,
J3%,4%=4.26, H-3%), 4.46 (dd, 1H, J4%,5%=8.59, H-4%), 4.51
(ddd, 1H, J5%,6%=2.35, J5%,6%%=4.99, H-5%), 4.05 (dd, 1H,
J6%,6%%=12.88, H-6%), 3.85 (dd, 1H, H-6%%). 13C NMR
(DMSO-d6), lTMS, ppm: 158.64 (C-6), 156.02 (C-2),
151.56 (C-4), 142.48 (C-8), 121.57 (C-5), 91.40 (C-3%),
85.84 (C-5%), 82.37 (C-1%), 73.18 (C-4%), 63.13 (C-6%), the
low intensity resonance of C-2% is either overlapped by the
resonances of the other pentofuranose carbons, or is
Hz: 7.58 (q, 1H, JH6,CH3=1.22, H-6), 4.24 (d, 1H, J1%,1%%
=
14.80, H-1%), 3.91 (d, 1H, H-1%%), 3.78 (d, 1H, J3%,4%=4.62,
H-3%), 4.15 (dd, 1H, J4%,5%=7.68, H-4%), 4.01 (m, 1H,
J5%,6%=3.00, J5%,6%%=6.65, H-5%), 3.76 (dd, 1H, J6%,6%%=12.07,
H-6%), 3.61 (dd, 1H, H-6%%), 1.87 (d, 3H, JCH3,H6=1.22,
5-CH6 3
). 13C NMR (CD3OD), lTMS, ppm: 166.71 (C-4),
153.63 (C-2), 143.81 (C-6), 110.88 (C-5), 108.98 (C-2%),
85.22 (C-5%), 75.48 (C-3%), 72.69 (C-4%), 64.10 (C-6%), 46.43
(C-1%), 12.30 (5-C6 H3).