Synthesis of 2-amino-2,4-anhydro-3-O-(2-tetrahydropyranyl)-psicofuranose: A versatile intermediate for S-type locked nucleosides

Article abstract of DOI:10.1016/j.tetlet.2005.12.072

2-Amino-2,4-anhydro-psicofuranose derivative was synthesized starting from d-fructose.

Full text of DOI:10.1016/j.tetlet.2005.12.072

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1283–1285
Synthesis of 2-amino-2,4-anhydro-3-O-(2-tetrahydropyranyl)-
psicofuranose: a versatile intermediate for S-type locked nucleosides
Chamakura V. N. S. Varaprasad,* Kanda S. Ramasamy and Zhi Hong
Drug Discovery, Valeant Pharmaceutical Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92614, USA
Received 12 November 2005; revised 14 December 2005; accepted 14 December 2005
Available online 10 January 2006
Abstract—2-Amino-2,4-anhydro-psicofuranose derivative was synthesized starting from D-fructose.
Ó 2005 Elsevier Ltd. All rights reserved.
The furanose ring in natural nucleosides exists in a
dynamic equilibrium between northern (N-type, 20-exo/
30-endo) and southern (S-type, 20-endo/30-exo) pucker
conformations.1 These conformations are recognized
by cellular enzymes in a selective manner.2 Whereas, in
the case of locked nucleosides, furanose ring adopts a
fixed conformation and may lead to a higher affinity
to the enzymes compared to the unlocked furanose moi-
ety. Hence the synthesis of nucleosides with a rigid con-
formation gained momentum in recent years.3 The
bicyclic nucleosides with N-type conformation are
found to be particularly interesting and found to have
greater potency and less toxicity than the corresponding
nucleosides with normal furanose ring systems.4
The desired azido bicyclic sugar 14 (Scheme 2) was envis-
aged to be obtained from the key intermediate 11
(Scheme 1). The synthesis of methyl glycoside 11 was
accomplished as shown in Scheme 1. Thus, di-acetonide
1 was synthesized from D-fructose in high yield following
a literature procedure.10 Alcohol 1 was protected as its
benzyl ether 2 under standard conditions. Di-acetonide
2 was selectively opened at glycosidic site under acidic
conditions to generate predominantly the desired methyl
glycoside 3.10 The free hydroxyl in 3 was derivatized as
its tosylate 4, which was then deisopropylenated to
obtain the corresponding diol 5. Exposure of 5 to hydro-
gen in the presence of 10% Pd/C generated the triol 6,
which was then selectively protected as the di-silyl deriva-
tive 7 using Markiewicz’s reagent.11 The secondary
hydroxyl in 7 was protected as its tetrahydropyranyl
(THP) ether 8 under standard conditions. The reaction
of silyl ether 8 with tetrabutylammonium fluoride
(TBAF) generated diol 9 for the formation of important
bicyclic intermediate 10. It is gratifying to note that
transformation of diol 9 to the bicyclic derivative 10 went
smoothly in the presence of excess NaOMe in MeOH
under reflux conditions. The primary hydroxyl 10 was
then esterified to the corresponding benzoate 11.
Modified nucleosides with S-type conformation have
not been studied thoroughly for their biological activi-
ties5 although they have been incorporated into DNA
and RNA duplexes to study the stability of their respec-
tive oligonucleotides.6 Our continued interest in the syn-
thesis of modified7 and conformationally locked8
nucleosides led us to further our research in this area.
To date, surprisingly, synthesis of only one rigid nucleo-
side wherein the 1, 3 positions in furanose ring are
locked is reported.9 In this letter, we delineate the syn-
thesis of 2-amino-2,4-anhydro-psicofuranose derivative
24 as a versatile intermediate to construct such locked
nucleosides with natural and unnatural bases.
Several of our attempts to convert glycoside 11 to the
corresponding di-acetate 12 (Scheme 2) under a variety
of conditions had failed. The di-acetate 12 may be used
for the synthesis of bicyclic nucleosides with natural
bases in oligonucleotides. Furthermore, a direct attempt
to couple thymine base with glycoside 11 under
Vorbruggen’s12 conditions also failed to give the desired
¨
product 13. Therefore, we thought to convert glycoside
11 to crucial bicyclic amino alcohol 24 via the corre-
sponding azido derivative 14. Repeated attempts to
Keywords: Locked nucleosides; Bicyclic sugars.
*
Corresponding author. Tel.: +1 714 545 0100; fax: +1 714 641
7233; e-mail: vchamakura@valeant.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.072

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C. V. N. S. Varaprasad et al. / Tetrahedron Letters 47 (2006) 1283–1285
BnO
O
BnO
OMe
HO
O
O
O
O
BnO
OMe
O
O
OR
O
a
d
b
O-pTs
O
O
O
O
O
O
HO
OH
1
5
2
3
4
R= H
R = pTs
c
e
O
O
HO
OMe
OMe
OMe
O
O
O
Si
O
Si
O
g
O-pTs
O-pTs
O-pTs
f
OTHP
OH
OH
O
O
HO
Si
Si
8
6
7
pTS = p-Toluenesulfonyl
THP = 2-Tetrahydropyranyl
h
BzO
HO
OMe
HO
OMe
OMe
O
O
O
O
j
O-pTs
OTHP
i
O
O
HO
O
THP
THP
11
10
9
Scheme 1. Reagents and conditions: (a) NaH (1.2 equiv), BnCl (1.25 equiv), DMF, rt, 16 h, quant.; (b) MeOH, concd H2SO4, rt, 16 h, 59%; (c) p-
TsCl (2.5 equiv), Py, 16 h, rt, 97%; (d) Concd H2SO4, MeOH, H2O (1.3 equiv), rt, 16 h, 95% (based on recovered starting material); (e) 10% Pd/C
(25% wt/wt), H2 (50 psi), rt, 16 h, 91%; (f) TiPSCl (1.25 equiv), Py, rt, 16 h, 74%; (g) DHP (7 equiv), PpTS (1.5 equiv), CH2Cl2, 45 °C, 4 h, quant.; (h)
TBAFÆ3H2O (3 equiv), Py–H2O (3:2), THF, rt, 16 h, 89%; (i) NaOMe, MeOH, reflux, 16 h, 55%; (j) BzCl, Py, rt, 16 h, quant.
T
BzO
BzO
OMe
BzO
OAc
b
O
a
O
O
X
O
X
O
O
O
O
O
Ac
THP
THP
13
11
12
T = Thymine
c
X
N3
BzO
O
O
O
THP
14
Scheme 2. Reagents and conditions: (a) H2SO4, acetic anhydride, acetic acid, 0–4 °C, 16 h; (b) (i) Thymine, HMDS, (NH4)2SO4, reflux, 5 h; (ii)
SnCl4, 1,2-dichloroethane, 0 °C to rt; (c) TMS–N3 (2 equiv), TMS–triflate (0.3 equiv), CH3CN, 0 °C to rt, 1 h.
convert 11 into 14 also failed. Only furanose ring opened
products were observed.
THP ether 21. This allowed us to selectively deprotect 4
and 6 hydroxyls by exposing disilylether 21 to TBAF
which afforded the diol 22. Conversion of diol 22 to
bicyclic sugar 23 was successful with NaOMe in reflux-
ing MeOH. No products were formed involving primary
hydroxyl group on C6 since it is in anti position to the
leaving tosylate on C1. Hydrogenation of azido com-
pound 23 in the presence of 10% Pd/C afforded the de-
sired amino alcohol 24 which was derivatized further for
ease of characterization to the corresponding acetamide
25 by treating it with acetic anhydride in pyridine.
However, altering the sequence of reactions afforded the
desired 2-amino-anhydro-psicofuranose derivative 24 as
shown in Scheme 3. Thus, di-acetonide 15, obtained
from alcohol 1 by treating with benzoyl chloride in pyr-
idine, was selectively opened with TMS-azide10 in the
presence of TMS-triflate to obtain azido-alcohol 16.
The alcohol was derivatized as its tosylate 17 under stan-
dard conditions. Benzoate 17 was hydrolyzed to alcohol
18, which was then deisopropylenated to give triol 19.
The 4 and 6 positions in 19 were protected as di-silyl
ether 20 by using Markiewicz’s reagent. Then, the sec-
ondary alcohol in 20 was protected as the corresponding
In summary, we have synthesized 2-amino-2,4-anhydro-
psicofuranose derivative 24. Further studies involving
the synthesis of locked nucleosides using intermediate

C. V. N. S. Varaprasad et al. / Tetrahedron Letters 47 (2006) 1283–1285
1285
HO
N3
BzO
O
N3
BzO
O
O
O
c
O-pTs
O
a
OR
b
O
O
O
O
O
O
16: R = H
15
18
17: R = pTs
d
HO
N3
O
O
N3
O
HO
N3
Si
O
O-pTs
O-pTs
g
e
O-pTs
O
OR
OH
O
Si
HO
HO
OTHP
19
22
20: R = H
21: R = THP
pTS = p-Toluenesulfonyl
THP = 2-Tetrahydropyranyl
f
h
N3
AcO
HO
HO
NH2
NHAc
O
O
O
j
i
O
O
O
O
O
O
THP
THP
THP
23
25
24
Scheme 3. Reagents and conditions: (a) TMS–N3 (2 equiv), TMS–triflate (0.3 equiv), CH3CN, 0 °C to rt, 1 h, 86%; (b) p-TsCl (2.5 equiv), Py, 16 h,
rt, quant.; (c) methanolic ammonia, rt, 16 h, 91%; (d) Dowex-50 H+, MeOH–H2O (2:1), 50 °C, 16 h, quant.; (e) TiPSCl (1.25 equiv), Py, rt, 16 h, 74%;
(f) DHP (7 equiv), PpTS (1.5 equiv), CH2Cl2, 45 °C, 4 h, quant.; (g) TBAFÆ3H2O (3 equiv), Py–H2O (3:2), THF, rt, 16 h, 89%; (h) NaOMe, MeOH,
reflux, 16 h, 63%, (i) 10% Pd/C (10% wt/wt), H2 (30 psi), rt, 2 h, 98%; (j) Ac2O (2 equiv), Py, rt, 6 h, quant.
Chem. 1996, 39, 3739–3747; (b) Zalah, L.; Huleihel, M.;
Manor, E.; Konson, A.; Ford, H., Jr.; Marquez, V. E.;
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75.
24 are currently underway. These synthetic efforts along
with the biological activity of the locked nucleosides
produced will be published in due course.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.12.072.
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