Synthesis of novel 3′-deoxy-3′-C-hydroxymethyl nucleosides with conformationally rigid sugar moiety as potential antiviral agents

Article abstract of DOI:10.1081/NCN-100002354

Based on the fact that the ring expanded 3′-C-hydroxymethyl analogue of oxetanocin A exhibited potent antiviral activity, two types of conformationally rigid 3′-C-hydroxymethyl derivatives in which 2′-hydroxyl group is linked to the 4′-position or to the 6′-position were synthesized starting from 1,2;5,6-di-O-isopropylidene-D-glucose, respectively.

Full text of DOI:10.1081/NCN-100002354

NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 699–702 (2001)
SYNTHESIS OF NOVEL
3ꢀ-DEOXY-3ꢀ-C-HYDROXYMETHYL
NUCLEOSIDES WITH CONFORMATIONALLY
RIGID SUGAR MOIETY AS POTENTIAL
ANTIVIRAL AGENTS
Moon Woo Chun,1,∗ Myung Jung Kim,1 Un Hee Jo,1
Joong Hyup Kim,2 Hee-Doo Kim,3 and Lak Shin Jeong4
1College of Pharmacy, Seoul National University, Seoul 151-742, Korea
2Korea Institute of Science and Technology, Seoul 136-791, Korea
3College of Pharmacy, Sookmyung Women’s University,
Seoul 140-742, Korea
4College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea
ABSTRACT
Based on the fact that the ring expanded 3ꢀ-C-hydroxymethyl analogue of ox-
etanocin A exhibited potent antiviral activity, two types of conformationally
rigid 3ꢀ-C-hydroxymethyl derivatives in which 2ꢀ-hydroxyl group is linked to
the 4ꢀ-position or to the 6ꢀ-position were synthesized starting from 1,2;5,6-di-
O-isopropylidene-D-glucose, respectively.
INTRODUCTION
Oxetanocin A is a naturally occurring nucleoside which shows potent anti-
HIV activity (1). The ring expanded 3ꢀ-C-hydroxymethyl analogue of oxetanocin A
also exhibited similar antiviral activity (2), but its carbocyclic analogue was totally
devoid of antiviral activity (3). This difference in antiviral activity might be due to
differences in the sugar conformation. Since antiviral activity of the ring expanded
∗Corresponding author.
699
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
700
CHUN ET AL.
O
N
O
N
R
H3C
NH
NH
O
O
HO
O
O
HO
O
3
O
HO
HO
1 (R = H)
2 (R = CH3)
analogue was reported to be due to the superposition of its 3ꢀ-C-hydroxymethyl
group and hydroxymethyl substituent of oxetanocin A (2), we synthesized con-
formationally rigid 3ꢀ-C-hydroxymethyl derivative in which 2ꢀ-hydroxyl group
is linked to the 4ꢀ-position. We also synthesized another conformationally rigid
3ꢀ-C-hydroxymethyl derivative in which the 2ꢀ-hydroxyl group is connected to
the 6ꢀ-position. These types of nucleosides will fix the orientations of 3ꢀ- or 5ꢀ-
hydroxymethyl group which will affect the affinity to kinases and finally antiviral
activity.
Here, we report the synthesis of conformationally rigid nucleosides starting
from 1,2;5,6-di-O-isopropylidene-D-glucose as potential antiviral agents.
RESULTS AND DISCUSSION
For the synthesis of the 2ꢀ,4ꢀ-linked nucleosides (1 and 2), 1,2;5,6-di-O-
isopropylidene-D-glucose (4) was oxidized with PDC to give ketone 5 as shown in
Scheme 1. Wittig reaction of 5 followed by hydroboration-oxidation of the result-
ing methylene 6 yielded hydroxymethyl derivative 7. Treatment of 7 with benzyl
bromide gave the benzylate 8, in which 5,6-O-isopropylidene was selectively re-
moved using 75% acetic acid to give diol 9. Oxidative cleavage of 9 with NaIO4
afforded aldehyde 10. Conversion of aldehyde 10 to the diol 11 was achieved using
NaOH and 37% HCHO in dioxane. Selective benzylation of one hydroxymethyl
group in 11 followed by acetylation of the resulting monobenzylate 12 produced
13. Treatment of 13 with 85% formic acid gave 1,2-diol which was reacted with
acetic anhydride to afford the glycosyl donor 14. Condensation of the acetate 14
with silylated thymine and uracil gave the protected nucleosides 15a and 15b, re-
spectively. Deacetylation of 15a and 15b followed by selective tosylation of the
primary hydroxyl group in the resulting diol 16a and 16b yielded 17a and 17b,
respectively. Cyclization of 17a and 17b to give the locked nucleosides 18a and
18b was successful with NaH Finally, debenzylation of 18a and 18b with catalytic
hydrogenation to afford the final nucleosides 1 and 2, respectively.

ORDER
REPRINTS
3ꢀ-DEOXY-3ꢀ-C-HYDROXYMETHYL NUCLEOSIDES
701
O
O
O
O
O
O
i) BH3
Ph3PCH3Br
PDC
O
O
6
O
5
OH
ii) H2O2
77%
BuLi
83% from 4
O
O
O
O
O
O
O
O
O
4
O
O
O
O
HO
HO
O
O
NaIO4
75%AcOH
BnBr
80%
O
O
O
O
O
BnO
O
HO
O
BnO
O
BnO
O
10
7
9
8
BnO
AcO
BnO
O
HO
HO
O
i) 85%HCO2H
O
Ac2O
85%
BnBr
58% HO
BnO
37%HCHO
O
ii) Ac2O,py.
93%
O
NaOH
70%
O
BnO
O
O
BnO
O
13
12
11
O
O
N
OTMS
N
R
R
O
R
O
NH
NH
BnO
N
O
O
TsCl
O
N
OTMS
NaOMe
BnO
AcO
BnO
HO
OAc
TMSOTf
AcO
BnO
OAc
BnO
OAc
BnO
OH
14
16a (R= Me): 93%
16b (R= H): 82%
15a (R= Me): 91%
15b (R= H): 70%
O
R
O
N
O
R
R
O
NH
NH
NH
O
N
N
O
O
Pd(OH)2/C
NaH
BnO
HO
BnO
TsO
O
O
BnO
HO
O
O
BnO
OH
18a (R= Me): 58% from 16a
18b (R= H): 38% from 16b
1 (R= Me): 85%
2 (R= H): 89%
17a (R= Me)
17b (R= H)
Scheme 1.
The 2ꢀ,6ꢀ-linked nucleoside 3 was synthesized from 9 (Scheme 2). The pri-
mary hydroxyl group of 9 was protected as benzoate 19 whose remaining secondary
hydroxyl was benzyalted to give 20. Hydrolysis of the 1,2-acetonide in 20 with
85% aqueous acetic acid followed by acetylation yielded diacetate 21 as a key in-
termediate. Condensation of diacetate 21 with silylated thymine gave the protected
nucleoside 22.
Deacetylation and debenzoylation of 22 followed by tosylation afforded
ditosylate 24 which was treated with aqueous sodium hydroxide to give the cy-
clized derivative 25. Debenzylation of 25 using catalytic hydrogenation yielded the
final locked nucleoside 3.
In summary, we synthesized two types of conformationally locked nucleo-
sides whose hydroxymethyl side chain might be superimposed well with those of

ORDER
REPRINTS
702
CHUN ET AL.
BzO
BnO
BzO
HO
HO
HO
1) 85%AcOH
2) Ac2O
BzCl
52%
BnBr
62%
O
O
O
9
88%
O
O
O
O
BnO
O
BnO
BnO
O
20
1
9
O
O
BzO
BnO
Thymine
TMSOTf
61%
NH
NH
NaOMe
95%
O
HO
BnO
BzO
BnO
N
O
OAc
N
O
O
O
BnO
OAc
21
BnO
OH
23
BnO
OAc
22
O
O
N
O
N
NH
NH
NH
H2
TsO
BnO
Pd(OH)2/C
N
aq. NaOH
66%
O
O
O
TsCl
O
HO
O
BnO
O
O
O
86%
HO
BnO
OTs
24
BnO
1
25
Scheme 2.
oxetanocin A. Antiviral assay and molecular modeling study are in progress in our
laboratory and will be reported in due course.
ACKNOWLEDGMENTS
This research was supported by the grant of the Good Health R & D Project,
Ministry of Health and Welfare, Korea (HMP-98-D-4-0057).
REFERENCES
1. Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.; Fujii, A.; Takita, T. J. Antibiot.
1986, 39, 1623.
2. Tseng, C. K.-H.;Marquez, V. E.;Milne, G. W. A.;Wysocki, R. J.;Mitsuya, H.;Shirasaki,
T.; Driscoll, J. S. J. Med. Chem. 1991, 10, 291.
3. Buenger, G.; Marquez, V. E. Tetrahedron Lett. 1992, 33, 3707.

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081NCN100002354