Facile synthesis of 9-[(1′R,2′S)-2′-hydroxy-3′-oxocyclopentan-1′ -yl]-9-H-adenine possessing inhibitory activity against human recombinant S-adenosyl-L-homocysteine hydrolase

Article abstract of DOI:10.1016/S0040-4039(00)01978-X

Treatment of 4′-O-methanesulfonyl-2′,3′-O-isopropylidenenoraristeromy cin with KOBu^t gave the corresponding 3′,4′-dehydro derivative, and subsequent deprotection resulted in the formation of 9-[(1′R,2′S)-2′-hydroxy-3′-oxocyclopentan-1′ -yl]-9-H

Full text of DOI:10.1016/S0040-4039(00)01978-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 433–435
Facile synthesis of
9-[(1%R,2%S)-2%-hydroxy-3%-oxocyclopentan-1%-yl]-9-H-adenine
possessing inhibitory activity against human recombinant
S-adenosyl- -homocysteine hydrolase
L
Yukio Kitade,* Atushi Kozaki and Chizuko Yatome
Laboratory of Molecular Biochemistry, Department of Biomolecular Science, Faculty of Engineering, Gifu University,
Yanagido 1-1, Gifu 501-1193, Japan
Received 2 October 2000; revised 1 November 2000; accepted 2 November 2000
Abstract—Treatment of 4%-O-methanesulfonyl-2%,3%-O-isopropylidenenoraristeromycin with KOBut gave the corresponding 3%,4%-
dehydro derivative, and subsequent deprotection resulted in the formation of 9-[(1%R,2%S)-2%-hydroxy-3%-oxocyclopentan-1%-yl]-9-H-
adenine possessing inhibitory activity against human recombinant S-adenosyl-L-homocysteine hydrolase (EC 3.3.1.1). In sharp
contrast to KOBut, when lithium azide was adopted as a base, 9-[(1%R,2%S,3%R)-2%,3%-O-isopropylidenedioxy-4%-cyclopenten-1%-yl]-9-
H-adenine was selectively obtained, and subsequent deprotection afforded DHCeA, which is a well-known potential antiviral
agent. © 2001 Elsevier Science Ltd. All rights reserved.
The cellular enzyme S-adenosyl-
L
-homocysteine (SAH)
teromycin possessing SAH hydrolase inhibitory activity
and its inhibitory effect against human recombinant
SAH hydrolase.
hydrolase (EC 3.3.1.1) has emerged as a target enzyme
for the molecular design of antiviral agents.1 SAH is
formed after the donation of the methyl group of
S-adenosyl-L-methionine (SAM) to a methyl acceptor
and is hydrolyzed to adenosine and homocysteine by
SAH hydrolase physiologically. Therefore, inhibition of
SAH hydrolase results in cellular accumulation of
SAH, which is a potent feedback inhibitor of SAM-de-
pendent biological methylation such as the cap-struc-
ture at the 5%-end of eukaryotic mRNA.1,2 The
eukaryotic mRNA must possess a methylated 5%-cap
structure for stability against phosphatases and ribonu-
cleases, for proper binding to ribosomes, and for the
promotion of splicing. An uncapped mRNA, therefore,
is much less likely to be translated into its respective
protein. In addition to the antiviral effects of SAH
hydrolase inhibitors, several SAH hydrolase inhibitors
have shown other pharmaceutical effects of clinical
importance including antiparasitic,3 antiarthritic4 and
immunosuppressive5 effects.
Compound 2 was prepared by palladium-coupling reac-
tion of (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol (1)
with N6-benzoyladenine.6 Osmium oxidation of 2 gave
N6-benzoylnoraristeromycin (3). Subsequent two-step
reaction from 3 afforded 2%,3%-O-isopropylidenenoraris-
teromycin (4). Reaction of 4 with methanesulfonyl
chloride in the presence of triethylamine and 4-N,N-
dimethylaminopyridine in dichloromethane gave the
corresponding 4%-O-methanelsulfonyl derivative (5) in
80% yield (Scheme 1). Treatment of 5 with potassium
tert-butoxide (KOBut) in DMF at room temperature
gave [(1%R,2%S)-2%,3%-O-isopropylidenedioxy-3%-cyclopen-
ten-1%-yl]-9-H-adenine (10) in 34% yield in Scheme 2.
Deprotection of 10 with aqueous trifluoroacetic acid
gave 9-[(1%R,2%S)-2%-hydroxy-3%-oxocyclopentan-1%-yl]-9-
H-adenine (11), quantitatively. In sharp contrast to
KOBut, when lithium azide was adopted as a base,
9-[(1%R,2%S,3%R)-2%,3%-O-isopropylidenedioxy-4%-cyclo-
penten-1%-yl]-9-H-adenine (12) was predominantly ob-
tained in 86% yield by the reaction of 5 with 2 equiv. of
LiN3 at 130°C. Deprotection of 12 with aqueous tri-
fluoroacetic acid afforded 9-[(1%R,2%S,3%R)-2%,3%-dihy-
droxy-4%-cyclopenten-1%-yl]-9-H-adenine (DHCeA, 13),
which is a well-known potential antiviral agent.7 This
In this paper, we describe a method for the preparation
of a new SAH hydrolase inhibitor derived from noraris-
Keywords: enzyme inhibitors; antivirals; nucleosides; hydrolysis.
* Corresponding author. Tel./Fax:+81-58-293-2640; e-mail: kitade@
biomol.gifu-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01978-X

434
Y. Kitade et al. / Tetrahedron Letters 42 (2001) 433–435
methodology is very convenient for the preparation of
antiviral DHCeA (13). The 4%-methanesulfonyl com-
pound 5 is a versatile precursor for the preparation of
modified carbocyclic nucleosides. On the other hand,
reaction of the 4%-enantimer (9) of 5 was prepared via
the Mitsunobu reaction of 1 with adenine as shown in
Scheme 1. Treatment of 9 with LiN3 in DMF for 7 h at
130°C gave 12 in 90% yield. Treatment of 9 with
KOBut resulted in the formation of 10 in 57% yield.
terms of the HSAB principle (see Scheme 3). Thus, a
hard base (−OBut) attacked the hard acid Ha of the
3%-position of 5 to give 10 according to cis-elimination
(pathway a). When the 4%-anomer 9 was adopted as the
starting material, −OBut also attacked the same hard
acid Ha to give 10 via trans-elimination (pathway b).
The trans-elimination of the 4%-anomer
9 would
smoothly proceed rather than the cis-elimination of 5.
In the case of NaN3, a soft base (−N3) attacked the
hydrogen (Hb) of 5 or the hydrogen (Hc) of 9 to afford
12 via the corresponding trans-elimination (shown in
pathways c and d).
Taking into consideration the above results, the mecha-
nism for the formation of 10 and 12 was explained in
NH2
NHBz
NHBz
N
N
N
N
N
N
N
RO
N
N
HO
N
d, e
a
c
HO
N
N
O
O
HO
OH
2 (35%)
3 (86%)
4; R = H (82%)
5; R = Ms (80%)
HO
OAc
f
NH2
1
NH2
N
NH2
N
N
N
N
N
N
N
N
N
N
d, e
b
c
N
RO
AcO
HO
AcO
O
O
OH
6 (74%)
7 (70%)
8; R = H (63%)
9; R = Ms (66%)
f
Scheme 1. (a) N6-benzoyladenine, NaH, (Ph3P)4Pd, Ph3P, DMSO, THF; (b) adenine, DEAD, Ph3P, THF; (c) OsO4, NMO, THF,
H2O; (d) acetone, PTSAM, CH(OEt)3; (e) NH3-MeOH; (f) MsCl, DMAP, Et3N, CH2Cl2.
NH2
N
NH2
N
NH2
N
NH2
N
N
N
N
N
N
N
N
N
R1
R2
N
N
N
N
a
b
O
O
O
O
HO
OH
O
OH
5; R1 = OMs, R2 = H
9; R1 = H, R2 = OMs
10 (34% from 5)
11 (quant.)
(57% from 9)
NH2
NH2
N
N
N
N
N
N
N
c or d
e
N
O
O
HO
OH
12 (86% from 5)
(90% from 9)
13 (quant.)
DHCeA
Scheme 2. (a) KOBut (5 equiv.), DMF, rt, 15 min; (b) TFA 67%, rt, 15 min; (c) for 5, LiN3 (2 equiv.), DMF, 130°C, 3 h; (d) for
9, LiN3 (3.5 equiv.), DMF, 130°C, 7 h; (e) TFA, rt, 15 min.

Y. Kitade et al. / Tetrahedron Letters 42 (2001) 433–435
435
B
soft base
N3
soft base
N3
pathway a
pathway b
cis-elimination
trans-elimination
O
O
c
Hb
d
Hc
MsO
B
MsO
B
10
a
b
O
O
O
O
Ha
Ha
OBut
hard base
B
OBut
hard base
5
9
pathway c
pathway d
trans-elimination
trans-elimination
O
O
12
Scheme 3.
The structure of these compounds (2–13) was fully
supported by spectral data (1H NMR, 13C NMR, MS,
and HRMS).8 Compound 11 showed inhibitory effect
against human recombinant SAH hydrolase9 with IC50
value of 15 mM.10
1849–1851. (b) Obara, T.; Shuto, S.; Saito, Y.; Snoeck,
R.; Andrei, G.; Balzarini, J.; De Clercq, E.; Matsuda, A.
J. Med. Chem. 1996, 39, 3847–3852.
8. Selected data for 10: 1H NMR (CDCl3, 400 MHz): l 1.41
(6H, s, isopropylidene), 2.79–2.93 (2H, m, H-5%), 4.90
(1H, t, J=5.6 Hz, H-1%), 5.47 (1H, d, J=6.0 Hz, H-2%),
6.33 (2H, brs, NH2), 6.68 (1H, m, H-4%), 8.28 and 8.39
(each 1H, each s, H-2 and H-8). MS m/z (%): 273 (M+,
28), 215 (100), 186 (63). HRMS m/z: 273.1219 (C1
3H15N5O2, requires 273.1226). Selected data for 11: 1H
NMR (D2O, 400 MHz): l 2.73 (1H, d, J=16.8 Hz,
H-5%), 2.73 (1H, d, J=16.8 Hz, H-5%), 4.37 (1H, m, H-1%),
4.94 (1H, d, J=5.2 Hz, H-2%), 6.37 (1H, s, H-4%), 8.27 and
8.32 (each 1H, each s, H-2 and H-8). MS m/z (%): 233
(M+, 36), 204 (100), 186 (21). HRMS m/z: 233.0919
(C10H11N5O2, requires 233.0913). Selected data for 12: 1H
NMR (CDCl3, 400 MHz): l 1.34 (3H, s, isop), 1.48 (3H,
s, isop), 4.68 (1H, d, J=5.2 Hz, H-2%), 5.47 (1H, d,
J=5.2 Hz, H-1%), 5.62 (1H, s, H-3%), 5.94 (1H, dd,
J=6.0, 1.0 Hz, H-5%), 6.05 (2H, brs, NH2), 6.31 (1H, dd,
J=6.0, 1.0 Hz, H-4%), 7.66 and 8.36 (each 1H, each s,
H-2 and H-8). 13C NMR (CDCl3, 100 MHz): l 25.73,
27.33, 65.65, 83.93, 84.67, 112.42, 119.89, 129.32, 138.41,
138.70, 149.96, 152.49, 155.10. MS m/z (%): 273 (M+, 12),
215 (100), 186 (86). HRMS m/z: 273.1220 (C13H15N5O2,
requires 273.1226). Selected data for 13 (DHCeA): 1H
NMR ((CD3)2SO, 400 MHz): l 4.30 (1H, m, H-2%), 4.54
(1H, d, J=3.2 Hz, H-3%), 5.38 (1H, d, J=5.8 Hz, H-1%),
5.98 (1H, m, H-5%), 6.13 (1H, m, H-4%), 7.42 (2H, brs,
NH2), 8.12 and 8.15 (each 1H, each s, H-2 and H-8). 13C
NMR ((CD3)2SO, 100 MHz): l 64.76, 72.49, 76.16,
119.75, 132.30, 136.02, 140.02, 151.36, 155.27. MS m/z
(%): 233 (M+, 8), 136 (100), 108 (13). HRMS m/z:
233.0913 (C10H11N5O2, requires 233.0913)
Acknowledgements
This research was in part supported by a Grant-in-Aid
for Scientific Research No. 10672086; Grants-in-Aid for
Scientific Research on Priority Area No. 10169222 and
11147211 from the Ministry of Education, Science,
Culture and Sports and a grant from the Gifu Life
Science Research Promotion Council.
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