5′-Homoaristeromycin. Synthesis and antiviral activity against orthopox viruses

Article abstract of DOI:10.1016/j.bmcl.2004.10.019

An efficient synthesis of 5′-homoaristeromycin has been developed. This permitted an extensive antiviral analysis, which found potent activity toward vaccinia, cowpox, and monkeypox viruses. For comparative purposes, 5′-homoadenosine was made available by a newly designed route and found to be inactive.

Full text of DOI:10.1016/j.bmcl.2004.10.019

Bioorganic & Medicinal Chemistry Letters 15 (2005) 149–151
50-Homoaristeromycin. Synthesis and antiviral
activity against orthopox viruses
Minmin Yang and Stewart W. Schneller*
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, USA
Received 9 September 2004; revised 6 October 2004; accepted 6 October 2004
Available online 28 October 2004
Abstract—An efficient synthesis of 50-homoaristeromycin has been developed. This permitted an extensive antiviral analysis, which
found potent activity toward vaccinia, cowpox, and monkeypox viruses. For comparative purposes, 50-homoadenosine was made
available by a newly designed route and found to be inactive.
Ó 2004 Elsevier Ltd. All rights reserved.
NH2
N
Inhibitors of S-adenosyl-L-homocysteine (AdoHcy)
hydrolase have shown promise as antiviral agents1,2 by
disrupting essential viral macromolecular methylation
processes.2 Carbocyclic nucleosides 3 represent a promi-
nent class of compounds whose antiviral potential has
been traced to such an effect.1 Within that group, carbo-
cyclic adenosine (aristeromycin, 1) is at the center of
these investigations4 but its promise is limited by a toxi-
city arising from 50-phosphate formation.5
N
N
X
N
HO
n
OH
HO
1, X = CH2, n = 1
2, X = CH2, n = 2
3, X=O, n=2
Structural modifications of 1 with the aim of reducing
phosphate-based toxicity have yielded meaningful drug
candidates.6 An approach not explored, however, is
extension of the C-50 hydroxymethyl side chain by a
methylene group to provide the C-50 homolog of ariste-
romycin (2). This analog can be expected7 to have dis-
placed the phosphate-susceptible hydroxyl from the
phosphate-transfer zone in the kinases responsible for
metabolism to 1 to its nucleotides. In support of this,
2 has been reported8 to be inactive against HSV-1 and
HSV-2, possibly, due to its failure to be phosphorylated
(Fig. 1).
Figure 1.
in the literature.9 The results of this effort are communi-
cated here.
Existing methods8,10,11 for preparing 50-homoaristero-
mycin (2) suffer from too many steps, limited scale-up,
low yields and, in one case, resulting in a racemic prod-
uct. Therefore, an efficient and stereoselective synthesis
of 2 was needed. Starting from enone 412 (Scheme 1),
1,4-addition of ethyl trimethylsilylacetate followed by
in situ cleavage of the trimethylsilyl group furnished,
stereoselectively, the ketone ester 5 as the only product.
The stereochemistry at C-4 of 5 was derived from the
fact (i) that a 1,4-addition to the concave structure of
5 can be expected13 to give a b (up) product and (ii) that
5 was converted into the known 2. Reduction of 5 with
sodium borohydride provided the coupling precursor 6,
which has been reported via a more tedious way.14
Mitsunubo coupling reaction of 6 with 6-chloropurine
furnished 7. Selective reduction of 7 with diisobutylalu-
minum hydride (DIBAL) yielded the desired alcohol 8.
To investigate 2 more thoroughly as a possible antiviral
agent a more practical synthesis of it was necessary. For
comparative antiviral purposes, 50-homoadenosine (3)
was also sought by a much more efficient way than exists
Keywords: Carbocyclic nucleosides; Nucleoside homologation;
Monkeypox.
*
Corresponding author. Tel.: +1 334 844 5737; fax: +1 334 844
5748; e-mail: schnest@auburn.edu
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.10.019

150
M. Yang, S. W. Schneller / Bioorg. Med. Chem. Lett. 15 (2005) 149–151
O
O
EtO2C
EtO2C
a
b
OH
4
O
O
O
O
O
O
412
5
6
Cl
X
N
N
N
N
N
N
N
N
HO
c
d
EtO2C
O
O
O
O
8, X = Cl
7
e
f
9 X = NH2
2
Scheme 1. Reagents and conditions: (a) (i) ethyl (trimethylsilyl)acetate, n-BuLi, DIPA, HMPA/THF, ꢀ78°C, (ii) KF, EtOH/H2O, rt, 84% for two
steps from 4; (b) NaBH4, MeOH, ice temp, 100%; (c) 6-chloropurine, Ph3P, DIAD, THF, 0–50°C, 52%; (d) DIBAL, CH2Cl2, ꢀ50°C, 80%; (e) NH3/
MeOH, 94%; (f) HCl/MeOH, 95%.
O
HO
OMe
O
O
OMe
OMe
HO
a
b
O
O
O
O
O
O
1016
11
12
NHPiv
N
N
N
N
c
O
d
AcO
O
AcO
OAc
OAc
AcO
OAc
AcO
e
3
13
14
Scheme 2. Reagents and conditions: (a) (i) DMSO, DIPEA, SO3-Py, CH2Cl2, 90%, (ii) Ph3PCH3Br, t-BuOK, Et2O, 75%; (b) 9-BBN, THF, then
NaOH, H2O2, 97%; (c) (i) 70% AcOH, 85°C; (ii) Ac2O, DMAP, pyridine, 85% for two steps from 12; (d) Adpiv, HMDS, TMSCl, TMSOTf, 60%; (e)
NH3/MeOH, 91%.
Ammonolysis of 8 (to 9) followed by hydrolytic
deprotection smoothly afforded 2 in good overall
yield.15
Compounds 2 and 3 were evaluated against a wide vari-
ety of both DNA viruses and RNA viruses.18 From this,
very significant effects were seen for 2 toward vaccinia
(IC50 1.2lg/mL), cowpox (IC50 0.12lg/mL), and mon-
keypox (IC50 0.12lg/mL) viruses, all in Vero 76 cells
with CC50 > 100lg/mL. This observation is particularly
noteworthy since it is well known that vaccinia is suscep-
tible to AdoHcy hydrolase inhibitors but cowpox was
thought not to be.18e In any case, details of this investi-
gation and the, possibly, less notable activity of 2 to-
ward other viruses18 will be forthcoming, including its
potency toward variola.19 Analog 3 was inactive in all
of the assays employed.18
The known syntheses of 60-homoadenosine9 (3) either
involved many steps9a or suffer a low yield of the final
product.9b,c Our plan (Scheme 2) envisioned beginning
with homologation of 10.16 Side chain oxidation of 10
followed by Wittig olefination afforded 11. Submitting
11 to regioselective hydroboration with 9-BBN followed
by oxidative hydrolysis, smoothly provided 12 in high
yield. Hydrolysis of 12 with acetic acid produced a
tetrol, which was fully protected with acetic anhydride
to provide the anomeric acetate 13. The coupling reac-
tion of 13 with N-pivaloyl protected adenine under
Vorbruggen glycosylation conditions yielded the desired
¨
Acknowledgements
N-9 product 14 as the only isolated product. Deprotec-
tion of 14 with ammonia furnished 3 in good overall
yield17 from D-ribose.
This research was supported by funds from the NIH (AI
56540). We are also indebted to the following individu-

M. Yang, S. W. Schneller / Bioorg. Med. Chem. Lett. 15 (2005) 149–151
151
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Dr. Brent Korba, Georgetown University, Washington,
DC; Dr. Robert Sidwell, Utah State University, Logan,
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1
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DMSO-d6) d 8.20 (s, 1H), 8.11 (s, 1H), 7.17 (s, 2H), 4.90
(d, J = 6.27Hz, 1H), 4.68 (d, J = 4.63Hz, 1H), 4.57 (m,
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3.46 (m, 2H), 2.24 (m, 1H), 1.97 (m, 1H), 1.74 (m, 2H),
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