5′-Fluoro-5′-deoxyaristeromycin

Article abstract of DOI:10.1016/j.bmcl.2007.10.095

5′-Fluoro-5′-deoxyaristeromycin (2) has been prepared via a Mitsunobu coupling of (1S,2S,3R,4S)-2,3-(cyclopentylidenedioxy)-4-fluoromethylcyclopentan-1-ol with N⁶-bis-boc protected adenine. This procedure is adaptable to preparing a number of 5

Full text of DOI:10.1016/j.bmcl.2007.10.095

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Bioorganic & Medicinal Chemistry Letters 18 (2008) 220–222
50-Fluoro-50-deoxyaristeromycin
Weikuan Li, Xueqiang Yin and Stewart W. Schneller*
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, USA
Received 2 October 2007; revised 22 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—50-Fluoro-50-deoxyaristeromycin (2) has been prepared via a Mitsunobu coupling of (1S,2S,3R,4S)-2,3-(cyclopentyliden-
edioxy)-4-fluoromethylcyclopentan-1-ol with N6-bis-boc protected adenine. This procedure is adaptable to preparing a number of
50-fluoro-50-deoxycarbocyclic nucleoside analogs with diversity in the heterocyclic base. Antiviral analysis found promising activity
for 2 toward measles but no other viruses. No cytotoxicity was observed for 2.
Ó 2007 Elsevier Ltd. All rights reserved.
Aristeromycin (1) owes its diverse biological properties
to (1) formation of its 50-mono-, di-, and triphosphate
nucleotides and (2) inhibition of biomethylations that
occur with S-adenosylmethionine (AdoMet) as cofactor
and S-adenosylhomocysteine as a product biofeedback
methylation control element.1 In an effort to investigate
aristeromycin derivatives that are participants in only
one of those pathways we, for some time, have sought
aristeromycin analogs where C-50 phosphorylation is
not likely2–4 or not possible.5 For this collection, 50-flu-
oro-50-deoxyaristeromycin (2) presents a relevant target
owing to the well-documented beneficial biological con-
sequences of a fluoro-for-hydroxyl exchange, which, for
the purposes here, also precludes the traditional hydro-
xyl reactions (such as, phosphate esterification).6 Addi-
tionally, 2 represents the carbocyclic analog of 50-
fluoro-50-deoxyadenosine, which has demonstrated a
broad range of biological properties.7 Our preliminary
results in this regard are reported (Fig. 1).
Attention then turned to creating a fluoro-bearing cyclo-
pentyl unit for coupling with an appropriately function-
alized purine base. Scheme 2 presents the steps
employed to the requisite precursor 15. To circumvent
the interference by the C-6 amino substituent of adenine
under the Mitsunobu coupling conditions,9 N6-bis-boc
protected adenine was employed with 15 in the presence
of diiso’propyl azodicarboxylate to yield 19. Acidic
deprotection of 19 led to the desired 2.10
To gain a glimpse into the biological potential of 2, it was
subjected to antiviral analysis versus herpes simplex-1,
herpes simplex-2, herpes simplex-1 (TKꢀ), vaccinia, cow-
pox, vesicular stomatitis, coxsackie B4, respiratory syn-
cytial, parainfluenza 3, reovirus-1, Sindbis, Punta Toro,
rhinovirus, adenovirus, hepatitis C, and West Nile, and
feline coronavirus.11 No activity was found for these
viruses. However, effects toward measles (MO6) were ob-
served (EC50 2.8 lM, neutral red assay; EC50 13 lM,
visual assay). As a member of the paramyxoviridae
Our original plan to 2 was to carry out a direct fluorina-
tion at the C-50 center of the known aristeromycin pre-
cursor 3 or 4.8 In that direction we found it synthetically
more practical to prepare the unknown cyclopentyl pro-
tected derivative 5 employing a series of new cyclopentyl
derivatives (via Scheme 1). However, various attempts at
converting 5–6 (e.g., using DAST shown as example in
Scheme 1) were unsuccessful.
NH2
X
N
N
N
N
N
N
N
N
HO
XH2C
HO
O
O
OH
Me
3, X=Cl
4, X=NH2
Me
1, X=OH
2, X=F
Keywords: Carbocyclic nucleoside; Grubbs reaction; Fluorinated cyc-
lopentyl derivative; Mitsunobu coupling.
*
Corresponding author. Tel.: +1 334 844 5737; fax: +1 334 844
5748; e-mail: schnest@auburn.edu
Figure 1.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.095

W. Li et al. / Bioorg. Med. Chem. Lett. 18 (2008) 220–222
XH2C
221
O
OMe
HOH2C
O
CHO
OH
OH
c
d
a
e
on 8
O
O
O
O
O
O
OH
HO
ribose
7, X=OH
8, X=I
9
10
b
OH
O
O
O
g
i
OH
O
h
f
O
O
O
O
O
O
12
11
13
Cl
Cl
N
Cl
N
N
N
N
N
N
N
N
N
N
HOH2C
N
FH2C
j
k
O
O
O
O
O
O
14
5
6
Scheme 1. Reagents and conditions: (a) cyclopentanone, MeOH, (MeO)3CH, 5% p-TSA, reflux, 85%; (b) I2, imidazole, TPP, tolune/MeCN, reflux,
80%; (c) n-BuLi, ꢀ78 °C, ether, 80%; (d) CH2CHMgBr, dry Et2O, ꢀ78 °C to rt, 80%; (e) 1st gen. Grubbs cat. 1% mol, reflux, CH2Cl2; (f) SO3–
pyrridine, DIPEA, DMSO, CH2Cl2, 0 °C, 70% two steps; (g) CH2CHMgBr, CuBr–Me2S, TMSCl, THF, ꢀ78 °C to rt; (h) LiAlH4, THF, 62% two
steps; (i) 6-Cl–purine, DIAD, THF, 60 °C, 2 days, 60%; (j) NaIO4, OsO4, MeOH/H2O, then NaBH4, MeOH, 68%; (k) one example, DAST, CH2Cl2,
reflux.
N(Boc)2
N
N
HOH2C
b
FH2C
N
OR
OPMB
c
N
OR
O
FH2C
f
e
2
O
O
O
O
O
O
O
13, R=H
16, R=PMB
18, R=PMB
15, R=H
17
a
d
19
PMB=pmethoxybenzyl
Scheme 2. Reagents and conditions: (a) NaH, PMBCl, DMF, 0 °C, 81%; (b) NaIO4, OsO4, MeOH/H2O, then NaBH4, MeOH, 53%; (c) DAST,
pyridine, CH2Cl2, 76%; (d) DDQ, CH2Cl2/H2O, 60%; (e) DIAD, TPP, Ad(Boc)2; (f) 3 N HCl/MeOH, 58% for two steps.
family of viruses it might be expected that some activity
would be seen with an aristeromycin analog since this
viral family is susceptible to inhibition of S-adenosylho-
mocysteine metabolism.12 It is surprising, however, that
the other paramyxo representatives (respiratory syncy-
tial and parainfluenza) and none of the other viruses
(e.g., vaccinia, cowpox, vesicular stomatitis, and reo)
that are vulnerable to such interference were not affected
by 2.12 Perhaps, another mechanism is selectively opera-
tive for 2 toward measles.13 No cytotoxicity arose in the
cell lines used for the antiviral assays.14
Acknowledgments
This research has been supported by funds from the
Department of Health and Human Services (Al
56540), which is appreciated. We are also indebted to
the following individuals for providing the antiviral
data11 following their standard protocols: Drs. Erik
De Clercq and Jan Balzarini, the Rega Institute, Leuven
Belgium; Drs. Earl Kern and Mark Prichard, University
of Alabama at Birmingham, Birmingham, AL; Drs.
Robert Sidwell and Don Smee, Utah State University,

222
W. Li et al. / Bioorg. Med. Chem. Lett. 18 (2008) 220–222
10. Selected data for 2: white solid; mp 168–169 °C. 1H NMR
(400 MHz, DMSO), d 8.19 (s, 1H), 8.12 (s, 1H), 7.20 (s,
2H), 5.06 (d, J = 6.0 Hz, 1H), 4.91 (d, J = 4.0 Hz, 1H),
4.70 (m, 1H), 4.58 (m, 1H), 4.45 (m, 1H), 4.35 (m, 1H),
3.89 (m, 1H), 2.27 (m, 2H), 1.80 (m, 1H). 13C NMR (100
MHz, DMSO) d 156.01, 152.11, 149.68, 140.17, 119.35,
84.55 (d, J = 165 Hz), 74.26, 70.76 (d, J = 5 Hz), 59.13,
43.40 (d, J = 18 Hz), 27.86 (d, J = 6 Hz). Calcd mass for
C11H14FN5O2: 267.1132. Found: 267.1131.
11. For leading references for the antiviral and cytotoxicity
procedures used, see (a) Rajappan, V. P.; Schneller, S. W.;
Williams, S. L.; Kern, E. R. Bioorg. Med. Chem. 2002, 10,
883;; (b) Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda,
S.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E.
J. Med. Chem. 1994, 37, 551; (c) http://www.usu.edu/iar/
Brochure/brochure.html (October 1, 2007).
12. De Clercq, E. Nucleosides Nucleotides 1998, 17, 625.
13. The 50-fluoro-50-deoxyneplanocin A analog of 2 also
shows activity toward measles but it also had an effect
on other viruses susceptible to inhibition of S-adenosyl-
homocysteine metabolism. Shuto, S.; Obara, T.; Toriya,
M.; Hosoya, M.; Snoeck, R.; Andrei, G.; Balzarini, J.; De
Clercq, E. J. Med. Chem. 1992, 35, 324.
Logan, UT; and, Dr. Brent Korba, Georgetown, Uni-
versity, Rockville, MD.
References and notes
1. Wolfe, M. S.; Borchardt, R. T. J. Med. Chem. 1991, 34,
1521.
2. For a recent 50-noraristeromycin leading reference, see
Roy, A.; Serbessa, T.; Schneller, S. W. Bioorg. Med.
Chem. 2006, 14, 4980.
3. Ye, W.; Schneller, S. W. J. Org. Chem. 2006, 71, 8641.
4. Yang, M.; Schneller, S. W. Bioorg. Med. Chem. Lett. 2005,
15, 149.
5. Siddiqi, S. M.; Schneller, S. W. Nucleosides Nucleotides
1993, 12, 185.
6. For a leading reference, see Kirk, K. L. J. Fluorine Chem
2006, 127, 1013.
7. Ashton, T. D.; Scammells, P. J. Bioorg. Med. Chem. Lett.
2005, 15, 3361.
8. Yang, M.; Ye, W.; Schneller, S. W. J. Org. Chem. 2004,
69, 3993.
9. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Hughes, D. L.
Org. Prep. Proced. Int. 1996, 28, 127.
14. Cell lines used for the antiviral assays: HEL, HeLa, Vero,
CV-1, MA-104, A-549, MDCK, CRFK, HFF, Huh7ET.