An efficient synthesis of (-)-3-deazaaristeromycin

Article abstract of DOI:10.1016/j.tetlet.2004.10.052

The coupling reaction of 4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deazapurine) and (3aS,4S,6R,6aR)-tetrahydro-2,2-dimethyl-6-vinyl- 3aH-cyclopenta-[d][1,3]dioxo-4-ol under Mitsunobu reaction conditions provides, after three subsequent straightforward reactions, ready access to the highly biologically active (-)-3-deazaaristeromycin. The versatility of this procedure opens access to a diverse pool of 3-deazapurine carbocyclic nucleosides.

Full text of DOI:10.1016/j.tetlet.2004.10.052

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8981–8982
An efficient synthesis of (À)-3-deazaaristeromycin
Minmin Yang, Jian Zhou and Stewart W. Schneller*
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, USA
Received 8 August 2004; revised 8 October 2004; accepted 11 October 2004
Abstract—The coupling reaction of 4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deazapurine) and (3aS,4S,6R,6aR)-tetrahydro-
2,2-dimethyl-6-vinyl-3aH-cyclopenta-[d][1,3]dioxo-4-ol under Mitsunobu reaction conditions provides, after three subsequent
straightforward reactions, ready access to the highly biologically active (À)-3-deazaaristeromycin. The versatility of this procedure
opens access to a diverse pool of 3-deazapurine carbocyclic nucleosides.
Ó 2004 Elsevier Ltd. All rights reserved.
NH2
N
NH2
N
Medicinal chemists and biochemists have long used
structural modification of naturally occurring nucleo-
sides as a source for new agents that fit their research
objectives.1 Replacing the N-3 of purine nucleosides
with a methine unit (hence, a 3-deazapurine) has been
particularly rewarding.2,3 Particularly noteworthy with-
in the 3-deazapurine collection are the carbocyclic nucleo-
sides 3-deazaaristeromycin (1)4 and 3-deazaneplanocin
(2),5 both of which display potent biological activity.
A limiting feature for an extensive study of 1 and ana-
logs derived therefrom has been the lack of a versatile,
high yielding synthetic pathway (Fig. 1).
Cl
N
N
N
N
N
N
HO
HO
N
H
OH
(-)-1
HO
OH
(-)-2
HO
35
Figure 1.
4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deaza-
purine, 3)5 and cyclopentanols had not been reported.
Thus, this reaction was investigated as the beginning
point to a practical synthesis of 3-deazaaristeromycin.
To address this situation our attention turned to the
Mitsunobu reaction,6 which has been widely used for
preparing carbocyclic nucleosides from 6-chloropurine
and various cyclopentanols in generally good yields. It
was surprising to find that the Mitsunobu reaction with
In that direction, reaction of 35 with the vinyl substi-
tuted cyclopentanol 47 under standard Mitsunobu
conditions
(diisopropyl
azodicarboxylate
and
Cl
X
N
N
N
N
N
N
d
OH
HO
a
b
(-)-1
on 7
O
O
O
O
O
O
47
5
6, X=Cl
7, X=NH2
c
Scheme 1. Reagents: (a) DIAD, Ph3P, THF, 70%; (b) i. OsO4, NaIO4, MeOH; ii. NaBH4, MeOH, 81% for two steps; (c) i. NH2NH2, THF; ii. Ra-Ni,
MeOH/H2O, 75% for two steps; (d) HCl/MeOH, 89%.
Keywords: Carbocyclic nucleosides; Aristeromycin; 3-Deazapurine; Mitsunobu reaction.
*
Corresponding author. Tel.: +1 3348445737; fax: +1 3348445748; e-mail:
schnest@auburn.edu
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.052

8982
M. Yang et al. / Tetrahedron Letters 45(2004) 8981–8982
triphenylphosphine) gave a 70% yield of the adduct 5.8
Manipulation of the vinyl group of 5 to the requisite
hydroxymethyl side chain (6)9 was accomplished in
two steps in the same reaction vessel: (i) osmium tetroxide/
sodium periodate oxidative (to the aldehyde) followed
by (ii) sodium borohydride reduction.7 Evoking a
standard procedure for introducing the C-6 amino
group to 6-chloro-3-deazapurine (i.e., hydrazinolysis
followed by Raney nickel reduction) yielded 7.10
Acidic deprotection of 7 completed the pathway to 111
(Scheme 1).
8. Selected data for 5: colorless oil (70%); dH (250MHz,
CDCl3) 8.23 (d, J = 5.7Hz, 1H), 8.04(s, 1H), 7.60 (d,
J = 5.7Hz, 1H), 5.94(m, 1H), 5.22 (m, 2H), 4.67 (m, 2H),
4.58 (m, 1H), 2.92 (m, 1H), 2.68 (m, 1H), 2.33 (m, 1H),
1.64(s, 3H), 1.33 (s, 3H); dC (62.9MHz, CDCl3) 143.2,
142.0, 141.8, 140.2, 138.3, 137.0, 117.0, 114.8, 106.6, 84.9,
83.9, 62.3, 47.7, 35.7, 27.5, 25.1. Anal. Calcd for
C16H18ClN3O2: C, 60.09; H, 5.67; N, 13.14. Found: C,
60.06; H, 5.60; N, 12.79.
9. Selected data for 6: white foam (81%); dH (400MHz,
CDCl3) 8.63 (s, 1H), 8.20 (d, J = 5.6Hz, 1H), 7.81 (d,
J = 5.6Hz, 1H), 4.86 (m, 2H), 4.80 (t, J = 6.5Hz, 1H),
4.57 (dd, J = 4.5, 7.0Hz, 1H), 3.55 (t, J = 5.5Hz, 2H), 2.46
(m, 1H), 2.21 (m, 1H), 2.19 (m, 1H), 1.58 (s, 3H), 1.26 (s,
3H); dC (100MHz, CDCl3) 145.3, 142.0, 141.7, 140.9,
138.2, 113.7, 108.2, 84.9, 81.8, 62.9, 62.8, 46.1, 33.7, 28.2,
26.0. Anal. Calcd for C15H18ClN3O3: C, 55.64; H, 5.60; N,
12.98. Found: C, 55.87; H, 5.67; N, 12.79.
Acknowledgements
This research was supported by funds from the NIH (AI
56540).
10. Selected data for 7: white solid (75%), mp 203–205°C; dH
(250MHz, DMSO-d6) 8.22 (s, 1H), 7.66 (d, J = 5.8Hz,
1H), 6.87 (d, J = 5.8Hz, 1H), 6.38 (br, 2H), 4.74 (q,
J = 6.8Hz, 1H), 4.69 (m, 1H), 4.55 (m, 1H), 3.51 (d,
J = 4.8Hz, 2H), 2.39–2.17 (m, 3H), 1.50 (s, 3H), 1.23 (s,
3H); dC (62.9MHz, DMSO-d6) 152.38, 139.97, 139.89,
138.07, 126.90, 112.57, 97.25, 84.00, 80.93, 61.81, 61.59,
45.24, 32.93, 27.42, 25.14. The proton NMR data
compares favorably with that reported for ( )-7 (Secrist,
J. A.; Comber, R. N.; Gray, R. J.; Gilroy, R. B.;
Montgomery, J. A. J. Med. Chem. 1993, 36, 2102–2106).
11. Montgomery, J. A.; Secrist, J. A. III World Patent,
9418971, Sept 1, 1994 presents a chemical and enzymatic
synthesis of (À)-1 by routes less practical and versatile than
the one described here. Similarly, Houston, D. M.;
Dolence, E. K.; Keller, B. T.; Patel-Thombre, U.; Bor-
chardt, R. T. J. Med. Chem. 1985, 28, 471–477, reported
the preparation of ( )-1. Selected data for 1ÆHCl: white
solid (89%), mp > 231°C (dec); dH (250MHz, DMSO-d6)
8.63 (s, 1H), 8.50 (br, 2H), 7.74(d, J = 7.0Hz, 1H), 7.30 (d,
J = 7.0Hz, 1H), 4.72 (q, J = 9.5Hz, 1H), 4.14 (dd, J = 9.3,
5.4Hz, 1H), 3.82 (dd, J = 5.4, 2.8Hz, 1H), 3.46 (d,
J = 5.3Hz, 2H), 2.31 (dt, J = 12.7, 8.8Hz, 1H), 2.09 (m,
1H), 1.75 (m, 1H); dC (62.9MHz, DMSO-d6) 148.9, 143.5,
140.1, 129.0, 126.1, 99.3, 76.1, 72.0, 62.7, 61.0, 45.4, 28.9.
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