The Mitsunobu reaction in preparing 3-deazapurine carbocyclic nucleosides

Article abstract of DOI:10.1016/j.tet.2005.10.052

The coupling reaction of 4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deazapurine, 3) with several cyclopentyl derivatives under Mitsunubo reaction conditions provides an efficient entry into N-7 and N-9 substituted 3-deazapurine carbocyclic nucleosides

Full text of DOI:10.1016/j.tet.2005.10.052

Tetrahedron 62 (2006) 1295–1300
The Mitsunobu reaction in preparing 3-deazapurine
carbocyclic nucleosides
*
Minmin Yang, Jian Zhou and Stewart W. Schneller
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, USA
Received 8 June 2005; revised 19 October 2005; accepted 20 October 2005
Available online 11 November 2005
Abstract—The coupling reaction of 4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deazapurine, 3) with several cyclopentyl derivatives
under Mitsunubo reaction conditions provides an efficient entry into N-7 and N-9 substituted 3-deazapurine carbocyclic nucleosides of
antiviral potential. The versatility of this procedure is illustrated with a new and efficient synthesis of (K)-3-deazaaristeromycin, a formal
preparation of 3-deazaneplanocin A, and a route to 3-deaza-50-homoaristeromycin.
q 2005 Elsevier Ltd. All rights reserved.
Table 1. Mitsunubo reaction of 4-chloro-1H-imidazo[4,5-c]pyridine
(3-deaza-6-chloropurine) with substituted cyclopentanols
1. Introduction
Cl
Cl
Nucleoside analogs based on the 3-deazapurine (1H-
imidazo[4,5-c]pyridine) framework have found significant
usefulness in antiviral agent design and biochemical
investigations.1,2 The carbocyclic nucleosides3 3-deazaris-
teromycin (1)4 and 3-deazaneplanocin (2)5 have been central
to these studies (Fig. 1). In our efforts to further exploit the
3-deazapurine carbocyclic nucleoside platform as a source
for new antiviral candidates, it was necessary to seek a more
versatile synthetic means to this series that would give access
to a number of structural variations. In this regard it
was surprising to find that the Mitsunobu reaction,6 which has
been successfully employed to produce traditional carbo-
cyclic nucleosides, had not been investigated in the
3-deazapurine genera. This paper describes the use of the
Mitsunobu reaction in the preparation of such derivatives.7
N
N
N
N
Ph3P, DIAD
THF
N
N
N
+
R-OH
+
N
N
H
4
R
R
Cl
35
5
6
inversion at *carbon
of 4a-e
Entry
R-OH
Products (%)
5
6
*
OH
1
86
0
0
O
O
a8
*
OH
2
70
O
O
b9
NH2
N
NH2
N
N
N
N
N
*
TrO
OH
HO
HO
3
4
5
42
38
32
53
c10
O
O
OH
(-)-1
HO
OH
(-)-2
HO
*
AcO
OH
d11
57
43
Figure 1.
*
OH
Keywords: 4-Amino-1H-imidazo[4,5-c]pyridine; Carbocyclic nucleosides;
Aristeromycin; Neplanocin.
O
O
e12
*
Corresponding author. Tel.: C1 334 844 5737; fax: C1 334 844 5748;
e-mail: schnest@auburn.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.052

1296
M. Yang et al. / Tetrahedron 62 (2006) 1295–1300
N
N
N
N
N
N
N
N
AcO
N
b
Cl
a
AcO
HO
Cl
AcO
O
O
Cl
OH
6d
Scheme 1. Reagents: a, OsO4, NMO, CH2Cl2; b, (MeO)2CMe2, acetone, pTSA, 83% (two steps).
7
8
2. Chemistry
demonstrate extended synthetic versatility by their conversion
into two important 3-deazapurine carbocyclic nucleosides,
3-deazaaristeromycin (1) and 3-deazaneplanocin (2).
Whereas compound 2 was obtained from 5c by modifying
a known procedure,5 manipulation of the vinyl group in 5b
to a hydroxymethyl moiety following our recently
reported procedure9a furnished (K)-1 in good overall yield
(Scheme 2).13 Compound 5b also provided access to 3-deaza-
50-homoaristeromycin (13), which is a compound of
potentially significant activity toward the orthopox viruses.14
Following standard Mitsunobu conditions (that is,
triphenylphosphine and diisopropyl azodicarboxylate in
tetrahydrofuran), the reaction of 4-chloro-1H-imidazo-
[4,5-c]pyridine (3)5 with various cyclopentanols gave the
results presented in the Table 1. Thus, reacting 4a with 3
cleanly gave 5a as the only isomer. Likewise, compound
4b provided 5b as the only regioisomer. The more reactive
allylic alcohols 4c–e, however, yielded the N-1 (purine
N-9) products 5c–e along with the N-3 (purine N-7)
isomers 6c–e, which were the major products.
Cl
X
N
N
N
N
N
N
Structural assignments for the N-1 (N-9) and N-3 (N-7)
isomers were possible because the proton on the cyclopentyl
carbon bearing the heterocyclic ring in the N-3 product is
downfield in the proton NMR spectrum compared to the N-1
product (by correlating the data of Ref. 5 with the data found
in this study that is supported by the X-ray structural
confirmation of 8, vide infra). A characteristic carbon-13
NMR peak (dZw106 ppm) was observed for the carbon
(possibly C-2) in the heterocyclic ring of all N-1 products
(5) while the peak moves to (dZ115 ppm) in all N-3
products (6). Supporting these NMR assignments for N-3
products was the conversion of 6d to 8 (Scheme 1), whose
structure was confirmed by X-ray crystallography (Fig. 2)
and whose NMR spectrum fit the diagnostic peaks used for
isomer distinction.
c
HO
a
1
O
O
O
O
5b
9, X =Cl
b
10, X = NH2
d
X
NH2
N
N
N
N
N
N
c
HOH2C
HOH2C
O
O
OH
HO
13
(as the hydrochloride)
11, X =Cl
12, X = NH2
b
Scheme 2. Reagents: a, (i) OsO4, NalO4, MeOH; (ii) NaBH4, MeOH, 81%;
b, (i) NH2NH2, THF; (ii) Ra-Ni, MeOH/H2O, 75% (two steps for 9); 80%
(two steps) for 12; c, HCl/MeOH, 89% for 1; 78% for 13; d, (i) 9-BBN,
THF; (ii) NaOH, H2O2, 80% (two steps).
3. Experimental
3.1. General
Melting points were recorded on a Meltemp II melting point
apparatus and the values are uncorrected. The combustion
analyses were performed at Atlantic Microlab, Norcross,
1
GA. H and 13C NMR spectra were recorded on either a
Bruker AC 250 spectrometer (250 MHz for proton and
62.9 MHz for carbon) or a Bruker AV 400 spectrometer
(400 MHz for proton and 100 MHz for carbon), referenced
to internal tetramethylsilane (TMS) at 0.0 ppm. The X-ray
Figure 2. X-ray structure for compound 8.
Further transformations of the coupled products 5b and 5c
were sought for additional structural confirmation and to

M. Yang et al. / Tetrahedron 62 (2006) 1295–1300
1297
crystal structure was determined using a Bruker APEX CCD
single crystal X-ray diffractometer. The HRMS measure-
ments were obtained using a VG 70S magnetic sector mass
spectrometer. The reactions were monitored by thin-layer
chromatography (TLC) using 0.25 mm Whatman Diamond
silica gel 60-F254 precoated plates with visualization by
irradiation with a Mineralight UVGL-25 lamp. Column
chromatography was performed on Whatman silica, 230–400
3.2.2. Compound 5b (70%). Colorless oil: 1H NMR
(250 MHz, CDCl3) d 8.23 (d, JZ5.7 Hz, 1H), 8.04
(s, 1H), 7.60 (d, JZ5.7 Hz, 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). 13C NMR
(62.9 MHz, CDCl3) d 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.
˚
mesh and 60 A using elution with the indicated solvent
system. Yields refer to chromatographically and spectro-
scopically (1H and 13C NMR) homogeneous materials.
3.2.3. Compound 5c (42%). White foam: 1H NMR
(400 MHz, CDCl3) d 8.25 (d, JZ5.6 Hz, 1H), 7.89
(s, 1H), 7.50 (m, 15H), 7.45 (d, JZ5.6 Hz, 1H), 6.16
(m, 1H), 5.48 (m, 1H), 5.22 (d, JZ5.8 Hz, 1H), 4.58 (d, JZ
5.8 Hz, 1H), 4.08 (d, JZ15.6 Hz, 1H), 3.92 (d, JZ15.6 Hz,
1H), 1.50 (s, 3H), 1.35 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 151.1, 143.8, 143.4, 142.6, 141.9, 139.7, 138.6, 128.7,
128.2, 127.5, 121.3, 113.3, 105.8, 87.6, 84.8, 83.9, 67.1,
61.5, 27.5, 26.0. Anal. Calcd for C34H30ClN3O3: C, 72.40;
H, 5.36; N, 7.45. Found: C, 72.06; H, 5.67; N, 7.19.
3.1.1. (3aS,4S,6aR)-Tetrahydro-2,2-dimethyl-3aH-cyclo-
penta[d][1,3]dioxol-4-ol (4a). A mixture of (3aR,6aR)-
2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one
(i)8,9a (2.0 g, 13.0 mmol), Pd/C and MeOH (30 mL) was
shaken under 18 psi of H2. The reaction was run until TLC
monitoring indicated no UV-active starting material was
present. After filtration, concentration of the filtrate gave an
oily product that was purified by silica gel chromatography
(EtOAc/hexanes, 1:2) to provide 1.9 g (93.8%) of
(3aR,6aR)-dihydro-2,2-dimethyl-3aH-cyclopenta[d][1,3]-
dioxol-4(5H)-one (ii)8as a white solid.9b
3.2.4. Compound 6c (53%). White foam: 1H NMR
(400 MHz, CDCl3) d 8.24 (d, JZ5.7 Hz, 1H), 7.86
(s, 1H), 7.66 (d, JZ5.7 Hz, 1H), 7.53 (m, 15H), 6.30
(m, 1H), 6.19 (m, 1H), 5.17 (d, JZ5.4 Hz, 1H), 4.67 (d, JZ
5.4 Hz, 1H), 4.11 (d, JZ15.5 Hz, 1H), 3.93 (d, JZ15.5 Hz,
1H), 1.47 (s, 3H), 1.35 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 152.0, 151.7, 144.6, 143.8, 143.7, 141.6, 134.3, 128.7,
128.2, 127.5, 121.4, 115.2, 112.9, 87.5, 85.1, 83.7, 66.3,
61.4, 27.7, 26.3. Anal. Calcd for C34H30ClN3O3: C, 72.40;
H, 5.36; N, 7.45. Found: C, 72.13; H, 5.60; N, 7.28
To a stirred solution of ketone ii (0.50 g, 3.20 mmol) in
MeOH (30 mL) at 0 8C NaBH4 (0.18 g, 4.76 mmol) was
added portion wise. After stirring at room temperature for
1 h, the mixture was quenched with H2O. Most of solvent
was removed under reduced pressure and the aqueous layer
exacted with CH2Cl2; the combined organic layers were
washed with H2O, dried (Na2SO4), concentrated, and
purified by flash chromatography to give 4a as colorless
1
oil (0.46 g, 88.8%): H NMR (400 MHz, CDCl3) d 4.61 (t,
3.2.5. Compound 5d (38%). Colorless oil: 1H NMR
(400 MHz, CDCl3) d 8.17 (d, JZ5.8 Hz, 1H), 8.00
(s, 1H), 7.30 (d, JZ5.8 Hz, 1H), 6.42 (ddd, JZ5.6, 2.7,
2.7 Hz, 1H), 6.26 (m, 1H), 5.95 (m, 1H), 5.78 (m, 1H), 2.60
(ddd, JZ14.9, 7.8, 2.6 Hz, 1H), 2.39 (ddd, JZ14.9, 7.3,
4.8 Hz, 1H), 2.08 (s, 3H). 13C NMR (100 MHz, CDCl3) d
170.7, 143.1, 142.9, 141.4, 139.1, 138.1, 136.4, 134.4,
105.7, 78.0, 61.2, 38.3, 21.0. Anal. Calcd for
C13H12ClN3O2: C, 56.22; H, 4.36; N, 15.13. Found: C,
56.59; H, 4.01; N, 15.36.
JZ5.2 Hz, 1H), 4.41 (t, JZ5.6 Hz, 1H), 3.84 (m, 1H), 2.40
(d, JZ9.8 Hz, 1H), 1.83 (m, 2H), 1.64 (m, 1H), 1.49 (s, 3H),
1.43 (m, 1H), 1.35 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 110.6, 79.6, 78.7, 73.5, 30.3, 27.7, 26.0, 24.3. Anal. Calcd
for C8H14O3: C, 60.74; H, 8.92. Found: C, 60.74; H, 9.17.
3.2. General procedure for the Mitsunobu reaction
of 6-chloro-3-deazapurine (4-chloro-1H-imidazo
[4,5-c]pyridine) with cyclopentanols
To a solution of cyclopentanol 4a–e (10 mmol) and
triphenylphosphine (15 mmol) in THF (50 mL) was added
4-chloro-1H-imidazo[4,5-c]pyridine (3) (10 mmol). This
suspension was cooled by ice to 0 8C and DIAD
(15 mmol) was added dropwise. After completion of the
addition, the reaction mixture was warmed to room
temperature and stirred at this temperature for 12 h and
50 8C for another 12 h. The solvent was removed under
reduced pressure and the residue purified by column
chromatography (CH2Cl2/EtOAc, 3:1 or CH2Cl2/acetone,
4:1) to afford the coupled product.
3.2.6. Compound 6d (57%). Colorless oil: 1H NMR
(400 MHz, CDCl3) d 8.22 (d, JZ5.5 Hz, 1H), 8.05
(s, 1H), 7.66 (d, JZ5.5 Hz, 1H), 6.46 (m, 1H), 6.41 (m,
1H), 6.35 (m, 1H), 5.91 (m, 1H), 2.67 (ddd, JZ14.7, 7.8,
3.3 Hz, 1H), 2.39 (ddd, JZ14.7, 7.3, 3.8 Hz, 1H), 2.09
(s, 3H). 13C NMR (100 MHz, CDCl3) d 170.7, 151.4, 143.8,
141.2, 137.3, 133.6, 133.5, 127.9, 115.0, 77.9, 61.6, 40.7,
21.1. Anal. Calcd for C13H12ClN3O2: C, 56.22; H, 4.36; N,
15.13. Found: C, 56.13; H, 4.60; N, 14.98.
3.2.1. Compound 5a (86%). White solid, mp 131–133 8C:
1H NMR (400 MHz, CDCl3) d 8.24 (d, JZ5.6 Hz, 1H), 7.94
(s, 1H), 7.47 (d, JZ5.6 Hz, 1H), 4.88 (m, 1H), 4.69 (m, 2H),
2.59 (m, 1H), 2.17 (m, 3H), 1.57 (s, 3H), 1.35 (s, 3H).
13C NMR (100 MHz, CDCl3) d 143.5, 142.1, 141.8, 140.3,
138.4, 112.2, 106.3, 85.7, 80.5, 63.2, 31.5, 28.6, 26.9, 24.6.
HRMS calcd for C14H16ClN3O2 (MC) 293.0931, found
293.0936.
3.2.7. Compound 5e (32%). White solid, mp 96–98 8C:
1H NMR (250 MHz, CDCl3) d 8.25 (d, JZ5.6 Hz, 1H), 7.90
(s, 1H), 7.50 (d, JZ5.6 Hz, 1H), 6.44 (m, 1H), 6.10 (dd, JZ
5.8, 2.3 Hz, 1H), 5.43 (m, 2H), 4.56 (d, JZ5.8 Hz, 1H), 1.52
(s, 3H), 1.36 (s, 3H). 13C NMR (62.9 MHz, CDCl3) d 143.4,
142.3, 141.9, 139.7, 139.0, 138.5, 129.0, 113.0, 105.8, 84.4,
84.2, 67.9, 27.3, 25.6. HRMS calcd for C14H14ClN3O2
(MC) 291.0775, found 291.0773.

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M. Yang et al. / Tetrahedron 62 (2006) 1295–1300
3.2.8. Compound 6e (43%). Colorless oil: 1H NMR
(400 MHz, CDCl3) d 8.22 (d, JZ5.5 Hz, 1H), 7.92
(s, 1H), 7.52 (d, JZ5.5 Hz, 1H), 6.44 (dd, JZ5.7, 1.5 Hz,
1H), 6.27 (s, 1H), 6.10 (dd, JZ5.7, 1.1 Hz, 1H), 5.38 (dd,
JZ5.3, 1.3 Hz, 1H), 4.66 (d, JZ5.4 Hz, 1H), 1.50 (s, 3H),
1.35 (s, 3H). 13C NMR (100 MHz, CDCl3) d 152.0, 144.5,
141.7, 140.0, 134.5, 129.4, 128.4, 115.3, 112.8, 84.7, 84.4,
67.4, 27.8, 26.3. HRMS calcd for C14H14ClN3O2 (MC)
291.0775, found 291.0776.
NaBH4 (0.80 g, 20 mmol) was added portion wise. After the
reaction was stirred at room temperature for 0.5 h, the
solvent was removed and the product obtained by short
column chromatography (EtOAc/MeOH, 10:1) to give 9 as
1
a white foam (0.82 g, 81%): H NMR (400 MHz, CDCl3)
d 8.63 (s, 1H), 8.20 (d, JZ5.6 Hz, 1H), 7.81 (d, JZ5.6 Hz,
1H), 4.86 (m, 2H), 4.80 (t, JZ6.5 Hz, 1H), 4.57 (dd, JZ4.5,
7.0 Hz, 1H), 3.55 (t, JZ5.5 Hz, 2H), 2.46 (m, 1H), 2.21
(m, 1H), 2.19 (m, 1H), 1.58 (s, 3H), 1.26 (s, 3H). 13C NMR
(100 MHz, CDCl3) d 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.
3.2.9. (1R,2R,3R,4R)-4-(4-Chloro-3H-imidazo[4,5-c]-
pyridin-3-yl)-2,3-dihydroxycyclopent-1-yl acetate (7).
Methylmorpholine-N-oxide (2.13 g, 18.2 mmol) was
added to a solution of 6d (2.67 g, 9.64 mmol) in CH2Cl2
(50 mL) containing a small amount of H2O (0.8 mL). After
the solution was cooled to 0 8C, a catalytic amount of solid
OsO4 (90 mg, 0.36 mmol) was added and the solution
stirred for 12 h at room temperature. The reaction mixture
was quenched by addition of sodium bisulfite. The solvent
was removed and the residue purified by flash column
chromatography (EtOAc) to afford 7 as white solid (2.55 g,
85%), mp 209–210 8C: 1H NMR (250 MHz, DMSO-d6)
d 8.75 (s, 1H), 8.15 (d, JZ5.5 Hz, 1H), 7.73 (d, JZ5.5 Hz,
1H), 5.64 (m, 1H), 5.38 (d, JZ3.0 Hz, 1H, OH), 5.37 (d, JZ
4.1 Hz, 1H, OH), 5.07 (m, 1H), 4.16 (m, 1H), 4.08 (m, 1H),
3.00 (m, 1H), 2.16 (m, 1H), 2.09 (s, 3H). 13C NMR
(62.9 MHz, DMSO-d6) d 171.2, 151.8, 148.8, 141.2, 133.5,
128.8, 115.6, 78.4, 76.8, 73.6, 56.1, 34.3, 21.8. Anal. Calcd
for C13H14ClN3O4: C, 50.09; H, 4.53; N, 13.48. Found: C,
49.84; H, 4.54; N, 13.31.
3.2.12. ((3aS,4R,6R,6aR)-4-(4-Amino-1H-imidazo[4,5-c]-
pyridin-1-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta-
[d][1,3]dioxol-6-yl)methanol (10). A solution of 9 (1.62 g,
5.00 mmol) in hydrazine (15 mL) and MeOH (6 mL) was
brought to reflux for 6 h. After cooling to room temperature,
the solution was concentrated. The residue was dissolved in
MeOH (30 mL) and freshly prepared W2-Raney Ni
(prepared from 40 g of alloy) was added to it. The reaction
mixture was heated to reflux for 1 h. The hot reaction
mixture was filtered and the solid recovered and washed
with hot MeOH (3!15 mL). The combined filtrates were
evaporated to dryness and the residue purified via column
chromatography (EtOAc/MeOH, 10:1) to afford 10 as white
1
solid (1.14 g, 75%), mp 203–205 8C: H NMR (250 MHz,
DMSO-d6) d 8.22 (s, 1H), 7.66 (d, JZ5.8 Hz, 1H), 6.87 (d,
JZ5.8 Hz, 1H), 6.38 (br, 2H), 4.74 (q, JZ6.8 Hz, 1H), 4.69
(m, 1H), 4.55 (m, 1H), 3.51 (d, JZ4.8 Hz, 2H), 2.39–2.17
(m, 3H), 1.50 (s, 3H), 1.23 (s, 3H). 13C NMR (62.9 MHz,
DMSO-d6) d 152.4, 140.0, 139.9, 138.1, 126.9, 112.6, 97.3,
84.0, 80.9, 61.8, 61.6, 45.2, 32.9, 27.4, 25.1.15
3.2.10. (3aR,4R,6R,6aS)-4-(4-Chloro-3H-imidazo[4,5-c]-
pyridin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta-
[d][1,3]dioxol-6-yl acetate (8). To a solution of 7 (3.12 g,
10.0 mmol) and 2,2-dimethoxypropane (15 mL) in dry
acetone (20 mL) was added a catalytic amount of
p-toluenesulfonic acid (50 mg). After the reaction mixture
was stirred at room temperature for 12 h, the solvent was
removed and the residue dissolved in CH2Cl2 (40 mL). This
solution was washed with saturated NaHCO3 solution, H2O
and brine. The organic phase was dried (MgSO4) and
concentrated. The residue was purified by flash column
chromatography (EtOAc/hexanes, 1:2) to afford 8 as a white
3.2.13. (1R,2S,3R,5R)-3-(4-Amino-1H-imidazo[4,5-c]-
pyridin-1-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol
((K)-3-deazaaristeromycin, 1). Compound 10 (304 mg,
1.00 mmol) was dissolved in a mixture of MeOH (5 mL)
and 1 N HCl (5 mL) and the resulting solution was stirred at
room temperature for 5 h. Basic resin (Amberlite IR 67) was
added to neutralize the solution. The mixture was filtered
and the filtrate removed under vacuum. The residue was
purified by column chromatography (EtOAc/MeOH/
NH4OH, 5:2:1) to afford 1 as a 1 mol HCl salt, white solid
(89%), mp O231 8C (dec): 1H NMR (250 MHz, DMSO-d6)
d 8.63 (s, 1H), 8.50 (br, 2H), 7.74 (d, JZ7.0 Hz, 1H), 7.30
(d, JZ7.0 Hz, 1H), 4.72 (q, JZ9.5 Hz, 1H), 4.14 (dd, JZ
9.3, 5.4 Hz, 1H), 3.82 (dd, JZ5.4, 2.8 Hz, 1H), 3.46 (d, JZ
5.3 Hz, 2H), 2.31 (dt, JZ12.7, 8.8 Hz, 1H), 2.09 (m, 1H),
1.75 (m, 1H). 13C NMR (62.9 MHz, DMSO-d6) d 148.9,
143.5, 140.1, 129.0, 126.1, 99.3, 76.1, 72.0, 62.7, 61.0, 45.4,
28.9.13
1
solid, mp 142–143 8C: H NMR (250 MHz, CDCl3) d 8.29
(s, 1H), 8.23 (d, JZ5.5 Hz, 1H), 7.68 (d, JZ5.5 Hz, 1H),
5.81 (ddd, JZ10.4, 5.5, 5.5 Hz, 1H), 5.17 (d, JZ4.4 Hz,
1H), 4.89 (dd, JZ4.8, 4.9 Hz, 1H), 4.65 (dd, JZ5.4, 1.5 Hz,
1H), 2.69 (ddd, JZ13.1, 4.5, 4.5 Hz, 1H), 2.37 (dd, JZ13.1,
5.8 Hz, 1H), 2.16 (s, 3H), 1.52 (s, 3H), 1.29 (s, 3H). 13C
NMR (62.9 MHz, CDCl3) d 169.9, 151.4, 146.2, 141.3,
133.3, 128.2, 115.4, 112.3, 83.5, 78.5, 74.7, 56.5, 33.2, 26.0,
24.0, 21.2. Anal. Calcd for C16H18ClN3O4: C, 54.63; H,
5.16; N, 11.94. Found: C, 54.83, H, 5.11, N, 11.85.
3.2.11. ((3aS,4R,6R,6aR)-4-(4-Chloro-1H-imidazo[4,5-c]-
pyridin-1-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta-
[d][1,3]dioxol-6-yl)methanol (9). To a solution of 5b
(1.00 g, 3.13 mmol) in MeOH (20 mL), H2O (8 mL) and
NaIO4 (1.39 g, 6.48 mmol) were added. After the mixture
was cooled to 0 8C, OsO4 (20 mg) was added. This reaction
mixture was stirred at the same temperature for 1 h and then
at room temperature for 2 h. The resulting white solid was
obtained by filtration and the filtrate cooled to 0 8C. To this
3.2.14. 2-((3aS,4R,6R,6aR)-4-(4-Chloro-1H-imidazo[4,5-c]-
pyridin-1-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta-
[d][1,3]dioxol-6-yl)ethanol (11). To a solution of 5b
(1.00 g, 3.13 mmol) in THF (20 mL) at 0 8C under N2 was
added 9-BBN-H (0.5 M in THF, 10.0 mL, 5.00 mmol), and
the resultant mixture stirred for 3 h. To this, NaOH solution
(1 M, 6 mL) followed by H2O2 (50% in H2O, 3 mL) was
added and the stirring continued an additional 30 min. The
reaction mixture was diluted with CH2Cl2 (100 mL) and this

M. Yang et al. / Tetrahedron 62 (2006) 1295–1300
1299
mixture washed with saturated NaHCO3 solution (30 mL).
2.3. X-ray data for compound 8
The organic layer was dried (MgSO4), filtered, and the
filtrate concentrated in vacuo to give the crude product as a
colorless oil, which was purified by flash column
chromatography (EtOAc/hexane, 1:4) to afford 11 as a
white solid (0.84 g, 80%), mp 190–191 8C: 1H NMR
(400 MHz, CDCl3) d 8.62 (s, 1H), 8.17 (d, JZ5.6 Hz,
1H), 7.81 (d, JZ5.6 Hz, 1H), 4.78 (m, 2H), 4.48 (t, JZ
5.1 Hz, 1H), 4.44 (dd, JZ5.6, 6.6 Hz, 1H), 3.48 (dd, JZ
11.9, 6.6 Hz, 2H), 2.48 (dd, JZ12.1, 6.1 Hz, 1H), 2.13 (m,
2H), 1.73 (ddd, JZ13.4, 6.3, 6.3 Hz, 1H), 1.61 (ddd, JZ
13.6, 6.4, 6.4 Hz, 1H), 1.52 (s, 3H), 1.24 (s, 3H). 13C NMR
(100 MHz, CDCl3) d 144.4, 141.0, 140.8, 140.0, 137.2,
113.0, 107.3, 84.2, 84.0, 61.6, 59.2, 40.0, 36.2, 35.9, 27.3,
25.1. Anal. Calcd for C16H20ClN3O3: C, 56.89; H, 5.97; N,
12.44. Found: C, 56.88; H, 6.09; N, 12.29.
Crystallographic data (excluding structure factors) for 8 has
been deposited with Cambridge Crystallographic Data
Centre as supplementary number CCDC 267776. Copies
of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
C44 1223 336033 or e mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
This research was supported by funds from the NIH (AI
56540). We thank Dr. Thomas Albrecht-Schmitt, Auburn
University, for securing the X-ray data for 8.
3.2.15. 2-((3aS,4R,6R,6aR)-4-(4-Amino-1H-imidazo[4,5-c]-
pyridin-1-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta-
[d][1,3]dioxol-6-yl)ethanol (12). A solution of 11 (1.69 g,
5.00 mmol) in hydrazine (20 mL) and MeOH (6 mL) was
brought to reflux for 6 h. After cooling to room temperature,
the solution was concentrated. The residue was dissolved in
MeOH (40 mL) and freshly prepared W2-Raney Ni
(prepared from 40 g of alloy) was added to it. The reaction
mixture was heated to reflux for 2 h and the hot reaction
mixture filtered and the solid washed with hot MeOH
(3!15 mL). The combined filtrates were evaporated to
dryness and the residue purified via column chromatography
(EtOAc/MeOH, 10:1) to afford 12 as a white solid (1.29 g,
80%), mp 192–194 8C: 1H NMR (400 MHz, DMSO-d6)
d 8.23 (s, 1H), 7.67 (d, JZ5.8 Hz, 1H), 6.89 (d, JZ5.8 Hz,
1H), 6.27 (br, 2H), 4.75 (m, 1H), 4.63 (m, 1H), 4.53
(br, 1H), 4.41 (m, 1H), 3.46 (m, 2H), 2.42 (m, 1H), 2.05 (m,
1H), 2.00 (m, 1H), 1.72 (m, 1H), 1.59 (m, 1H), 1.50 (s, 3H),
1.23 (s, 3H). 13C NMR (100 MHz, DMSO-d6) d 153.2,
140.8, 140.7, 139.0, 127.7, 113.8, 98.1, 85.1, 84.9, 62.0,
60.1, 41.0, 37.1, 37.0, 28.2, 26.0. Anal. Calcd for
C16H22N4O3: C, 60.36; H, 6.97; N, 17.60. Found: C,
60.16; H, 7.06; N, 17.49.
References and notes
1. Gordon, R. K.; Ginalski, K.; Rudnicki, W. R.; Rychlewski, L.;
Pankaskie, M. C.; Bujnicki, J. M.; Chiang, P. K. Eur.
J. Biochem. 2003, 270, 3507–3517.
2. Maki, A. S.; Kim, T. W.; Kool, E. T. Biochemistry 2004, 43,
1102–1110.
3. (a) Schneller, S. W. Curr. Top. Med. Chem. 2002, 2,
1087–1092. (b) Rodriguez, J. B.; Comin, M. J. Mini Rev.
Med. Chem. 2003, 3, 95–114.
4. Montgomery, J. A.; Clayton, S. J.; Thomas, H. J.; Shannon, W. M.;
Arnett, G.; Bodner, A. J.; Kion, I.-K.; Cantoni, G. L.; Chiang, P. K.
J. Med. Chem. 1982, 25, 626–629.
5. Tseng, C. K. H.; Marquez, V. E.; Fuller, R. W.; Goldstein, B. M.;
Haines, D. R.; McPherson, H.; Parsons, J. L.; Shannon, W. M.;
Arnett, G.; Hollingshead, M.; Driscoll, J. S. J. Med. Chem.
1989, 32, 1442–1446.
6. (a) Mitsunobu, O. Synthesis 1981, 1–28. (b) Hughes, D. L.
Org. Prep. Proced. Int. 1996, 28, 127–164.
7. A preliminary account of this work has appeared ( Yang, M.;
Zhou, J.; Schneller, S. W. Tetrahedron Lett. 2004, 45,
8981–8982).
8. Hydrogenation of i9a to ii9b followed by reduction with sodium
borohydride provided 4a (see Section 2).
3.2.16. (1R,2S,3R,5R)-3-(4-Amino-1H-imidazo[4,5-c]-
pyridin-1-yl)-5-(2-hydroxyethyl)cyclopentane-1,2-diol
(3-deaza-50-homoaristeromycin, 13). Compound 12
(0.64 g, 2.01 mmol) was dissolved in a mixture of MeOH
(10 mL) and 1 N HCl (10 mL) and the resulting solution
was stirred at room temperature for 5 h. Basic resin
(Amberlite IR 67) was added for neutralization. The
solution was filtered, the filtrate removed under vacuum
and the residue purified by column chromatography
(EtOAc/MeOH/NH4OH, 6:2:1) to afford 13$HCl as a
white solid (436 mg, 78%), mp 205–206 8C: 1H NMR
(400 MHz, DMSO-d6) d 8.19 (s, 1H), 7.64 (d, JZ5.8 Hz,
1H), 6.81 (d, JZ5.8 Hz, 1H), 6.18 (br, 2H), 5.00 (d, JZ
6.3 Hz, 1H), 4.80 (d, JZ4.8 Hz, 1H), 4.48 (m, 2H), 4.14 (q,
JZ6.3 Hz, 1H), 3.67 (q, JZ4.8 Hz, 1H), 3.46 (m, 2H), 2.30
(ddd, JZ12.6, 7.8, 7.8 Hz, 1H), 1.96 (m, 1H), 1.76 (ddd, JZ
13.1, 6.8, 6.8 Hz, 1H), 1.52 (m, 2H). 13C NMR (100 MHz,
DMSO-d6) d 151.6, 139.4, 139.0, 137.5, 126.1, 96.4, 74.1,
74.0, 60.1, 58.6, 39.5, 36.5, 31.6. Anal. Calcd for
C13H19N4O3Cl: C, 49.60; H, 6.08; N, 17.80. Found: C,
49.40; H, 5.84; N, 17.49.
O
O
TrO
O
O
O
O
O
O
O
i9a
ii9b
iii
9. (a) Yang, M.; Ye, W.; Schneller, S. W. J. Org. Chem. 2004, 69,
3993–3996. (b) Vonlanthen, D.; Leumann, C. J. Synthesis
2003, 1087–1090.
10. Compound 4c is readily available from ketone iii (Choi, W. J.;
Moon, H. R.; Kim, H. O.; Yoo, B. N.; Lee, J. A.; Shin, D. H.;
Jeong, L. S. J. Org. Chem. 2004, 69, 2634–2636) by sodium
borohydride reduction (Schneller, S. W.; Yang, M. Antiviral
Drug Discovery for Emerging Diseases and Bioterrorism
Threats; Torrence, P., Ed.; Wiley: Hoboken, NJ, 2005,
pp 139–152).
11. Siddiqi, S. M.; Chen, X.; Schneller, S. W. Nucleosides
Nucleotides 1993, 12, 267–278.

1300
M. Yang et al. / Tetrahedron 62 (2006) 1295–1300
12. Seley, K. L.; Schneller, S. W.; Rattendi, D.; Lane, S.; Bacchi,
C. J. J. Med. Chem. 1997, 40, 625–629.
Borchardt, R. T. J. Med. Chem. 1985, 28, 471–477
reported the preparation of (G)-1.
13. Montgomery, J. A.; Secrist, J. A., III World Patent
9418971, Sept. 1, 1994 presents a chemical and enzymatic
synthesis of (K)-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.;
14. Yang, M.; Schneller, S. W. Bioorg. Med. Chem. Lett. 2005, 15,
149–151.
15. This data compares favorably with that reported for (G)-10
Secrist, J. A.; Comber, R. N.; Gray, R. J.; Gilroy, R. B.;
Montgomery, J. A. J. Med. Chem. 1993, 36, 2102–2106.