Carbocyclic 4-deazaformycins

Article abstract of DOI:10.1055/s-0031-1289688

The preparation of carbocyclic 4-deazaformycin and its 5-homoanalogue from a common vinyl precursor, and its N-1 and N-2 methyl derivatives is reported. The syntheses began with a highly stereoselective S_N2 reaction between lithio 4-picolines and a protected 2,3-dihydroxy-4-vinylcyclopentyl triflate. The requisite fused pyrazole ring was created by an intramolecular diazonium reaction that was followed by vinyl transformation into the hydroxymethyl and the hydroxyethyl groups. The N-methyl derivatives arose by standard methylation conditions and the resultant N-Me regiochemistry was assigned by homo- and heteronuclear NMR spectroscopy. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289688

PAPER
723
Carbocyclic 4-Deazaformycins
C
arbocyclic 4-De
a
a
zaformycin
n
s
Zhang, Wei Ye, Haisheng Wang, Stewart W. Schneller*
The Molette Laboratory for Drug Discovery, Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312,
USA
Fax +1(334)8440239; E-mail: schnest@auburn.edu
Received 13 November 2011; revised 22 December 2011
to 3-deazaadenines with ammonia6 and were uncertain if
Abstract: The preparation of carbocyclic 4-deazaformycin and its
the same difficulty would be encountered in this resem-
5¢-homoanalogue from a common vinyl precursor, and its N-1 and
bling deaza study. To evaluate this possibility, a model
N-2 methyl derivatives is reported. The syntheses began with a
study was carried out with 7-chloropyrazolo[3,4-c]pyri-
highly stereoselective SN2 reaction between lithio 4-picolines and a
protected 2,3-dihydroxy-4-vinylcyclopentyl triflate. The requisite dine (10),9 which found that no reaction with ammonia
fused pyrazole ring was created by an intramolecular diazonium re-
occurred (Scheme 1). However, ammonolysis of the me-
action that was followed by vinyl transformation into the hy-
thylated derivatives 11 and 12 was successful producing
droxymethyl and the hydroxyethyl groups. The N-methyl
13 and 14 [the isomeric products were assigned by an X-
derivatives arose by standard methylation conditions and the result-
ray crystallographic determination of the side-product
ant N-Me regiochemistry was assigned by homo- and heteronuclear
NMR spectroscopy.
2510 formed by the ammonolysis of 12]. This difference in
reactivity was likely the consequence of an acid/base re-
action between the pyrazole NH of 10 and ammonia that
deactivated the chloro-bearing carbon to displacement by
Key words: C-nucleosides, carbocyclic nucleosides, pyrazolo[3,4-
c]pyridines
ammonia. With the methyl derivatives 11 and 12 this sit-
uation was rendered inoperative. In any case, from this
Formycin (1), as a C-nucleoside,1 and aristeromycin (2),
observation, we concluded that a route to 7 and 8 could in-
as a carbocyclic nucleoside,2 represent unique natural
clude an ammonolysis step, but a scheme to 6 and 9 would
products. Because of their structural relationship to ade-
necessitate alternative considerations for introducing the
nosine, they have spawned numerous studies that have fo-
requisite amino group. Our synthetic investigations began
cused on chemotherapeutic discovery and biomechanistic
with seeking 6 and 9.
endeavors.1c,3 With formycin, for example, the N-1 and N-
2 methylated derivatives, 3 and 4, respectively, have
X
X
X
shown biological properties different from formycin4
while 3-deazaaristeromycin (5) has found its own biolog-
ical place beyond aristeromycin.5 In continuing our inves-
tigations on 3-deaza carbocyclic nucleosides,6 we sought
synthetic means that would combine all of these features
into the carbocyclic C-nucleoside7 target compounds 6–8
(Figure 1). Derivative 9 was also included in this study
because of its similarity to 5¢-homoaristeromycin, which
has displayed an encouraging biological profile.8 The suc-
cesses in this direction are reported here.
H
Me
N
N
N
N
N
N
b
+
MeN
N
N
11 X = Cl
13 X = NH2
10a X = Cl
10b X = NH2
12 X = Cl
14 X = NH2
a
c
c
Scheme 1 Reagents and conditions: a) NH3–MeOH, 165 °C; b)
NaH, MeI, THF, 0 °C to r.t., overnight, 24% for 11 and 64% for 12;
c) same as a, 85% for 13 and 90% for 14.
In designing pathways to 6–9 we were well acquainted
with the difficulty of converting 6-chloro-3-deazapurines
The preparation of these latter targets was envisioned as
arising from a common C-4¢ substituent (as in 15,
N
NR
N
MeN N
Y
Y
NH2
NH2
NH2
Z
N
HO
HO
N
N
N
X
X
X
HO
HO
OH
OH
OH
HO
1 X = N; Y = O; Z = CH2OH; R = H
3 X = N; Y = O; Z = CH2OH; R = Me
6 X = CH; Y = CH2; Z = CH2OH; R = H
7 X = CH; Y = CH2; Z = CH2OH; R = Me
2 X = N
5 X = CH
4 X = N; Y = O
8 X = CH; Y = CH2
9 X = CH; Y = CH2; Z = CH2CH2OH; R = H
Figure 1 Aristeromycin, formycin, and related compounds
SYNTHESIS 2012, 44, 723–730
x
x
.x
x
.2
0
1
1
Advanced online publication: 06.02.2012
DOI: 10.1055/s-0031-1289688; Art ID: M106811SS
© Georg Thieme Verlag Stuttgart · New York

724
Y. Zhang et al.
PAPER
AcHN
N
NR
X
X
OR
N
O
O
N
O
O
O
O
e
b
on
20
16 R = H
17 R = Tf
a12
15 R = Ac; X = phthalimido
23 R = H; X = NH2
18 X = NHBoc
19 X = NH2
20 X = phthal-
imido
c
f
d
NHAc
NHBoc
N
2611c
Scheme 2 Reagents and conditions: a) Tf2O, Py, CH2Cl2, 0 °C, 30 min, 92%; b) 26, THF, –78 °C, then n-BuLi followed by 17, then r.t., 57%;
c) TFA (20 equiv), 0 °C to r.t., 5 h; d) phthalic anhydride, toluene, 50 °C, 1 d, 80% for 2 steps; e) KOAc, Ac2O, isoamyl nitrite, benzene, reflux,
79%; f) NH3–MeOH, r.t., overnight, 84%.
Scheme 2) that was foreseen as accessible by adapting a Ammonolysis of 15 to 23 (Scheme 2) followed by a meth-
literature procedure.11 Thus, the synthesis of 15 began od used previously in our laboratories6 of Brown hydro-
with the nucleophilic substitution reaction of the triflate boration with 9-borabicyclo[3.3.1]nonane (BBN) and,
1712 by the lithio salt of tert-butyl-N-(3-acetamido-4- subsequent, oxidation with hydrogen peroxide yielded 24
methylpyridin-2-yl) carbamate (26 in Scheme 2),11c (Scheme 4). Deprotection of 24 formed 9. Similarly,
which also served as the source of the final C-7 amino deprotection of 23 produced 27 whose structure was con-
substituent. This reaction proceeded from the less hin- firmed by NMR spectroscopic analysis, which established
dered b-face of the cyclopentyl ring of 17 (verified by the stereochemistry of the heterocyclic ring-to-cyclopen-
NMR analysis of 27, vide infra) to give 18. To circumvent tyl unit arising out of the 17 to 18 conversion. In this di-
potential subsequent side reactions,9 the Boc group was rection, the vinyl H-5¢ signal of 27 appeared at d = 5.08.
removed and the resulting free amine 19 protected as its Using HHCOSY, the following assignments could then be
N-phthalimino derivative 20.
made: H-4¢ (2.06 ppm), H-3¢ (3.70 ppm), H-2¢ (4.02 ppm),
and H-1¢ (3.37 ppm). A NOESY correlation was found be-
tween H-4¢ and H-1¢ indicating they were both in the
‘down’ orientation.
Construction of the fused pyrazole ring took place by
treating 20 with isoamyl nitrite in the presence of potassi-
um acetate and acetic anhydride in refluxing benzene to
result in the desired 15 (Scheme 2).
N
NH
Transformation of ethylene unit of 15 to the hydroxy-
methyl of 6 was achieved (Scheme 3) by, first, glycoliza-
tion with N-methlymorpholine N-oxide (NMO) and
osmium tetroxide followed by oxidation using sodium
periodate and, then, reduction with sodium borohydride to
provide 21 in which one of the carbonyl centers of the
phthalimido unit was reduced. Treatment of 21 with meth-
anolic ammonia (to 22) and subsequent hydrolytic depro-
tection produced 6.
NH2
HO
a
N
O
O
9
24
23
N
NH
5'
NH2
b
4'
3'
1'
N
NH
N
2'
X
OH
27
HO
HO
a
c
15
6
N
on 22
O
Scheme 4 Reagents and conditions: a) i. 9-BBN, THF, 0 °C to r.t.,
12 h, ii. 50% H2O2 in H2O, NaOH, 30 min, 81% for two steps; b)
TFA–H2O (2:1), r.t., 3 h, 86% for 9, 81% for 27.
O
H
OH
N
21, X =
Construction of 7 and 8 began with 3-acetamido-2-chloro-
4-picoline (28)13 that was prepared from 3-amino-2-chlo-
ro-4-picoline (29) on treatment with Ac2O (Scheme 5).
Compound 28 was transformed to its lithio derivative and
this reacted with triflate 17 in a nucleophilic substitution
manner from the less hindered cyclopentyl b-face, as ex-
pected (see 18), to yield 30 as the only product. Construc-
tion of the fused pyrazole ring onto 30 occurred via the
b
O
22, X = NH2
Scheme 3 Reagents and conditions: a) i. NMO/OsO4 (cat.), THF,
0 °C to r.t., 12 h, ii. NaIO4, CH2Cl2/H2O, r.t., 1 h, iii. NaBH4 (excess),
0 °C, 1 h, 51% for 3 steps; b) NH3–MeOH, r.t., overnight, 92%; c) aq
1 M HCl–THF (1:1), r.t., 6 h, 88%.
Synthesis 2012, 44, 723–730
© Thieme Stuttgart · New York

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Carbocyclic 4-Deazaformycins
725
NHR
N
AcHN
N
NR
Cl
Cl
Cl
b
N
N
O
a
O
O
O
on 28
ref.
13
29, R = H
28, R = Ac
30
31, R = Ac
32, R = H
c
d
N
NMe
MeN N
X
X
R
R
g
g
N
N
8
7
+
on 35a
on 35b
O
O
O
O
h
a series
b series
6
33, R = vinyl, X = Cl
34, R = CH2OH, X = Cl
35, R = CH2OH, X = NH2
e
f
Scheme 5 Reagents and conditions: a) n-BuLi, THF, –78 °C, then to 0 °C, add 17, –78 °C, then to 0 °C, 57%; b) KOAc, Ac2O, isoamyl nitrite,
benzene, reflux, 60%; c) NH3–MeOH, r.t., quant.; d) NaH/MeI in THF, 0 °C, then to r.t., 55% for 33a, 41% for 33b; e) i. NMO/OsO4 (cat.),
THF, 0 °C to r.t., ii. NaIO4, CH2Cl2/H2O, r.t., 1 h, iii. NaBH4 (excess), 86% for 34a, 84% for 34b for 3 steps; f) NH3–MeOH, 0 to 165 °C, 45%
for 35a, 84% for 35b; g) aq 1 M HCl, THF, r.t., 80% for 7, 81% for 8; h) i. DMFDMA, DMF, 70 °C, ii. NH4OH, 71%.
same procedure as the 20 to 15 transformation to give 31. been developed. This offers an effective pathway into for-
The N-1/N-2 methyl derivatives 33a/33b were prepared mycin analogues where substitution can occur at N-1 and
in the ratio of 4:3 by reacting deacetylated 32 (ammonia– N-2, C-4 (which is a nitrogen center in formycin), and the
methanol) with methyl iodide/sodium hydride. The vinyl cyclopentyl ring at C-6¢ (which is an oxygen in formycin).
unit of the products 33a/33b was transformed to the de-
sired hydroxymethyl functional center of 34a/34b in the
same manner as described for 15 to 21 in Scheme 3 (i.e.,
NMO, OsO4; NaIO4; NaBH4).
1H and 13C NMR spectra were recorded on a Bruker AV-400 spec-
trometer or Bruker AC-250 spectrometer. 1H chemical shifts are re-
ported relative to CDCl3 at d = 7.27 ppm (or CD3OD at d = 3.51 ppm
or DMSO-d6 at d = 2.51 ppm) and TMS as an internal standard. 13
C
Ammonolysis of 34a/34b to 35a/35b followed by weak
acid deprotection gave 7 and 8, respectively. A more con-
venient route to 7 was found by treating 6 with dimethyl-
formamide dimethyl acetal. However, these conditions
chemical shifts are reported relative to CDCl3/CD3OD/DMSO-d6.
Standard abbreviations are used to indicate spin multiplicities. The
mass spectral data was determined using a Waters Micromass Q-
TOF Premier Mass Spectrometer. Atlantic Microlabs, Atlanta,
failed when applied to the protected form of 6 (that is, 22). Georgia, performed elemental analyses. Reactions were monitored
by TLC using 0.25 mm E. Merck silica gel 60-F254 precoated silica
gel plates with visualization by irradiation with a Mineral light
UVGL-25 lamp or exposure to I2 vapor. Column chromatography
The structures of isomers 33a and 33b, were assigned by
an HMBC 13C spectroscopic analysis: (i) the N-1 methyl
of 33a (d = 38.9 ppm) displayed a strong correlation with
C-7a (d = 134.1 ppm) but no correlation with C-3, C-3a,
and C-7 whereas (ii) the N-2 methyl of 33b (d = 39.6
ppm) offered a strong correlation with C-3 (d = 137.2
ppm) but no correlation with C-3a, C-7a, and C-1¢
(Figure 2).
was performed on Whatman silica gel (average particle size 5–25
mm, 60 Å) and elution with the indicated solvent system. Yields re-
fer to chromatographically and spectroscopically (1H and 13C NMR)
homogeneous materials. The reactions were generally carried out in
a N2 atmosphere under anhydrous conditions.
7-Chloro-1-methylpyrazolo[3,4-c]pyridine (11) and 7-Chloro-
2-methylpyrazolo[3,4-c]pyridine (12)
Compound 109 (0.95 g, 6.19 mmol) was partly suspended in anhyd
THF (30 mL) and cooled to 0 °C. To this, NaH (0.21 g, 8.67 mmol)
was added portionwise and the mixture was kept at 0 °C for another
10 min. MeI (0.48 mL, 7.73 mmol) was added dropwise to the mix-
ture and the system gradually warmed to r.t. and then stirred over-
night to give a clear solution. After addition of sat. aq NH4Cl (5 mL)
dropwise, the solvent was evaporated under reduced pressure. To
the residue was added H2O (10 mL) and this mixture extracted by
CH2Cl2 (30 mL), and the extracts dried (Na2SO4) and concentrated
to dryness. The crude product was isolated by flash chromatography
using a mixture of hexanes–EtOAc (2:1) to give 11 (0.25 g, 24%)
and hexanes–EtOAc (1:2) to provide 12 (0.66 g, 63%).
1
2
N
NMe
7a
MeN
N
7a
Cl
Cl
3
3
7
1'
3a
3a
N
N
O
O
O
O
33a
33b
Figure 2 Relevant ring atoms for 33a and 33b
In conclusion, an efficient synthesis of various carbocylic
formycin derivatives related to 3-deazaaristeromycin has
© Thieme Stuttgart · New York
Synthesis 2012, 44, 723–730

726
11
Y. Zhang et al.
PAPER
to –78 °C. To this was added n-BuLi (4.64 mL, 11.61 mmol, 2.5 M
solution in hexanes) slowly under N2. The resulting yellow solution
was stirred at this same temperature for 15 min and then warmed to
0 °C over 30 min. The orange solution was cooled to –78 °C and a
solution of the triflate 17 (1.02 g, 3.23 mmol) in anhyd THF (20 mL)
added dropwise. The resulting mixture was stirred at –78 °C for 15
min and then at r.t. overnight. Sat. aq NH4Cl (20 mL) was added to
the reaction mixture at 0 °C and this mixture was stirred for 10 min.
The solvent was removed under reduced pressure and to the residue
H2O (20 mL) was added. This aqueous mixture was extracted with
CH2Cl2 (3 × 50 mL). The organic extracts were combined, dried
(Na2SO4), and concentrated to dryness under reduced pressure. The
residue was then purified by flash chromatography using a mixture
of CH2Cl2–EtOAc (1:1) and the resultant residue, following solvent
evaporation, was recrystallized from CH2Cl2–hexanes to give 18 as
white needles (0.79 g, 57%); mp 116–118 °C.
Light yellow solid; mp 68–69 °C.
1H NMR (250 MHz, CDCl3): d = 8.03–8.00 (m, 2 H), 7.53 (dt,
J = 5.8, 1.0 Hz, 1 H), 4.44 (s, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 138.2, 134.3, 133.7, 132.5,
130.6, 114.7, 39.3.
HRMS: m/z calcd for C7H6ClN3: 167.0250; found: 167.0248.
12
Light yellow solid; mp 110–111 °C.
1H NMR (250 MHz, CDCl3): d = 8.00 (s, 1 H), 7.88 (d, J = 5.8 Hz,
1 H), 7.42 (d, J = 6.0 Hz, 1 H), 4.29 (s, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 143.3, 142.7, 137.4, 126.0,
125.2, 113.6, 41.4.
1H NMR (400 MHz, CDCl3): d = 8.60 (br, 1 H), 8.20 (d, J = 5.2 Hz,
1 H), 7.71 (br, 1 H), 7.18 (d, J = 5.2 Hz, 1 H), 5.83 (ddd, J = 17.2,
10.4, 6.8 Hz, 1 H), 5.09 (dd, J = 16.9, 0.9 Hz, 1 H), 5.03 (dd,
J = 10.4, 0.9 Hz, 1 H), 4.34 (t, J = 6.4 Hz, 1 H), 4.25 (dd, J = 6.8,
4.8 Hz, 1 H), 2.98–2.93 (m, 1 H), 2.66–2.59 (m, 2 H), 2.44–2.39 (m,
1 H), 2.14 (s, 3 H), 2.05–2.02 (m, 1 H), 1.64 (m, 1 H), 1.54 (s, 9 H),
1.51 (s, 3 H), 1.28–1.25 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 168.9, 154.5, 150.4, 146.7, 146.4,
139.5, 124.7, 122.3, 115.2, 112.9, 85.8, 85.5, 82.2, 49.4, 44.4, 37.4,
35.5, 28.4 (3 ×), 27.8, 25.3, 23.6.
HRMS: m/z calcd for C7H6ClN3: 167.0250; found: 167.0253.
7-Amino-1-methylpyrazolo[3,4-c]pyridine (13)
To MeOH saturated with NH3 (40 mL) at 0 °C was added 11 (0.24
g, 1.56 mmol). This mixture was heated to 165 °C and then kept at
this temperature for 2 d. The solvent was removed under reduced
pressure and the residue purified by column chromatography using
MeOH–CH2Cl2 (1:10) to give 13 (0.19 g, 85%) as a light yellow sol-
id; mp 114–115 °C.
1H NMR (400 MHz, DMSO-d6): d = 8.12 (s, 1 H), 7.35 (d, J = 6.8
Hz, 1 H), 6.69 (d, J = 6.4 Hz, 1 H), 6.37 (br, 2 H), 4.13 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 150.6, 136.4, 133.1, 124.6, 124.5,
104.4, 40.9.
HRMS: m/z calcd for C23H33N3O5: 431.2420; found: 431.2425.
N-{4-[(3aS,4S,6R,6aR)-2,2-Dimethyl-6-vinyltetrahydrocyclo-
penta[1,3]dioxol-4-methyl]-2-phthalimidopyridin-3-yl}acet-
amide (20)
HRMS: m/z calcd for C7H8N4: 148.0749; found: 148.0749.
Compound 18 (2.00 g, 4.63 mmol) was dissolved in CH2Cl2 (50
mL) and this solution was cooled to 0 °C. The yellow solution
changed into bright yellow immediately when TFA (7.14 mL, 92.69
mmol) was added dropwise over 5 min. The mixture was gradually
warmed to r.t., kept at this temperature for 5 h, and then poured
slowly into chilled sat. aq NaHCO3 (15 mL). The aqueous layer was
extracted with CH2Cl2 (5 × 25 mL), and the combined organic phas-
es dried (Na2SO4), evaporated under reduced pressure, and purified
by flash chromatography using a mixture of MeOH–CH2Cl2 (1:10)
to give crude 19 as a yellow solid. To a solution of this 19 in anhyd
toluene was added phthalic anhydride (0.69 g, 4.63 mmol). The
mixture was heated at 50 °C for one day, then filtered through
Celite, washed with CH2Cl2 (25 mL), evaporated under reduced
pressure, and the residue purified by flash chromatography using a
mixture of EtOAc–CH2Cl2, (1:1) to give 20 as a white solid (1.71 g,
80% for 2 steps). Compound 20 was further purified by recrystalli-
zation from CH2Cl2–hexane system to form white needles; mp 202–
203 °C.
1H NMR (400 MHz, CDCl3): d = 8.62 (d, J = 4.8 Hz, 0.13 H), 8.52
(d, J = 4.8 Hz, 0.87 H), 7.98–7.95 (m, 2 H), 7.82–7.80 (m, 2 H),
7.48 (br, 1 H), 7.42 (d, J = 5.2 Hz, 1 H), 5.12 (dd, J = 16.9, 0.8 Hz,
1 H), 5.05 (dd, J = 10.4, 0.8 Hz, 1 H), 4.37 (t, J = 6.4 Hz, 1 H), 4.27
(t, J = 6.4 Hz, 1 H), 3.01–2.95 (m, 1 H), 2.72–2.62 (m, 2 H), 2.39
(sext, J = 5.6 Hz, 1 H), 2.08 (quint, J = 6.4 Hz, 1 H), 2.03 (s, 3 H),
1.53 (s, 3 H), 1.35 (q, J = 11.2 Hz, 1 H), 1.31 (s, 3 H).
7-Amino-2-methylpyrazolo[3,4-c]pyridine (14)
Using an identical procedure for preparing 13, 12 (0.24 g, 1.56
mmol) yielded 14 (0.20 g, 90%) as a light yellow solid; mp 156–157
°C.
1H NMR (400 MHz, DMSO-d6): d = 7.86 (s, 1 H), 7.50 (d, J = 5.6
Hz, 1 H), 6.88 (d, J = 5.6 Hz, 1 H), 6.20 (br, 2 H), 4.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 145.3, 137.3, 132.4, 129.7, 127.4,
107.3, 39.1.
HRMS: m/z calcd for C7H8N4: 148.0749; found: 148.0756.
(3aS,4S,6R,6aR)-2,2-Dimethyl-4-trifluoromethanesulfonyl-6-
vinyltetrahydrocyclopenta[1,3]dioxole (17)
Tf2O (0.35 mL, 2.50 mmol) in CH2Cl2 (5 mL) was added to a mix-
ture of alcohol 1611 (0.64 g, 3.5 mmol) and anhyd pyridine (5.61
mL, 70 mmol) in anhyd CH2Cl2 (10 mL) at 0 °C. The mixture was
stirred for 30 min and then cold H2O (5 mL) was added. The layers
were separated and the organic layer was washed with H2O (3 × 20
mL), dried (Na2SO4), and evaporated to dryness to give a brown oil,
which was purified by flash column chromatography using hex-
anes–EtOAc (8:1) to give 17 as a colorless syrup (1.02 g, 92%) for
the next step.
1H NMR (250 MHz, CDCl3): d = 5.77 (ddd, J = 27.2, 17.6, 10.0 Hz,
1 H), 5.17–5.09 (m, 3 H), 4.62 (t, J = 9.2 Hz, 1 H), 4.53–4.50 (m, 1
H), 2.92–2.75 (m, 1 H), 2.43–2.32 (m, 1 H), 2.12–2.05 (m, 1 H),
1.54 (s, 3 H), 1.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.6, 166.6, 150.7, 147.9, 143.7,
139.1, 134.8, 131.9, 129.5, 125.4, 124.1, 115.3, 113.1, 85.5, 85.4,
49.1, 44.5, 37.5, 35.1, 27.7, 25.2, 23.3.
tert-Butyl-N-{3-acetamido-4-[(3aS,4S,6R,6aR)-2,2-dimethyl-6-
vinyltetrahydrocyclpenta[1,3]dioxol-4-methyl]pyridin-2-yl}
Carbamate (18)
HRMS: m/z calcd for C26H27N3O5: 461.1951; found: 461.1939.
Anal. Calcd for C26H27N3O5: C, 67.66; H, 5.90; N, 9.10; found: C,
67.73; H, 5.80; N, 8.92.
tert-Butyl-N-(3-acetamido-4-methylpyridin-2-yl) carbamate (26;11c
1.03 g, 3.87 mmol) dissolved in anhyd THF (100 mL) was cooled
Synthesis 2012, 44, 723–730
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Carbocyclic 4-Deazaformycins
727
1-Acetyl-7-phthalimido-3-[(3aS,4S,6R,6aR)-2,2-dimethyl-6-vi-
nyltetrahydrocyclopenta[1,3]dioxol-4-yl]pyrazolo[3,4-c]pyri-
dine (15)
7-Amino-3-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-hydroxymeth-
yltetrahydrocyclopenta[1,3]dioxol-4-yl]pyrazolo[3,4-c]pyri-
dine (22)
Compound 20 (1.00 g, 2.17 mmol) was suspended in anhyd benzene
(100 mL) and to this was added KOAc (0.25 g, 2.23 mmol) and
Ac2O (0.61 mL, 6.46 mmol). Isoamyl nitrite (0.43 mL, 3.25 mmol)
was subsequently added dropwise to the reaction mixture once it
was heated to 70 °C. The resultant mixture was heated at reflux for
10 h, cooled to r.t., filtered through Celite, and washed with hot tol-
uene (3 × 10 mL). The filtrates were evaporated and the residue was
purified by flash chromatography using a mixture of EtOAc–hex-
anes (2:3) to give 15 as a white solid (0.81 g, 79%); mp 191–192 °C.
Compound 21 (0.35 g, 0.8 mmol) was dissolved in sat. methanolic
NH3 (50 mL) at r.t. and this solution was stirred overnight. The sol-
vent was removed under vacuum and the residue purified by flash
chromatography using a mixture of MeOH–CH2Cl2 (1:9) to give
pure 22 (0.22 g, 92%) as a yellow powder; mp 104–106 °C.
1H NMR (400 MHz, CD3OD): d = 7.45 (d, J = 6.0 Hz, 1 H), 7.03 (d,
J = 6.0 Hz, 1 H), 4.81 (t, J = 6.4 Hz, 1 H), 4.55 (dd, J = 6.8, 4.0 Hz,
1 H), 3.64–3.50 (m, 3 H), 2.44–2.33 (m, 2 H), 2.00–1.92 (m, 1 H),
1.53 (s, 3 H), 1.30 (s 3 H).
1H NMR (400 MHz, CDCl3): d = 8.67 (d, J = 5.6 Hz, 1 H), 8.00–
7.96 (m, 3 H), 7.81–7.79 (m, 2 H), 5.93 (ddd, J = 16.9, 10.4, 7.2 Hz,
1 H), 5.21 (dt, J = 16.9, 1.6 Hz, 1 H), 5.17 (dt, J = 10.0, 1.2 Hz, 1
H), 4.82 (dd, J = 6.8, 6.0 Hz, 1 H), 4.54 (dd, J = 7.2, 6.0 Hz, 1 H),
3.66 (quint, J = 6.0 Hz, 1 H), 2.92 (sept, J = 6.0 Hz, 1 H), 2.66 (s, 3
H), 2.53 (quint, J = 6.4 Hz, 1 H), 2.10 (dt, J = 12.4, 1.6 Hz, 1 H),
1.65 (s, 3 H), 1.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.0, 166.8, 151.5, 143.1, 138.5,
135.2, 134.5, 133.7, 133.0, 132.6, 124.2, 116.3, 115.9, 113.9, 85.5,
84.6, 49.6, 44.1, 35.3, 27.8, 25.3, 23.9.
13C NMR (100 MHz, CD3OD): d = 148.0, 147.4, 135.9, 130.2,
126.1, 114.0, 105.8, 86.8, 84.4 (2 ×), 64.4, 45.5, 34.5, 28.1, 25.5.
HRMS: m/z calcd for C15H20N4O3: 304.1535; found: 304.1532.
7-Amino-3-[(1S,2S,3R,5R)-5-hydroxymethylcyclopentane-1,2-
diol-1-yl]pyrazolo[3,4-c]pyridine (6)
A mixture of aq 1 M HCl–THF (5 mL, 1:1) was cooled to ice bath
temperature and then added to the flask containing 22 (0.15 g, 0.50
mmol). This mixture was stirred for 6 h at r.t. and the solvent re-
moved in vacuo. The residue was purified by flash column chroma-
HRMS: m/z calcd for C26H24N4O5: 427.1747; found: 427.1748.
tography (EtOAc–MeOH–Et3N, 40:4:1) to afford 6 as a pale brown
22.9
solid (0.12 g, 88%); mp 175–177 °C; [a]D
MeOH).
–45.18 (c 0.04,
Anal. Calcd for C26H24N4O5: C, 66.09; H, 5.12; N, 11.86. Found: C,
66.18; H, 5.22; N, 11.90.
1H NMR (400 MHz, DMSO-d6): d = 8.27 (s, 1 H), 7.41 (d, J = 6.0
Hz, 1 H), 6.93 (d, J = 6.0 Hz, 1 H), 6.77 (br, 2 H), 4.25 (br, 3 H),
4.02–3.98 (m, 1 H), 3.77–3.74 (m, 1 H), 3.51–3.33 (m, 3 H), 2.13–
2.02 (m, 2 H), 1.67–1.60 (m, 1 H).
7-(2,3-Dihydro-3-hydroxy-1H-isoindol-1-one-2-yl)-3-
[(3aS,4R,6R,6aR)-2,2-dimethyl-6-hydroxymethyltetrahydrocy-
clopenta[1,3]dioxol-4-yl]pyrazolo[3,4-c]pyridine (21)
Methylmorpholine N-oxide (0.49 mL 50% wet in THF, 2.38 mmol)
was added to a solution of 15 (0.75 g, 1.59 mmol) in THF (20 mL).
After the solution was cooled to 0 °C, a catalytic amount of solid
OsO4 (4 mg, 0.016 mmol) was added and the solution stirred for 12
h at r.t. The reaction mixture was quenched by the addition of
NaHSO3 (5 g). The solvent was removed under reduced pressure
and the residue purified by flash column chromatography (EtOAc).
To the material obtained upon evaporation of the EtOAc dissolved
in CH2Cl2 (3.2 mL) was added NaIO4 (0.68 g, 3.18 mmol) dissolved
in H2O (6.4 mL). This reaction mixture was stirred at r.t. for 1 h and
then extracted with CH2Cl2 (3 × 20 mL), and the combined extracts
were dried (Na2SO4). The CH2Cl2 was removed under reduced pres-
sure at r.t. and the residue dissolved in anhyd MeOH (20 mL). This
solution was cooled to 0 °C and NaBH4 (1.2 g, 30.8 mmol) was add-
ed portionwise. After stirring the reaction at the same temperature
for 1 h, the solvent was removed and CH2Cl2 (30 mL) and H2O (15
mL) were added to the residue. The organic layer was separated and
washed with brine (10 mL) and dried (Na2SO4). The existing sol-
vent was removed under reduced pressure and the product obtained
by short column chromatography (EtOAc–hexanes, 7:3) to give 21
as a white solid, which could be further purified by recrystallization
from CH2Cl2–hexanes to form needles (0.35 g, 51% for 3 steps); mp
124–125 °C.
13C NMR (400 MHz, DMSO-d6): d = 146.7, 139.3, 134.3, 128.7,
123.9, 103.9, 77.0, 73.6, 63.1, 46.6, 32.4, 29.7.
HRMS: m/z calcd for C12H16N4O3: 264.1222; found: 264.1224.
7-Amino-3-[(3aS,4S,6R,6aR)-2,2-dimethyl-6-vinyltetrahydro-
cyclopenta[1,3]dioxol-4-yl]pyrazolo[3,4-c]pyridine (23)
Compound 15 (0.8 g, 1.69 mmol) was dissolved in sat. methanolic
NH3 (50 mL) at r.t. and the solution was stirred overnight. The sol-
vent was removed in vacuo and the residue purified by flash chro-
matography using MeOH–CH2Cl2 (1:9) as the eluent, to give pure
23 (0.43 g, 84%) as a yellow powder; mp 172–173 °C.
1H NMR (400 MHz, DMSO-d6): d = 12.57 (s, 1 H, NH), 7.50 (d,
J = 4.4 Hz, 1 H), 6.91 (d, J = 5.6 Hz, 1 H), 6.28 (s, 2 H, NH2), 5.89
(ddd, J = 16.9, 10.0, 7.2 Hz, 1 H), 5.11 (d, J = 16.9 Hz, 1 H), 5.01
(d, J = 10.8 Hz, 1 H), 4.82 (t, J = 6.4 Hz, 1 H), 4.48 (t, J = 6.4 Hz,
1 H), 3.47 (quint, J = 6.0 Hz, 1 H), 2.73 (sext, J = 6.4 Hz, 1 H), 2.33
(quint, J = 6.4 Hz, 1 H), 1.94 (q, J = 12.0 Hz, 1 H), 1.49 (s, 3 H),
1.25 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 145.9, 145.5, 139.5, 136.7,
127.5, 124.3, 115.0, 112.3, 103.2, 84.6, 49.4, 43.6, 36.7, 27.5 25.1.
HRMS: m/z calcd for C16H20N4O2: 300.1586; found: 300.1586.
1H NMR (250 MHz, CDCl3): d = 12.55 (s, 1 H, NH), 7.95–7.84 (m,
2 H), 7.65–7.50 (m, 4 H), 7.27 (s, 1 H), 6.28 (br, 1 H), 4.83–4.78 (m,
1 H), 4.58–4.52 (m, 1 H), 3.64–3.58 (m, 3 H), 3.08–3.04 (m, 1 H),
2.55–2.46 (m, 2 H), 2.19–2.08 (m, 1 H), 1.60 (s, 3 H), 1.34 (s, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 166.8, 147.0, 143.0, 137.3,
135.5, 134.0, 130.8, 130.3, 129.3, 128.6, 124.4, 123.7, 112.6, 111.8,
86.0, 83.6, 83.3, 64.0, 47.7, 44.1, 32.2, 27.7, 25.2.
Anal. Calcd for C16H20N4O2: C, 63.98; H, 6.71; N, 18.65. Found: C,
64.13; H, 6.71; N, 18.52.
7-Amino-3-[(1S,2S,3R,5R)-5-vinylmethylcyclopentane-1,2-diol-
1-yl]pyrazolo[3,4-c]pyridine (27)
Following the same procedure for obtaining 9 (see below), com-
pound 23 (0.170 g, 0.57 mmol) yielded 27 (0.12 g, 81%) as white
granules following purification by flash chromatography using a
mixture of EtOAc–MeOH–Et3N (40:4:1) followed by recrystalliza-
tion from MeOH–CH2Cl2–pentane as a white solid; mp 218–
219 °C.
HRMS: m/z calcd for C23H24N4O5: 436.1747; found: 436.1750.
1H NMR (400 MHz, DMSO-d6): d = 12.94 (br, 1 H, NH), 7.44 (d,
J = 6.0 Hz, 1 H), 6.92 (d, J = 6.0 Hz, 1 H), 6.28 (br, 2 H, NH2), 5.92
© Thieme Stuttgart · New York
Synthesis 2012, 44, 723–730

728
Y. Zhang et al.
PAPER
(ddd, J = 16.9, 10.0, 7.2 Hz, 1 H, H-5¢), 5.08 (ddd, J = 16.9, 2.0, 1.2
Hz, 1 H), 5.00 (ddd, J = 9.2, 2.0, 0.8 Hz, 1 H), 4.74 (br, 2 H), 4.02
(t, J = 5.6 Hz, 1 H, H-2¢), 3.70 (dd, J = 6.8, 5.6 Hz, 1 H, H-3¢), 3.37
(dt, J = 9.2, 6.0 Hz, 1 H, H-1¢), 2.60 (quint, J = 8.4 Hz, 1 H, H-4¢),
2.19 (dt, J = 12.8, 8.0 Hz, 1 H, H-6¢), 1.71 (dt, J = 12.8, 10.0 Hz, 1
H, H-6¢).
then at r.t. overnight. Sat. aq NH4Cl (25 mL) was then added to the
reaction mixture at 0 °C followed by stirring for 10 min. The solvent
was removed in vacuo and to the residue H2O (25 mL) was added.
This mixture was extracted with CH2Cl2 (3 × 50 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in
vacuo to dryness and the residue purified by flash chromatography
using a mixture of CH2Cl2–EtOAc (1:1) as with subsequent recrys-
tallization from CH2Cl2–hexanes to give white needles that became
a foam upon attempts to dry under vacuum (0.79 g, 57%).
1H NMR (400 MHz, CDCl3): d = 8.45 (br, 1 H), 8.07 (d, J = 4.8 Hz,
1 H), 7.14 (d, J = 5.2 Hz, 1 H), 5.72 (ddd, J = 17.2, 10.4, 7.2 Hz, 1
H), 4.99 (dt, J = 16.9, 1.2 Hz, 1 H), 4.94 (dt, J = 11.6, 1.2 Hz, 1 H),
4.26 (t, J = 6.4 Hz, 1 H), 4.13 (dd, J = 7.2, 5.6 Hz, 1 H), 2.78 (dd,
J = 10.8, 7.2 Hz, 1 H), 2.52–2.47 (m, 2 H), 2.27–2.19 (m, 1 H), 2.09
(s, 3 H), 1.92 (quint, J = 6.4 Hz, 1 H), 1.40 (s, 3 H), 1.19 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 147.0, 146.7, 141.5, 134.9,
129.0, 124.3, 114.8, 104.1, 77.0, 48.6, 43.2, 32.4.
HRMS: m/z calcd for C13H16N4O2: 260.1273; found: 260.1274.
7-Amino-3-[(3aS,4S,6R,6aR)-2,2-dimethyl-6-hydroxyethyltet-
rahydrocyclopenta[1,3]dioxol-4-yl)pyrazolo[3,4-c]pyridine (24)
To a solution of 23 (0.30 g, 1 mmol) in THF (20 mL) at 0 °C under
N2 was added 9-BBN (0.5 M in THF, 3.2 mL, 1.5 mmol), and the
resultant mixture was stirred at this temperature for 12 h. To this
was added, aq NaOH (1 M, 2.4 mL) followed by H2O2 (50% in H2O,
1.2 mL) and the stirring continued for an additional 30 min. The re-
action mixture was diluted with CH2Cl2 (70 mL) and this mixture
was washed with sat. aq NaHCO3 (30 mL). The organic layer was
dried (Na2SO4), filtered, and the filtrate concentrated in vacuo to
give the crude product as a colorless oil, which was subsequently
purified by flash column chromatography (EtOAc–hexanes, 1:4) to
afford 24 as a white solid (0.27 g, 81%); mp 125–126 °C.
1H NMR (400 MHz, CD3OD): d = 7.47 (br, 1 H), 7.03–7.02 (m, 1
H), 4.81 (t, J = 6.0 Hz, 1 H), 4.37 (t, J = 5.6 Hz, 1 H), 3.66–3.63 (m,
2 H), 3.51–3.46 (m, 1 H), 2.43 (quint, J = 6.0 Hz, 1 H), 2.30–2.18
(m, 1 H), 1.87–1.74 (m, 2 H), 1.66–1.61 (m, 1 H), 1.52 (s, 3 H), 1.29
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 169.7, 151.0, 149.8, 147.2, 138.9,
130.1, 123.8, 115.1, 112.8, 85.4, 85.1, 48.8, 44.2, 37.2, 35.3, 27.4,
25.0, 22.9.
HRMS: m/z calcd for C18H23ClN2O3: 350.1397; found: 350.1397.
1-Acetyl-7-chloro-3-[(3aS,4S,6R,6aR)-2,2-dimethyl-6-vinyltet-
rahydrocyclopenta[1,3]dioxol-4-yl]pyrazolo[3,4-c]pyridine (31)
Compound 30 (1.32 g, 3.76 mmol) was suspended in anhyd benzene
(100 mL) and to this was added KOAc (0.37 g, 3.76 mmol) and
Ac2O (1.43 mL, 11.29 mmol). Isoamyl nitrite (0.75 mL, 5.64 mmol)
was added dropwise to the reaction mixture as it was heated to
70 °C. This mixture was heated at reflux for 10 h and cooled to r.t.,
filtered through Celite, and washed with hot toluene (3 × 10 mL).
The filtrates were combined, evaporated in vacuo, and the residue
purified by flash chromatography using a mixture of EtOAc–hex-
anes (1:4) to give (0.89 g, 60%) as a white solid, together with a
small amount of 32 (0.09 g, 8%).
1H NMR (400 MHz, CDCl3): d = 8.30 (dd, J = 5.2, 0.8 Hz, 1 H),
7.72 (d, J = 5.2 Hz, 1 H), 5.88 (ddd, J = 17.2, 10.4, 7.2 Hz, 1 H),
5.16 (dt, J = 17.2, 1.2 Hz, 1 H), 5.07 (dt, J = 10.4, 1.2 Hz, 1 H), 4.78
(dd, J = 6.8, 6.0 Hz, 1 H), 4.51 (t, J = 5.6 Hz, 1 H), 3.57 (pent,
J = 6.0 Hz, 1 H), 2.86 (pent, J = 6.0 Hz, 1 H), 2.78 (s, 3 H), 2.49
(pent, J = 6.4 Hz, 1 H), 2.14 (dt, J = 13.2, 11.6 Hz, 1 H), 1.60 (s, 3
H), 1.32 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 148.0, 147.5, 136.4, 130.1,
126.3, 114.3, 105.8, 87.7, 86.8, 61.7, 45.5, 43.9, 38.0, 37.6, 28.1,
25.5.
HRMS: m/z calcd for C16H22N4O3: 318.1692; found: 318.1685.
7-Amino-3-[(1S,2S,3R,4R)-4-hydroxyethylcyclopentane-2,3-
diol-1-yl]pyrazolo[3,4-c]pyridine (9)
A mixture of TFA–H2O (6 mL, 2:1) was cooled and added to a flask
containing compound 24 (0.20 g, 0.58 mmol). This mixture was
stirred for 3 h at r.t. and the solvent was removed in vacuo. The res-
idue was purified by flash column chromatography (EtOAc–
MeOH–Et3N, 40:4:1) to afford 9 as a white solid (0.16 g, 86%); mp
155–157 °C; [a]D23.1 –18.81 (c 0.08, MeOH).
1H NMR (400 MHz, DMSO-d6): d = 12.45 (br, 1 H), 7.47 (d, J = 4.8
Hz, 1 H), 6.87 (d, J = 5.2 Hz, 1 H), 6.25 (br, 2 H), 4.61–4.44 (m, 3
H), 4.01 (br, 1 H), 3.57–3.46 (m, 3 H), 3.35–3.26 (m, 1 H), 2.21–
2.14 (m, 1 H), 1.98–1.94 (m, 1 H), 1.79–1.73 (m, 1 H), 1.50–1.40
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 168.2, 150.7, 142.2, 138.3, 137.2,
134.4, 134.1, 115.5, 113.9, 113.4, 85.2, 84.3, 49.2, 43.9, 35.0, 27.5,
25.0, 24.0.
7-Chloro-3-[(3aS,4R,6R,6aR)-2,2-dimethyl- 6-vinylmethyltet-
rahydrocyclopenta[1,3]dioxol-4-yl]pyrazolo[3,4-c]pyridine (32)
Compound 31 (0.89 g, 2.46 mmol) was dissolved in sat. methanolic
NH3 (50 mL) at r.t. and this solution was stirred overnight. The sol-
vent was removed in vacuo and the residue purified by flash chro-
matography using a mixture of MeOH–CH2Cl2 (1:9) to give pure 32
(0.79 g, quant.) as a white powder; mp 140–141 °C.
13C NMR (100 MHz, DMSO-d6): d = 147.4, 145.9, 136.4, 127.5,
124.5, 103.6, 77.1, 76.5, 59.9, 43.1, 40.9, 37.3, 32.8.
HRMS: m/z calcd for C13H18N4O3: 278.1379; found: 278.1377.
1H NMR (250 MHz, CDCl3): d = 12.01 (br, 1 H), 8.05 (d, J = 5.8
Hz, 1 H), 7.65 (d, J = 5.5 Hz, 1 H), 5.88 (ddd, J = 17.3, 10.3, 7.3 Hz,
1 H), 5.14 (td, J = 17.3, 1.3 Hz, 1 H), 5.08 (dd, J = 11.3, 1.0 Hz, 1
H), 4.90 (t, J = 6.6 Hz, 1 H), 4.52 (dd, J = 8.8, 5.8 Hz, 1 H), 3.63
(quint, J = 10.0 Hz, 1 H), 2.88 (sext, J = 6.3 Hz, 1 H), 2.51 (quint,
J = 6.5 Hz, 1 H), 2.12 (t, J = 12.5 Hz, 1 H), 1.64 (s, 3 H), 1.35 (s, 3
H).
13C NMR (62.5 MHz, CDCl3): d = 148.1, 138.7, 138.2, 135.9,
134.3, 127.7, 115.6, 114.3, 113.8, 85.4, 85.3, 49.6, 44.3, 36.5, 27.8,
25.3.
Anal. Calcd for C13H18N4O3: C, 56.10; H, 6.52; N, 20.13. Found: C,
56.16; H, 6.49; N, 20.06.
3-Acetamido-2-chloro-4-[(3aS,4S,6R,6aR)-2,2-dimethyl-6-vi-
nyltetrahydrocyclopenta[1,3]dioxol-4-methyl]pyridine (30)
3-Acetamido-2-chloro-4-methylpyridine (28;13 1.04 g, 5.63 mmol)
was dissolved in anhyd THF (100 mL) and cooled to –78 °C. To this
was slowly added n-BuLi (5.18 mL, 12.96 mmol, 2.5 M solution in
hexanes) under N2. The resulting yellow solution was stirred at the
same temperature for 15 min and then warmed to 0 °C for 30 min.
The orange solution was cooled to –78 °C and a solution of the tri-
flate 17 (1.48 g, 4.69 mmol) in anhyd THF (20 mL) was added drop-
wise. The resulting mixture was stirred at –78 °C for 15 min and
HRMS: m/z calcd for C16H18ClN3O2: 319.1088; found: 350.1397.
Synthesis 2012, 44, 723–730
© Thieme Stuttgart · New York

PAPER
Carbocyclic 4-Deazaformycins
729
7-Chloro-3-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-vinylmethyltet-
rahydrocyclopenta[1,3]dioxol-4-yl]-1-methylpyrazolo[3,4-c]py-
ridine (33a) and 7-Chloro-3-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-
vinylmethyltetrahydrocyclopenta[1,3]dioxol-4-yl]-2-methyl-
pyrazolo[3,4-c]pyridine (33b)
Compound 32 (0.85 g, 2.66 mmol) was dissolved in anhyd THF (30
mL) and this solution was cooled to 0 °C. NaH (0.089 g, 3.72 mmol)
was then added portionwise and the mixture kept at 0 °C for another
10 min. MeI (0.21 mL, 3.32 mmol) was added dropwise to the re-
sultant mixture and the system gradually warmed to r.t. followed by
stirring overnight. After adding sat. aq NH4Cl (5 mL) dropwise, the
solvent was evaporated in vacuo. To the residue was added H2O (10
mL) and this mixture was extracted with CH2Cl2 (3 × 20 mL), and
the combined extracts were dried (Na2SO4) and evaporated dryness
in vacuo. The crude product was isolated by flash chromatography
using a mixture of hexanes–EtOAc (1:4) to provide 33a (0.49 g,
55%), and hexanes–EtOAc (1:2) to yield 33b (0.36 g, 41%).
mL), and the combined extracts were dried (Na2SO4). The solvent
was removed under reduced pressure at r.t. and the residue dis-
solved in anhyd MeOH (20 mL). After the solution was cooled to
0 °C, NaBH4 (0.27 g, 7.13 mmol) was added portionwise. The reac-
tion mixture was stirred at the same temperature for 1 h and after re-
moving the solvent, CH2Cl2 (30 mL) and H2O (15 mL) were added.
The organic layer was separated and washed with brine (10 mL) and
dried (Na2SO4). The solvent was removed in vacuo and the product
obtained by short column chromatography (EtOAc–hexanes, 2:3) to
give 34a as a white solid (0.28 g, 86% for 3 steps); mp 108–109 °C.
1H NMR (400 MHz, CDCl3): d = 7.99 (d, J = 5.6 Hz, 1 H), 7.64 (d,
J = 5.6 Hz, 1 H), 4.77 (t, J = 6.4 Hz, 1 H), 4.57 (dd, J = 6.8, 4.0 Hz,
1 H), 4.36 (s, 3 H), 3.73–3.68 (m, 2 H), 3.62–3.56 (m, 1 H), 2.51 (m,
3 H), 2.11 (m, 1 H), 1.60 (s, 3 H), 1.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 145.8, 137.8, 134.6, 134.1, 129.2,
114.6, 113.0, 85.9, 83.6, 64.2, 47.8, 44.2, 38.9, 32.5, 27.7, 25.2.
HRMS: m/z calcd for C16H20ClN3O3: 337.1193; found: 337.1189.
33a
White solid; mp 69–70 °C.
7-Chloro-3-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-hydroxymeth-
yltetrahydrocyclopenta[1,3]dioxol-4-yl]-2-methylpyrazolo[3,4-
c]pyridine (34b)
Product 34b (0.20 g, 84%) was obtained by the same method as for
34a from 33a (0.25 g, 0.76 mmol) and purified by short column
chromatography (EtOAc–hexanes, 3:2) as a foam.
1H NMR (400 MHz, CDCl3): d = 7.79 (d, J = 6.0 Hz, 1 H), 7.64 (d,
J = 6.0 Hz, 1 H), 4.72–4.65 (m, 2 H), 4.29 (s, 3 H), 3.92–3.60 (m, 2
H), 3.63 (quint, J = 6.4 Hz, 1 H), 2.70 (br, 1 H), 2.52–2.44 (m, 1 H),
2.39 (quint, J = 6.4 Hz, 1 H), 2.30 (quint, J = 12.4 Hz, 1 H), 1.58 (s,
3 H), 1.29 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 143.2, 142.2, 137.67, 136.4,
123.5, 114.0, 113.8, 86.0, 82.7, 63.4, 47.2, 44.5, 39.6, 33.1, 27.8,
25.2.
1H NMR (400 MHz, CDCl3): d = 7.98 (d, J = 5.52 Hz, 1 H, H-5),
7.62 (d, J = 5.5, 1 H, H-4), 5.89 (ddd, J = 17.3, 10.3, 7.1 Hz, 1 H,
H-5¢), 5.16 (dt, J = 17.2, 1.4 Hz, 1 H, HCH=CH), 5.06 (dt, J = 10.3,
1.3 Hz, 1 H, HCH=CH), 4.82 (dd, J = 7.1, 6.0 Hz, 1 H, H-2¢), 4.48
(dd, J = 7.1, 5.9 Hz, 1 H, H-3¢), 4.36 (s, 3 H, N1-CH3), 3.59 (quint,
J = 6.5 Hz, 1 H, H-1¢), 2.84 (m, 1 H, H-4¢), 2.45 (quint, J = 6.5 Hz,
1 H, H-6¢a), 2.07 (q, J = 12.4 Hz, 1 H, H-6¢b), 1.59 (s, 3 H, CCH3),
1.32 (s, 3 H, CCH3).
13C NMR (CDCl3, 100 MHz): d = 145.4 (C-3), 138.8 (C-5¢), 137.7
(C-5), 134.6 (C-7), 134.1 (C-7a), 129.3 (C-3a), 115.6 (CH2=CH),
114.5 (C-4), 113(C-4), 6 [C(CH3)2], 85.4 (C-2¢ or C-3¢), 85.3 (C-2¢
or C-3¢), 49.8 (C-4¢), 43.9 (C-1¢), 38.9 (N1-CH3), 36.5 (C-6¢), 27.8
(CCH3), 25.3 (CCH3).
HRMS: m/z calcd for C17H20ClN3O2: 333.1244; found: 333.1240.
HRMS: m/z calcd for C16H20ClN3O3: 337.1193; found: 337.1185.
33b
7-Amino-3-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-hydroxymeth-
yltetrahydrocyclopenta[1,3]dioxol-4-yl]-1-methylpyrazolo[3,4-
c]pyridine (35a)
Compound 34a (0.20 g, 0.63 mmol) was added to MeOH 50 mL)
saturated with NH3 at 0 °C. This mixture was heated to 165 °C and
kept at this temperature for 2 d. The solvent was removed under re-
duced pressure and the product 35a was purified by chromatogra-
phy (MeOH–CH2Cl2, 1:10) as a white solid (90 mg, 45%); mp 153–
154 °C.
1H NMR (400 MHz, CD3OD): d = 7.46 (d, J = 6.0 Hz, 1 H), 7.07
(d, J = 5.6 Hz, 1 H), 4.82 (t, J = 6.4 Hz, 1 H), 4.56 (m, 1 H), 4.27
(s, 3 H), 3.59 (m, 2 H), 3.49 (m, 1 H), 2.37 (m, 2 H), 1.97 (m, 1 H),
1.57 (s, 3 H), 1.28 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 148.0, 146.3, 136.0, 129.3,
128.8, 114.0, 106.9, 86.9, 84.4, 64.4, 49.2, 45.4, 39.1, 34.6, 28.1,
25.5.
White solid; mp 110–111 °C.
1H NMR (400 MHz, CDCl3): d = 7.80 (d, J = 5.6 Hz, 1 H, H-5),
7.39 (d, J = 6.0 Hz, 1 H, H-4), 5.93 (ddd, J = 16.9, 10.4, 6.8 Hz, 1
H, H-5¢), 5.20 (dt, J = 16.9, 1.2 Hz, 1 H, HCH=CH), 5.13 (dt,
J = 10.0, 1.2 Hz, 1 H, HCH=CH), 4.71 (t, J = 6.8 Hz, 1 H, H-2¢),
4.53 (dd, J = 7.0, 6.4 Hz, 1 H, H-3¢), 4.28 (s, 3 H, N2-CH3), 3.63
(quint, J = 6.3 Hz, 1 H, H-1¢), 2.84 (sext, J = 6.4 Hz, 1 H, H-4¢),
2.42 (quint, J = 6.3 Hz, 1 H, H-6¢a), 2.24 (q, J = 12.8 Hz, 1 H, H-
6¢b), 1.57 (s, 3 H, CCH3), 1.28 (s, 3 H, CCH3).
13C NMR (100 MHz, CDCl3): d = 143.2 (C-7), 142.2 (C-7a),
137.8(C-5¢), 137.2 (C-3), 136.6 (C-5), 123.4 (C-3a), 116.3
(CH2=CH), 114.3 [C(CH3)2], 113.5 (C-4), 85.5 (C-2¢), 84.9 (C-3¢),
49.6 (C-4¢), 44.0 (C-1¢), 39.6 (N2-CH3), 36.4 (C-6¢), 27.7 (CCH3),
25.2 (CCH3).
HRMS: m/z calcd for C17H20ClN3O2: 333.1244; found: 333.1241.
HRMS: m/z calcd for C16H22N4O3: 318.1692; found: 318.1699.
7-Chloro-3-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-hydroxymeth-
yltetrahydrocyclopenta[1,3]dioxol-4-yl]-1-methylpyrazolo[3,4-
c]pyridine (34a)
7-Amino-3-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-hydroxymeth-
yltetrahydrocyclopenta[1,3]dioxol-4-yl]-2-methylpyrazolo[3,4-
c]pyridine (35b)
Following an identical procedure for obtaining 35a, compound 34b
(0.2 g, 0.63 mmol) yielded 35b (0.17 g, 84%), which was purified
by column chromatography using MeOH–CH2Cl2 (1:8) as a foam.
1H NMR (400 MHz, CD3OD): d = 7.29 (dd, J = 1.7, 6.4 Hz, 1 H),
6.87 (dd, J = 1.7, 6.4 Hz, 1 H), 4.72 (t, J = 6.9 Hz, 1 H), 4.62 (m, 1
H), 4.62 (s, 3 H), 3.71 (m, 2 H), 3.63 (m, 1 H), 2.38 (m, 2 H), 2.17
(q, J = 12.7 Hz, 1 H), 1.56 (s, 3 H), 1.29 (s, 3 H).
Methylmorpholine N-oxide (0.32 mL 50% wet in THF, 1.53 mmol)
was added to a solution of 33a (0.34 g, 1.02 mmol) in THF (20 mL).
After the solution was cooled to 0 °C, a catalytic amount of solid
OsO4 (4 mg, 0.016 mmol) was added and the solution stirred for 12
h at r.t. The reaction mixture was quenched by addition of NaHSO3
(200 mg). The solvent was removed and the residue purified by
flash column chromatography (hexanes–EtOAc, 3:1). To this isolat-
ed material dissolved in CH2Cl2 (3.2 mL) was added NaIO4 (0.44 g,
2.04 mmol) dissolved in H2O (4 mL). This reaction mixture was
stirred at r.t. for 1 h followed by extraction with CH2Cl2 (3 × 20
© Thieme Stuttgart · New York
Synthesis 2012, 44, 723–730

730
Y. Zhang et al.
PAPER
1061. (e) Hori, M.; Ito, E.; Takita, T.; Koyama, G.;
Takeuchi, T.; Umezawa, H. J. Antibiot., Ser. A 1964, 17, 96.
(f) Koyama, G.; Umezawa, H. J. Antibiot., Ser. A 1965, 18,
175.
13C NMR (100 MHz, CD3OD): d = 152.9, 137.6, 136.8, 135.9,
122.9, 114.8, 105.0, 87.1, 83.9, 63.9, 48.8, 45.2, 39.2, 34.4, 28.1,
25.5.
HRMS: m/z calcd for C16H22N4O3: 318.1692; found: 318.1691.
(3) Rodriguez, J. B.; Comin, M. J. Mini Rev. Med. Chem. 2003,
3, 95.
(1R,2S,3S,5R)-3-(7-Amino-1-methyl-1H-pyrazolo[3,4-c]pyri-
din-3-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (7)
Method A: A mixture of aq 1 M HCl–THF (5 mL, 1:1) was cooled
and added to a flask containing 35a (85 mg, 0.27 mmol). This mix-
ture was stirred for 6 h at r.t., neutralized with Amberlite IRA-67,
and the solvent removed under vacuum. The residue was purified by
flash column chromatography (EtOAc–MeOH–Et3N, 40:4:1) to af-
ford 7 as a light brown solid (60 mg, 80%); mp 151–153 °C; [a]D
–23.05 (c 0.05, MeOH).
1H NMR (400 MHz, CD3OD): d = 7.45 (d, J = 1.6, 6.0 Hz, 1 H),
7.07 (dd, J = 1.6, 6.2 Hz, 1 H), 4.27 (s, 3 H), 4.21 (m, 1 H), 3.95 (m,
1 H), 3.65 (m, 2 H), 3.51 (m, 1 H), 2.29 (m, 2 H), 1.74 (m, 1 H).
(4) (a) Giziewicz, J.; De Clercq, E.; Luczak, M.; Shugar, D.
Biochem. Pharmacol. 1975, 24, 1813. (b) Crabtree, G. W.;
Agarwal, R. P.; Parks, R. E. Jr.; Lewis, A. F.; Wotring, L. L.;
Townsend, L. B. Biochem. Pharmacol. 1979, 28, 1491.
(c) Lewis, A. F.; Townsend, L. B. J. Am. Chem. Soc. 1980,
102, 2817.
(5) (a) 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.
(b) Huggins, J.; Zhang, Z.-X.; Bray, M. J. Infect. Dis. 1999,
179, S240.
22.5
(6) Yang, M.; Zhou, J.; Schneller, S. W. Tetrahedron 2006, 62,
1295.
13C NMR (100 MHz, CD3OD): d = 148.3, 147.3, 136.5, 129.6,
129.2, 107.3, 79.0, 76.0, 65.4, 48.4, 44.0, 39.3, 31.3.
(7) Leading references for carbocyclic C-nucleosides:
(a) Boyer, S. J.; Leahy, J. W. J. Org. Chem. 1997, 62, 3976.
(b) Chun, B. K.; Song, G. Y.; Chu, C. K. J. Org. Chem. 2001,
66, 4852; and references cited therein. (c) Tuncbilek, M.;
Schneller, S. W. Bioorg. Med. Chem. 2003, 11, 3331.
(d) Zhou, J.; Yang, M.; Schneller, S. W. Tetrahedron Lett.
2004, 45, 8233. (e) Zhou, J.; Yang, M.; Akdag, A.;
Schneller, S. W. Tetrahedron 2006, 62, 7009.
(8) Yang, M.; Schneller, S. W. Bioorg. Med. Chem. Lett. 2005,
15, 149.
(9) Kourafalos, V. N.; Marakos, P.; Pouli, N.; Terzis, A.;
Townsend, L. B. Heterocycles 2002, 12, 2335.
(10) Crystallographic data (Figure 3) for 25, which was a minor
product in the ammonolysis of 12 have been deposited with
Cambridge Crystallographic Data Centre (e mail:
ccdc@code.cam.ac.uk) and allocated the deposition number
CCDC 851387.
HRMS: m/z calcd for C13H18N4O3: 278.1379; found: 278.1374
Method B: By adapting a literature procedure,14 a solution of com-
pound 6 (200 mg, 0.76 mmol) in anhyd DMF (10 mL) containing
DMF dimethyl acetal (1.6 mL) was heated at 70 °C overnight. The
solvent was evaporated and the resultant syrup was dissolved in
NH4OH and stirred at r.t. for 3 d. After evaporation, the residue was
purified by flash column chromatography (EtOAc–MeOH–Et3N,
40:4:1) to afford 7 (150 mg, 71%) as a light brown solid and whose
spectral properties were identical to 7 obtained above from 35a.
(1R,2S,3S,5R)-3-(7-Amino-2-methyl-2H-pyrazolo[3,4-c]pyri-
din-3-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (8)
Following an identical procedure for obtaining 7, target 8 was
achieved from 35b (150 mg, 0.47 mmol) as a light yellow solid (106
mg, 81%); mp 160–162 °C; [a]D23.0 –43.23 (c 0.42, MeOH).
1H NMR (400 MHz, CD3OD): d = 7.16 (d, J = 1.7, 6.4 Hz, 1 H),
6.96 (dd, J = 6.2 Hz, 1 H), 4.24 (m, 1 H), 4.12 (s, 3 H), 3.95 (m, 1
H), 3.64 (m, 3 H), 2.22 (m, 2 H), 1.76 (m, 1 H).
13C NMR (100 MHz, CD3OD): d = 152.3, 139.7, 136.2, 131.9,
122.6, 105.8, 78.6, 75.5, 64.6, 48.4, 43.1, 39.2, 30.1.
OH
N
N
MeN
25
HRMS: m/z calcd for C13H18N4O3: 278.1379; found: 278.1371.
Figure 3 Hydrolyis side-product from 12
Acknowledgment
(11) (a) Marakos, P.; Pouli, N.; Wise, D. S.; Townsend, L. B.
Synlett 1997, 561. (b) Kourafalos, V. N.; Marakos, P.; Pouli,
N.; Townsend, L. B. Synlett 2002, 1479. (c) Kourafalos, V.
N.; Marakos, P.; Pouli, N.; Townsend, L. B. J. Org. Chem.
2003, 68, 6466. (d) Korouli, S.; Lougiakis, N.; Marakos, P.;
Pouli, N. Synlett 2008, 181. (e) Kourafalos, V. N.; Tite, T.;
Mikros, E.; Marakos, P.; Pouli, N.; Balzarini, J. Synlett 2008,
3129. (f) Tite, T.; Lougiakis, N.; Marakos, P.; Pouli, N.
Synlett 2009, 2927. (g) Tite, T.; Lougiakis, N.;
Myrianthopoulos, V.; Marakos, P.; Mikros, E.; Pouli, N.;
Tenta, R.; Fragopoulou, E.; Nomikos, T. Tetrahedron 2010,
66, 9620.
(12) Adapting a procedure reported in: Wang, P.; Agrofoglio, L.
A.; Gary Newton, M.; Chu, C. K. Tetrahedron Lett. 1997,
38, 4207.
(13) Chapman, D.; Hurst, J. J. Chem. Soc., Perkin Trans. 1 1980,
2398.
This research was supported by funds from Department of Health
and Human Services (AI 56540). Also, support from the Molette
Fund and Auburn University is appreciated. The assistance of Asim
Ali in adapting this manuscript for the template is acknowledged.
References
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Synthesis 2012, 44, 723–730
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