Regioselective synthesis of 3-deazacarbovir and its 3-deaza-adenosine analogues

Article abstract of DOI:10.1016/j.tet.2009.08.087

We herein report the hitherto unknown synthesis of 3-deazacarbovir and its adenosine analogue. The major highlight in the synthesis of adenosine analogs is to use 6-N,N-diboc protected 3-deazapurines 9 and 11 for regioselective Mitsunobu coupling as well

Full text of DOI:10.1016/j.tet.2009.08.087

Tetrahedron 65 (2009) 9362–9367
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective synthesis of 3-deazacarbovir and its 3-deaza-adenosine analogues
*
Ashok K. Jha, Ashoke Sharon, Ramu Rondla, Chung K. Chu
The University of Georgia, College of Pharmacy, Athens, GA 30602-2352, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2009
Received in revised form 28 August 2009
Accepted 31 August 2009
Available online 10 September 2009
We herein report the hitherto unknown synthesis of 3-deazacarbovir and its adenosine analogue. The
major highlight in the synthesis of adenosine analogs is to use 6-N,N-diboc protected 3-deazapurines 9
and 11 for regioselective Mitsunobu coupling as well as unexplored palladium catalyzed coupling with
these substrates. Synthesis of 3-deazacarbovir 1 has been accomplished by the regioselective palladium
catalyzed coupling of 6-N,N-diphenylcarbamoyl protected 3-deazaguanine base 18 with dicarbonate 14.
All the target nucleosides were screened for anti-HIV-1 activity and none of them have significant
Keywords:
activity as well as toxicity up to 100 mM.
3-Deaza nucleosides
Palladium catalyzed coupling
Carbocyclic nucleosides
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
corresponding carbohydrate counterpart.1 Since the discovery of the
naturally occurring aristeromycin and neplanocin A as biologically
interesting carbocyclic nucleosides, a numberof synthetic carbocyclic
nucleosides have been synthesized and have shown interesting an-
tiviral activity (Fig. 1).2–9 Two carbocyclic nucleosides abacavir10 and
Carbocyclic nucleosides have emerged as the target of intense
investigation due to their interesting biological activity and greater
metabolic stability to nucleoside phosphorylase, than the
Figure 1. Some important carbocyclic nucleoside and its 3-deaza analogs.
entecavir11 have been approved by the US FDA for the treatment of
HIV and HBV, respectively. The discovery of 20,30-olefinic carbocyclic
nucleosides, such as carbovir and abacavir having potent anti-HIV
activity, has increased interests in the search for novel nucleosides in
* Corresponding author. Tel.: þ1 706 542 5379; fax: þ1 706 542 5381.
E-mail address: dchu@rx.uga.edu (C.K. Chu).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.087

A.K. Jha et al. / Tetrahedron 65 (2009) 9362–9367
9363
this class of compounds. Carbocyclic 20,30-didehydro-20,30-dideoxy
adenosine has also shown potent anti-HIV-1 activity equivalent to
dideoxyinosine (ddI) but one third to carbovir.10,12
product (Scheme 1). Compound 6 was reacted with trimethyl
orthoformate and pyridinium p-toluenesulfonate (PPTS) to obtain
cyclic 20,30-orthoester followed by heating in acetic anhydride at
120 ꢀC to obtain compound 7 in moderate yield. Finally, removal of
the benzoyl group using LiOH gave compound 8. Mitsunobu cou-
pling of 3-deazapurine with 20,30-unsaturated carbocyclic alcohol
has been recently reported to produce a mixture of N-7 and N-9
Nucleoside analogs based on the 3-deazapurine (1H-imid-
azo[4,5-c]pyridine) framework have found significant usefulness in
the design of antiviral agent and biochemical investigations.13–15
Carbocyclic analogs of 3-deazapurines such as 3-deazaaristero-
mycin16 and 3-deazaneplanocin A17,18 are potent inhibitors of
S-adenosylhomocysteine hydrolase, which display wide variety of
antiviral activity against DNA and RNA viruses. In our efforts to
further explore the carbocyclic 3-deazanucleoside, it was of interest
to synthesize hitherto unknown 3-deazacarbovir 1 and carbocyclic
20,30-didehydro-20,30-dideoxy-3-deaza-adenosine analogs 2 and 3.
Several synthetic methodologies have been reported for the
synthesis of carbovir19–28 among them palladium catalyzed cou-
pling and convergent approach to construct base ring are most
isomers.31 Introduction of bulkier group at 6-amino group in ade-
32
nine
shields the reaction at N-7 position and produce N-9
regioselectivity. However, the use N,N-diboc protected 3-deaza-
purines 933 have not been much explored for the synthesis of car-
bocyclic 3-deaza nucleosides. Mitsunobu coupling of compound 8
with diboc protected nucleobase 9 gave the desired N-9 isomer 10
as major isolable product. On TLC, it appears another isomer may be
present <5–7%, but could not be isolated pure. Removal of diboc
and tert butyl groups using either TFA/H2O (2:1 or 3:1) or 2 M HCl
in methanol at 30–50ꢀ resulted in the cleavage of nucleosidic bond
within 45 min. However, deprotection was finally effected with TFA
in anhydrous DCM at rt for 3–4 h to get the target compound 2 in
moderate yield (Scheme 1).
prominent. Our group has reported the synthesis of L-carbovir us-
ing Mitsunobu coupling.29 Our aim was to explore the synthesis of
carbocyclic 20,30-didehydro-20,30-dideoxy-3-deaza-adenosine ana-
logs 2 and 3 using Mitsunobu coupling of suitable protected
Scheme 1. Reagents and conditions: (a) BzCl, Pyr, rt, 12 h; (b) concentrated HCl/MeOH (1:70, v/v), rt, 2.5 h; (c) (i) CH(OMe)3, pyridinium p-toluenesulfonate, rt, 2 h; (ii) Ac2O,
120–130 ꢀC, 6 h; (d) LiOH, MeOH/THF/H2O (5:3:2) rt, 1.5 h (e) Ph3P, DIAD, THF, 0 ꢀC to rt; (f) DCM, TFA rt 3–4 h.
3-deaza bases 9 and 11 with cyclopentenol 8 as well as explore
these bases for hitherto unknown palladium catalyzed coupling
with dicarbonate 14. For the regioselective synthesis of 3-deaza-
carbovir, we developed N,N-diphenylcarbamoyl protected 3-dea-
zaguanine base 18, which was found to be good substrate for the
palladium catalyzed coupling with dicarbonate 14.
To explore the palladium catalyzed coupling to generate carbo-
cyclic 3-deazanucleoside, we used Crimmins method23 to obtain
dicarbonate 14 in 5 steps (Scheme 2). Palladium catalyzed coupling
of dicarbonate 14 with 4-chloro-1H-imidazo-[4,5-c]pyridine 1234 or
4,6-dichloro-1H-imidazo-[4,5-c]pyridine 1334 resulted in a difficult
separable mixture of N-9 and N-7 isomers in moderate yields. Al-
though the N,N-diboc protected adenine31 have been explored for
the regioselective Mitsunobu coupling in the synthesis of carbocyclic
nucleoside, however, this base hasn’t been explored for a palladium
catalyzed coupling. Therefore, we focused our strategy to explore 6-
N,N-diboc protected 3-deaza nucleobases33 9 and 11, which un-
derwent smooth regioselective Palladium catalyzed coupling with
dicarbonate 14 using standard condition23 to yield nucleosides 15
and 16, respectively. Similar to the Mitsunobu coupling with com-
pound 8, the palladium catalyzed coupling reaction also indicates the
2. Chemistry
Intermediate 4 was prepared from
reported previously.30 Cyclopentanol 8 was prepared analogously
to the reported method published for
-sugar from our group.29
D-ribose in 10 steps as
L
Protection of hydroxyl group in compound 4 using benzoyl chloride
gave compound 5, which was treated with MeOH/conc HCl to ob-
tain compound 6 along with the 2-benzoyl migrated undesired
Scheme 2. Reagents and conditions: (a) Pd(PPh3)4, THF/DMSO (1:1), rt, 1 h; (b) (i) DCM, TFA, rt 5–7 h; (ii) K2CO3/MeOH, 1 h, rt.

9364
A.K. Jha et al. / Tetrahedron 65 (2009) 9362–9367
Scheme 3. Reagents and conditions: (a) (i) Diphenyl carbamoyl chloride, diisopropyl amine, pyridine, 1 h, 85%; (ii) K2CO3, MeOH, 45 min; (b) Pd(PPh3)4, THF/DMSO (1:1), rt,
45 min–1 h; (c) NH3 (l), MeOH, 80 ꢀC, 16 h.
presence of another isomer <5–7% (by TLC). However, in the case of
compound 11, the N-9 isomer was the only isomer visible on TLC as
well as isolable. Removal of protecting groups in compounds 15 and
16 were effected with TFA in anhyd DCM followed by treating the
crude with K2CO3/MeOH yielded the smooth conversion to com-
pounds 2 and 3, respectively in good yield.
6-N,N-doboc protected bases 9, 11 and 6-N,N-diphenylcarbamoyl
3-deazaguanosine 18, with dicarbonate 14 was found to be highly
regioselective. These bases can be explored further for the regio-
selective synthesis of various other carbocyclic as well as ribose-3-
deazaguanosine analogs. Carbocyclic nucleosides 1–3 were tested
for anti-HIV activity in human peripheral blood mononuclear
(PBM) cells infected with HIV-1. Cytotoxicity was tested in three
cell lines (PBM, CEM, and Vero). Unfortunately, all the compounds
did not show anti-HIV-1 activity as well as cytotoxicity up to
Carbocyclic 3-deazaguanosine analogs are hitherto unknown in
literature and are difficult to synthesize due to the limited avail-
ability of synthetic methodology as well as the regioselectivity for
N-7/N-9 isomers. Palladium catalyzed coupling of N-acetyl-3-de-
azaguanosine 1735 with dicarbonate 14 gave a complex reaction
mixture. Finally, we aimed to prepare a novel N,N-diphenyl car-
bamoyl protected 3-dezaguanine base, similarly to the case of pu-
rines.36 This may completely shield the reaction at N-7 position,
moreover deprotection can also be effected in mild basic condition
(Scheme 3). Reaction of N-acetyl-3-deazaguanosine 17 with N,N-
diphenylcarbamoyl chloride gave the 6-(O),9-di-N,N-diphenyl
carbamate protected N-acetyl-3-deazaguanosine, which was se-
lectively deprotected to compound 18. Palladium catalyzed cou-
pling of base 18 with dicarbonate 14 proceeded smoothly to give
exclusively N-9 product 19 as a white solid in good yield. All the
protecting groups were removed with heating compound 19 using
NH3/MeOH in steel reaction vessel at 80 ꢀC to obtain 3-deaza-
carbovir 1 in good yield, which was recrystallized in methanol/
acetonitrile. It is worthwhile to mention that during deprotection
increasing temperature >100 ꢀC leads to the epimerization at C-1
in w7–10% (by 1H NMR) (Scheme 3).
100 mM.
4. Experimental
4.1. Materials and methods
NMR spectra were recorded on Varian Inova 500 MHz with
tetramethylsilane as the internal standard. Chemical shifts (d) are
reported as s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), or bs (broad singlet). Optical rotations were measured by
a Jasco DIP-370 digital polarimeter. High-resolution mass spectra
(HRMS) were recorded on a Micromass Autospec high-resolution
mass spectrometer using electrospray ionization (ESI) in positive
mode. Microanalyses have been performed at Atlantic microanal-
ysis labs, Atlanta. Melting points were taken on Mel-Temp II
melting point apparatus and were uncorrected. TLC was performed
on 0.25 mm silica gel. Purifications were carried out using flash
silica gel (60 Å, 32–63 mm) or C18 reversed silica gel (230–400
mesh).
The nucleosides obtained were characterized by spectroscopic
methods, and the structure of 3-deazacarbovir 1 was further con-
firmed by a single-crystal X-ray diffraction study, and the ORTEP
diagram37 is shown in Figure 2 with their corresponding atomic
numbering. The crystal structural studies show a planar confor-
mation of cyclopentene ring with anti-base disposition.
4.1.1. 6-(tert-Butoxymethyl)-2,2-dimethyltetrahydro-3aH-cyclo-
penta[d][1,3]dioxol-4-yl benzoate (5). To a solution of alcohol 4
(2.75 g, 11.18 mmol) in pyridine (10 mL) at 0 ꢀC was added benzoyl
chloride (2.0 mL, 17 mmol) dropwise and the reaction mixture was
stirred at room temperature for 4 h. Reaction mixture was quenched
by adding ice, and extracted by EtOAc, washed with aq NaHCO3
(2ꢁ10 mL), followed by satd NH4Cl soln The solvent was removed
under reduced pressure and the residue purified by column chro-
matography (EtOAc/hexanes, 20:1) to afford compound 3 (3.5 g, 90%)
25
as viscous oil: [
a]
ꢂ52.38 (c 1.60, CH2Cl2). 1H NMR (500 MHz,
D
CDCl3)
d
8.13 (m, 2H), 7.57 (m, 1H), 7.46 (m, 2H), 5.24 (m, 1H), 4.80 (t,
J¼5.5, 8.5 Hz, 1H), 4.54 (d, J¼5.5 Hz, 1H), 3.42 (dd, J¼4.5, 8.5 Hz, 1H),
3.34 (dd, J¼4.5, 8.5 Hz, 1H), 2.48 (m, 1H), 2.32 (m, 1H), 2.02 (m, 1H),
1.44 (s, 3H),1.34 (s, 3H),1.22(s, 9H).13C NMR(125 MHz, CDCl3)
d 166.2,
132.7,130.4,129.7,128.2,111.0, 83.6, 79.0, 74.7, 2.8, 63.0, 41.8, 32.1, 27.4,
26.3, 24.8. HRMS (ESI) calcd [MþH]þ (C20H29O5): 349.2015, found
349.2016.
4.1.2. (1S,2R,3R,4R)-4-(tert-butoxymethyl)-2,3-dihydroxycyclopentyl
benzoate (6). To a solution of compound 5 (3.15 g, 9.04 mmol) in
MeOH and conc HCl (100 mL, conc HCl/MeOH 1:70, v/v) was stirred
at room temperature for 3 h. The reaction mixture was cooled using
ice bath, neutralized with solid NaHCO3, and filtered. The filtrate
was concentrated to dryness, and the residue was purified by col-
umn chromatography (EtOAc/hexanes, 1:4) to afford 6 as well as
2-benzoyl migrated compound (7–10% by 1H NMR) (1.9 g, 68%) as
Figure 2. ORTEP diagram showing displacement ellipsoid plot (30% probability) of the
X-ray crystal structure of compound 1.
3. Conclusion
We have described the hitherto unknown synthesis of 3-de-
azacabovir 1 and 20,30-didehydro-20,30-dideoxy-3-deaza-adenosine
analogs 2 and 3. Exploration of palladium catalyzed coupling for

A.K. Jha et al. / Tetrahedron 65 (2009) 9362–9367
9365
syrup: 1H NMR (500 MHz, CD3OD)
d
8.12 (m, 2H), 7.62 (m, 1H), 7.5
methanol and neutralized with solid NaHCO3 and purified by col-
umn chromatography (methanol/DCM/NH4OH, 1:8.9:0.1) to get the
(m, 2H), 5.24 (m, 1H), 4.20 (m, 1H), 3.95 (m, 1H), 3.50 (m, 2H), 2.37
(m, 1H), 2.18 (m, 1H), 1.99 (m, 1H), 1.23 (s, 9H). 13C NMR (125 MHz,
compound 8 as white solid (80 mg, 34.7% over 2 steps): mp 206 ꢀC.
24
CD3OD)
d
166.4, 132.7, 130.2, 129.3, 128.0, 74.9, 73.1, 72.9, 72.4, 62.5,
[a
]
ꢂ10.28 (c¼0.35, MeOH). UV (pH 2.0) lmax¼264 ( ¼35 600),
3
D
43.4, 30.2, 26.4. HRMS (ESI) calcd [MþH]þ (C17H25O5): 309.1702,
(pH 7.4) lmax¼265 (
3
¼28 700), (pH 11) lmax¼266 (
3
¼31000); 1H
found 309.1690.
NMR (500 MHz, DMSO-d6)
d
8.07 (s, 1H), 7.69 (d, 1H, J¼6.0 Hz), 6.90
(d, 1H, J¼6.0 Hz), 6.20 (m, 1H), 6.15 (s, 2H, NH2) 5.98 (m, 1H), 5.60
(m, 1H), 4.79 (t, 1H, J¼5.0 Hz, OH), 3.48 (m, 2H), 2.91 (bs, 1H), 2.69–
2.63 (m, 1H), 1.67–1.62 (m, 1H). 13C NMR (125 MHz, DMSO-d6),
153.8, 141.8, 141.6, 139.8, 139.2, 131.4, 128.6, 99.1, 65.3, 62.8, 56.5,
49.3, 35.6. Anal. Calcd for C12H14N4O 0.15H2O: C, 61.88; H, 6.01; N,
24.06. Found: C, 61.82; H, 6.06; N, 24.07.
4.1.3. (1S,4S)-4-(tert-butoxymethyl)cyclopent-2-enyl benzoate (7). A
suspension of compound 6 (1.0 g, 5.48 mmol) and pyridinium
p-toluenesulfonate (1.2 g, 6.0 mmol) in trimethyl orthoformate
(12 mL) was stirred at room temperature for 2 h. The reaction
mixture was diluted with ethyl acetate (50 mL) and washed with
aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4),
filtered, concentrated to dryness. The residue, after being co-evap-
orated with toluene (2ꢁ10 mL) treated with acetic anhydride
(15 mL). The reaction mixture was heated at 120–130 ꢀC for 8 h,
after completion of reaction (monitored by TLC), it was concen-
trated under reduced pressure to dryness. The residue was purified
4.1.7. ((1S,4S)-(4-(4-(N,N0-Di-tert-butyloxycarbonyl)-amino-1H-
imidazo[4,5-c]pyridin-1-yl)) cyclopent-2-enyl)methyl ethyl carbonate
(15). A solution of compound 9 (0.26 g, 0.775 mmol) and tetrakis
(triphenylphosphine) palladium (0) (115 mg, 10 mol %) in 5 mL
DMSO was degassed and stirred at room temperature for 5 min
under nitrogen atmosphere. A solution of dicarbonate 14 (0.2 g,
0.775 mmol) in 5 mL THF was added dropwise and reaction mix-
ture continued stirring for 1 h (color turns light yellow to orange
color). It was quenched with water, extracted with EtOAc, washed
with water, dried (Na2SO4) and concentrated. The crude was puri-
fied by column chromatography (EtOAc/hexane, 1:1) to afford the
compound 15 as yellow syrup (337 mg; contaminated with 5–7%
PPh3O by 1H NMR): UV (MeOH), lmax¼265 nm; 1H NMR (500 MHz,
by column chromatography (EtOAc/hexane, 1:50) to afford com-
25
pound 7 as oil (0.48 g, 53.9%): [
NMR (500 MHz, CDCl3)
a
]
ꢂ215.0 (c 0.316, CH2Cl2) 1H
D
d
8.01 (m, 2H), 7.53 (m,1H), 7.43 (m, 2H), 6.15
(m,1H), 5.97 (m,1H), 5.94 (m,1H), 3.3 (d, J¼7.0 Hz, 2H), 3.14 (m,1H),
2.02–2.16 (m, 2H), 1.19 (S, 9H). 13C NMR (125 MHz, CDCl3)
d
166.6,
140.0,132.7,130.6,130.1,129.5,128.2, 80.6, 72.7, 65.5, 45.7, 34.3, 27.5.
HRMS (ESI) calcd [MþH]þ (C17H23O3): 275.1647, found 275.1643.
4.1.4. (1S,4S)-4-(tert-butoxymethyl)cyclopent-2-enol (8). To a solu-
tion of (1S,4S)-4-(tert-butoxymethyl)cyclopent-2-enyl benzoate (7)
(0.4 g, 1.45 mmol) in MeOH/THF/H2O (5:3:2) was added LiOH$H2O
(0.1 g, 2.1 mmol) The reaction mixture was stirred at room tem-
perature for 1.5 h, after completion of reaction, solvent was evap-
orated under reduced pressure and crude was extracted with EtOAc
and washed with brine (2ꢁ10 mL). The organic layer was dried
(Na2SO4), concentrated under reduced pressure and the crude was
CDCl3)
d
8.32 (d, 1H, J¼5.5 Hz), 8.00 (s, 1H), 7.45 (d, 1H, J¼5.5 Hz),
6.21 (m, 1H), 5.99 (m, 1H), 5.54 (m, 1H), 4.29 (dd, 1H, J¼5.5 Hz,
11.0 Hz), 4.20 (m, 3H, OCHþOCOCH2), 3.23 (m, 1H), 2.85 (m, 1H),
1.86 (m, 1H), 1.43 (s, 18H), 1.32 (t, 3H). 13C NMR (125 MHz, CDCl3)
d
155.1, 151.4, 150.0, 144.5, 143.0, 140.6, 139.9, 130.5, 106.5, 82.8,
69.0, 64.3, 61.9, 44.6, 34.2, 27.9, 14.2. HRMS (ESI) calcd [MþH]þ
(C25H35ClN4O7): 503.2506, found 503.2505.
purified by column chromatography (EtOAc/hexane, 1:5) to get the
4.1.8. ((1S,4S)-4-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-
2-enyl)methanol (2). To a solution of 15 in DCM was added TFA
(0.7 mL, excess) and reaction mixture stirred at room temperature
for 5 h. After complete consumption of starting material, solvent
was evaporated under reduced pressure and dried under high
vacuum to get the crude as foam, which was dissolved in 10 mL
methanol and added 0.2 mL of 10% aq K2CO3 and stirred for 1 h.
Solvent was evaporated under reduced pressure and purified by
column chromatography (methanol/DCM/NH4OH, 1:8.9:0.1) to get
the compound 2 as white solid. 80 mg (45% over 2 steps).
25
desired compound 8 as syrup (0.18 g, 73%): [
CH2Cl2); 1H NMR (500 MHz, CDCl3)
4.88 (m, 1H), 3.22 (m, 2H), 3.06 (m, 1H), 1.92 (m, 1H), 1.86 (m, 1H),
a
]
D ꢂ219.25 (c 0.234,
d
6.00 (m, 1H), 5.88 (m, 1H),
1.36 (bs, 1H, OH), 1.16 (s, 9H). 13C NMR (125 MHz, CDCl3)
d 137.6,
133.9, 77.1, 72.6, 65.8, 45.4, 37.6, 27.5. HRMS (ESI) calcd [2MþH]þ
(C20H38O4) 341.2692, found 341.2838.
4.1.5. (1S,4S)-4-N,N-Di tert butyl carbonyl-1-(4-(tert-butoxymethyl)-
cyclopent-2-enyl)-1H-imidazo[4,5-c] pyridine (10). To a solution of
compound 8 (0.17 g, 1 mmol), diboc protected base 933 (0.5 g,
1.5 mmol) and PPh3 (0.78 g, 3.0 mmol) in THF was added DIAD
(0.58 mL, 3.0 mmol) dropwise at 0 ꢀC under inert condition. Re-
action mixture was stirred at room temperature for 4–5 h, then
concentrated and purified by column chromatography (EtOAc/
hexane, 1:5) to afford compound 10 as light yellow oil (contami-
nated with DIAD by product): UV (MeOH), lmax¼278.0, 250. nm; 1H
4.1.9. ((1S,4S)-(4-(4-(N,N0-Di-tert-butyloxycarbonyl)-amino-6-
chloro-1H-imidazo[4,5-c]pyridin-1-yl))cyclopent-2-enyl)methyl ethyl
carbonate (16)
4.1.9.1. Experimental procedure same as for compound 15. White
23
foam, 70.8%:
[
a]
ꢂ19.67 (c¼0.7, DCM). UV (MeOH),
D
lmax¼278.0 nm, 262.0 nm (s); 1H NMR (500 MHz, CDCl3)
d 8.00 (s,
NMR (500 MHz, CDCl3)
d
8.32 (d, J¼6.0 Hz), 8.30 (s, 1H), 7.69 (d,
1H), 7.44 (s, 1H), 6.24 (m, 1H), 5.98 (m, 1H), 5.48 (m, 1H), 4.30 (dd,
1H, J¼4.5 Hz, 5.5 Hz), 4.20 (m, 3H), 3.23 (bs, 1H), 2.81–2.88 (m, 1H),
1.82–1.88 (m, 1H), 1.43 (s, 9H), 1.31 (t, 2H). 13C NMR (125 MHz,
J¼6.0 Hz, 1H), 6.20 (m, 1H), 5.8 (m, 1H), 5.58 (m, 1H), 3.41 (d, J¼5.0,
9.0 Hz, 1H), 3.33 (d, J¼5.0, 9.0 Hz, 1H), 3.04 (m, 1H), 2.77 (m, 1H),
1.70 (m, 1H), 1.38 (s, 9H), 1.35 (s, 9H), 1.13 (s, 9H). 13C NMR
CDCl3)
d 155.1, 150.9, 144.1, 143.0, 141.7, 141.3, 137.9, 136.7, 130.0,
(125 MHz, CDCl3)
d 151.7, 150.8, 150.6, 145.3, 140.3, 140.1, 136.7,
106.0, 83.2, 68.7, 64.3, 62.0, 44.6, 34.2, 27.9, 14.2. HRMS (ESI) calcd
128.5, 127.2, 115.5, 83.5, 83.4, 72.9, 63.7, 61.7, 46.2, 35.8, 27.9, 27.5,
27.4. HRMS (ESI) calcd [MþH]þ (C26H39N4O5): 487.2920, found
487.2927.
[MþH]þ (C25H34ClN4O7): 537.2116, found 537.2123.
4.1.10. ((1S,4S)-(4-(4-amino-6-chloro-1H-imidazo[4,5-c]pyridin-1-
yl)cyclopent-2-enyl)) methanol (3)
4.1.6. ((1S,4S)-4-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-
2-enyl)methanol (2). To a solution of crude compound 10 in DCM
was added TFA (0.7 mL, excess) and reaction mixture stirred at
room temperature for 5 h. After complete consumption of starting
material, solvent was evaporated under reduced pressure and dried
under high vacuum to get the crude as foam. Crude was dissolved in
4.1.10.1. Experimental procedure same as for compound 2 in
4.1.8. White solid (81.8%), mp 190 ꢀC: [
24
a]
ꢂ7.058 (c¼0.19,
D
MeOH): UV (pH 2.0) lmax¼286 (s), 269 (
lmax¼270 ( ¼23 800), (pH 11) lmax¼271 (
(500 MHz, DMSO-d6)
3
¼18 600) (pH 7.4)
3
3
¼23 200); 1H NMR
d
8.04 (s, 1H), 6.92 (s, 1H), 6.68 (s, 2H, NH2),

9366
A.K. Jha et al. / Tetrahedron 65 (2009) 9362–9367
6.16 (m, 1H), 5.94 (m, 1H), 5.56 (m, 1H), 4.80 (bs, 1H, OH), 3.49 (m,
2H, OCH2), 2.90 (bs, 1H), 2.65 (m, 1H), 1.65 (m, 1H). 13C NMR
6.23 (m, 1H, olefin-H), 5.99 (m, 1H, olefin-H), 5.76 (s, 1H), 5.41 (m,
1H), 3.64 (m, 2H), 3.03 (m, 1H), 2.76 (m, 1H), 1.72 (m, 1H). 13C NMR
(125 MHz, DMSO-d6)
d
145.0, 142.6, 141.3, 141.0, 139.8, 138.7, 129.3,
(CD3OD) d 157.6, 147.4, 143.2, 138.4, 138.0, 129.5, 122.9, 72.7, 64.1,
95.9, 63.9, 61.7, 47.9, 33.9. Anal. Calcd for C12H14N4ClO: C, 54.45; H,
4.95; N, 21.17. Found: C, 54.67; H, 4.95; N, 20.88.
61.5, 53.2, 33.8. Anal. Calcd for C12H14N4O2; C, 58.53; H, 5.73; N,
22.75. Found: C, 58.43; H, 5.76; N, 22.68.
4.1.11. 6-Acetamido-1H-imidazo[4,5-c]pyridin-4-yl diphenylcarba-
mate (18). Diphenyl carbamoyl chloride (1.72 g, 7.41 mmol) was
added to a suspension of compound 1735 (570 mg, 2.96 mmol) in
diisopropyl amine (1.03 mL, 5.92 mmol) and anhydrous pyridine
(5 mL) and stirring was continued at room temperature for 1 h. The
reaction was quenched with water and stirring was continued for
10 min and the volatiles were evaporated under reduced pressure.
The residue was purified by column chromatography using 50%
EtOAc/hexane to get 6-(O),9-di-N,N-diphenyl carbamate protected
N-acetyl-3-deazaguanosine in 85% yield. 1H NMR (500 MHz,
4.2. X-ray data for compound 1
4.2.1. Crystal data of 1. C12H14N4O2, M¼246.27, monoclinic, space
group P2, a¼9.127(2), b¼11.812(2), c¼11.642(2) Å,
b
¼106.37(3)ꢀ,
V¼1204.2(4) Å3, T¼293 K, Z¼2, R1¼0.0465 for 1610 Fo>4sig(Fo) and
0.0591 for all 1707 data. Crystallographic data have been deposited
with Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 737517. These data can be obtained free of
charge from www.ccdc.cam.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Center, 12 Union Road, Cambridge,
CB2 1EZ, UK; E-mail: deposit@ccdc.cam.ac.uk].
DMSO-d6):
d 10.72 (s, 1H, NH), 8.53 (s, 1H), 8.03 (s, 1H), 7.32–7.45
(m, 20H), 2.11 (s, 3H). 13C NMR (125 MHz, DMSO-d6): 167.5, 151.6,
150.0, 149.5, 146.9, 146.5, 144.2, 142.7, 142.6, 136.6, 130.2, 129.8,
128.0, 127.4, 127.3, 124.3, 97.1, 24.3. HRMS (ESI) calcd [MþH]þ
(C34H27N6O4): 583.2094, found 583.2073.
Acknowledgements
This research was supported by U.S. Public Health Service Re-
search grants NIH AI25899 from the National Institute of Allergy
and Infectious Diseases, NIH. We are grateful to Dr. Raymond F.
Schinazi, Emory University School of Medicine/Veterans Affairs
Medical Center, Atlanta, Georgia, USA for Anti-HIV-1 and cytotox-
icity studies.
To a solution of di-N,N-diphenylcarbamoyl protected compound
(600 mg, 1.03 mmol) in methanol and potassium carbonate
(213 mg, 1.54 mmol) was added and the reaction was stirred at
room temperature for 45 min. The solvent was evaporated under
reduced pressure and the residue was purified by column chro-
matography (MeOH–CH2Cl2, 1:25) to afford compound 18 as light
brown solid (0.31 g, 78%): 1H NMR (500 MHz, DMSO-d6):
d 12.93 (s,
Supplementary data
1H, NH), 10.60 (s, 1H, NH), 8.38 (s, 1H), 8.25 (s, 1H), 7.37–7.52 (m,
10H), 2.14 (s, 3H). 13C NMR (125 MHz, DMSO-d6): 169.3, 152.0,
150.0, 146.8, 144.4, 144.3, 143.7, 142.4, 129.7, 128.4, 127.3, 95.1, 24.27.
HRMS (ESI) calcd [MþH]þ (C21H18N5O3): 388.1410, found 388.1396.
The supplementary data associated with this article can be
found in the on-line version, at doi:10.1016/j.tet.2009.08.087.
References and notes
4.1.12. 6-Acetamido-1-(4-((ethoxycarbonyloxy)methyl)cyclopent-2-
enyl)-1H-imidazo[4,5-c]pyridin-4-yl diphenylcarbamate (19). A so-
lution of 18 (0.31 g, 0.8 mmol) and tetrakis (triphenylphosphine)
palladium (0) (92 mg, 10 mol %) in 5 mL DMSO was degassed and
stirred at room temperature for 5 min under nitrogen atmosphere.
A solution of dicarbonate 14 (0.21 g, 0.8 mmol) in 5 mL THF was
added dropwise and reaction mixture continued stirring for 2 h
(color turns light yellow to orange color). It was quenched with
water, extracted with EtOAc, washed with water, dried (Na2SO4)
and concentrated. The crude was purified over flash silica gel
(EtOAc/hexane, 2:3) to afford the compound, which was recrys-
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tallized with EtOAc/hexane to get the compound 19 as white solid.
26
(330 mg, 64.8%), mp 192 ꢀC: [
a
]
ꢂ58.12 (c¼0.31, MeOH), UV
D
(MeOH), lmax¼269 nm. 1H NMR (500 MHz, CDCl3)
d 8.23 (s, 1H),
7.96 (s, 1H), 7.92 (s, 1H, NH), 7.46 (m, 4H), 7.36 (m, 4H), 7.22 (m, 2H),
6.23 (m, 1H), 5.98 (m, 1H), 5.51 (m, 1H), 4.17–4.24 (m, 4H, 2ꢁOCH2),
3.22 (bs, 1H), 2.89 (m, 1H), 2.18 (s, 3H), 1.71 (m, 1H), 1.30 (t, 3H). 13C
NMR (125 MHz, CDCl3)
d 168.4, 155.0, 151.9, 150.0, 147.5, 143.4,
142.8, 142.2, 137.6, 135.0, 132.1, 132.0, 131.9, 130.1, 129.4, 129.0,
128.5, 128.4, 128.0, 93.6, 69.3, 64.2, 61.3, 44.6, 34.7, 24.6, 14.2. HRMS
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4.1.13. 6-Amino-1-(4-(hydroxymethyl)cyclopent-2-enyl)-1H-imid-
azo[4,5-c]pyridin-4(5H)-one (1). To a solution of compound 19
(255 mg) in methanol was passed NH3 (g) at ꢂ30 ꢀC for 1 h in steel
bomb. Sealed reaction vessel was then heated at 80 ꢀC for 24 h.
Solvent was evaporated and the crude solid was purified over
amine functionalized silica gel (MeOH/DCM, 1:10). Compound 1
was further recrystallized with MeOH/acetonitrile to get the com-
23
pound as transparent crystals. (95 mg, 84.8%), mp >260 ꢀC: [
a]
D
ꢂ10.39 (c¼0.41, MeOH). UV (pH 2.0) lmax¼313 (
3
¼28 700), 280
¼45 600), (pH
7.75 (s, 1H),
(3
¼56 400), (pH 7.4) lmax¼299 (s,
3
¼32 000), 269 (
3
11) lmax¼303 (s), 271 (
3
¼55 800). 1H NMR (CD3OD)
d

A.K. Jha et al. / Tetrahedron 65 (2009) 9362–9367
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