2′-Fluoro-3-deazaaristeromycin

Article abstract of DOI:10.1016/j.tet.2012.03.023

The carbocyclic nucleoside 3-deazaaristeromycin has shown biological promise but a library of its derivatives upon which to expand this property is lacking. To address this situation, the synthesis of the two diastereomers of 2′-fluoro-3-deazaaristeromyci

Full text of DOI:10.1016/j.tet.2012.03.023

Tetrahedron 68 (2012) 3908e3914
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
20-Fluoro-3-deazaaristeromycin
*
Chun Chen, Wei Ye, Chong Liu, Stewart W. Schneller
Molette Laboratory for Drug Discovery, Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The carbocyclic nucleoside 3-deazaaristeromycin has shown biological promise but a library of its de-
rivatives upon which to expand this property is lacking. To address this situation, the synthesis of the two
diastereomers of 20-fluoro-3-deazaaristeromycin is described in a multistep convergent process that calls
Received 3 January 2012
Received in revised form 6 March 2012
Accepted 7 March 2012
upon
D
-ribose for construction of the cyclopentyl fluoro units.
Available online 13 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Carbocyclic nucleosides
Mitsunobu coupling
Grubbs reaction
DAST fluorination
1. Introduction
NH2
NH2
N
N
The carbocyclic nucleoside aristeromycin (1) represents a unique
structure among nature’s library of small molecules.1 Its potential as
a medicinal agent has been limited due to associated toxicity.2
However, its synthetic partner 3-deazaaristeromycin (2)3 has
demonstrated less restrictive properties but its further development
has been lacking. To address this situation, we have undertaken
a more extensive investigation of 2 by preparing a variety of de-
rivatives. Our recent attention was drawn to fluoro substituted tar-
gets because of their potential biological significance.4 Here we
report the synthesis of the two diastereomers of 20-fluoro-3-
deazaaristeromycin 3 and 4 (Fig. 1).
N
N
N
X
N
HO
HO
Y
HO
OH
HO
X
1, X=N
2, X=CH
3, X=F,Y=H
4, X=H,Y=F
The retrosynthetic analysis guiding the synthesis of 3 and 4
(Scheme 1) required the preparation of the unknown cyclo-
pentylidene protected cyclopentenone 5, which was selected over
the more common isopropylidene cyclopentenone,5 because 5
would be less volatile under the planned reaction pathways. Thus,
Fig. 1. Aristeromycin and related compounds.
protection of the resultant secondary alcohol via the p-methox-
ybenzyl accessory provided 13. To expose the C-2 center for in-
troducing the desired fluorine atom, 13 was deprotected to the diol
14 that was, in turn, selectively mono-protected at the C-2 and C-3
hydroxyls as tert-butyldiphenylsilyl units (i.e., 15 and 16).
To proceed toward 3, the free hydroxyl of 16 was inverted by
a Mitsunobu reaction6 (to 17) and, subsequent, lithium hydroxide
saponification resulted in 18. Fluroination (DAST) to 19 was fol-
lowed by construction of the C-4 protected hydroxymethylene that
proceeded via (i) oxidative glycolization (NMO), cleavage (NaIO4),
and reduction (NaBH4) (to 20), (ii) protection as the tert-butyldi-
phenylsilyl derivative (21), and (iii) removal of the p-methox-
ybenzyl provided the requisite cyclopentanol 22 for coupling with
an appropriate 3-deazapurine.
beginning with -ribose (6, Scheme 2) and, following established
D
conditions,5 5 was realized via a Grubbs metathesis conversion5
(step e).
With 5 in hand, we moved to appending the 50-hydroxyl-
methylene precursor (arrow, Scheme 1) prior to bringing the fluoro
atoms into the process. In that regard, treatment of 5 vinyl-
magnesium bromide in the presence of cuprous bromide gave the
1,4-adduct 11 (Scheme 3). Subsequent keto reduction (to 12) and
* Corresponding author. Tel.: þ1 334 844 6947; fax: þ1 334 844 0239; e-mail
address: schnest@auburn.edu (S.W. Schneller).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.023

C. Chen et al. / Tetrahedron 68 (2012) 3908e3914
3909
O
ROH2C
3 and 4
OPMB
OR
OR'
F
O
O
R'O
TBDPSO
5
Scheme 1. Retrosynthetic approach to 3 and 4.
O
O
X
OMe
HO
OH
OH
OH
O
O
a
c
d
O
O
O
HO
O
O
on 8
6
D-ribose
7, X=OH
8, X=I
9
10
b
e
5
Reaction conditions: a, cyclopentanone, HC(OMe)3, MeOH, H2SO4, 78%; b, I2, PPh3,
MeCN/toluene, imidazole, rt, 80%; c, Zn, MeOH/AcOH, reflux, 80%; d, CH2=CHMgBr,
CH2Cl2,THF, 84%; e, (i) Grubbs 1st generation catalyst, CH2Cl2, rt; (ii) MnO2, CH2Cl2,
70% for 2 steps.
Scheme 2. Preparation of cyclopentenone 5.
The C-2
a
-fluoro coupling partner 26 was achieved beginning
generally carried out in an N2 atmosphere under anhydrous
conditions.
with 16 (Scheme 4) via the same sequence that was described for
22 from 16 except, of course, for the initial inversion necessitated in
the latter process to carry out the DAST fluorination.
The target syntheses (Scheme 5) were completed by subjecting
22/26 to a Mitsunobu coupling7 with the Boc protected 3-
deazaadenine 278 to 28a/28b. Removal of the protecting groups
of these latter products with HCl in methanol gave 3 and 4,
respectively.9
2.1.1. ((3a0R,60R,6a0R)-40-Methoxytetrahydrospiro[cyclopentane-1,20-
furo[3,4-d]-[1,3]dioxole]-60-yl)methanol (7).
D
-Ribose (6, 15 g,
100 mmol), cyclopentanone (88 mL, 1 mol), MeOH (100 mL), and
trimethyl orthoformate (55 mL, 500 mmol) were added to a 500 mL
flask. To this, concd H2SO4 (0.5 mL) was added carefully. The mix-
ture was stirred at room temperature for 2 days. Ammonium hy-
droxide (29.6%) was added to neutralize the mixture. The solvent
was removed under reduced pressure and the residue dissolved in
EtOAc, which was, in turn, washed with brine, dried (Na2SO4), and
concentrated to give 7 as yellow oil (17.8 g, 78.0%). 1H NMR
The availability of 3 and 4 adds to the growing list of fluoro
nucleosides of potential biological relevance.4
2. Experimental
2.1. General
(400 MHz, CDCl3)
d
4.98 (s, 1H), 4.79 (d, J¼6.0 Hz, 1H), 4.55 (d,
J¼6.0 Hz, 1H), 4.44 (t, J¼2.8 Hz, 1H), 3.67 (m, 2H), 3.44 (s, 3H), 3.29
(dd, J¼3.6, 9.6 Hz, 1H), 1.95 (m, 2H), 1.68 (m, 6H); 13C NMR
1H and 13C NMR spectra were measured on a Bruker AV-400
spectrometer or Bruker AC-250 spectrometer. 1H chemical shifts
are reported relative to CDCl3 at
(100 MHz, CDCl3),
d 121.8, 109.8, 88.2, 85.6, 81.5, 64.1, 55.6, 35.8,
35.7, 23.8, 23.3. Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C,
57.27; H, 7.96.
d 7.27 ppm (or MeOD at d 3.51 ppm
or DMSO-d6 at 2.51 ppm) and tetramethylsilane as an internal
d
2.1.2. (3a0S,40S,6a0R)-40-Iodomethyl-60-methoxytetrahydrospiro[cy-
clopentane-1,20-furo[3,4-d][1,3]dioxole] (8). Compound 7 (17.81 g,
78 mmol) was dissolved in MeCN/toluene (1:1, 250 mL). To this
imidazole (7.97 g, 117 mmol) and triphenylphosphine (TPP) (22.5 g,
86 mmol) were added. This was followed by the addition of I2
(21.8 g, 86 mmol) in portions until the solution turned black. The
resulting solution was stirred at room temperature for 2 h. Water
(100 mL) and sodium thiosulfate (5 g) were then added until the
solution became clear. The organic layer was separated, dried
(Na2SO4), concentrated, and the residue purified with column
chromatography (hexanes/EtOAc¼5:1). The product 8 was isolated
standard. 13C chemical shifts are reported in relative to CDCl3/
MeOD/DMSO-d6. The spin multiplicities are indicated by the sym-
bols s (singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of
doublets). Elemental analyses were performed by Atlantic Micro-
labs, Atlanta, Georgia. Reactions were monitored by thin layer
chromatography (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 iodine vapor. Column
chromatography was performed on Whatman silica gel (average
ꢀ
particle size 5e25 mm, 60 A) and elution with the indicated solvent
system. Yields refer to chromatographically and spectroscopically
as colorless oil (21.13 g, 80.1%). 1H NMR (400 MHz, CDCl3)
d 5.06 (s,
(1H and 13C NMR) homogeneous materials. The reactions were

3910
C. Chen et al. / Tetrahedron 68 (2012) 3908e3914
Scheme 3. Synthesis of precursor to 3.
R
a
b
16
OPMB
F
OR'
F
TBDPSO
TBDPSO
23
24 R=CH2OH;R'=PMB
c
Note: the following are isomeric pairs,
25, R=CH2OTBDPS;R'=PMB
26, R=CH2OTBDPS;R'=H
19/23, 20/24, 21/25, 22/26.
d
Reaction conditions: a, see step h of Scheme 3, 65%; b, see step i of Scheme 3, 59% for
2 steps; c, see step e of Scheme 3, 94%; d, see step k of Scheme 3, 66%.
Scheme 4. Synthesis of precursor to 4.
1H), 4.71 (d, J¼5.6 Hz,1H), 4.7 (d, J¼5.6 Hz,1H), 4.45 (m,1H), 3.37 (s,
was followed by the addition of AcOH (0.23 mL, 7.5 mmol) in one
portion via syringe. The resultant reaction mixture was heated to
reflux for 5 h followed by cooling to room temperature, filtering
through a short plug of Celite, and washing with a mixture of
THF/hexanes (1:1, 100 mL). The filtrate was concentrated in vacuo
to provide a colorless oil, which was purified by silica gel column
chromatography (hexanes/EtOAc, 2:1) to afford (2R,3R)-3-vinyl-
1,4-dioxaspiro[4.4]nonane-2-carbaldehyde (9) (9.07 g, 80.1%) as
3H), 3.3 (m, 1H), 3.18 (m, 1H), 1.90 (m, 2H), 1.68 (m, 6H); 13C NMR
(100 MHz, CDCl3),
d 123.1, 109.9, 87.9, 85.8, 82.7, 55.2, 35.8, 35.7,
23.6, 23.2, 6.7. Anal. Calcd for C11H17O4I: C, 38.84; H, 5.04. Found: C,
39.08; H, 5.09.
2.1.3. (3aR,6aR)-3aH-Spiro[cyclopenta[d][1,3]dioxole-2,10-cyclo-
pentan]-4(6aH)-one (5). To a stirred solution of iodide 8 (21.13 g,
62 mmol) in MeOH (200 mL) at room temperature was added zinc
a colorless oil. 1H NMR (400 MHz, CDCl3)
5.75 (m, 1H), 5.3e5.5 (m, 2H), 4.76 (m, 1H), 4.34 (m, 1H), 2.09 (m,
d
9.55 (d, J¼3.2 Hz, 1H),
powder (4.47 g, 68 mmol, Aldrich, dust, <10 m) in one batch. This

C. Chen et al. / Tetrahedron 68 (2012) 3908e3914
3911
Scheme 5. Final steps in the preparation of 3 and 4.
2H), 1.75 (m, 6H); 13C NMR (100 MHz, CDCl3)
120.0, 81.9, 79.4, 36.9, 36.8, 24.1, 23.3.
d
200.8, 131.2, 121.1,
residue was purified by silica gel column chromatography (hexanes/
EtOAc, 4:1) to afford 11 as a colorless oil (1.92 g, 66%): 1H NMR
Compound 9 (9.07 g, 49.8 mmol) was dissolved in CH2Cl2 (50 mL)
and to this vinylmagnesium bromide (59.7 mL, 59.7 mmol, 1 M in
THF) was added at ꢀ78 ꢁC. The resultant mixture was warmed to
(400 MHz, CDCl3)
d
5.85 (m,1H), 5.17e5.08 (m, 2H), 4.56 (d, J¼5.6 Hz,
1H), 4.18 (d, J¼5.2 Hz,1H), 3,13 (m,1H), 2.85 (dd, J¼8.40 Hz,1H), 2.32
(m, J¼18.0 Hz, 1H), 1.94e1.65 (m, 8H); 13C NMR (100 MHz, CDCl3)
0
ꢁC and saturated aqueous NH4Cl (40 mL) added to quench the
d 213.2,137.3, 122.3, 116.5, 81.6, 77.7, 40.0, 38.8, 36.3, 36.2, 23.9, 23.1.
reaction. The organic layer was separated, dried (Na2SO4), and
concentrated using a rotavapor (bath temperature <10 ꢁC). The
residue was purified by silica gel column chromatography (hexanes/
EtOAc, 5:1) to give 1-((2S,3R)-3-vinyl-1,4-dioxaspiro[4.4]nonan-2-
yl)prop-2-en-1-ol (10) as colorless oil (8.77 g, 83.8%, as a mixture
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.34; H, 7.8.
2.1.5. 2,3-(Cyclopentylidenedioxy)-4-vinylcyclopentanol (12). To
a stirred solution of cyclopentenone 11 (1.92 g, 9.2 mmol) and
CeCl3$7H2O (2.93 g, 10.1 mmol) in MeOH (30 mL) at 0 ꢁC was added
NaBH4 (0.698 g, 18.4 mmol) in small portions. After stirring at room
temperature for 1 h the mixture was neutralized with concd HCl,
reduced to 2:3 volume, extracted with brine and Et2O, and the
organic layers combined, dried (MgSO4), and concentrated to give
of two diastereomers).1H NMR (400 MHz, CDCl3)
d
6.13 (m,1H), 5.79
(m,1H), 5.35 (m, 4H), 4.55 (m,1H), 4.2 (m,1H), 4.02 (m,1H), 2.01 (m,
2H), 1.65 (m, 6H); 13C NMR (100 MHz, CDCl3),
137.7, 136.9, 134.0,
d
133.9, 119.8, 119.0, 118.7, 117.2, 116.6, 80.7, 80.6, 79.0, 78.7, 71.3, 70.9,
37.1, 37.0, 36.9, 36.6, 24.2, 24.1, 23.4, 23.3.
12 as a colorless oil (1.84 g, 94.7%). 1H NMR (400 MHz, CDCl3)
d 5.72
Compound 10 (8.77 g, 41.7 mmol) was dissolved in dry CH2Cl2
(100 mL) and through this solution N2 was bubbled for 30 min to
remove O2. To this was added Grubbs first generation catalyst
(343 mg, 0.417 mmol) and the solution stirred at room temperature
for 12 h. Then the solution was cooled to 0 ꢁC and then warmed to
60 ꢁC for the addition of activated MnO2 powder (10.88 g,
125 mmol, commercially available). The mixture was cooled to
room temperature, stirred overnight, and H2O (200 mL) was added.
The organic layer was separated, filtered, dried (Na2SO4), concen-
trated under reduced pressure, and purified by silica gel column
chromatography (hexanes/EtOAc, 2:1) to give 5 as white solid
(m, 1H), 5.06e5.10 (m, 2H), 4.4 (m, 2H), 4.07e4.13 (m, 1H), 2.76 (m,
1H), 2.41 (d, J¼7.6 Hz, 1H), 1.89e1.96 (m, 4H), 1.7 (m, 6H); 13C NMR
(100 MHz, CDCl3)
d 138.5, 121.6, 115.3, 84.4, 79.0, 71.3, 44.3, 36.3,
35.7, 35.5, 24.2, 23.1. Anal. Calcd for C12H18O3: C, 68.54; H, 8.63.
Found: C, 68.33; H, 8.60.
2.1.6. (3aS,4S,6R,6aR)-4-(4-Methoxybenzyloxy)-6-vinyltetrahydro-
3aH-spiro-[cyclopenta[d][1,3]dioxole-2,10-cyclopentane]
(13). Compound 12 (3.00 g, 14.3 mmol) was dissolved in dry DMF
(15 mL) and this solution cooled to 0 ꢁC. Then, NaH (685 mg,
17.1 mmol, 60% in mineral oil) was added in one portion. The re-
sultant solution was stirred for 30 min and then p-methoxybenzyl
chloride (PMBCl) (4.15 mL, 28.5 mmol) added at 0 ꢁC in one portion.
The solution was stirred at room temperature for 3 h and then the
solvent was removed under reduced pressure. To this saturated
aqueous NH4Cl solution (40 mL) was added and the mixture
extracted with EtOAc (3ꢂ50 mL). The combined organic layers were
dried (Na2SO4), concentrated, and the residue purified by silica gel
column chromatography (hexanes/EtOAc, 8:1) to provide 13 as
(5.28 g, 70.2%), mp 53e55 ꢁC. 1H NMR (400 MHz, CDCl3)
d 7.63 (dd,
J¼2.4, 4.8 Hz, 1H), 6.28 (d, J¼6.0 Hz, 1H), 5.23 (dd, J¼2.0, 5.2 Hz, 1H),
4.40 (d, J¼5.2 Hz,1H),1.86 (m, 2H),1.66 (m, 6H); 13C NMR (100 MHz,
CDCl3),
d 204.0, 159.9, 135.5, 124.3, 78.2, 76.2, 37.9, 37.4, 24.1, 23.3.
Anal. Calcd for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.79; H, 7.02.
2.1.4. (3aR,6R,6aR)-6-Vinyldihydro-3aH-spiro[cyclopenta[d][1,3]di-
oxole-2,10-cyclopentan]-4(6aH)-one (11). Vinylmagnesium bromide
(17.34 mL, 17.34 mmol, 1.0 M in THF) was added, dropwise by sy-
ringe, to a suspension of CuBr$Me2S (0.285 g, 1.39 mmol) in anhy-
drous THF (20 mL) at ꢀ78 ꢁC. This reaction mixture was stirred at the
same temperature for 30 min before a solution of 10 (2.5 g,
13.9 mmol), TMSCl (3.68 mL, 29.1 mmol), and HMPA (6.28 mL,
36.1 mmol) in THF (20 mL) was added dropwise via a cannula. The
reaction mixture was kept stirring at ꢀ78 ꢁC for 5 h and then
warmed to room temperature. Saturated aqueous NH4Cl (15 mL)
and tetra-N-butylammonium fluoride (TBAF, 3.0 mL) were added to
quench the reaction and this mixture stirred for 30 min. The reaction
mixture was diluted with EtOAc (100 mL) and extracted with EtOAc
(3ꢂ50 mL). The combined organic phases were washed with brine,
dried (MgSO4), and concentrated under reduced pressure. The
a colorless oil (4.06 g, 86.2%). 1H NMR (400 MHz, CDCl3)
d 7.32 (d,
J¼8.8 Hz, 2H), 6.89 (d, J¼8.8 Hz, 2H), 5.68 (m, 1H), 5.03 (m, 1H), 4.97
(m, 1H), 4.65 (d, J¼10.4 Hz, 1H), 4.55 (d, J¼10.4 Hz, 1H), 4.43 (t,
J¼6.4, 5.6 Hz, 1H), 4.30 (d, J¼5.6 Hz, 1H), 3.81 (m, 4H), 2.66 (t,
J¼7.2 Hz, 6.75, 1H), 2.03e2.16 (m, 2H), 1.70e1.94 (m, 8H); 13C NMR
(100 MHz, CDCl3) d 159.5, 138.9,130.8,129.7,121.0,115.0,114.0, 84.0,
78.5, 77.9, 71.7, 55.5, 44.1, 35.8, 35.6, 32.1, 24.3, 23.3. Anal. Calcd for
C20H26O4: C, 72.70; H, 7.93. Found: C, 72.35; H, 8.01.
2.1.7. (1R,2R,3S,5R)-3-(4-Methoxybenzyloxy)-5-vinylcyclopentane-
1,2-diol (14). Compound 13 (4.06 g, 12.29 mmol) was dissolved in
3 N HCl (0.41 mL) in MeOH and stirred at 25 ꢁC overnight. Neu-
tralization of this solution with NaHCO3 was conducted and the

3912
C. Chen et al. / Tetrahedron 68 (2012) 3908e3914
mixture filtered. The filtrate was removed under reduced pressure,
and the residue purified by silica gel column chromatography
(hexanes/EtOAc, 3:1) to provide 14 as a colorless oil (2.82 g, 86.7%).
(m, 2H), 4.42e4.48 (m, 2H), 3.8 (s, 3H), 3.73e3.79 (m, 2H),
2.82e2.89 (m, 1H), 2.5 (s, 1H), 2.01e2.09 (m, 1H), 1.56e1.61 (m, 1H),
1.05 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 159.6, 136.2, 134.2, 133.2,
1H NMR (400 MHz, CDCl3)
d
7.26 (d, J¼8.8 Hz, 2H), 6.88 (d, J¼8.8 Hz,
131.3, 130.2, 129.3, 128.1,120.9, 114.2, 85.1, 79.2, 77.8, 72.7, 55.4, 47.2,
33.2, 27.1, 19.4. Anal. Calcd for C31H38O4Si: C, 74.06; H, 7.62. Found:
C, 74.03; H, 7.51.
2H), 5.77 (m, 1H), 5.05 (m, 1H), 4.97 (m, 1H), 4.65 (d, J¼11.6 Hz, 1H),
4.55 (d, J¼11.6 Hz, 1H), 4.02 (t, J¼6.4, 5.6 Hz, 1H), 3.99 (m, 1H), 3.81
(s, 3H), 3.66 (t, J¼6.4, 7.6, 1H), 2.63e2.7 (m, 1H), 2.05e2.09 (m, 1H),
1.59e1.67 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
159.7, 138.7, 131.1,
2.1.10. tert-Butyl((1R,2S,3S,5R)-2-fluoro-3-(4-methoxybenzyloxy)-5-
vinylcyclo-pentyloxy)diphenylsilane (19). Compound 18 (1.5 g,
2.98 mmol) was dissolved in dry CH2Cl2 (12 mL) and to this pyridine
(0.7 mL, 8.95 mmol) and DAST (0.59 mL, 4.48 mmol) were added.
The resultant solution was warmed to room temperature under N2
for 12 h and then reaction quenched with saturated aqueous
Na2CO3 solution (15 mL). The mixture was extracted with EtOAc
(3ꢂ20 mL) and the combined organic layers dried (Na2SO4), con-
centrated under reduced pressure, and purified by silica gel column
chromatography (hexanes/EtOAc, 6:1) to provide 19 as a colorless
129.5, 121.1, 114.0, 84.0, 78.5, 77.9, 71.7, 55.5, 44.3, 32.2. Anal. Calcd
for C15H20O4: C, 68.16; H, 7.63. Found: C, 68.14; H, 7.52.
2.1.8. (1R,2R,3S,5R)-2-(tert-Butyldiphenylsilyloxy)-3-(4-
methoxybenzyloxy)-5-vinylcyclopentanol (15) and (1S,2R,3R,5S)-2-
(tert-butyldiphenylsilyloxy)-5-(4-methoxybenzyloxy)-3-
vinylcyclopentanol (16). Compound 14 (2.82 g, 10.67 mmol) was
dissolved in dry CH2Cl2 (20 mL) and to this 4-(dimethylamino)
pyridine (DMAP) (65 mg, 0.53 mmol) was added. The resultant
solution was treated with imidazole (726 mg, 10.67 mmol) and
TBDPSCl (3.0 mL, 11.74 mol) at 0 ꢁC. This was followed by warming
the solution to room temperature and stirring for an additional 2 h.
Water (20 mL) was added to quench the reaction. The mixture was
extracted with EtOAc (3ꢂ20 mL) and the combined organic layers
dried (Na2SO4), concentrated under reduced pressure, and the
residue purified by silica gel column chromatography (hexanes/
EtOAc, 5:1) to provide 15 (2.2 g, 41%) and 16 (1.82 g, 34%) as col-
oil (0.956 g, 63.5%). 1H NMR (400 MHz, CDCl3)
d 7.69e7.72 (m, 4H),
7.27e7.42 (m, 6H), 7.25 (d, J¼2 Hz, 2H), 6.86 (d, J¼2 Hz, 2H),
5.32e5.42 (m, 1H), 4.83e4.92 (m, 2H), 4.39e4.44 (m, 2H),
3.81e3.92 (m, 2H), 3.76 (s, 3H), 2.80e2.86 (m, 1H), 2.5 (s, 1H),
2.02e2.12 (m, 1H), 1.55e1.65 (m, 1H), 1.08 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d 158.2, 138.6, 135.4, 133.4, 130.9, 130.3, 129.5,
127.6, 121.2, 114.1, 85.3, 79.3, 78, 71.6, 55.4, 44.3, 33.1, 25.2, 19.5.
Anal. Calcd for C31H37FO3Si: C, 73.77; H, 7.39. Found: C, 73.82; H,
7.33.
orless oil. Compound 15: 1H NMR (400 MHz, CDCl3)
d 7.68e7.71 (m,
4H), 7.27e7.42 (m, 6H), 7.25 (d, J¼2 Hz, 2H), 6.86 (d, J¼2 Hz, 2H),
5.32e5.42 (m, 1H), 4.83 (m, 1H), 4.71e4.81 (m, 1H), 4.49 (d,
J¼11.6 Hz, 1H), 4.42 (d, J¼11.6 Hz, 1H), 3.78 (m, 5H), 2.74e2.8 (m,
1H), 2.7 (s, 1H), 2.02e2.12 (m, 1H), 1.55e1.65 (m, 1H), 1.07 (s, 9H);
2.1.11. ((1R,2R,3S,4S)-2-(tert-Butyldiphenylsilyloxy)-3-fluoro-4-(4-
methoxybenzyloxy)cyclopentyl)methanol (20). Compound 19 (2.2 g,
4.36 mmol) was dissolved in MeOH (20 mL) and to this 4-
methylmorpholine N-oxide (1.8 mL, 8.72 mmol, 50% in water),
H2O (14 mL), and NaIO4 (2.05 g, 9.59 mmol) were added. The
mixture was cooled to 0 ꢁC and OsO4 (55 mg, 0.218 mmol, 5 mol%)
was added. This mixture was stirred at 0 ꢁC for 2 h and then filtered
followed by removing the MeOH under reduced pressure. The
residue was extracted with CH2Cl2 (3ꢂ50 mL) and the combined
organic layers washed with brine, dried (Na2SO4), and concen-
trated. The residue was dissolved in MeOH (20 mL) and to this was
added NaBH4 (412 mg, 10.9 mmol) portionwise at 0 ꢁC. The mixture
was stirred at 0 ꢁC for 1 h and saturated aqueous NH4Cl solution
(20 mL) was added. The mixture was filtered through Celite and the
filtrate removed under reduced pressure. The residue was extracted
with EtOAc (3ꢂ15 mL) and the combined organic layers dried
(Na2SO4), then concentrated to give a residue that was purified by
silica column chromatography (hexanes/EtOAc, 5:1) to provide 20
as a colorless oil (1.29 g, 58.3%). 1H NMR (400 MHz, CDCl3)
13C NMR (100 MHz, CDCl3)
d 158.1, 138.4, 135.5, 133.5, 131.1, 130.1,
129.7, 127.6, 121.1, 114.0, 84.0, 78.5, 77.9, 71.7, 55.5, 44.3, 32.2, 25.3,
19.3. Anal. Calcd for C31H38O4Si: C, 74.06; H, 7.62. Found: C, 74.01; H,
7.53. Compound 16: 1H NMR (400 MHz, CDCl3)
d 7.68e7.71 (m, 4H),
7.34e7.43 (m, 6H), 7.25 (d, J¼4.8 Hz, 2H), 6.85 (d, J¼4.8 Hz, 2H),
5.30e5.42 (m, 1H), 4.8e4.92 (m, 2H), 4.41e4.49 (m, 2H), 3.79 (s,
3H), 3.71e3.79 (m, 2H), 2.81e2.9 (m,1H), 2.49 (s,1H), 2.02e2.12 (m,
1H), 1.55e1.65 (m, 1H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
159.7, 136.3, 134.1, 133.1, 131.2, 130.3, 129.2, 128.1, 120.9, 114.3,
85.2, 79.3, 77.9, 72.8, 55.5, 47.3, 33.3, 27.2, 19.4. Anal. Calcd for
C31H38O4Si: C, 74.06; H, 7.62. Found: C, 74.15; H, 7.59.
2.1.9. (1R,2R,3R,5S)-2-(tert-Butyldiphenylsilyloxy)-5-(4-
methoxybenzyloxy)-3-vinylcyclopentanol (18). Compound 16 (2 g,
3.98 mmol) was dissolved in THF (20 mL) and to this chloroacetic
acid (489 mg, 5.17 mmol) and Ph3P (2.09 g, 7.96 mmol) were added.
The resultant solution was cooled to ꢀ40 ꢁC and diisopropyl azo-
dicarboxylate (DIAD) (1.16 mL, 5.97 mmol) added dropwise.
The mixture was warmed to room temperature, and then heated
to 60 ꢁC for 24 h. The solvent was removed under reduced
pressure and the residue purified by silica column chromatography
(hexanes/EtOAc, 6:1) to give (1R,2R,3R,5S)-2-(tert-butyldiphe-
d
7.67e7.70 (m, 4H), 7.28e7.41 (m, 6H), 7.25 (d, J¼8.4 Hz, 2H), 6.86
(d, J¼8.4 Hz, 2H), 4.41e4.48 (m, 2H), 3.80e3.88(m, 2H), 3.74 (s, 3H),
3.69e3.72(m, 2H), 2.81e2.89 (m, 1H), 2.5 (s, 1H), 1.71e1.85 (m, 2H),
1.14 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 157.9, 138.3, 133.4, 131.2,
129.8, 129.6, 127.5, 121.2, 85.3, 79.1, 77.8, 71.5, 61.4, 55.2, 44.2, 32.8,
25.4, 19.6. Anal. Calcd for C30H37FO4Si: C, 70.83; H, 7.33. Found: C,
70.63; H, 7.44.
nylsilyloxy)-5-(4-methoxybenzyloxy)-3-vinyl
cyclopentyl
2-
chloroacetate (17) as colorless oil (1.52 g, 66%). The crude prod-
uct, which was contaminated with diisopropyl hydrazine-1,2-
dicarboxylate, was used in next step without further purification.
Compound 17 (1.72 g, 2.97 mmol) was dissolved in 1 N LiOH
(5.9 mL) in MeOH (20 mL) and this solution stirred at 25 ꢁC for 2 h.
To this, 0.5 N HCl (aqueous) solution was added to neutralize the
solution. This was followed by the addition of H2O (10 mL) and the
mixture was extracted with EtOAc (3ꢂ20 mL). The combined or-
ganic layers were dried (Na2SO4), concentrated under reduced
pressure, and purified by silica gel column chromatography (hex-
anes/EtOAc, 6:1) to provide 18 as a colorless oil (1.27 g, 84.8%). 1H
2.1.12. tert-Butyl(((1R,2R,3S,4S)-2-(tert-butyldiphenylsilyloxy)-3-
fluoro-4-(4-methoxybenzyloxy)cyclopentyl)methoxy)diphenylsilane
(21). Compound 20 (1.1 g, 2.16 mmol) was dissolved in dry CH2Cl2
(10 mL) and to this DMAP (13 mg, 0.11 mmol) was added. To the
solution was then added with imidazole (177 mg, 2.59 mmol) and
TBDPSCl (0.66 mL, 2.59 mol) at 0 ꢁC. Following the additions, the
solution was warmed to room temperature and stirred for 2 h.
Water (10 mL) was added to quench the reaction and the mixture
extracted with EtOAc (3ꢂ10 mL). The combined organic layers were
dried (Na2SO4), concentrated under reduced pressure, and the
residue purified by silica gel column chromatography (hexanes/
EtOAc, 8:1) to provide 21 as a colorless oil (1.49 g, 92%). 1H NMR
NMR (400 MHz, CDCl3)
d 7.65e7.72 (m, 4H), 7.35e7.42 (m, 6H), 7.24
(d, J¼4.8 Hz, 2H), 6.84 (d, J¼4.8 Hz, 2H), 5.35e5.44 (m,1H), 4.7e4.93

C. Chen et al. / Tetrahedron 68 (2012) 3908e3914
3913
(400 MHz, CDCl3)
d
7.69e7.72 (m, 8H), 7.23e7.33 (m, 12H), 7.26 (d,
same procedure for obtaining 22, compound 25 (1.45 g,
2.31 mmol) provided 26 as a colorless oil (1.14 g, 66%). 1H NMR
(400 MHz, CDCl3) d 7.66e7.70 (m, 8H), 7.28e7.37 (m, 12H), 4.62 (d,
J¼8.4 Hz, 2H), 6.93 (d, J¼8.4 Hz, 2H), 4.57 (d, J¼5.6 Hz, 1H),
4.47e4.51 (m, 2H), 4.26 (m, 1H), 3.75 (s, 3H), 3.66e3.72 (m, 2H),
3.41 (m, 1H), 2.19e2.23 (m, 2H), 1.81e1.89 (m, 1H), 0.94 (s, 9H), 0.89
J¼5.6 Hz, 1H), 4.24e4.27 (m, 1H), 3.71e3.76 (m, 2H), 3.21e3.25 (m,
(s, 9H); 13C NMR (100 MHz, CDCl3):
d 158.5, 138.3, 134.2, 133.4,
1H), 2.29e2.3 (m, 2H), 1.81e1.88 (m, 1H), 0.91 (s, 9H), 0.87 (s, 9H);
132.2, 131.2, 130.4, 130.1, 129.7, 128.6, 127.5, 121.2, 85.2, 79.2, 77.9,
71.8, 61.2, 55.6, 44.3, 33.2, 25.3, 25.1, 19.2, 19.0. Anal. Calcd for
C46H55O4FSi2: C, 73.95; H, 7.42. Found: C, 73.78; H, 7.32.
13C NMR (100 MHz, CDCl3)
d 137.6, 134.5, 133.4, 132.1, 131.4, 130.2,
130.8, 127.5, 85.3, 79.1, 77.1, 61.3, 44.1, 32.9, 25.4, 25.2, 19.3, 19.2.
Anal. Calcd for C38H47O3Si2F: C, 72.80; H, 7.56. Found: C, 72.68;
H, 7.53.
2.1.13. (1S,2S,3R,4R)-3-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldi-
phenylsilyloxy)methyl)-2-fluorocyclopentanol (22). Compound 21
(1.5 g, 2.39 mmol) was dissolved in CH2Cl2 (20 mL). To this, DDQ
(652 mg, 2.87 mmol) was added in one portion and the mixture
stirred at room temperature for 2 h. Saturated aqueous Na2CO3
solution (20 mL) was added. The mixture was then extracted with
EtOAc (3ꢂ15 mL) and the organic layers combined, washed with
saturated aqueous Na2CO3 solution (20 mL), brine (20 mL), dried
(Na2SO4), concentrated under reduced pressure and purified by
silica gel column chromatography (hexanes/EtOAc, 5:1) to provide
22 as a colorless oil (1.14 g, 64%). 1H NMR (400 MHz, CDCl3)
2.1.18. (1R,2S,3R,5R)-3-(4-Amino-1H-imidazo[4,5-c]pyridin-1-yl)-2-
fluoro-5-(hydroxylmethyl)cyclopentanol (3). Compound 22 (2 g,
3.19 mmol) was dissolved inTHF (20 mL) and tothis deazapurine 278
(1.6 g, 4.79 mmol) and Ph3P (1.67 g, 6.38 mmol) were added. The
solution was cooled to ꢀ40 ꢁC and diisopropyl azodicarboxylate
(DIAD) (0.93 mL, 4.79 mmol) was added dropwise. The mixture was
warmed to room temperature, and then heated to 60 ꢁC for 24 h. The
solvent was removed under reduced pressure and the residue pu-
rified by silica gel column chromatography (hexanes/EtOAc, 2:1) to
give crude 1-((1R,2S,3R,4R)-3-(tert-butyldiphenylsilyloxy)-4-((tert-
d
7.69e7.73 (m, 8H), 7.32e7.42 (m, 12H), 4.66 (d, J¼5.6 Hz, 1H),
butyldiphenylsilyloxy)
methyl)-2-fluorocyclopentyl)-4-(N,N-di-
4.28e4.31 (m, 1H), 3.71e3.79 (m, 2H), 3.23e3.26 (m, 1H),
(tert-butyl-O-carbonyl)amino)-1H-imidazo[4,5-c]pyridine (28a) as
yellow oil (1.01 g). This crude product, which was contaminated
with diisopropyl hydrazine-1,2-dicarboxylate, was used in next step
without further purification.
2.29e2.32 (m, 2H), 1.82e1.92 (m, 1H), 0.91 (s, 9H), 0.87 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 138.2, 134.1,133.5,132.1, 131.3, 130.3, 130.7,
127.6, 85.2, 79.2, 77.2, 61.3, 44.3, 33.2, 25.3, 25.2, 19.3, 19.0. Anal.
Calcd for C38H47O3FSi2: C, 72.80; H, 7.56. Found: C, 72.81; H, 7.44.
Crude 28a (0.9 g, 0.954 mmol) was dissolved in 1 N HCl
(0.174 mL) in MeOH and stirred at 25 ꢁC overnight. Amberlite
IRA-400(Cl) ion exchange resin was then added to neutralize the
solution to pH 7. The mixture was filtered and the filtrate re-
moved under reduced pressure giving a residue that was puri-
fied by silica gel column chromatography (EtOAc/MeOH/NH4OH,
20:2:1) to provide 3 as a white solid (0.14 g, 18.7% for two steps).
2.1.14. tert-Butyl((1R,2R,3S,5R)-2-fluoro-3-(4-methoxybenzyloxy)-5-
vinylcyclopentyloxy)diphenylsilane (23). Following the procedure
for preparing 19, compound 16 (1.4 g, 2.78 mmol) provided 23 as
a colorless oil (0.911 g, 64.8%). 1H NMR (400 MHz, CDCl3)
d 7.7e7.74
(m, 4H), 7.29e7.42 (m, 6H), 7.26 (d, J¼2 Hz, 2H), 6.87 (d, J¼2 Hz, 2H),
5.34e5.43 (m, 1H), 4.83e4.92 (m, 2H), 4.4e4.45 (m, 2H),
3.81e3.90(m, 2H), 3.73 (s, 3H), 2.81e2.86 (m, 1H), 2.51 (s, 1H),
2.06e2.14 (m,1H),1.53e1.63 (m,1H),1.07 (s, 9H); 13C NMR(100 MHz,
Mp 238e241 ꢁC. 1H NMR (400 MHz, DMSO-d6)
(d, J¼6 Hz, 1H), 6.84 (d, J¼6 Hz, 1H), 6.14 (br, 2H), 5.46 (d, J¼2 Hz,
1H), 4.81e4.92 (m, 2H), 4.80 (d, J¼2 Hz, 1H), 3.92e4.00 (m, 2H),
3.71e3.79 (m, 2H), 2.32e2.37 (m, 1H), 1.98e2.02 (m, 1H); 13C
d 8.13 (s, 1H), 7.69
CDCl3)
d 157.3, 137.5, 135.1, 133.3, 130.9, 130.3, 129.6, 127.6, 121.3,
114.2, 85.3, 79.3, 78.0, 71.5, 55.6, 44.3, 33.2, 25.1,19.5. Anal. Calcd for
C31H37O3FSi: C, 73.77; H, 7.39. Found: C, 73.71; H, 7.29.
NMR (100 MHz, DMSO-d6) d 151.8, 141.5, 141.3, 135.5, 135.1,
108.6, 94.1, 78.8, 72.8, 62.8, 32.4, 24.9. Anal. Calcd for
C12H15N4O2F: C, 54.13; H, 5.68; N, 21.04. Found: C, 54.14; H, 5.61;
N, 20.93.
2.1.15. ((1R,2R,3R,4S)-2-(tert-Butyldiphenylsilyloxy)-3-fluoro-4-(4-
methoxybenzyloxy)cyclopentyl)methanol (24). By following the
procedure for preparing 20, compound 23 (2.15 g, 4.26 mmol)
yielded 24 as a colorless oil (1.287 g, 59.4%). 1H NMR (400 MHz,
2.1.19. (1R,2R,3R,5R)-3-(4-Amino-1H-imidazo[4,5-c]pyridin-1-yl)-2-
fluoro-5-(hydroxylmethyl)cyclopentanol (4). In the same way that 3
was achieved, 26 (1.8 g, 2.87 mmol) gave crude 1-((1R,2R,3R,4R)-
3-(tert-butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy)
methyl)-2-fluorocyclopentyl)-4-(N,N-di-(tert-butyl-O-carbonyl)
amino)-1H-imidazo[4,5-c]pyridine (28b) as yellow oil (1.11 g).
This crude product, which contaminated with diisopropyl
hydrazine-1,2-dicarboxylate, was used in next step without further
purification.
CDCl3)
d
7.67e7.70 (m, 4H), 7.27e7.38 (m, 6H), 7.25 (d, J¼8.4 Hz,
2H), 6.87 (d, J¼8.4 Hz, 2H), 4.42e4.48 (m, 2H), 3.82e3.89(m, 2H),
3.73 (s, 3H), 3.69e3.72(m, 2H), 2.82e2.88 (m, 1H), 2.49 (s, 1H),
1.71e1.85 (m, 2H), 1.13 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 157.4,
138.3, 133.3, 131.2, 130.1, 129.5, 127.5, 121.3, 85.4, 79.1, 77.9, 71.5,
61.4, 55.3, 44.3, 32.7, 25.5, 19.7. Anal. Calcd for C30H37O4FSi: C,
70.83; H, 7.33. Found: C, 70.71; H, 7.41.
As with 28a, crude 28b (1 g, 1.06 mmol) yielded 4 as a white
2.1.16. tert-Butyl(((1R,2R,3R,4S)-2-(tert-butyldiphenylsilyloxy)-3-
fluoro-4-(4-methoxybenzyloxy)cyclopentyl)methoxy)diphenylsilane
(25). Calling on the procedure that gave 22, compound 24 (1.5 g,
2.95 mmol) led to 25 as a colorless oil (2.07 g, 94%). 1H NMR
solid (0.16 g, 23.3% for two steps), mp 239e242 ꢁC. 1H NMR
(400 MHz, DMSO-d6)
d
8.14 (s, 1H), 7.67 (d, J¼6 Hz, 1H), 6.82 (d,
J¼6 Hz, 1H), 6.15 (br, 2H), 5.44 (d, J¼2 Hz, 1H), 4.79e4.89 (m, 2H),
4.75(d, J¼2 Hz, 1H), 3.90e3.97 (m, 2H), 3.70e3.79 (m, 2H),
2.31e2.36 (m, 1H), 1.98e2.02 (m, 1H); 13C NMR (100 MHz, DMSO-
(400 MHz, CDCl3)
d 7.7e7.74 (m, 8H), 7.25e7.33 (m, 12H), 7.26 (d,
J¼8.4 Hz, 2H), 6.92 (d, J¼8.4 Hz, 2H), 4.56 (d, J¼5.6 Hz, 1H),
4.46e4.50 (m, 2H), 4.25 (m, 1H), 3.75 (s, 3H), 3.64e3.70 (m, 2H),
3.40 (m, 1H), 2.17e2.22 (m, 2H), 1.82e1.89 (m, 1H), 0.93 (s, 9H), 0.88
d6) d 151.6, 141.3, 141.1, 135.1, 135.0, 107.9, 94.4, 78.6, 72.5, 62.6, 32.4,
24.8. Anal. Calcd for C12H15N4O2F: C, 54.13; H, 5.68; N, 21.04. Found:
C, 54.05; H, 5.59; N, 20.94.
(s, 9H); 13C NMR (100 MHz, CDCl3)
d 159.1, 138.3, 134.2, 133.3, 132.1,
131.1, 130.3, 130.1, 129.5, 128.4, 127.1, 121.1, 85.4, 79.5, 77.3, 71.8, 61.1,
55.4, 44.2, 33.2, 25.3, 25.1, 19.2, 19.0. Anal. Calcd for C46H55FO4Si2: C,
73.95; H, 7.42. Found: C, 73.87; H, 7.36.
Acknowledgements
Partial support of this research was provided by the Department
of Health and Human Services (AI 56540). Also, support from the
Molette Fund and Auburn University is appreciated.
2.1.17. (1S,2R,3R,4R)-3-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldi-
phenylsilyloxy)methyl)-2-fluorocyclopentanol (26). Employing the

3914
C. Chen et al. / Tetrahedron 68 (2012) 3908e3914
5. Yang, M.; Ye, W.; Schneller, S. W. J. Org. Chem. 2004, 69, 3993e3996.
References and notes
6. Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127e164.
7. (a) Yang, M.; Zhou, J.; Schneller, S. W. Tetrahedron 2006, 62, 1295e1300; (b) Yang,
M.; Zhou, J.; Schneller, S. W. Tetrahedron Lett. 2004, 45, 8981e8982.
8. (a) Unpublished results. (b) Radi, M.; Rao, J. R.; Jha, A. K.; Chu, C. K.
Nucleosides, Nucleotides Nucleic Acids 2009, 28, 504e518; (c) Jha, A. K.; Sharon,
S.; Rondla, R.; Chu, C. K. Tetrahedron 2009, 65, 9362e9367; (d) Li, T.-S.; Lu,
S.-F.; Xing, L.; Lin, G.-C.; Guan, Z.; Yang, Z.-J. J. Chin. Pharm. Sci. 2010, 19,
436e442.
1. (a) Wang, J.; Rawal, R. K.; Chu, C. K. Med. Chem. Nucleic Acids 2011, 1e100; (b)
Rodriguez, J. B.; Comin, M. J. Mini Rev. Med. Chem. 2003, 3, 95e114; (c) Schneller,
S. W. Curr. Top. Med. Chem. 2002, 2, 1087e1092.
2. Wolfe, M. S.; Borchardt, R. T. J. Med. Chem. 1991, 34, 1521e1530.
3. (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,
626e629; (b) Huggins, J.; Zhang, Z.-X.; Bray, M. J. Infect. Dis. 1999, 179,
S240eS247.
9. Roy, A.; Serbessa, T.; Schneller, S. W. Bioorg. Med. Chem. 2006, 14,
4980e4986.
4. Liu, P.; Sharon, A.; Chu, C. K. J. Fluorine Chem. 2008, 129, 743e766.