Synthesis of phenol and pyridone C -ribo- and 2-deoxyribonucleosides by palladium-catalyzed hydroxylations of haloaryl C -nucleosides

Article abstract of DOI:10.1055/s-0030-1258318

Phenol and pyridone C-nucleosides in both ribo- and deoxyribo series were prepared by palladium-catalyzed hydroxylations reactions from the corresponding TBS-protected bromophenyl and bromo- or chloropyridyl C-nucleosides using Buchwald-type ligand under

Full text of DOI:10.1055/s-0030-1258318

PAPER
4199
Synthesis of Phenol and Pyridone C-Ribo- and 2¢-Deoxyribonucleosides by
Palladium-Catalyzed Hydroxylations of Haloaryl C-Nucleosides
P
alladium-Catalyze
d
H
a
ydroxylati
r
ons of
H
a
loaryl
i
C
-Nuc
n
leosides Štefko, Michal Hocek*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead & IOCB Research Center,
Flemingovo nam. 2, 16610, Prague 6, Czech Republic
Fax +420 220183559; E-mail: hocek@uochb.cas.cz
Received 25 August 2010; revised 21 September 2010
tion/oxodeamination,11 by deprotection of tert-butoxy,12
p-nitrophenylethoxy14 or benzyloxy derivatives,15 or by
rearrangement of pyridine-N-oxide nucleosides.16 To
complement our cross-coupling methodology, we report
Abstract: Phenol and pyridone C-nucleosides in both ribo- and
deoxyribo series were prepared by palladium-catalyzed hydroxyla-
tions reactions from the corresponding TBS-protected bromophenyl
and bromo- or chloropyridyl C-nucleosides using Buchwald-type
ligand under mild conditions. Partial or complete desilylation of 5¢- here on direct palladium-catalyzed hydroxylations of bro-
OH was observed in some cases. Free nucleosides (7 examples)
were obtained in good overall yields by cleavage of TBS-protecting
groups with Et3N·3HF.
mobenzene and bromo- or chloropyridine C-nucleosides
to important phenol and pyridone C-nucleosides both in
ribo and 2¢-deoxyribo series.
Key words: C-nucleoside, palladium-catalyzed, hydroxylations,
Transition metal-catalyzed hydroxylations are one of the
phenol, pyridone
most recent additions to the repertoire of C–X cross-cou-
plings enabling direct conversions of aryl halides to phe-
nols.17 Although considerable progress has been achieved
C-Nucleosides, characterized by replacement of the nu-
using copper18 or iron catalysis,19 these reactions usually
cleosidic bond by a chemically stable carbon–carbon
require harsh conditions hardly compatible with rather
bond, exert wide range of biological activities and are ex-
fragile C-glycoside derivatives. Therefore, focus was di-
tensively applied in chemical biology.1 Some of them are
rected to palladium-catalyzed hydroxylations.20,21 The
promising candidates for novel base-pairs in the quest for
Buchwald procedure20 was adopted for studying the scope
extension of the genetic alphabet2 due to formation of se-
and limitation of hydroxylation reactions of haloaryl C-
lective hydrophobic pairs in DNA duplexes and efficient
nucleosides.
and specific incorporation by DNA polymerases.3 Some
The reactions were tested on TBS-protected 4- or 3-bro-
mophenyl C-ribonucleosides 1a,b either with CsOH or
KOH as hydroxide source (Scheme 1). Commercially
available Buchwald-type ligand L1 and L2 were used in
combination with Pd2dba3·CHCl3 with a loading of 2.5
mol% (5% Pd) with respect to the substrate. The reaction
of 3-bromophenyl C-nucleoside 1b with CsOH in the
presence of Pd2dba3 and L1 in dioxane at 100 °C gave
complete conversion of starting material within three
hours. However, the only isolated product was the partial-
ly 5¢-desilylated phenol nucleoside 4b in low yield of 30%
(Table 1, entry 1) accompanied by some highly polar by-
products (not isolated). Apparently, the stability of TBS-
protecting groups (at least on the primary OH) is limited
under these conditions. When the same reaction was per-
formed at 40 °C for 12 hours, the yield of 4b was slightly
improved to 40% (entry 2). Other reactions were per-
formed in the presence of KOH. A prolonged reaction at
50 °C for 48 hours gave the 5¢-deprotected nucleoside 4b
as a single product in 70% isolated yield (entry 3). Short-
ening of the reaction time to 24 hours at 55 °C resulted in
the formation of the desired fully protected phenol nucleo-
side 3b in 55% yield accompanied by the minor product
4b in 25% yield (entry 4). Application of the same condi-
tions for 4-bromophenyl C-nucleoside 1a gave very simi-
lar results. The desired protected 4-hydroxyphenyl C-
ribonucleoside 3a was isolated in 50% accompanied by
partially deprotected nucleoside 4a (30%) (entry 5). The
phenol-type C-nucleosides were used for formation of
metalla-base pairs in DNA4 and simple phenol C-nucleo-
side triphosphates were shown to inhibit DNA polymeras-
es.5 Diverse pyridone C-nucleosides were used as deletion
analogues of natural pyrimidine nucleosides in extension
of genetic alphabet,6 in studying mechanism of poly-
merases or primases7 and for construction of modified
RNA.8
Most of the current approaches1,9 to the synthesis of C-nu-
cleosides are not general and some suffer from low effi-
ciency and stereoselectivity. Therefore, we have been
developing a modular approach10–13 based on synthesis of
halo(het)aryl C-nucleoside intermediates and their fol-
low-up functionalizations to afford a series of C-nucleo-
side derivatives from each haloaryl intermediate.
Palladium-catalyzed cross-coupling reactions were used
for the introduction of alkyl or aryl groups,10–12 Hartwig–
Buchwald aminations for attachment of N-substituents,10–12
and palladium-catalyzed aminocarbonylations for carbox-
amides formation.13 However, a direct conversion of the
haloaryl C-nucleoside intermediates to phenol or pyri-
done C-nucleosides has not been achieved so far. Thus,
pyridone derivatives were prepared indirectly via amina-
SYNTHESIS 2010, No. 24, pp 4199–4206
x
x.
x
x
.
2
0
1
0
Advanced online publication: 28.10.2010
DOI: 10.1055/s-0030-1258318; Art ID: Z21510SS
© Georg Thieme Verlag Stuttgart · New York

4200
M. Štefko, M. Hocek
PAPER
(entry 8). The same reaction of 1b gave the TBS-protected
phenol nucleoside 3b in 81% yield. Thus, the optimized
conditions for hydroxylations of TBS-protected bro-
mobenzene C-ribonucleosides are the use of KOH,
Pd2dba3 (2.5 mol%), and L2 (10 mol%) under mild reac-
tion conditions (55 °C) for three hours. Under these con-
ditions, the conversion of bromobenzenes to phenols is
excellent and the partial desilylation of the sugar is sup-
pressed.
TBSO
Ar Hal
TBSO
Ar OH
O
O
see Table 1
OTBS
OTBS
TBSO
TBSO
TBSO
1a,b
3a,b
+
HO
Ar OH
O
OTBS
4a,b
With optimized conditions in hand, we turned our atten-
tion to the preparation of series of hydroxylated (het)aryl
C-nucleosides (Scheme 2, Table 2). Applying the above
mentioned conditions to the hydroxylation of TBS-pro-
OH
Br
OH
Br
OH
Hal
Ar =
Ar =
TBSO
Ar Hal
RO
Ar OH
O
O
see Table 2
3, 4
a
b
a
b
1
X
X
TBSO
TBSO
3 R = TBS X = OTBS
4 R = H X = OTBS
1 X = OTBS
2 X = H
i-Pr
i-Pr
i-Pr
i-Pr
P(t-Bu)2
P(t-Bu)2
5 R = TBS X = H
6 R = H
X = H
i-Pr
i-Pr
HO
Ar OH
O
Et3N•3HF
L1
L2
X
HO
Scheme 1 Optimization of palladium-catalyzed hydroxylations of
TBS-protected bromophenyl C-nucleosides
7 X = OH
8 X = H
Br
Cl
N
Table 1 Optimization of Palladium-Catalyzed Hydroxylations of
TBS-Protected Bromophenyl C-Nucleosidesa
Br
Br
N
Hal
Ar =
Entry Starting
compound
Ligand Time TempHydroxide Hydroxylation
(h) (°C)
(yield, %)
a
b
c
d
1, 2
1
2
3
4
5
6
7
8
9
1b
L1
L1
L1
L1
L1
L2
L2
L2
L2
3
12
48
24
24
24
12
3
100 CsOH
3b (0)
4b (30)
4b (41)
4b (70)
OH
O
OH
O
1b
1b
1b
1a
1a
1a
1a
1b
40 CsOH
50 KOH
55 KOH
55 KOH
55 KOH
55 KOH
55 KOH
55 KOH
3b (0)
NH
OH
NH
Ar =
3b (0)
3b (55) 4b (25)
3a (50) 4a (30)
3a (45) 4a (38)
3a (62) 4a (12)
3a (85) 4a traces
3b (81) 4b traces
3–8
a
b
c
d
Scheme 2 Synthesis of phenol and pyridone C-nucleosides
Table 2 Synthesis of Phenol and Pyridone C-Nucleosidesa
Entry Starting Time Hydroxylation (yield, %)
compound
Deprotection
(yield, %)
7a (77)
8a (80)
7b (76)
8b (77)
7c (73)
8c (79)
8d (75)
3
1
2
3
4
5
6
7
1a
2a
1b
2b
1c
2c
2d
3
4
3
6
4
6
3
3a (85)
5a (74)
3b (81)
5b (44)
3c (0)
4a (traces)
6a (0)
a Conditions: 2.5 mol% Pd2dba3·CHCl3, 10 mol% ligand L1 or L2,
1,4-dioxane.
4b (traces)
6b (29)
use of air-stable L2 ligand under the same conditions also
gave similar results: 45% of 3a and 38% of 4a (entry 6),
but the reaction was cleaner and better reproducible in
larger quantities. Reducing the reaction time to 12 hours
under the same conditions increased the yield of fully pro-
tected nucleoside 3a to 62% and diminished the formation
of partially deprotected nucleoside 4a to 12% (entry 7).
Finally, shortening of the reaction time to three hours gave
good yield (85%) of 3a with only traces of 5¢-deprotection
4c (76)
5c (0)
6c (73)
5d (74)b
6d (traces)b
a Conditions: 2.5 mol% Pd2dba3·CHCl3, 10 mol% L2, 1,4-dioxane,
55 °C, KOH.
b Conditions: 5 mol% Pd2dba3·CHCl3, 20 mol% L2.
Synthesis 2010, No. 24, 4199–4206 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Hydroxylations of Haloaryl C-Nucleosides
4201
septum-sealed bottle. All reagents were purchased from commer-
cial suppliers and used as received. NMR spectra were recorded on
a 400 MHz spectrometer (1H at 400 MHz, 13C at 100.6 MHz), 500
MHz spectrometer (1H at 500 MHz and 125.8 MHz at 13C) and/or
600 MHz spectrometer (1H at 600 MHz, 13C at 151 MHz). The sam-
ples were measured in CDCl3 using TMS as an internal standard or
in DMSO-d6 referenced to the residual solvent signal (1H NMR:
d = 2.50, 13C NMR: d = 39.7). Chemical shifts are given in ppm
(d-scale), coupling constants (J) in Hz. Complete assignment of all
NMR signals was performed using a combination of 2D-NMR
(H,H-COSY, H,C-HSQC, and H,C-HMBC) experiments and con-
figurations were established by two-dimensional ROESY spectra.
Mass spectra were measured with ESI ionization. Optical rotations
were measured at 25 °C; [a]D values are given in 10–1·cm2 ·g–1.
tected 4-bromophenyl-C-2¢-deoxyribonucleoside 2a, the
desired nucleoside 5a was prepared in good yield of 74%
(entry 2). In the case of 3-bromophenyl-C-2¢-deoxyribo-
nucleoside 2b, the reaction required 6 hours to complete
the conversion resulting in a mixture of TBS-protected
nucleoside 5b (44%) and partially deprotected derivative
6b (29%) (entry 4). Protected 6-bromopyridin-2-yl ribo-
and deoxyribonucleosides 1c10e and 2c11 yielded only 5¢-
OH pyridone nucleosides 4c and 6c as exclusive products
in 76 and 73% yield, respectively (not even traces of the
5¢-TBS-protected derivatives 3c and 5c were observed,
entries 5 and 6). Due to lower reactivity of protected 6-
chloropyridin-3-yl nucleoside 2d,12 10 mol% of palladi-
um (5% Pd2dba3) was used yielding the fully protected 5d Hydroxylation of TBS-Protected Halo(het)aryl C-Nucleosides;
General Procedure
An argon-purged septum-sealed flask was charged with Pd2dba3
(74%) and only traces of the deprotected derivative 6d af-
ter 3 hours at 55 °C (entry 7). It seems that the presence of
(2.5 mol%, 5% Pd), L2 (10 mol%), KOH (4.0 equiv), and bromo-
an OH group (or a pyridone C=O) in the meta-position of
or chloro(het)aryl C-nucleoside (1.0 equiv). The flask was evacuat-
the (het)aryl moiety (relative to the sugar) facilitates the
ed and backfilled with argon and then 1,4-dioxane (5 mL/1 mmol of
cleavage of the silyl group at 5¢-OH, since in the synthesis
of 3-hydroxyphenyl and 6-oxo-1,6-dihydropyridin-2-yl
derivatives, the 5-deprotected derivatives were formed
even under mild conditions and in short times as a major
side-product 6b or as the only products 4c and 6c.
the substrate) was added. The mixture was stirred in a preheated oil
bath (55 °C) until the complete consumption of starting material
was achieved (TLC). The reaction mixture was cooled to r.t., dilut-
ed with hexanes (200 mL/mmol), acidified with AcOH (0.4 mL/
mmol) and filtered through Celite. After evaporation of solvents un-
der reduced pressure, the crude reaction mixture was dissolved in
hexanes and directly chromatographed on silica gel column (Table
For the final deprotection of the silylated nucleosides 3a,
5a, 4b, 4c, 6c, and 5d, the treatment with Et3N·3HF fol- 1).
lowed by basic (NaHCO3) workup was used. In the prep-
aration of 8b, the deprotection was performed on a
combined mixture of 5b and 6b. Chromatographic purifi-
cation on reversed-phase flash chromatography and sub-
sequent lyophylization gave free phenol or pyridone
ribonucleosides 7a–c and 2¢-deoxyribonucleosides 8a–d
in good yields (75–80%) (Table 2, entry 7).
1b-(4-Hydroxyphenyl)-1-deoxy-2,3,5-tri-O-(tert-butyldimethyl-
silyl)-D-ribofuranose (3a)
According to the general procedure, 1a (189 mg, 0.3 mmol),
Pd2dba3·CHCl3 (8 mg, 0.007 mmol, 2.5 mol%), L2 (14 mg, 0.03
mmol, 10 mol%), KOH (67 mg, 1.2 mmol, 4 equiv) in 1,4-dioxane
(1.2 mL) were allowed to react at 55 °C for 3 h. The crude material
was purified by column chromatography (gradient elution: hexanes
to 4.6% EtOAc in hexanes) to give the title compound 3a as a clear
oil (145 mg, 85%).
In conclusion, an efficient and straightforward method for
a direct conversion of easily available halo(het)aryl C-nu-
cleosides to important phenol and pyridone C-nucleosides
was developed based on palladium-catalyzed hydroxyla-
tions with KOH under mild conditions. TBS-protecting
groups were found to be suitable, although the stability of
this group in 5¢-OH was limited and was partially or fully
cleaved during the hydroxylation in presence of KOH, es-
IR (CCl4): 3612, 2956, 2930, 2897, 2887, 2858, 1616, 1599, 1516,
1472, 1463, 1257, 1154, 967, 838 cm–1.
1H NMR (500 MHz, DMSO-d6): d = –0.45, –0.17, 0.07, 0.86, 0.092,
and 0.10 (6 s, 6 × 3 H, CH3Si), 0.75, 0.90 and 0.91 [3 s, 3 × 9 H,
(CH3)3C], 3.73 (m, 2 H, H-5¢), 3.84 (dd, J2¢,1¢ = 8.0 Hz, J2¢,3¢ = 4.5
Hz, 1 H, H-2¢), 3.86 (td, J4¢,5¢a = J4¢,5¢b = 3.7 Hz, J4¢,3¢ = 1.6 Hz, 1 H,
H-4¢), 4.07 (dd, J3¢,2¢ = 4.5 Hz, J3¢,4¢ = 1.6 Hz, 1 H, H-3¢), 4.49 (d,
pecially for the meta-substituted hydroxy(het)aryl nucleo-
sides. Complete deprotection of the silylated
intermediates by Et3N·3HF gave the desired free nucleo-
J
1¢,2¢ = 7.9 Hz, 1 H, H-1¢), 6.68 (m 2 H, H-3), 7.16 (m, 2 H, H-2),
9.30 (s, 1 H, OH-4).
13C NMR (125.7 MHz, DMSO-d6): d = –5.44, –5.35, –5.29, –4.53,
sides. This methodology represents one of the first practi- –4.44, and –4.38 (CH3Si), 17.81, 17.97 and 18.14 [(CH3)3C], 25.86,
25.94, and 25.97 [(CH3)3C], 63.61 (CH2-5¢), 73.92 (CH-3¢), 79.07
(CH-2¢), 82.26 (CH-1¢), 85.35 (CH-4¢), 114.79 (CH-3), 128.33
(CH-2), 130.52 (C-1), 157.13 (C-4).
cal applications of the recently developed palladium-
catalyzed hydroxylations20,21 to the synthesis of important
analogues of natural compounds with potential use in me-
dicinal chemistry and chemical biology and shows the
compatibility of this protocol with silyl-protected hydrox-
ylated compounds. It also significantly extends the reper-
toire of the follow-up transformations of haloaryl C-
nucleosides in our modular methodology of C-nucleoside
synthesis.10–13
HRMS (ESI): m/z [M – H] calcd for C29H55O5Si3: 567.3363; found:
567.3368.
1b-(3-Hydroxyphenyl)-1-deoxy-2,3,5-tri-O-(tert-butyldimethyl-
silyl)-D-ribofuranose (3b)
According to the general procedure, 1b (182 mg, 0.29 mmol),
Pd2dba3·CHCl3 (7.5 mg, 0.007 mmol, 2.5 mol%), L2 (13.8 mg,
0.029 mmol, 10 mol%), and KOH (65 mg, 1.1 mmol, 4 equiv) in
1,4-dioxane (1.2 mL) were allowed to react at 55 °C for 3 h. The
crude material was purified by column chromatography (gradient
elution: hexanes to 4.6% EtOAc in hexanes) to give the title com-
pound 3b as a clear oil (133 mg, 81%).
All cross-coupling reactions were carried out in evacuated flame-
dried glassware with magnetic stirring under argon atmosphere.
KOH was finely grounded prior to use. Commercially available an-
hydrous 1,4-dioxane (H2O <0.01%) was used as received from a
Synthesis 2010, No. 24, 4199–4206 © Thieme Stuttgart · New York

4202
M. Štefko, M. Hocek
PAPER
IR (CCl4): 3612, 3363, 1956, 2930, 2897, 2858, 1602, 1594, 1472,
1463, 1256, 1153, 1114, 967, 838 cm–1.
mmol, 10 mol%), and KOH (101 mg, 1.8 mmol, 4 equiv) in 1,4-di-
oxane (1.8 mL) were allowed to react at 55 °C for 4 h. The crude
material was purified by column chromatography (gradient elution:
CHCl3 to 1.6% MeOH in CHCl3) to give the title compound 4c as a
yellow foam (156 mg, 76%).
1H NMR (500 MHz, DMSO-d6): d = –0.43, –0.17, 0.07, 0.88, 0.094,
and 0.11 (6 s, 6 × 3 H, CH3Si), 0.77 and 0.90 [3 s, 3 × 9 H,
(CH3)3C], 3.73 (m, 2 H, H-5¢), 3.83 (dd, J2¢,1¢ = 7.9 Hz, J2¢,3¢ = 4.5
Hz, 1 H, H-2¢), 3.89 (td, J4¢,5¢a = J4¢,5¢b = 3.8 Hz, J4¢,3¢ = 1.7 Hz, 1 H,
H-4¢), 4.07 (dd, J3¢,2¢ = 4.5 Hz, J3¢,4¢ = 1.7 Hz, 1 H, H-3¢), 4.49 (d,
IR (CCl4): 3268, 2955, 2930, 2897, 2858, 1651, 1611, 1472, 1463,
1362, 1254, 1155, 1098, 950 cm–1.
J1¢,2¢ = 7.9 Hz, 1 H, H-1¢), 6.65 (ddd, J4,5 = 8.0 Hz, J4,2 = 2.5 Hz,
1H NMR (500 MHz, DMSO-d6): d = –0.23, –0.06, 0.08, and 0.09
(4 s, 4 × 3 H, CH3Si), 0.80 and 0.89 [2 s, 2 × 9 H, (CH3)3C], 3.57
(ddd, Jgem = 11.9 Hz, J5¢a,OH = 5.5 Hz, J5¢a,4¢ = 2.6 Hz, 1 H, H-5¢a),
3.66 (br dt, Jgem = 12.0 Hz, J5¢b,4¢ = J5¢b,OH = 4.2 Hz, 1 H, H-5¢b), 3.88
(m, 1 H, H-4¢), 4.12 – 4.16 (m, 2 H, H-2¢, 3¢), 4.44 (br d, J1¢,2¢ = 6.4
Hz, 1 H, H-1¢), 5.53 (br s, 1 H, OH-5¢), 6.19 (m, 1 H, H-3), 6.26 (br
d, 1 H, J5,4 = 9.0 Hz, H-5), 7.37 (br t, J4,5 = J4,6 = 7.9 Hz, 1 H, H-4),
11.11 (br s, 1 H, NH).
13C NMR (125.7 MHz, DMSO-d6): d = –5.35, –4.53, and –4.44
(CH3Si), 17.85 and 17.96 [(CH3)3C], 25.85 and 25.93 [(CH3)3C],
61.35 (CH2-5¢), 74.02 (CH-3¢), 77.30 (CH-2¢), 79.73 (CH-1¢), 87.01
(CH-4¢), 104.49 (CH-3), 119.96 (CH-5), 140.67 (CH-4), 146.64 (C-
2), 162.77 (C=O).
J4,6 = 1.0 Hz, 1 H, H-4), 6.74 (br dd, J2,4 = 2.3 Hz, J2,6 = 1.8 Hz, 1
H, H-2), 6.79 (dm, J6,5 = 7.6 Hz, 1 H, H-6), 7.07 (t, J5,4 = J5,6 = 7.8
Hz, 1 H, H-5), 9.24 (br s, 1 H, OH-3).
13C NMR (125.7 MHz, DMSO-d6): d = –5.42, –5.34, –5.31, –4.56,
–4.43, and –4.35 (CH3Si), 17.83, 17.98 and 18.17 [(CH3)3C], 25.90,
25.95, and 26.01 [(CH3)3C], 63.57 (CH2-5¢), 73.89 (CH-3¢), 79.12
(CH-2¢), 82.40 (CH-1¢), 85.49 (CH-4¢), 113.97 (CH-2), 114.75
(CH-4), 117.53 (CH-6), 128.93 (CH-5), 141.86 (C-1), 157.32 (C-3).
HRMS (ESI): m/z [M + Na] calcd for C29H56O5Si3 + Na: 591.3328;
found: 591.3328.
1b-(4-Hydroxyphenyl)-1-deoxy-2,3-di-O-(tert-butyldimethylsi-
lyl)-D-ribofuranose (4a)
HRMS (ESI): m/z [M + H] calcd for C22H42NO5Si2: 456.2596;
found: 456.2598.
IR (CCl4): 3361, 2955, 2930, 1858, 1616, 1518, 1472, 1463, 1362,
1257, 1156, 1041, 872, 838 cm–1.
1H NMR (500 MHz, DMSO-d6): d = –0.43, –0.15, 0.07, and 0.09
(4 s, 4 × 3 H, CH3Si), 0.75 and 0.90 [2 s, 2 × 9 H, (CH3)3C], 3.53
(m, 2 H, H-5¢), 3.79 (td, J4¢,5¢a = J4¢,5¢b = 4.7 Hz, J4¢,3¢ = 1.7 Hz, 1 H,
H-4¢), 3.83 (dd, J2¢,1¢ = 7.9 Hz, J2¢,3¢ = 4.5 Hz, 1 H, H-2¢), 4.10 (dd,
1b-(4-Hydroxyphenyl)-1,2-dideoxy-2,3-di-O-(tert-butyldimeth-
ylsilyl)-D-ribofuranose (5a)
According to general procedure, 2a (187 mg, 0.37 mmol),
Pd2dba3·CHCl3 (9.6 mg, 0.009 mmol, 2.5 mol%), L2 (16 mg, 0.037
mmol, 10 mol%), and KOH (84 mg, 1.5 mmol, 4 equiv) in 1,4-di-
oxane (1.5 mL) were allowed to react at 55 °C for 4 h. The crude
material was purified by column chromatography (gradient elution:
hexanes to 5.7% EtOAc in hexanes) to give the title compound 5a
as a yellow oil (122 mg, 74%).
J3¢,2¢ = 4.5 Hz, J3¢,4¢ = 1.7 Hz, 1 H, H-3¢), 4.47 (d, J1¢,2¢ = 7.9 Hz, 1 H,
H-1¢), 4.90 (t, JOH,5¢a = JOH,5¢b = 5.5 Hz, 1 H, OH-5¢), 6.69 (m, 2 H,
H-3), 7.15 (m, 2 H, H-2), 9.29 (s, 1 H, OH-4)
13C NMR (125.7 MHz, DMSO-d6): d = –5.19, –4.49, –4.39, and –
4.34 (CH3Si), 17.83 and 17.98 [(CH3)3C], 25.91 and 25.98
[(CH3)3C], 62.07 (CH2-5¢), 73.84 (CH-3¢), 78.96 (CH-2¢), 82.24
(CH-1¢), 85.86 (CH-4¢), 114.86 (CH-3), 128.45 (CH-2), 130.58 (C-
1), 157.14 (C-4).
IR (CCl4): 3612, 3356, 2956, 2930, 2897, 2886, 2858, 1517, 1272,
1463, 1362, 1257, 1169, 1112, 1091, 1031, 838 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 0.057, 0.060, and 0.08 (4 s,
4 × 3 H, CH3Si), 0.88 and 0.89 [2 s, 2 × 9 H, (CH3)3C], 1.86 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 10.4 Hz, J2¢a,3¢ = 5.5 Hz, 1 H, H-2¢a), 1.97
(ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.3 Hz, J2¢b,3¢ = 1.7 Hz, 1 H, H-2¢b),
3.56 (dd, Jgem = 10.8 Hz, J5¢a,4¢ = 6.1 Hz, 1 H, H-5¢a), 3.65 (dd,
Jgem = 10.8 Hz, J5¢b,4¢ = 4.1 Hz, 1 H, H-5¢b), 3.76 (ddd, J4¢,5¢a = 6.1
Hz, J4¢,5¢b = 4.1 Hz, J4¢,3¢ = 2.0 Hz, 1 H, H-4¢), 4.34 (br dt, J3¢,2¢a = 5.4
Hz, J3¢,2¢b = J3¢,4¢ = 1.9 Hz, 1 H, H-3¢), 4.89 (dd, J1¢,2¢a = 10.3 Hz,
J1¢,2¢b = 5.3 Hz, 1 H, H-1¢), 6.68 (m, 2 H, H-3), 7.14 (m, 2 H, H-2),
9.30 (s, 1 H, OH-4).
13C NMR (125.7 MHz, DMSO-d6): d = –5.33, –5.24, –4.61, and
–4.51 (CH3Si), 17.95 and 18.15 [(CH3)3C], 25.94 and 25.93
[(CH3)3C], 43.52 (CH2-2¢), 63.71 (CH2-5¢), 74.36 (CH-3¢), 79.37
(CH-1¢), 87.31 (CH-4¢), 114.97 (CH-3), 127.62 (CH-2), 132.22 (C-
1), 156.89 (C-4).
HRMS (ESI): m/z [M – H] calcd for C23H41O5Si2: 453.2498; found:
453.2501.
1b-(3-Hydroxyphenyl)-1-deoxy-2,3-di-O-(tert-butyldimethylsi-
lyl)-D-ribofuranose (4b)
IR (CCl4): 3379, 2956, 2930, 2896, 2887, 1603, 1472, 1462, 1362,
1254, 1156, 1028, 873, 838 cm–1.
1H NMR (500 MHz, CDCl3): d = –0.25, –0.06, 0.06, and 0.07 (4 s,
4 × 3 H, CH3Si), 0.84 and 0.91 [2 s, 2 × 9 H, (CH3)3C], 2.95 (br s, 1
H, OH-5¢), 3.66 (dd, Jgem = 11.9 Hz, J5¢a,4¢ = 4.9 Hz, 1 H, H-5¢a),
3.84 (dd, J2¢,1¢ = 5.7 Hz, J2¢,3¢ = 4.5 Hz, 1 H, H-2¢), 3.86 (dd,
Jgem = 11.9 Hz, J5¢b,4¢ = 4.5 Hz, 1 H, H-5¢b), 4.02 (t, J3¢,4¢ = J3¢,2¢ = 4.4
Hz, 1 H, H-3¢), 4.08 (ddd, J4¢,5¢a = 4.9 Hz, J4¢,3¢ = 4.3 Hz, J4¢,5¢b = 3.1
Hz, 1 H, H-4¢), 4.79 (d, J1¢,2¢ = 5.7 Hz, 1 H, H-1¢),6.65 (br s, 1 H,
OH-3), 6.74 (ddd, J4,5 = 8.1 Hz, J4,2 = 2.5 Hz, J4,6 = 1.0 Hz, 1 H, H-
4), 6.83 (dm, J6,5 = 7.7 Hz, 1 H, H-6), 6.92 (br dd, J2,4 = 2.2 Hz,
J2,6 = 2.0 Hz, 1 H, H-2), 7.16 (br t, J5,6 = J5,4 = 7.8 Hz, 1 H, H-5).
HRMS (ESI): m/z [M + Na] calcd for C23H42O4Si2 + Na: 461.2514;
found: 461.2512.
13C NMR (125.7 MHz, CDCl3): d = –5.02, –4.67, –4.53, and –4.37
(CH3Si), 17.96 and 18.02 [(CH3)3C], 25.83 and 25.85 [(CH3)3C],
62.76 (CH2-5¢), 72.73 (CH-3¢), 79.32 (CH-2¢), 84.31 and 84.40
(CH-1¢, 4¢), 112.84 (CH-2), 115.12 (CH-4), 119.05 (CH-6), 129.52
(CH-5), 141.56 (C-1), 156.16 (C-3).
1b-(3-Hydroxyphenyl)-1,2-dideoxy-2,3-di-O-(tert-butyldimeth-
ylsilyl)-D-ribofuranose (5b)
According to the general procedure, 2b (306 mg, 0.61 mmol),
Pd2dba3·CHCl3 (15.8 mg, 0.015 mmol, 2.5 mol%), L2 (29.3 mg,
0.061 mmol, 10 mol%), and KOH (137 mg, 2.4 mmol, 4 equiv) in
1,4-dioxane (2.4 mL) were allowed to react at 55 °C for 6 h. The
crude material was purified by column chromatography (gradient
elution: hexanes to 25% EtOAc in hexanes) to give the title com-
pound 5b as a yellow oil (119 mg, 44%) and compound 6b as a yel-
low solid (57 mg, 29%).
HRMS (ESI): m/z calcd for [M – H] C23H41O5Si2: 453.2498; found:
453.2492.
1b-(6-Oxo-1H-pyridin-2-yl)-1-deoxy-2,3-di-O-(tert-butyldi-
methylsilyl)-D-ribofuranose (4c)
According to the general procedure, 1c (285 mg, 0.45 mmol),
Pd2dba3·CHCl3 (12 mg, 0.011 mmol, 2.5 mol%), L2 (22 mg, 0.045
IR (CCl4): 3612, 3363, 2956, 2930, 2859, 1602, 1594, 1362, 1256,
1153, 1114, 967, 939, 838 cm–1.
Synthesis 2010, No. 24, 4199–4206 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Hydroxylations of Haloaryl C-Nucleosides
4203
1H NMR (500 MHz, DMSO-d6): d = 0.06, 0.07, 0.082, and 0.085
(4 s, 4 × 3 H, CH3Si), 0.88 and 0.89 [2 s, 2 × 9 H, (CH3)3C], 1.82
(ddd, Jgem = 12.7 Hz, J2¢a,1¢ = 10.4 Hz, J2¢a,3¢ = 5.4 Hz, 1 H, H-2¢a),
2.04 (ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.5 Hz, J2¢b,3¢ = 1.7 Hz, 1 H, H-
2¢b), 3.55 (dd, Jgem = 10.7 Hz, J5¢a,4¢ = 6.3 Hz, 1 H, H-5¢a), 3.68 (dd,
Jgem = 10.7 Hz, J5¢b,4¢ = 4.3 Hz, 1 H, H-5¢b), 3.79 (ddd, J4¢,5¢a = 6.3
Hz, J4¢,5¢b = 4.3 Hz, J4¢,3¢ = 2.0 Hz, 1 H, H-4¢), 4.34 (br dt, J3¢,2¢a = 5.3
Hz, J3¢,2¢b = J3¢,4¢ = 1.9 Hz, 1 H, H-3¢), 4.91 (br dd, J1¢,2¢a = 10.4 Hz,
J1¢,2¢b = 5.5 Hz, 1 H, H-1¢), 6.63 (ddd, J4,5 = 8.0 Hz, J4,2 = 2.5 Hz,
J4,6 = 1.1 Hz, 1 H, H-4), 6.72 (m, 1 H, H-2), 6.75 (dm, J6,5 = 7.6 Hz,
1 H, H-6), 7.08 (t, J5,4 = J5,6 = 7.8 Hz, 1 H, H-5), 9.29 (s, 1 H, OH-
3).
13C NMR (125.7 MHz, DMSO-d6): d = –5.32, –5.24, –4.61, and
–4.51 (CH3Si), 17.95 and 18.15 [(CH3)3C], 25.92 and 25.95
[(CH3)3C], 43.55 (CH2-2¢), 62.68 (CH2-5¢), 74.26 (CH-3¢), 79.38
(CH-1¢), 87.48 (CH-4¢), 112.90 (CH-2), 114.33 (CH-4), 116.64
(CH-6), 129.23 (CH-5), 143.84 (C-1), 157.41 (C-3).
13C NMR (125.7 MHz, DMSO-d6): d = –4.53 and –4.49 (CH3Si),
17.97 [(CH3)3C], 25.97 [(CH3)3C], 43.71 (CH2-2¢), 62.31 (CH2-5¢),
74.39 (CH-3¢), 79.31 (CH-1¢), 88.09 (CH-4¢), 112.92 (CH-2),
114.34 (CH-4), 116.81 (CH-6), 129.27 (CH-5), 143.97 (C-1),
157.41 (C-3).
HRMS (ESI): m/z [M + Na] calcd for C17H28O4Si + Na: 347.1649;
found: 347.1649.
1b-(6-Oxo-1H-pyridin-2-yl)-1,2-dideoxy-3-O-(tert-butyldimeth-
ylsilyl)-D-ribofuranose (6c)
According to the general procedure, 2c (322 mg, 0.64 mmol),
Pd2dba3·CHCl3 (17 mg, 0.016 mmol, 2.5 mol%), L2 (31 mg, 0.064
mmol, 10 mol%), and KOH (144 mg, 2.6 mmol, 4 equiv) in 1,4-di-
oxane (2.6 mL) were allowed to react at 55 °C for 6 h. The crude
material was purified by column chromatography (gradient elution:
CHCl3 to 3.8% MeOH in CHCl3) to give the title compound 6c as
an orange solid (151 mg, 73%).
HRMS (ESI): m/z [M + Na] calcd for C23H42O4Si2 + Na: 461.2514;
found: 461.2512.
IR (CCl4): 2955, 2930, 1858, 1658, 1626, 1549, 1471, 1463, 1432,
1406, 1328, 1258, 1096, 1049, 1031, 838 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 0.07 and 0.08 (2 s, 2 × 3 H,
1b-(6-Oxo-1H-pyridin-3-yl)-1,2-dideoxy-2,3-di-O-(tert-butyl-
dimethylsilyl)-D-ribofuranose (5d)
CH3Si), 0.88 [s, 9 H, (CH3)3C], 1.95 (ddd, Jgem = 12.7 Hz,
J2¢a,1¢ = 9.9 Hz, J2¢a,3¢ = 5.5 Hz, 1 H, H-2¢a), 2.13 (ddd, Jgem = 12.7
According to the general procedure, 2d (258 mg, 0.56 mmol),
Pd2dba3·CHCl3 (29 mg, 0.028 mmol, 5 mol%), L2 (54 mg, 0.11
mmol, 20 mol%), and KOH (126 mg, 1.1 mmol, 4 equiv) in 1,4-di-
oxane (2.2 mL) were allowed to react at 55 °C for 5 h. The crude
material was purified by column chromatography (gradient elution:
CHCl3 to 3.8% MeOH in CHCl3) to give the title compound 5d as a
yellow oil (184 mg, 74%).
Hz, J2¢b,1¢ = 6.1 Hz, J2¢b,3¢ = 2.0 Hz, 1 H, H-2¢b), 3.50 (m, 2 H, H-5¢),
3.80 (ddd, J4¢,5¢a = 4.7 Hz, J4¢,5¢b = 4.1 Hz, J4¢,3¢ = 2.1 Hz, 1 H, H-4¢),
4.37 (dt, J3¢,2¢a = 5.5 Hz, J3¢,2¢b = J3¢,4¢ = 2.0 Hz, 1 H, H-3¢), 4.85 (dd,
J1¢,2¢a = 9.9 Hz, J1¢,2¢b = 6.0 Hz,
1 H, H-1¢), 5.16 (br t,
JOH,5¢a = JOH,5¢b = 4.7 Hz, 1 H, OH-5¢), 6.21 (d, 1 H, J5,4 = 9.1 Hz, H-
5), 6.22 (br m, 1 H, H-3), 7.37 (dd, J4,5 = 9.1 Hz, J4,3 = 6.9 Hz, 1 H,
H-4), 11.36 (br s, 1 H, NH).
IR (CCl4): 3329, 3288, 2923, 2858, 1665, 1632, 1549, 1467, 1429,
1308, 1253, 1232, 1086, 1048, 1010, 848 cm–1.
13C NMR (125.7 MHz, DMSO-d6): d = –4.63 and –4.57 (CH3Si),
17.95 [(CH3)3C], 25.92 [(CH3)3C], 42.03 (CH2-2¢), 61.79 (CH2-5¢),
74.15 (CH-3¢), 76.1 (CH-1¢), 88.42 (CH-4¢), 101.5 (CH-3), 118.7
(CH-5), 140.98 (CH-4), 149.3 (C-2), 162.82 (C-6).
1H NMR (500 MHz, DMSO-d6): d = 0.049, 0.051, 0.071, and 0.074
(4 s, 4 × 3 H, CH3Si), 0.87 and 0.88 [2 s, 2 × 9 H, (CH3)3C], 1.90
(m, 2 H, H-2¢), 3.55 (dd, Jgem = 10.8 Hz, J5¢a,4¢ = 6.0 Hz, 1 H, H-5¢a),
3.62 (dd, Jgem = 10.8 Hz, J5¢b,4¢ = 4.1 Hz, 1 H, H-5¢b), 3.74 (ddd,
J4¢,5¢a = 6.0 Hz, J4¢,5¢b = 4.1 Hz, J4¢,3¢ = 1.9 Hz, 1 H, H-4¢), 4.33 (m, 1
H, H-3¢), 4.81 (dd, J1¢,2¢a = 9.7 Hz, J1¢,2¢b = 6.1 Hz, 1 H, H-1¢), 6.29
(d, J5,4 = 9.5 Hz, 1 H, H-5), 7.33 (br d, J2,4 = 2.6 Hz, 1 H, H-2), 7.44
(dd, J4,5 = 9.5 Hz, J4,2 = 2.6 Hz, 1 H, H-4), 11.48 (br s, 1 H, NH).
13C NMR (125.7 MHz, DMSO-d6): d = –5.34, –5.26, –4.64, and
–4.53 (CH3Si), 17.95 and 18.14 [(CH3)3C], 25.92 and 25.94
[(CH3)3C], 41.95 (CH2-2¢), 63.67 (CH2-5¢), 74.43 (CH-3¢), 76.63
(CH-1¢), 87.37 (CH-4¢), 118.12 (C-3), 120.15 (CH-5), 133.12 (CH-
2), 139.95 (CH-4), 162.40 (C-6).
HRMS (ESI): m/z [M + H] calcd for C16H28NO4Si: 326.1782;
found: 326.1782.
1b-(6-Oxo-1H-pyridin-3-yl)-1,2-dideoxy-3-O-(tert-butyldimeth-
ylsilyl)-D-ribofuranose (6d)
IR (CCl4): 3381, 3284, 2955, 2930, 2858, 1666, 1658, 1626, 1549,
1471, 1463, 1258, 1096, 1049, 1031, 838 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 0.073 and 0.075 (2 s, 2 × 3 H,
CH3Si), 0.88 [s, 9 H, (CH3)3C], 1.88 (m, 2 H, H-2¢), 3.41 (m, 2 H,
H-5¢), 3.69 (ddd, J4¢,5¢a = 5.7 Hz, J4¢,5¢b = 4.4 Hz, J4¢,3¢ = 2.0 Hz, 1 H,
H-4¢), 4.34 (m, 1 H, H-3¢), 4.78 (dd, J1¢,2¢´a = 9.4 Hz, J1¢,2¢b = 6.4 Hz,
1 H, H-1¢), 4.81 (t, JOH,5¢a = JOH,5¢b = 5.7 Hz, 1 H, OH-5¢), 6.31 (d,
J5,4 = 9.5 Hz, 1 H, H-5), 7.36 (br d, J2,4 = 2.6 Hz, 1 H, H-2), 7.45
(dd, J4,5 = 9.5 Hz, J4,2 = 2.6 Hz, 1 H, H-4), 11.50 (br s, 1 H, NH).
HRMS (ESI): m/z [M + H] calcd for C22H42NO4Si2: 440.2647;
found: 440.2646.
1b-(3-Hydroxyphenyl)-1,2-dideoxy-3-O-(tert-butyldimethylsi-
lyl)-D-ribofuranose (6b)
13C NMR (125.7 MHz, DMSO-d6): d = –4.56 and –4.52 (CH3Si),
17.97 [(CH3)3C], 25.96 [(CH3)3C], 42.26 (CH2-2¢), 62.16 (CH2-5¢),
74.46 (CH-3¢), 76.56 (CH-1¢), 88.00 (CH-4¢), 118.29 (C-3), 120.17
(CH-5), 133.13 (CH-2), 140.15 (CH-4), 162.41 (C-6).
IR (CCl4): 3360, 1956, 2930, 2896, 2886, 2858, 1603, 1472, 1462,
1362, 1259, 1097, 836 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 0.08 and 0.09 (2 s, 2 × 3 H,
CH3Si), 0.89 [s, 9 H, (CH3)3C], 1.80 (ddd, Jgem = 12.8 Hz,
HRMS (ESI): m/z [M + H] calcd for C16H28NO4Si: 326.1782;
found: 326.1782.
J2¢a,1¢ = 10.4 Hz, J2¢a,3¢ = 5.5 Hz, 1 H, H-2¢a), 2.01 (ddd, Jgem = 12.8
Hz, J2¢b,1¢ = 5.4 Hz, J2¢b,3¢ = 1.7 Hz, 1 H, H-2¢b), 3.37 (dd, Jgem = 11.4
Hz, J5¢a,4¢ = J5¢a,OH = 6.1 Hz, 1 H, H-5¢a), 3.49 (dd, Jgem = 11.4 Hz,
Cleavage of the TBS Group; General Procedure
Et3N·3HF (163 mL, 1.0 mmol, 10 equiv) was added to a solution of
silylated compound 3a, 5a, 4b, 4c, 6c, 5d, or 5b/6b (0.10 mmol) in
THF (1.0 mL). In the case of ribonucleosides, the resulting mixture
was stirred at 40 °C for 2 days. In the case of 2¢-deoxyribonucleo-
sides, the mixture was stirred at r.t. overnight. After the reaction was
complete (monitored by TLC eluted in CHCl3–MeOH, 8:2), the sol-
vent was evaporated under reduced pressure, the crude product was
dissolved in H2O (6 mL), and solid NaHCO3 was added until pH 8.
Solvents were evaporated under reduced pressure and crude product
J
5¢b,4¢ = J5¢b,OH = 5.1 Hz, 1 H, H-5¢b), 3.76 (ddd, J4¢,5¢a = 6.4 Hz,
J4¢,5¢b = 4.8 Hz, J4¢,3¢ = 2.0 Hz, 1 H, H-4¢), 4.34 (dt, J3¢,2¢a = 5.5 Hz,
J3¢,2¢b = J3¢,4¢ = 1.9 Hz, 1 H, H-3¢), 4.81 (br t, JOH,5¢a = JOH,5¢b = 5.6 Hz,
1 H, OH-5¢), 4.89 (dd, J1¢,2¢a = 10.4 Hz, J1¢,2¢b = 5.3 Hz, 1 H, H-1¢),
6.63 (ddd, J4,5 = 8.1 Hz, J4,2 = 2.4 Hz, J4,6 = 1.2 Hz, 1 H, H-4), 6.73–
6.76 (m, 2 H, H-2, 6), 7.09 (t, J5,4 = J5,6 = 8.0 Hz, 1 H, H-5), 9.30 (s,
1 H, OH-3).
Synthesis 2010, No. 24, 4199–4206 © Thieme Stuttgart · New York

4204
M. Štefko, M. Hocek
PAPER
purified by reversed-phase chromatography (H2O–MeOH as elu-
ent) to obtain the free C-ribonucleosides 7a–c and 8a–d.
5¢), 6.16 (br s, 1 H, H-3), 6.22 (d, J5,4 = 9.1 Hz, 1 H, H-5), 7.37 (dd,
J4,5 = 9.1 Hz, J4,3 = 6.7 Hz, 1 H, H-4), 11.14 (br s, 1 H, NH).
13C NMR (125.7 MHz, DMSO-d6): d = 61.43 (CH2-5¢), 71.40 (CH-
3¢), 76.52 (CH-2¢), 80.5 (CH-1¢), 85.55 (CH-4¢), 102.7 (CH-3),
118.9 (CH-5), 140.91 (CH-4), 147.7 (C-2), 162.79 (C-6).
1b-(4-Hydroxyphenyl)-1-deoxy-D-ribofuranose (7a)
Compound 7a was prepared from 3a (309 mg, 0.54 mmol) accord-
ing to the general procedure in 77% yield as a white solid, which
after lyophylization furnished white hygroscopic powder; [a]D
–30.4 (c 3.32, MeOH).
20
HRMS (ESI): m/z [M + H] calcd for C10H14NO5: 228.0866; found:
228.0867; m/z [M + Na] calcd for C10H13NO5 + Na: 250.0686;
found: 250.0686.
IR (KBr): 3409, 1616, 1449, 1260, 1108, 1027, 832 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 3.51 (m, 2 H, H-5¢), 3.65 (m,
1 H, H-2¢), 3.74 (td, J4¢,5¢a = J4¢,5¢b = 4.7 Hz, J4¢,3¢ = 3.7 Hz, 1 H, H-4¢),
3.85 (br dd, J3¢,2¢ = 5.3 Hz, J3¢,4¢ = 3.9 Hz, 1 H, H-3¢), 4.43 (d,
1b-(4-Hydroxyphenyl)-1,2-dideoxy-D-ribofuranose (8a)
Compound 8a was prepared from 5a (258 mg, 0.59 mmol) accord-
ing to the general procedure in 80% yield as a white solid, which
after lyophylization furnished white hygroscopic powder;
[a]D20 +37.3 (c 2.28, MeOH).
J
1¢,2¢ = 7.1 Hz, 1 H, H-1¢), 4.75 (br t, JOH,5¢a = JOH,5¢b = 5.5 Hz, 1 H,
OH-5¢), 4.80–4.86 (m, 2 H, OH-2¢, 3¢), 6.70 (m, 2 H, H-3), 7.16 (m,
2 H, H-2), 9.29 (s, 1 H, OH-4).
13C NMR (125.7 MHz, DMSO-d6): d = 62.34 (CH2-5¢), 71.59 (CH-
3¢), 77.46 (CH-2¢), 83.22 (CH-1¢), 85.01 (CH-4¢), 114.89 (CH-3),
127.85 (CH-2), 131.57 (C-1), 156.85 (C-4).
IR (KBr): 3349, 3323, 2932, 1615, 1597, 1523, 1473, 1378, 1277,
1224, 1174, 1104, 1064, 1035, 990 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 1.75 (ddd, Jgem = 12.8 Hz,
J2¢a,1¢ = 10.5 Hz, J2¢a,3¢ = 5.7 Hz, 1 H, H-2¢a), 1.96 (ddd, Jgem = 12.8
Anal. Calcd for C11H14O5·1/3 H2O: C, 56.89; H, 6.37. Found: C,
56.83; H, 6.07.
Hz, J2¢b,1¢ = 5.3 Hz, J2¢b,3¢ = 1.6 Hz, 1 H, H-2¢b), 3.39 (dd, Jgem = 11.3
Hz, J5¢a,4¢ = 5.9 Hz, 1 H, H-5¢a), 3.45 (dd, Jgem = 11.3 Hz, J5¢b,4¢ = 5.0
Hz, 1 H, H-5¢b), 3.71 (ddd, J4¢,5¢a = 5.8 Hz, J4¢,5¢b = 5.0 Hz, J4¢,3¢ = 2.2
Hz, 1 H, H-4¢), 4.15 (dt, J3¢,2¢a = 5.7 Hz, J3¢,2¢b = J3¢,4¢ = 1.9 Hz, 1 H,
H-3¢), 4.87 (dd, J1¢,2¢a = 10.5 Hz, J1¢,2¢b = 5.2 Hz, 1 H, H-1¢), 6.68 (m,
2 H, H-3), 7.12 (m, 2 H, H-2).
HRMS (ESI): m/z [M – H] calcd for C11H13O5: 225.0768; found:
225.0770.
1b-(3-Hydroxyphenyl)-1-deoxy-D-ribofuranose (7b)
Compound 7b was prepared from 3b (364 mg, 0.64 mmol) accord-
ing to the general procedure in 76% yield, as a white solid, which
13C NMR (125.7 MHz, DMSO-d6): d = 43.61 (CH2-2¢), 62.77 (CH2-
5¢), 72.69 (CH-3¢), 79.31 (CH-1¢), 87.71 (CH-4¢), 115.07 (CH-3),
127.65 (CH-2), 132.38 (C-1), 157.17 (C-4).
20
after lyophylization furnished white hygroscopic powder; [a]D
–30.8 (c 3.67, MeOH).
HRMS (ESI): m/z [M + Na] calcd for C11H14O4 + Na: 233.0784;
IR (KBr): 3413, 2929, 2884, 1603, 1592, 1459, 1281, 1232, 1113,
1048, 867 cm–1.
found, 233.0784.
Anal. Calcd for C11H14O4·2/3 H2O: C, 59.52; H, 6.63. Found: C,
59.45; H, 6.95.
1H NMR (500 MHz, DMSO-d6): d = 3.51 (dt, Jgem = 11.6 Hz,
J5¢a,OH = J5¢a,4¢ = 5.2 Hz, 1 H, H-5¢a), 3.54 (ddd, Jgem = 11.6 Hz,
J5¢b,OH = 5.6 Hz,
2¢,1¢ = J2´,OH = 6.9 Hz, J2¢,3¢ = 5.5 Hz, 1 H, H-2¢), 3.78 (td,
J4¢,5¢a = J4¢,5¢b = 4.8 Hz, J4¢,3¢ = 3.8 Hz, 1 H, H-4¢), 3.84 (td,
3¢,2¢ = J3¢,OH = 5.2 Hz, J3¢,4¢ = 3.8 Hz, 1 H, H-3¢), 4.46 (d, J1¢,2¢ = 7.0
J5¢b,4¢ = 4.6 Hz,
1
H, H-5¢b), 3.64 (td,
1b-(3-Hydroxyphenyl)-1,2-dideoxy-D-ribofuranose (8b)
J
Compound 8b was prepared from mixture of 5b (201 mg, 0.459
mmol) and 6b (99 mg, 0.306 mmol) according to the general proce-
dure in 77% yield as a white solid, which after lyophylization fur-
nished white hygroscopic powder; [a]D20 +33.0 (c 2.85, MeOH).
J
Hz, 1 H, H-1¢), 4.77 (t, JOH,5¢a = JOH,5¢b = 5.6 Hz, 1 H, OH-5¢), 4.86
(d, JOH,3¢ = 4.9 Hz, 1 H, OH-3¢), 4.94 (d, JOH,2¢ = 6.9 Hz, 1 H, OH-
2¢), 6.63 (ddd, J4,5 = 8.1 Hz, J4,2 = 2.6 Hz, J4,6 = 1.1 Hz, 1 H, H-4),
6.78–6.82 (m, 2 H, H-2, 6), 7.09 (br t, J5,6 = J5,4 = 7.8 Hz, 1 H, H-5),
9.28 (s, 1 H, OH-3).
13C NMR (125.7 MHz, DMSO-d6): d = 62.34 (CH2-5¢), 71.62 (CH-
3¢), 77.62 (CH-2¢), 83.25 (CH-1¢), 85.08 (CH-4¢), 113.21 (CH-2),
114.28 (CH-4), 116.98 (CH-6), 129.08 (CH-5), 143.09 (C-1),
157.27 (C-3).
IR (KBr): 3413, 1929, 2884, 1603, 1592, 1488, 1459, 1312, 1232,
1159, 1113, 1048, 867 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 1.72 (ddd, Jgem = 12.8 Hz,
J2¢a,1¢ = 10.5 Hz, J2¢a,3¢ = 5.7 Hz, 1 H, H-2¢a), 2.03 (ddd, Jgem = 12.8
Hz, J2¢b,1¢ = 5.4 Hz, J2¢b,3¢ = 1.6 Hz, 1 H, H-2¢b), 3.38 (dd, Jgem = 11.2
Hz, J5¢a,4¢ = 6.0 Hz, 1 H, H-5¢a), 3.47 (dd, Jgem = 11.2 Hz, J5¢b,4¢ = 5.0
Hz, 1 H, H-5¢b), 3.76 (ddd, J4¢,5¢a = 6.0 Hz, J4¢,5¢b = 5.0 Hz, J4¢,3¢ = 2.2
Hz, 1 H, H-4¢), 4.16 (dm, J3¢,2¢a = 5.7 Hz, 1 H, H-3¢), 4.75 (br s, 1 H,
OH-5¢), 4.90 (dd, J1¢,2¢a = 10.4 Hz, J1¢,2¢b = 5.3 Hz, 1 H, H-1¢), 5.04
(br s, 1 H, OH-3¢), 6.62 (dm, J4,5 = 8.0 Hz, 1 H, H-4), 6.72–6.76 (m,
2 H, H-2,6), 7.08 (br t, J5,4 = J5,6 = 8.0 Hz, 1 H, H-5), 9.33 (br s, 1
H, OH-3).
HRMS (ESI): m/z [M – H] calcd for C11H13O5: 225.0768; found:
225.0764.
Anal. Calcd for C11H14O5·1/3 H2O: C, 56.89; H, 6.37. Found: C,
56.85; H, 6.34.
13C NMR (125.7 MHz, DMSO-d6): d = 43.68 (CH2-2¢), 62.74 (CH2-
5¢), 72.60 (CH-3¢), 79.29 (CH-1¢), 87.88 (CH-4¢), 112.90 (CH-2),
114.23 (CH-4), 116.74 (CH-6), 129.26 (CH-5), 144.41 (C-1);
157.42 (C-3).
1b-(6-Oxo-1H-pyridin-2-yl)-1-deoxy-D-ribofuranose (7c)
Compound 7c was prepared from 4c (267 mg, 0.59 mmol) accord-
ing to the general procedure in 73% yield as a white solid, which
20
after lyophylization furnished white hygroscopic powder; [a]D
–133.2 (c 2.71, DMSO).
HRMS (ESI): m/z [M + Na] calcd for C11H14O4 + Na: 233.0784;
found: 233.0784.
IR (KBr): 3400, 2929, 1650, 1609, 1548, 1456, 1119, 1088, 803
cm–1.
1b-(6-Oxo-1H-pyridin-2-yl)-1,2-dideoxy-D-ribofuranose (8c)
Compound 8c was prepared from 6c (183 mg, 0.56 mmol) accord-
ing to the general procedure in 79% yield, as a white solid, which
after lyophylization furnished white hygroscopic powder. [a]D
–17.5 (c 2.85, MeOH).
1H NMR (500 MHz, DMSO-d6): d = 3.53 (dd, Jgem = 11.8 Hz,
J5¢a,4¢ = 3.1 Hz, 1 H, H-5¢a), 3.63 (dd, Jgem = 11.8 Hz, J5¢b,4¢ = 3.3 Hz,
20
1 H, H-5¢b), 3.83 (br q, J4¢,5¢a = J4¢,5¢b = J4¢,3¢ = 3.3 Hz, 1 H, H-4¢),
3.87 (dd, J2¢,1¢ = 6.5 Hz, J2¢,3¢ = 5.1 Hz, 1 H, H-2¢), 3.92 (m, 1 H, H-
3¢), 4.42 (d, J1¢,2¢ = 6.5 Hz, 1 H, H-1¢), 4.88–5.50 (m, 3 H, OH-2¢, 3¢,
IR (KBr): 3413, 3308, 2935, 1643, 1599, 1442, 1415, 1334, 1260,
1171, 1109, 1091, 1058, 815 cm–1.
Synthesis 2010, No. 24, 4199–4206 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Hydroxylations of Haloaryl C-Nucleosides
4205
1H NMR (500 MHz, DMSO-d6): d = 1.91 (ddd, Jgem = 12.7 Hz,
2¢a,1¢ = 9.8 Hz, J2¢a,3¢ = 5.6 Hz, 1 H, H-2¢a), 2.11 (ddd, Jgem = 12.7
Hz, J2¢b,1¢ = 6.2 Hz, J2¢b,3¢ = 2.0 Hz, 1 H, H-2¢b), 3.52 (m, 2 H, H-5¢),
3.81 (td, J4¢,5¢a = J4¢,5¢b = 4.1 Hz, J4¢,3¢ = 2.2 Hz, 1 H, H-4¢), 4.20 (m, 1
H, H-3¢), 4.85 (dd, J1¢,2¢a = 9.7 Hz, J1¢,2¢b = 6.1 Hz, 1 H, H-1¢), 5.14
(br s, 1 H, OH-3¢), 5.20 (br s, 1 H, OH-5¢), 6.21 (br d, 1 H, J5,4 = 9.1
Hz, H-5), 6.22 (m, 1 H, H-3), 7.37 (dd, J4,5 = 9.1 Hz, J4,3 = 6.8 Hz,
1 H, H-4), 11.33 (br s, 1 H, NH).
Romesberg, F. E. Nucleic Acids Res. 2006, 34, 2037.
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(d) Matsuda, S.; Henry, A. A.; Romesberg, F. E. J. Am.
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Hari, Y.; Romesberg, F. E. Angew. Chem. Int. Ed. 2006, 45,
7809. (f) Matsuda, S.; Fillo, J. D.; Henry, A. A.; Rai, P.;
Wilkens, S. J.; Dwyer, T. J.; Geierstanger, B. H.; Wemmer,
D. E.; Schultz, P. G.; Spraggon, G.; Romesberg, F. E. J. Am.
Chem. Soc. 2007, 129, 10466. (g) Matsuda, S.; Leconte, A.
M.; Romesberg, F. E. J. Am. Chem. Soc. 2007, 129, 5551.
(h) Hari, Y.; Hwang, G. T.; Leconte, A. M.; Joubert, N.;
Hocek, M.; Romesberg, F. E. ChemBioChem 2008, 9, 2796.
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Hari, Y.; Romesberg, F. E. J. Am. Chem. Soc. 2008, 130,
2336. (b) Seo, Y. J.; Romesberg, F. E. ChemBioChem 2009,
10, 2394. (c) Malyshev, D.; Seo, Y. J.; Ordoukhanian, P.;
Romesberg, F. E. J. Am. Chem. Soc. 2009, 131, 14620.
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8, 592. (b) Tanaka, K.; Tasaka, M.; Cao, H.; Shionoya, M.
Supramol. Chem. 2002, 14, 255. (c) Clever, G. H.; Polborn,
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Chem. Eur. J. 2006, 12, 8708.
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H.; Tengeiji, A.; Hiraoka, S.; Shiro, M.; Shionoya, M.
J. Med. Chem. 2002, 45, 5594.
(6) Hirao, I.; Ohtsuki, T.; Fujiwara, T.; Mitsui, T.; Yokogawa,
T.; Okuni, T.; Nakayama, H.; Takio, K.; Yabuki, T.;
Kigawa, T.; Kodama, K.; Yokogawa, T.; Nishikawa, K.;
Yokoyama, S. Nat. Biotechnol. 2002, 20, 177.
(7) (a) Guo, M. J.; Hildebrand, S.; Leumann, C. J.; McLaughlin,
L. W.; Waring, M. J. Nucleic Acids Res. 1998, 26, 1863.
(b) Urban, M.; Joubert, N.; Hocek, M.; Alexander, R. E.;
Kuchta, R. D. Biochemistry 2009, 48, 10866. (c)Urban,M.;
Joubert, N.; Purse, B.; Hocek, M.; Kuchta, R. D.
Biochemistry 2010, 49, 727.
(8) Burgin, A. B.; Gonzales, C.; Matulic-Adamic, J.; Karpiesky,
A. M.; Usman, N.; McSwiggen, J. A.; Beigelman, L.
Biochemistry 1996, 35, 14090.
13C NMR (125.7 MHz, DMSO-d6): d = 42.10 (CH2-2¢), 62.17 (CH2-
5¢), 72.43 (CH-3¢), 76.43 (CH-1¢), 88.17 (CH-4¢), 101.9 (CH-3),
118.7 (CH-5), 141.05 (CH-4), 149.8 (C-2), 162.89 (C-6).
HRMS (ESI): m/z [M + H] calcd for C10H14NO4: 212.0917; found:
212.0916; m/z [M + Na] calcd for C10H13NO4 + Na: 234.0737;
found: 234.0736.
Anal. Calcd for C10H13NO4: C, 56.86; H, 6.20; N, 6.63. Found: C,
56.34; H, 5.85; N, 6.42.
1b-(6-Oxo-1H-pyridin-3-yl)-1,2-dideoxy-D-ribofuranose (8d)
Compound 8d was prepared from 5d (230 mg, 0.52 mmol) accord-
ing to the general procedure in 75% yield as a white solid, which
after lyophylization furnished white hygroscopic powder;
[a]D20 +32.3 (c 2.52, MeOH).
IR (KBr): 3329, 2856, 2665, 1632, 1549, 1253, 1048, 848 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 1.78 (ddd, Jgem = 12.7 Hz,
J2¢a,1¢ = 10.5 Hz, J2¢a,3¢ = 5.6 Hz, 1 H, H-2¢a), 1.90 (ddd, Jgem = 12.7
Hz, J2¢b,1¢ = 5.4 Hz, J2¢b,3¢ = 1.6 Hz, 1 H, H-2¢b), 3.41 (m, 2 H, H-5¢),
3.70 (br td, J4¢,5¢a = J4¢,5¢b = 5.1 Hz, J4¢,3¢ = 2.1 Hz, 1 H, H-4¢), 4.16 (m,
1 H, H-3¢), 4.74 (m, 1 H, OH-5¢), 4.78 (dd, J1¢,2¢a = 10.5 Hz,
J1¢,2¢b = 5.4 Hz, 1 H, H-1), 5.02 (m, 1 H, OH-3¢), 6.30 (d, J5,4 = 9.5
Hz, 1 H, H-5), 7.32 (br d, J2,4 = 2.6 Hz, 1 H, H-2), 7.46 (dd,
J4,5 = 9.5 Hz, J4,2 = 2.6 Hz, 1 H, H-4), 11.46 (br s, 1 H, NH).
13C NMR (125.7 MHz, DMSO-d6): d = 42.25 (CH2-2¢), 62.57 (CH2-
5¢), 72.59 (CH-3¢), 76.53 (CH-1¢), 87.73 (CH-4¢), 118.76 (C-3),
120.17 (CH-5), 132.87 (CH-2), 140.23 (CH-4), 162.48 (C-6).
HRMS (ESI): m/z [M + H] calcd for C10H14NO4: 212.0917; found:
212.0917.
(9) Recent examples: (a) Singh, I.; Seitz, O. Org. Lett. 2006, 8,
4319. (b) Hainke, S.; Singh, I.; Hemmings, J.; Seitz, O.
J. Org. Chem. 2007, 72, 881. (c) Redpath, P.; Macdonald,
S.; Migaud, M. E. Org. Lett. 2008, 10, 3323. (d) Spadafora,
M.; Postupalenko, V. Y.; Shvadchak, V. V.; Klymchenko,
A. S.; Mely, Y.; Burger, A.; Benhida, R. Tetrahedron 2009,
65, 7809.
Anal. Calcd for C10H13NO4: C, 56.86; H, 6.20; N, 6.63. Found: C,
56.84; H, 6.15; N, 6.43.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(10) (a) Hocek, M.; Pohl, R.; Klepetářová, B. Eur. J. Org. Chem.
2005, 4525. (b) Štefko, M.; Pohl, R.; Klepetářová, B.;
Hocek, M. Eur. J. Org. Chem. 2008, 1689. (c) Joubert, N.;
Urban, M.; Pohl, R.; Hocek, M. Synthesis 2008, 1918.
(d) Bárta, J.; Pohl, R.; Klepetářová, B.; Ernsting, N. P.;
Hocek, M. J. Org. Chem. 2008, 73, 3798. (e) Štefko, M.;
Slavětínská, L.; B. Klepetářová, ; Hocek, M. J. Org. Chem.
2010, 75, 442. (f) Kubelka, T.; Slavětínská, L.;
Acknowledgment
This work is a part of the research project Z4 055 0506 supported
by the Academy of Sciences of the Czech Republic. It was specifi-
cally supported by the Ministry of Education of the Czech Republic
(LC512), by the Grant Agency of the ASCR (IAA400550902), and
by Gilead Sciences, Inc. (Foster City, CA, U.S.A.). The authors
thank Dr. Lenka Slavetinska for the help with measurement and in-
terpretation of NMR spectra.
Klepetářová, B.; Hocek, M. Eur. J. Org. Chem. 2010, 2666.
(g) Bárta, J.; Slavětínská, L.; Klepetářová, B.; Hocek, M.
Eur. J. Org. Chem. 2010, 5432.
(11) Urban, M.; Pohl, R.; Klepetářová, B.; Hocek, M. J. Org.
Chem. 2006, 71, 7322.
(12) Joubert, N.; Pohl, R.; Klepetářová, B.; Hocek, M. J. Org.
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Synthesis 2010, No. 24, 4199–4206 © Thieme Stuttgart · New York