Reinvestigation of the synthesis of 1-deazauridine

Article abstract of DOI:10.1080/15257771003762170

A thorough study for the synthesis of 1-deazauridine is described. 3-Bromo-2,6-dimethoxy-5-(-d-ribofuranosyl)pyridine, a synthetic precursor for 1-deazauridine, was prepared in seven steps from 2,6-dimethoxypyridine and d-ribose via the ribonolactone approach. Subsequent demethylation was unsuccessful but led to presumable anomerization and isomerization. The effort concluded that the synthesis of 1-deazauridine remained unachieved. Copyright Taylor and Francis Group, LLC.

Full text of DOI:10.1080/15257771003762170

Nucleosides, Nucleotides and Nucleic Acids, 29:523–534, 2010
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257771003762170
REINVESTIGATION OF THE SYNTHESIS OF 1-DEAZAURIDINE
Cheng-Hung Jen and Tun-Cheng Chien
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan
A thorough study for the synthesis of 1-deazauridine is described. 3-Bromo-2,6-dimethoxy-5-(β-
2
d-ribofuranosyl)pyridine, a synthetic precursor for 1-deazauridine, was prepared in seven steps from
2,6-dimethoxypyridine and d-ribose via the ribonolactone approach. Subsequent demethylation was
unsuccessful but led to presumable anomerization and isomerization. The effort concluded that the
synthesis of 1-deazauridine remained unachieved.
Keywords 1-deazauridine; C-nucleoside; d-ribonolactone; 2,6-dimethoxypyridine
INTRODUCTION
Pyridine C-nucleosides featuring a carbon-carbon glycosyl bond could
be considered as 1-deaza analogs of naturally occurring pyrimidine N -
nucleosides. They are comparatively more stable toward chemical and enzy-
matic hydrolysis than their pyrimidine N -nucleoside counterparts.[1–6] The
structural resemblance and the intrinsic stability have made the pyridine C-
nucleosides useful isosteres for investigating the interactions with biological
targets.[7–11] As part of our research interest, we embarked on a study to
investigate feasible synthetic routes for 1-deazauridine (2) and its derivatives
as potential mechanistic probes for uridine-related enzymes.
RESULTS AND DISCUSSION
A review of the literature disclosed that the synthesis of 1-deazauridine
(2) is a challenging task. The first attempt to synthesize 1-deazauridine (2)
was reported by M. P. Mertes et al. in 1967, in which 3-(β-d-ribofuranosyl)-
2,6-dibenzyloxypyridine was prepared by the direct condensation of bis
(2,6-dibenzyloxypyrid-3-yl)cadmium with 2,3,5-tri-O-benzoyl-d-ribofuranosyl
Received 23 November 2009; accepted 9 March 2010.
This work was supported by Research Grant 96-2113-M-003-004 from the National Science Council,
Taiwan. We are grateful to the National Center for High-Performance Computing of Taiwan for the
electronic resources and facilities.
Address correspondence to Tun-Cheng Chien, Department of Chemistry, National Taiwan Normal
University, Taipei 11677, Taiwan. E-mail: tcchien@ntnu.edu.tw
523

524
C.-H. Jen and T.-C. Chien
chloride followed by debenzoylation. Subsequent hydrogenolysis to remove
the benzyl groups gave chemically unstable l-deazauridine (2). Mertes ra-
tionalized that the instability of 1-deazauridine (2) was attributed to spon-
taneous air-oxidation of the base to the corresponding 2,5,6-trihydroxypyri
dine or azaquinone derivatives.[12]
Several 1-deazauridine analogs have also been reported in the liter-
ature, including 2,6-dihydroxy-5-phenyldiazo-3-d-ribopyranosylpyridine
(5),[13] 5-(β-d-ribofuranosyl)-2,6-dihydroxynicotinamide (6),[14] (d-
ribofuranosyl)glutarimides 3a and 3b (4,5-dihydro-1-deazauridines),[15,16]
and (E)-3-(d-ribofuranosylidene)piperidine-2,6-dione (4).[17] (Figure 1)
Some of the analogs were claimed to be unstable and, thus far, there is
no confirmative synthesis of 1-deazauridine (2). It is noticeable that both
Knackmuss’s and Watanabe’s examples possessed deactivating substituents
at the 5-position of the base, the most nucleophilic site of the base, which
might stabilize the 2,6-dihydroxypyridine nucleosides against air-oxidation.
These facts have prompted us to re-investigate an alternative synthetic
route to 1-deazauridine derivatives. 5-Bromo-1-deazauridine (7) was se-
lected as the target molecule. The bromo-substituent at 5-position (the
most nucleophilic site) of 1-deazauridine (2) was anticipated to prevent
2,6-dihydroxypyridine from air-oxidation and could also be used for chemi-
cal manipulation afterwards. We opted to adopt the ribonolactone approach
for the synthesis of 1-deazauridine derivatives,[18–20] whereas the addition of
an organometallic heterocycle to a protected ribonolactone has been one of
the most straightforward approaches for the synthesis of C-nucleosides.[21–25]
O
O
O
R2
R1
4
6
3
1
5
6
5
4
HN
HN
HN
2
2
O
N1
HO
O
3
O
H
HO
HO
HO
HO
NH
O
O
O
O
O
HO
OH
HO
OH
HO
OH
HO
OH
O
1
2
1
2
3a
4
uridine
1-deazauridine
R = R = H
3b R1, R2 = H2C
O
O
N NPh
CONH2
Br
HN
HN
HO
HN
HO
HO
O
HO
HO
O
O
HO
OH
HO
OH
HO
OH
HO
5
6
7
FIGURE 1 Uridine and synthetic 1-deazauridine analogs reported in the literature.

Reinvestigation of the Synthesis of 1-Deazauridine
525
OMe
OMe
OMe
N
N
N
a
c
MeO
MeO
MeO
H
Li
TBSO
O
O
8
9
OH
TBSO
O
O
O
d
b
O
O
11α/β
OMe
Br
OMe
Br
10
N
N
MeO
MeO
(i) reductive dehydroxylation
(ii) bromination
D/H
8
12
8'
/
SCHEME 1 Direct lithiation and bromination of 2,6-dimethoxypyridine (8). Reagents and conditions: a)
n-BuLi, THF, −78◦C, 4 hours; b) D2O, THF, 0◦C ∼ room temperature; c) 5-O-tert-butyldimethylsilyl-2,3-O-
isopropylidene-d-ribonolactone (10), THF, 0◦C ∼ room temperature; d) Br2, CHCl3, room temperature,
4 hours, 80%.
Direct lithiation of 2,6-dimethoxypyridine (8) was achieved with n-
butyllithium in THF at −78◦C. The formation of the lithiated intermediate
9 was confirmed by quenching the reaction with D2O to give 3-deutero-
1
2,6-dimethoxypyridine (8ꢁ, 75–80%, based on the H NMR integration).
However, the addition of 5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-d-
1,4-ribonolactone[26,27] (10) to the lithiated 2,6-dimethoxypyridine (9) did
not yield the expected ribonolactol 11 (Scheme 1). Hence, 3,5-dibromo-
2,6-dimethoxypyridine[12,28] (12) was prepared by dibromination of 2,6-
dimethoxypyridine (8), and was subjected to the metal-halogen exchange
with n-butyllithium in THF at −78◦C. The resulting lithiated pyridine deriva-
tive 13 was treated with the protected ribono-1,4-lactone 10 to afford an
1
anomeric mixture (in a ratio of 2.5 : 1 determined by H NMR) of the ri-
bonolactol 14α/β in a good yield. Individual anomers could be separated
by flash column chromatography, but the anomeric configuration remained
undetermined. It is notable that, during the prolonged NMR experiments,
gradual epimerization of the single anomeric ribonolactol 14 in solution was
observed.
A literature survey on the reduction of the aryl ribonolactols suggested
that two major approaches could be employed, including Wilcox’s[18] and
Watanabe’s[19] reductive ring opening/reclosing approach and Czernecki’s
directly reductive dehydroxylation.[20] In our attempts to utilize an improved
method by S. Hanessian et al.,[29] reductive ring-opening of ribonolactol 14
with K-selectride in the presence of zinc(II) chloride led to a diastereomeric
mixture of diols 15. Immediate ring-closure by Mitsunobu reaction, however,
gave a complex result and the desired product was not observed (Scheme 2).

526
C.-H. Jen and T.-C. Chien
OMe
N
OMe
Br
Br
OMe
Br
OMe
Li
N
Br
Br
N
N
a
b
MeO
MeO
OH
TBSO
MeO
MeO
O
TBSO
HO
H
OH
12
13
O
O
O
O
15
14
α/β
c
d
OMe
OMe
Br
Br
N
N
TBSO
H
O
e
MeO
MeO
+
OMe
HO
TBSO
O
O
O
O
N
H
HO
OH
O
O
Br
OMe
17
16
16
α
β
SCHEME 2 Synthesis of 3-bromo-2,6-dimethoxy-5-(β-d-ribofuranosyl) pyridine (17). Reagents and con-
ditions: a) (i) n-BuLi, THF, −78◦C, 30 minutes; (ii) 5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-d-
ribonolactone (10), THF, −78◦C ∼ room temperature, 2 hours, 73%; b) (i) ZnCl2/ether, CH2Cl2,
−78◦C, 30 minutes; (ii) K-Selectride, THF, −78◦C ∼ room temperature; c) DIRD, PPh3, THF; d) toluene,
.
Et3SiH, BF3 OEt2, −78 ∼ 0◦C, 2.5 hours, 56%; e) (i) TBAF, THF, room temperature, 1 hour; (ii) Dowex
H+, H2O, 70◦C, 1 hour, 35%.
Alternatively, the direct reductive dehydroxylation of ribonolactol 14 us-
ing triethylsilane in the presence of boron trifluoride etherate, an improved
protocol by S. A. Benner et al.,[6] was then investigated. It is worth noting
that, in the initial trials, the reduction gave approximately the same α/β ra-
tio regardless of whether the ribonolactol 14 was purified as a single anomer
or obtained as a mixture of anomeric diastereoisomers from the glycosyla-
tion step. Since the stereoselectivity of the glycosylation was lost during the
reduction step, the anomeric mixture of 14 was subjected to the subsequent
optimization study without further separation. Under the tested conditions,
a mixture of α- and β-anomeric diastereoisomers (16α and 16β) was ob-
tained and the α-isomer (16α) always appeared to be predominant. (Table 1)
The desired β-isomer (16β) was separated from the α-isomer (16α) by re-
peated flash column chromatography.
The structural elucidation of nucleosides 16α and 16β was carried out
by intensive NMR studies including 1H, 13C, DEPT-135, COSY, HMQC, and
NOESY experiments. The α-anomeric configuration of 16α was established
on the basis of the NOE correlation between H-1ꢁ and H-5ꢁ observed in 2D
NOESY, whereas the β-isomer 16β showed the NOE correlation between
H-1ꢁ and H-4ꢁ. Furthermore, the chemical shift differences (ꢀδ) of two iso-
propylidene methyl groups in 16α and 16β are 0.11 (< 0.15) and 0.25 (>
0.15) ppm, which suggest the α- and β-anomeric configuration, respectively,
based on Imbach’s empirical rule.[30] These predictions are consistent with

Reinvestigation of the Synthesis of 1-Deazauridine
527
TABLE 1 Optimization for the reductive dehydroxylation of 14
Et3SiH
Entry
Solvent
(equiv.) Lewis acida T (◦C) t (hour)
Yieldb
α/βc
.
1
2
3
4
5
6
7
8
9
THF
CH2Cl2
CH2Cl2/toluene (1 : 1, v/v)
toluene
10
10
10
3
10
10
10
10
10
BF3 Et2O
0
0
0
0
4.5
4
4
2.5
3.5
1
2
2.5
3.3
no reaction
27%
.
BF3 Et2O
9.8/1
7.9/1
.
BF3 Et2O
34%
.
BF3 Et2O
trace
trace
31%
46%
56%
.
toluene
toluene
toluene
toluene
BF3 Et2O −78 ∼ 0
.
BF3 Et2O −40 ∼ 0
1.9/1
1.5/1
1.25/1
2.2/1
.
BF3 Et2O −40 ∼ 0
.
BF3 Et2O −40 ∼ 0
.
toluene
BF3 Et2O −40 ∼ 0
45%
.
a1.2 equivalent of BF3 Et2O.
bIsolated yields; during the optimization process, the α- and β-anomers were isolated as a mixture.
cDuring the optimization process, the α/β ratio were determined by 1H NMR.
the NOESY results and, therefore, the anomeric configurations of 16α and
16β were determined unambiguously (Figures 2 and 3).
The t-butyldimethylsilyl (TBS) group of 16β was deprotected by tetra-
butylammonium fluoride (TBAF) in THF and the removal of isopropylidene
group was accomplished by DOWEX H+ resin in H2O to give 3-bromo-
2,6-dimethoxy-5-(β-d-ribofuranosyl)pyridine (17). Attempts to remove the
methyl groups from the base with trimethylsilyl iodide or boron tribromide
were unsuccessful but led to a mixture of several possible isomerized prod-
1
ucts. The demethylation was then monitored by mass spectrometry and H
NMR. The results indicated that no oxidation products were observed dur-
ing the reaction. However, the isomerization/anomerization occurred prior
to the demethylation, which resulted in several possible isomeric products
(7, 17–21) proposed in Scheme 3.
In conclusion, our efforts have shown that the instability of 1-
deazauridine was due to the anomerization/isomerization caused by the keto
-enol tautomerism of the base. Since many 3-(d-ribofuranosl)-2-pyridone
derivatives have been previously synthesized and characterized,[2,4,31–36] in-
cluding 1-deazacytidine,[2] we rationalized that the additional hydroxyl
group at 6-position enhanced the tautomerism and, therefore, acceler-
ated the anomerization and isomerization. Accordingly, the synthesis of
1-deazauridine (2) still remained unachieved.
EXPERIMENTAL
3-Bromo-2,6-dimethoxy-5-(5-O-tert-butyldimethylsilyl-1-hydroxy-
2,3-O-isopropylidene-α/β-D-ribofuranosyl)pyridine
(14α/β)
3,5-Dibromo-2,6-dimethoxypyridine[12,28] (12, 7.20 g, 24.0 mmol) was
dissolved in anhydrous THF (70 mL) and the solution was stirred under an

528
C.-H. Jen and T.-C. Chien
FIGURE 2 a) H-H COSY of 16α; b) NOESY of 16α.

Reinvestigation of the Synthesis of 1-Deazauridine
529
FIGURE 3 a) H-H COSY of 16β; (b) NOESY of 16β.

530
C.-H. Jen and T.-C. Chien
OMe
OMe
O
Br
Br
Br
N
N
HN
Me
Me
O
O
O
(b)
(a)
HO
HO
HO
O
OH
OH
H
H
HO
OH
HO
18
OH
E/ Z
HO
20
OH
17β
E/ Z
(a)
(b)
OR
OR
R = H
Br
Br
N
N
O
RO
RO
+
+ tautomers
HO
O
HO
OH
H
OH
H
HO
17 /
HO
19α/β
21α/β
α β R = Me
7 /
R = Me
R = H
α β R = H
SCHEME 3 Proposed mechanism for the isomerization/anomerization during the demethylation of
3-bromo-2,6-dimethoxy-5-(β-d-ribofuranosyl) pyridine (17).
argon atmosphere at −78◦C. n-Butyllithium (1.6 M, 18.0 mL, 28.8 mmol,
1.2 equiv.) was added to the solution and the reaction mixture was kept stir-
ring for 30 minutes at the same temperature. To the reaction mixture was
then added a solution of 5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-d-
1,4-ribonolactone[26,27] (10, 7.28 g, 24.0 mmol, 1 equiv.) in anhydrous THF
(50 mL). The reaction mixture was stirred for an additional 2 hours while
the temperature was allowed to raise to room temperature. H2O (20 mL)
was added to quench the reaction. The reaction mixture was extracted with
EtOAc (100 mL) and the organic layer was washed with saturated NaCl
solution (30 mL), dried over anhydrous Na2SO4 and the solvent was evap-
orated under reduced pressure. The residue was purified by flash column
chromatography (Hex/EtOAc = 9 : 1, Rf = 0.16) to give a product mixture
containing α/β anomers (14α/β, in a ratio of 2.5 : 1 approximately, deter-
1
1
mined by H NMR) as light yellow oil (7.93 g, 15.2 mmol, 63%). H NMR
(CDCl3, 500 MHz) δ 8.07 (s, 0.28 H), 8.03 (s, 0.72 H), 4.90 (d, 0.72 H), 4.87
(m, 1.44 H), 4.75 (m, 0.56 H), 4.72 (m, 0.28 H), 4.36 (m, 0.72 H), 4.28 (m,
0.28 H), 3.993 (s, 2.16 H), 3.990 (s, 2.16 H), 3.98 (s, 0.84 H), 3.95 (s, 0.84
H), 3.94–3.78 (m, 2 H), 1.65 (s, 0.84 H), 1.41 (s, 0.84 H), 1.27 (s, 2.16 H),
1.25 (s, 2.16 H), 0.94 (s, 6.48 H), 0.83 (s, 2.52 H), 0.15 (s, 2.16 H), 0.14 (s,
2.16 H), 0.05 (s, 0.84 H), 0.02 (s, 0.84 H).
The major anomer of 14 (14α): The major anomer was collected by re-
crystallization from Hex. Attempts to determine the anomeric configuration

Reinvestigation of the Synthesis of 1-Deazauridine
531
by NOE were unsuccessful. Thus, the anomeric configuration was assigned
as α, based on Imbach’s empirical rule[30] without spectroscopic support.
m.p. 106–108◦C (Hex); 1H NMR (CDCl3, 400 MHz) δ 8.03 (s, 1 H, H-4), 4.90
(d, 1 H, J = 5.8 Hz), 4.87 (d, 1 H, J = 4.9 Hz), 4.87 (s, 1 H, OH), 4.36 (m,
1 H), 3.993 (s, 3 H, OCH3), 3.990 (s, 3 H, OCH3), 3.88 (dd, 1 H, J = 4.0
and 10.9 Hz, H-5ꢁ), 3.82 (dd, 1 H, J = 3.0 and 10.9 Hz, H-5ꢁ), 1.27 (s, 3 H,
CH3), 1.25 (s, 3 H, CH3), 0.94 (s, 9 H, t-Bu), 0.15 (s, 3 H, CH3), 0.14 (s, 3 H,
CH3); 13C NMR (CDCl3, 100 MHz) δ 158.2, 158.0, 142.0 (CH), 115.4, 112.4,
105.5, 94.7, 87.6 (CH), 86.2 (CH), 81.9 (CH), 64.7 (CH2), 54.3 (CH3), 54.0
(CH3), 26.7 (CH3), 25.8 (3 × CH3), 25.6 (CH3), 18.4, −5.51 (2 × CH3); MS
(ES) m/z 502 (90, M–OH), 504 (100, M–OH + 2), 542 (19, M + Na), 544
(32, M + Na + 2); HRMS Calcd for C21H34NO7SiBr.Na (M + Na): 542.1186.
Found: 542.1156; Anal. Calcd. for C21H34NO7SiBr: C, 48.46; H, 6.58; N, 2.69.
Found: C, 48.36; H, 6.71; N, 2.47.
3-Bromo-2,6-dimethoxy-5-(5-O-tert-butyldimethylsilyl-2,3-O-
isopropylidene-α/β-D-ribofuranosyl)pyridine
(16α/β)
Compound 14α/β (0.51 g, 0.99 mmol) was dissolved in dry toluene (20
mL) and the solution was stirred under an argon atmosphere at −40◦C. To
the solution was added triethylsilane (1.6 mL, 1.15 g, 9.9 mmol, 10 equiv.),
followed by boron trifluoride etherate (0.15 mL, 0.168 g, 1.18 mmol, 1.2
equiv.) and the reaction mixture was kept stirring for an additional 2 hours
while the temperature was allowed to raise to 0◦C. The reaction mixture
was quenched at 0◦C with saturated aqueous NaHCO3 solution (20 mL)
and extracted with CH2Cl2 (50 mL). The organic layer was washed with
saturated NaCl solution (30 mL), dried over anhydrous Na2SO4 and the
solvent was evaporated under reduced pressure. The residue was purified
by flash column chromatography (Hex/EtOAc = 9.7 : 0.3, Rf = 0.2, the
α-anomer is slightly less polar than the β-anomer) to give compounds 16α
and 16β (syrup, 0.23 g, 0.45 mmol, 45%).
1
α-anomer (16α): H NMR (CDCl3, 500 MHz) δ 7.86 (s, 1 H, H-4), 5.39
(d, 1 H, J = 4.0 Hz, H-1ꢁ), 4.91 (d, 1 H, J = 6.0 Hz, H-3ꢁ), 4.85 (dd, 1 H, J
= 4.1 & 5.9 Hz, H-2ꢁ), 4.22 (t, 1 H, J = 3.2 Hz, H-4ꢁ), 3.97 (s, 3 H, OCH3),
3.91 (s, 3 H, OCH3), 3.83 (dd, 1 H, J = 3.4 & 10.9 Hz, H-5ꢁ), 3.77 (dd, 1 H,
J = 3.1 & 11.0 Hz, H-5ꢁ), 1.40 (s, 3 H, CH3), 1.29 (s, 3 H, CH3), 0.93 (s, 9 H,
t-Bu), 0.08 (s, 3 H, CH3), 0.07 (s, 3 H, CH3); 13C NMR (CDCl3, 125 MHz)
δ 157.5, 157.4, 142.6 (CH), 112.6, 112.1, 95.2, 83.7 (CH), 83.3 (CH), 81.5
(CH), 78.2 (CH), 65.3 (CH2), 54.2 (CH3), 53.5 (CH3), 26.1 (CH3), 25.8 (3
× CH3), 24.8 (CH3), 18.0, −5.68 (CH3), −5.71 (CH3); MS (ES) m/z 504 (70,
M + 1), 506 (73, M + 3), 526 (93, M + Na), 528 (100, M + Na + 2); HRMS
Calcd for C21H35NO6SiBr (M+1): 504.1417. Found: 504.1451.

532
C.-H. Jen and T.-C. Chien
β-anomer (16β): H NMR (CDCl3, 500 MHz) δ 7.83 (s, 1 H, H-4), 5.07
1
(d, 1 H, J = 4.2 Hz, H-1ꢁ), 4.68 (dd, 1 H, J = 6.4 and 4.4 Hz, H-3ꢁ), 4.52 (dd,
1 H, J = 6.4 and 4.2 Hz, H-2ꢁ), 4.10 (dd, 1 H, J = 3.7 and 7.5 Hz, H-4ꢁ), 3.98
(s, 3 H, OCH3), 3.95 (s, 3 H, OCH3), 3.87 (dd, 1 H, J = 3.2 and 11.2 Hz,
H-5ꢁ), 3.79 (dd, 1 H, J = 3.8 and 11.2 Hz, H-5ꢁ), 1.60 (s, 3 H, CH3), 1.35 (s, 3
H, CH3), 0.91 (s, 9 H, t-Bu), 0.10 (s, 3 H, CH3), 0.09 (s, 3 H, CH3); 13C NMR
(CDCl3, 125 MHz) δ 158.5, 157.8, 141.5 (CH), 115.3, 113.9, 95.3, 86.3 (CH),
84.6 (CH), 81.2 (CH), 80.1 (CH), 63.2 (CH2), 54.3 (CH3), 53.8 (CH3), 27.7
(CH3), 26.0 (3 × CH3), 25.7 (CH3), 18.4, −5.3 (CH3), −5.4 (CH3); MS (ES)
m/z 504 (46, M + 1), 506 (47, M + 3), 526 (92, M + Na), 528 (100, M + Na
+ 2); HRMS Calcd for C21H35NO6SiBr (M+1): 504.1417. Found: 504.1456.
3-Bromo-2,6-dimethoxy-5-(β-D-ribofuranosyl)pyridine (17)
To a solution of compound 16β (0.59 g, 1.17 mmol) in THF (8 mL)
at room temperature was added tetra-n-butylammonium fluoride (TBAF; 1
M solution in THF with approximately 5% of H2O, 1.3 mL; containing 1.3
mmol of TBAF, 1.1 equiv.) and the solution was stirred at room temperature
for 1 hour. The solvent was removed under reduced pressure. The residue
was redissolved in H2O (30 mL) and the aqueous solution was extracted with
CHCl3 (2 × 60 mL). The organic portions were combined and washed with
saturated aqueous NaCl solution (50 mL), dried over anhydrous Na2SO4,
and the solvent was then evaporated under reduced pressure to give the
crude product that was used without further purification. A mixture of the
crude product and Dowex-H+ 50W × 8 (2.30 g) in H2O (6 mL) was stirred at
70◦C for 1 hour. The solvent was removed under reduced pressure and the
residue was purified by flash column chromatography (Hex/EtOAc = 3 : 7,
Rf = 0.16) to give compound 17 (solid, 0.14 g, 0.40 mmol, 35%). 1H NMR
(CD3OD, 400 MHz) δ 8.02 (s, 1 H, H-4), 4.94 (d, 1 H, J = 4.4 Hz, H-1ꢁ), 3.98
(s, 3 H, OCH3), 3.97 (s, 3 H, OCH3), 4.00–3.91 (m, 3 H, H-2ꢁ, H-3ꢁ and H-4ꢁ),
3.85 (dd, 1 H, J = 2.9 and 12.0 Hz, H-5ꢁ), 3.72 (dd, 1 H, J = 4.4 and 12.0 Hz,
H-5ꢁ); 13C & DEPT135 NMR (CDCl3, 100 MHz) δ 160.3, 159.3, 143.1 (CH),
116.9, 96.2, 85.0 (CH), 80.8 (CH), 77.7 (CH), 72.3 (CH), 63.1 (CH2), 54.9
(CH3), 54.4 (CH3); MS (ES) m/z 350 (92, M + 1), 352 (100, M + 3), 372
(46, M + Na), 374 (45, M + Na + 2); HRMS Calcd for C12H17NO6Br (M+1):
350.0239. Found (M): 350.0218.
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