Synthesis of conformationally locked methanocarba-uridine as a precursor for nucleotides agonizing P2Y6 receptor

Article abstract of DOI:10.1055/s-2007-973902

Conformationally locked uridine in the 'southern' conformation, which could be an important precursor for corresponding nucleotides, was stereoselectively synthesized. Southern uridine nucleotides are expected to be full agonists for the P2Y₆ r

Full text of DOI:10.1055/s-2007-973902

LETTER
1055
Synthesis of Conformationally Locked Methanocarba-uridine as a Precursor
for Nucleotides Agonizing P2Y6 Receptor
Synthesis of
C
o
onformationa
o
lly Locked
n
M
ethanocarb
-
a-uridin
A
e
i Kim,a Hyun Min Lee,a Jae-Sang Ryu,b Hak Sung Kim*a
a
College of Pharmacy, Wonkwang University, 344-2 Shinyong-Dong, Iksan, Jeonbuk 570-749, South Korea
Fax +82(63)8431581; E-mail: hankidad@wku.ac.kr
b
College of Pharmacy, Ewha Womans University, Seoul 120-750, South Korea
Received 4 January 2007
O
NH2
Me
Abstract: Conformationally locked uridine in the ‘southern’ con-
formation, which could be an important precursor for corresponding
nucleotides, was stereoselectively synthesized. Southern uridine
nucleotides are expected to be full agonists for the P2Y6 receptor.
Poor diastereoselectivity in the osmium-mediated dihydroxylation
on the allyl amine was overcome by introduction of an allyl azide
on which osmium medium hydroxylation, and subsequent cycliza-
tion yielded 6-oxabicyclo[3.2.0]heptane in a 9:1 ratio. High regio-
selectivity between the 2¢- and 3¢-hydroxyl groups in the
intramolecular O-alkylation and construction of uracil moiety from
the azido group provided the final target, a southern 2¢-benzoylated
uridine derivative.
O
N
N
NH
O
N
HO
O
HO
O
NH
"PP"O
N
O
N
N
HO
HO
O
H
H
OH
southern
northern LNA
Wengel et al.
J. Med. Chem. (2005)
northern cLNA
Jacobson et al.
Org. Lett. (2003)
full agonist to P2Y6
Jacobson et al.
J. Med. Chem. (2005)
O
O
NH
NH
Key words: nucleoside, nucleotide, carbohydrate, carbocycle, ste-
reoselective synthesis
HO
O
RO
N
O
N
O
O
OBz
OH
O
In general, the ribose rings of nucleosides and nucleotides
may adopt a range of conformations; this has been de-
scribed as the pseudorotational cycle.1 The LNA approach
(2,5-dioxabicyclo[2.2.1]heptane system) by the Wengel
group,2 and a methanocarba approach (bicyclo[3.1.0]hex-
ane system) introduced by the Marquez group,3 were used
to constrain the pseudosugar ring of the nucleoside to
either a northern or a southern conformation.
southern
Imanishi et al.
Tetrahedron (2002)
A target carbocyle
for uridine diphosphate
locked in southern conformation
Figure 1 Conformationally locked nucleosides and nucleotides.
tane, as prepared by Imanishi group,7 could increase the
stability in acid-catalyzed hydrolysis conditions.
As shown in Scheme 1, the target molecule, 2¢-benzoyl-
ated methanocarba-uridine 1 (nomenclature like 2¢ or 3¢ is
used in numbering the pseudosugar ring despite the in-
herent bicyclic system, vide infra) might be obtained from
well-known intermediate, diol 2.8 Benzoyl group can be
used as a protecting group because the diphosphate group
is stable in basic aqueous ammonia, which is required for
deprotection of the benzoyl group. However, hydrogen-
bonding interactions between OsO4 and amine group can
Conformationally locked uridine diphosphate (UDP),
built on the 2-oxabicyclo[2.2.1]heptane scaffold4 as uri-
dine diphosphate, reportedly has a northern conformation
preferable to the adenosine A3 receptor and the P2Y1 re-
ceptor.5 Recently, however, the southern conformation of
the ribose, constructed from a bicyclo[3.1.0]hexane sys-
tem restricted in southern conformation, was found to be
preferred for ligand recognition by the P2Y6 receptor
(Figure 1).6 Southern 2¢-deoxymethanocarbaUDP was a
full agonist with 10-fold higher potency than a corre-
sponding normal 2¢-deoxyUDP.
O
O
NH
O
NH
O
To determine whether the binding site of P2Y6 can adopt
another southern conformation of UDP at a different angle
in the pseudorotational cycle, we attempted stereoselec-
tive and asymmetric synthesis of conformationally locked
methanocarba-uridine built on 6-oxabicyclo[3.2.0]hep-
tane system. Replacement of the oxygen atom with carbon
in the pseudosugar ring of 2,6-dioxabicyclo[3.2.0]hep-
BnO
N
HO
"PP"O
N
N
OH
OBz
OH
O
O
O
1
proper nitrogen
source
BnO
HO
BnO
N
BnO
TsO
N
OH
TsO
HO
OH
SYNLETT 2007, No. 7, pp 1055–1058
2
4.
0
4.
2
0
0
7
2
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-973902; Art ID: U00207ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis.

1056
S.-A. Kim et al.
LETTER
affect the direction of dihydroxylation, causing poor dia- ing the J1¢2¢ value of fused oxetane 7 to that of 2-
stereoselectivity.9 Therefore, an azido group was found to oxabicyclo[2.2.1]heptane made clear the rigid southern
be the proper nitrogen source to improve diastereoselec- conformation of 6-oxabicyclo[3.2.0]heptane 7.
tivity of dihydroxylation. Construction of an uracil ring
from an amine group can be accomplished coupled with
b-ethoxyacryloyl cyanate and ring closure in acidic or
Convinced of the correct configuration for the fused oxe-
tane 7, our focus shifted to improving the diastereoselec-
tivity in dihydroxylation. The allyl amine or amide system
basic conditions. Chemoselectivity in the intramolecular
might be problematic, causing low diastereoselectivity
O-alkylation in a system similar to Imanishi’s was anti-
due to strong hydrogen bonding with osmium species.9
cipated to yield the desired southern 6-oxabicyc-
A nitrogen source was needed that lacked the ability to
lo[3.2.0]heptane as the major isomer over the northern
hydrogen bond but that could provide steric hindrance in
conformation.
dihydroxylation, and the azido group met these criteria
(Scheme 3).
O
BnO
HO
EtO
6 steps
ref. 8
BnO
TsO
i–iii
BnO
BnO
TsO
BnO
TsO
N3
OH
N3
OH
i
N3
ii
iii
3
OH
OH
EtO
O
O
HO
3
2
8
9
10
diethyl diallyl
malonate
O
O
OH
BnO
BnO
UBz
v
BnO
HO
UBz
iv
UBz
NH
O
NH
O
+
iv
v
HO
N
OBz
OH
BnO
TsO
TsO
N
TsO
5
HO
6
4
OH
O
O
BnO
O
O
7
1
U
vi
U =
UBz =
NBz
O
NH,
O
OH
Scheme 3 Conversion of azido group into uracil. Reagents and con-
ditions: i) diphenylphosphoryl azide, DBU, toluene, 0 °C to r.t., 6 h
(96%): ii) OsO4, NMO, acetone–H2O–THF–t-BuOH (4:1:2:2), 0 °C,
18 h (93%); iii) NaH, THF, –10 °C to r.t., 5 h (78%); iv) a) 5% Pd/
CaCO3, H2, MeOH, r.t., 1 d; b) b-ethoxyacryloyl cyanate, benzene,
r.t., 10 min; c) NH4OH, EtOH, sealed tube, 100 °C (47% for three
steps); v) a) BzCl, pyridine, 0 °C, 3 h (63%); b) 10% Pd/C, H2,
MeOH, r.t., 4 h (100%).
N
N
O
7
Scheme 2 Introduction of uracil moiety in the early stage. Reagents
and conditions: i) TBDPSCl, cat. DMAP, Et3N, CH2Cl2, r.t., 18 h
(79%); ii) TsCl, DMAP, CH2Cl2, r.t., 1 d (75%); iii) TBAF, THF, r.t.,
6 h (96%); iv) benzoyluracil, PPh3, DIAD, THF, r.t., 3 h (77%); v) cat.
OsO4, NMO, acetone–H2O (4:1), r.t., 18 h (68%); vi) NaH, THF,
–10 °C to r.t., 3 h (60%).
Allyl alcohol 3 was treated with diphenylphosphoryl
azide and DBU in toluene9 to produce a 96% yield of the
desired allyl azide 8 in which the configuration of C-1¢
was inverted. The crucial step, osmium-mediated dihy-
droxylation on the allyl azide 8 resulted in 9:1 diastereo-
selectivity of desired isomer 9 over unwanted isomer. As
expected, base-promoted cyclization of a mixture of tosyl
diol 9 and an isomeric diol afforded the desired and sepa-
rable hydroxyl oxetane 10 as a single isomer with the iso-
meric diol remaining unchanged. Conversion of hydroxyl
oxetane 10 into the final target 1 for nucleotide synthesis
required sequential steps, including construction of the
uracil moiety from the azido group and benzolyation on
the C-3¢ alcohol, followed by deprotection of the 5¢-O-
benzyl group. To conserve a labile 5¢-O-benzyl group in
catalytic hydrogenation conditions usually applied to re-
duction of azido group to amine, the azido group in 10 was
transformed to amine with poisoned catalyst (5% Pd/
CaCO3). Uracil was formed from amine in two steps.
After coupling with b-ethoxyacryloyl cyanate,11 the inter-
mediate, ethoxyacrylamide, was heated in a sealed tube in
ammonia water at 100 °C, to furnish hydroxy benzyluri-
dine 7 in 47% yield (three steps) from 10. Benzyluridine
7 was readily converted into our final target 1 by benzo-
ylation of the 2¢-hydroxy and debenzylation of 5¢-ben-
zylether by catalytic hydrogenation. In 1H NMR spectra,
As previously discussed,4 the less-hindered secondary
alcohol group in 2 {[a]D –77.0 (c 0.57, MeOH), lit. [a]D
–77.0 (c 6.1, CHCl3)}8 was selectively protected with a
tert-butyldiphenylsilyl group, followed by tosylation of
neopentyl hydroxyl group and successive deprotection of
silyl ether for a 57% yield (three steps) of hydroxytosylate
3 (Scheme 2). For easy introduction of uracil moiety, hy-
droxytosylate 3 was directly coupled to monobenzoylated
uracil10 via Mitsunobu reaction, which afforded 4. Dihy-
droxylation of N-allyluracil 4 with treatment of catalytic
osmium tetraoxide and N-methylmorpholine oxide fur-
nished a 1:1 mixture of 5 and 6. This ratio was confirmed
1
by integration of H NMR spectra and by weighing the
two separated isomers. After ring closure of dihydroxy-
tosylate 6 under basic conditions (NaH, THF, –10 °C to
r.t.), the correct structure of the desired 6-oxabicyc-
lo[3.2.0]heptane 7 was confirmed. In the southern confor-
mation of 6-oxabicyclo[3.2.0]heptane 7, the two protons
at C-1¢ and C-2¢ should have a pseudoaxial–pseudoaxial
relationship. The observed J1¢2¢ value of 7 was 9.6 Hz; in
the case of 1, the J1¢2¢ value was 10.1 Hz. This value was
evidence of the southern conformation. In a previous pub-
lication,4 the coupling constant of J1¢2¢ in 2-oxabicyc-
lo[2.2.1]heptane with an adenine moiety was 0 Hz, which
reflects the pseudoequatorial–pseudoequatorial relation-
ship derived from a rigid northern conformation. Compar-
Synlett 2007, No. 7, 1055–1058 © Thieme Stuttgart · New York

LETTER
Synthesis of Conformationally Locked Methanocarba-uridine
1057
Preparation of Azido Diol 9
the 2¢-H peak at C-2¢ in hydroxyl benzoate 1 was shifted
1.6 ppm downfield after benzoylation of 2¢-OH of 7,
which was evidence that 2¢-OH did not participate in ring
cyclization. Also, from HMQC and HMBC spectra, we
concluded that the carbonyl carbon peak of benzoyl
group is related to the C-2¢ peak. As mentioned, J1¢2¢ value
of 1 was 10.1 Hz, reflecting the pseudoaxial–pseudoaxial
relationship in southern conformation.
A homogeneous solution of tosyl azide 8 (1.06 g, 2.56 mmol), NMO
(390 mg, 3.33 mmol) and cat. 2% osmium hydroxide (in H2O, 0.2
mL) in acetone–H2O–THF–t-BuOH (4:1:2:2, 18 mL) was stirred at
0 °C for 18 h. After treatment with solid Na2S2O3 (900 mg) and stir-
ring for another 10 min, solvents were evaporated and the residual
aqueous phase was extracted with EtOAc (5 × 10 mL), then the
combined organic extracts were dried over anhyd Na2SO4, filtered
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane–EtOAc–MeOH, 10:10:1, 2
times) to afford a diol 9 (1.07 g, 93%) as a mixture (9:1). 1H NMR
(500 MHz, CDCl3): d = 7.77 (d, 2 H, J = 8.8 Hz), 7.35–7.27 (m, 5
H), 7.22–7.19 (m, 2 H), 4.44–4.36 (m, 2 H), 4.22 (d, 1 H, J = 9.6
Hz), 4.05 (d, 1 H, J = 9.2 Hz), 3.99–3.97 (m, 2 H), 3.83–3.76 (m, 1
H), 3.39 and 3.28 (ABq, 2 H, J = 9.2 Hz), 2.42 (s, 3 H), 1.94 (dd, 1
H, J = 14.2, 8.2 Hz), 1.45 (dd, 1 H, J = 14.2, 7.4 Hz).
In conclusion, the introduction of an azido group success-
fully raised the diastereoselectivity of dihydroxylation.
An exclusive intramolecular O-alkylation produced the
desired 6-oxabicyclo[3.2.0]heptane with a southern
conformation. After conversion into the corresponding
nucleotide, this compound is expected to show agonistic
effects on P2Y6 receptor.
Preparation of Azido Oxetane 10
To a stirred suspension of NaH (60% in mineral oil, 31 mg, 0.77
mmol) in THF (3 mL) at –10 °C was added a solution of hydroxy
azide 9 (230 mg, 0.51 mmol) in THF. After stirring at 0 °C for 30
min, the reaction temperature was spontaneously raised to r.t. over
1 h. After additional stirring for 4 h at the same temperature, the re-
sulting mixture was cooled to 0 °C, quenched by addition of H2O
through a syringe and partitioned between EtOAc (30 mL) and 10%
aq NaCl solution. The organic layer was separated. The aqueous
layer was extracted with EtOAc (10 mL) and the combined organic
extracts were washed with brine (5 mL), and dried over anhyd
Na2SO4, filtered and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (hexane–EtOAc–
Preparation of Tosylate 3 from Silylether of 2
A mixture of monosilylated neopentyl alcohol4 (3.47 g, 7.60 mmol),
p-toluenesulfonyl chloride (1.68 g, 8.81 mmol), dimethylamino-
pyridine (0.132 g, 1.08 mmol), and Et3N (1.54 mL, 11.0 mmol) in
CH2Cl2 (30 mL) was stirred for 1 d at r.t. After the reaction complet-
ed, the resulting mixture was partitioned between EtOAc (80 mL)
and 10% aq NaCl solution (10 mL), and the organic layer was sep-
arated. The aqueous layer was extracted with EtOAc (20 mL) and
the combined organic extracts were washed with brine (10 mL),
dried over anhyd Na2SO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (hex-
1
MeOH, 20:10:1) to afford azido oxetane 10 (110 mg, 78%). H
1
NMR (500 MHz, CDCl3): d = 7.38–7.27 (m, 5 H), 4.75 (d, 1 H,
J = 4.2 Hz), 4.72 (dd, 1 H, J = 6.4, 1.4 Hz), 4.54 (s, 2 H), 4.25 (d, 1
H, J = 6.4 Hz), 4.25–4.21 (m, 1 H), 3.79 (m, 1 H), 3.55 and 3.48
(ABq, 2 H, J = 9.2 Hz), 2.08–2.04 (m, 1 H), 1.64 (m, 1 H).
ane–EtOAc, 10:1) to give silyl tosylate (3.56 g, 75%). H NMR
(500 MHz, CDCl3): d = 7.78 (dt, 2 H, J = 8.7, 1.9 Hz), 7.62–7.58
(m, 4 H), 7.44–7.33 (m, 6 H), 7.30–7.24 (m, 5 H), 7.17–7.15 (m, 2
H), 5.68 (s, 2 H), 4.76 (dd, 1 H, J = 6.9, 3.2 Hz), 4.33 (s, 2 H), 4.12
(m, 2 H), 3.23 and 3.21 (ABq, 2 H, J = 9.2 Hz), 2.37 (s, 3 H), 1.89
(dd, 1 H, J = 13.8, 6.9 Hz), 1.63 (dd, 1 H, J = 13.8, 3.2 Hz), 0.99 (s,
9 H).
Preparation of 5¢-Benzylmethanocarba-uridine 7
A mixture of hydroxy azide 10 (60 mg, 0.22 mmol) and 5% Pd/
CaCO3 (7 mg) and dry MeOH (4 mL) was overnight stirred at r.t.
with a balloon filled with H2. The resulting mixture was filtrated
through a plug of Celite® to remove the Lindlar catalyst and the
filtrate was concentrated in vacuo. The residue was used in the next
reaction without further purification.
To a solution of the pure silyl tosylate (2.61 g, 4.16 mmol) in THF
(30 mL) was added 1 M TBAF (in THF, 5.0 mL, 5.00 mmol) at r.t.
After stirring for 6 h at the same temperature, the volatile THF was
removed in vacuo and the residue was directly applied to column
chromatography on silica gel (hexane–EtOAc, 1:1) to furnish a de-
sired hydroxyl tosylate 3 (1.55 g, 96%) as a colorless oil. 1H NMR
(500 MHz, CDCl3): d = 7.77 (d, 2 H, J = 8.3 Hz), 7.34–7.28 (m, 5
H), 7.23–7.19 (m, 2 H), 5.92 (dd, 1 H, J = 5.5, 1.8 Hz), 5.74 (d, 1 H,
J = 5.9 Hz), 4.79–4.74 (m, 1 H), 4.40 (s, 2 H), 4.08 and 4.02 (ABq,
2 H, J = 9.2 Hz), 3.30 and 3.26 (ABq, 2 H, J = 9.2 Hz), 2.42 (s, 3
H), 2.08 (dd, 1 H, J = 14.2, 7,8 Hz), 1.66 (d, 1 H, J = 9.3 Hz), 1.55
(dd, 1 H, J = 14.2, 2.8 Hz).
A solution of b-ethoxyacryloyl cyanate (0.5 mmol) in anhyd ben-
zene (1 mL) was added rapidly to a stirred solution of crude hydrox-
yl amine (54 mg, 0.22 mmol) in anhyd benzene (2 mL) at r.t. The
reaction mixture was stirred at the same temperature for 10 min, di-
luted with EtOAc (20 mL), and treated with sat. aq NaHCO3 (5 mL).
After the solution was stirred for 20 min at r.t., the organic layer was
separated, washed with brine (10 mL), dried (Na2SO4), filtered, and
concentrated in vacuo to give the crude intermediate (100% crude
yield). The residue was used in the next reaction without further
purification.
Preparation of Tosylate Azide 8
To a stirred solution of tosyl alcohol 3 (1.04 g, 2.68 mmol) and DBU
(0.52 mL, 3.48 mmol) in dry toluene (15 mL) was added neat di-
phenylphosphoryl azide (0.69 mL, 3.22 mmol) at 0 °C. After stir-
ring for 6 h at r.t., the resulting mixture was partitioned between
EtOAc (30 mL) and 10% aq NaCl solution (5 mL), and the organic
layer was separated. The aqueous layer was extracted with ethyl
acetate (15 mL) and the combined organic extracts were washed
with brine (10 mL), dried over anhyd Na2SO4, filtered and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy on silica gel (hexane–EtOAc, 4:1) to afford tosylate azide 8
(1.06 g, 96%) as a colorless oil. 1H NMR (500 MHz, CDCl3): d =
7.75 (dd, 2 H, J = 8.7, 2.3 Hz), 7.35–7.16 (m, 7 H), 5.84 (s, 2 H),
4.45–4.37 (m, 3 H), 3.98 (d, 2 H, J = 2.3 Hz), 3.37 (ddd, 2 H,
J = 6.9, 6.0, 1.9 Hz), 2.42 (s, 3 H), 2.16–2.10 (m, 1 H), 1.72–1.66
(m, 1 H).
The acryloylureidohexane (85 mg, 0.22 mmol) in a mixed solution
of 33% NH4OH (3 mL) and EtOH (4 mL) was heated at 100 °C in
the sealed tube for 3 h. The resulting mixture was evaporated in
vacuo and the residue was purified by column chromatography on
silica gel (hexane–EtOAc–MeOH, 10:10:1) to afford 5¢-O-benzyl-
methanocarba-uridine 7 (35 mg, 47% three steps yield); [a]D –44.2
(c 1.01, MeOH). 1H NMR (500 MHz, CDCl3): d = 8.60 (br s, 1 H),
7.40–7.20 (m, 6 H), 5.77 (d, 1 H, J = 8.3 Hz), 5.22 (ddd, 1 H,
J = 11.5, 9.6, 6.9 Hz), 4.82 (d, 1 H, J = 4.1 Hz), 4.74 (d, 1 H, J = 5.5
Hz), 4.55 (m, 2 H), 4.38 (d, 1 H, J = 6.9 Hz), 4.13–4.06 (m, 1 H),
3.65 and 3.50 (ABq, 2 H, J = 9.2 Hz), 2.09 (dd, 1 H, J = 13.3, 6.9
Hz), 2.00 (dd, 1 H, J = 13.3, 11.5 Hz).
Synlett 2007, No. 7, 1055–1058 © Thieme Stuttgart · New York

1058
S.-A. Kim et al.
LETTER
Preparation of 2¢-Benzoylmethanocarba-uridine 1
Acknowledgment
To a stirred solution of 5¢-O-benzylmethanocarba-uridine 7 (50 mg,
0.15 mmol) and pyridine (0.037 mL, 0.46 mmol) in dry CH2Cl2 (2
mL) was added benzoyl chloride (0.027 mL, 0.23 mmol) at 0 °C.
After stirring for 3 h at the same temperature, the resulting mixture
was partitioned between EtOAc (30 mL) and 10% aq NaCl (10 mL),
and the organic layer was separated. The aqueous layer was extract-
ed with EtOAc (10 mL) and the combined organic extracts were
washed with brine (10 mL), dried over anhyd Na2SO4, filtered and
concentrated in vacuo. The residue was purified by column chroma-
tography on silica gel (hexane–EtOAc–MeOH, 10:10:1) to afford
5¢-benzyl-2¢-benzoylmethanocarba-uridine (41 mg, 63%). 1H NMR
(500 MHz, CDCl3): d = 8.45 (br s, 1 H), 8.02–7.99 (m, 2 H), 7.56–
7.51 (m, 1 H), 7.44–7.27 (m, 8 H), 5.80–5.73 (m, 2 H), 5.38 (dd, 1
H, J = 10.5, 4.2 Hz), 5.13 (d, 1 H, J = 4.1 Hz), 4.74 (d, 1 H, J = 6.4
Hz), 4.58 (s, 2 H), 4.44 (d, 1 H, J = 6.4 Hz), 3.68 and 3.54 (ABq, 2
H, J = 9.2 Hz), 2.24–2.15 (m, 2 H). 13C NMR (125 MHz, CD3OD):
d = 166.1, 162.7, 150.9, 141.2, 137.7, 133.7, 130.1 (2 × C), 128.9,
128.7 (2 × C), 128.6 (2 × C), 128.1, 127.8 (2 × C), 103.2, 83.6, 77.8,
75.9, 73.6, 71.5, 59.0, 45.1, 33.0.
This research was supported by Wonkwang University in 2005.
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A mixture of 5¢-benzyl-2¢-benzoylmethanocarba-uridine (33 mg,
mmol) and 10% Pd/C (5 mg) and dry MeOH (3 mL) was stirred at
r.t. for 4 h with a balloon filled with H2. The resulting mixture was
filtrated through a plug of Celite® to remove the palladium catalyst.
The filtrate was concentrated in vacuo and the residue was purified
by column chromatography on silica gel to give the final product,
2¢-benzoylmethanocarba-uridine 1 (26 mg, 100%) as a white solid;
1
[a]D –93.8 (c 0.016, MeOH). H NMR (500 MHz, CD3OD): d =
8.01–7.95 (m, 2 H), 7.84 (d, 1 H, J = 8.3 Hz), 7.60 (tt, 1 H, J = 7.4,
1.4 Hz), 7.45 (t, 2 H, J = 8.3 Hz), 5.77 (ddd, 1 H, J = 11.9, 10.1, 7.8
Hz), 5.74 (d, 1 H, J = 8.3 Hz), 5.48 (dd, 1 H, J = 10.1, 4.2 Hz), 5.15
(d, 1 H, J = 4.2 Hz), 4.48 (d, 1 H, J = 6.4 Hz), 3.75 and 3.69 (ABq,
2 H, J = 11.5 Hz), 3.34 (s, 1 H), 2.20 (dd, 1 H, J = 12.8, 11.9 Hz),
2.16 (dd, 1 H, J = 12.8, 7.8 Hz). 13C NMR (125 MHz, CD3OD):
d = 166.0, 164.8, 151.8, 143.1, 133.4, 129.5 (2 × C), 129.1, 128.3
(2 × C), 101.9, 83.6, 77.4, 76.5, 63.2, 58.9, 46.5, 31.6. MS (EI):
m/z 357 [M – H].
(9) Ainai, T.; Wang, Y.-G.; Tokoro, Y.; Kobayashi, Y. J. Org.
Chem. 2004, 69, 655.
(10) Lee, Y.-S.; Hyean Kim, B. Bioorg. Med. Chem. Lett. 2002,
12, 1395.
(11) Jeong, L. S.; Beunger, G.; McCormack, J. J.; Cooney, D. A.;
Hao, Z.; Marquez, V. E. J. Med. Chem. 1998, 41, 2572.
Synlett 2007, No. 7, 1055–1058 © Thieme Stuttgart · New York

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