Antimalarial spiro-bridged 1,2-dioxolanes Via intramolecular addition of peroxycarbenium ions to C-C double bonds

Article abstract of DOI:10.3987/COM-12-S(N)5

Several 1,2-dioxolanes embedded in a rigid spiro-bridge framework fused with a built-in UV chromophore were synthesized through intramolecular [3+2] addition of in situ generated peroxycarbenium ions to C-C double bonds.

Full text of DOI:10.3987/COM-12-S(N)5

HETEROCYCLES, Vol. 86, No. 1, 2012
245
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 245 - 254. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 13th March, 2012, Accepted, 10th April, 2012, Published online, 12th April, 2012
DOI: 10.3987/COM-12-S(N)5
ANTIMALARIAL
SPIRO-BRIDGED
1,2-DIOXOLANES
VIA
INTRAMOLECULAR ADDITION OF PEROXYCARBENIUM IONS TO
C-C DOUBLE BONDS
Yun Li,a Sergio Wittlin,b,c and Yikang Wu*a
a) State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China, e-mail: yikangwu@sioc.ac.cn. b) Swiss Tropical and
Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland. c)
University of Basel, CH-4051 Basel, Switzerland
Abstract – Several 1,2-dioxolanes embedded in a rigid spiro-bridge framework
fused with a built-in UV chromophore were synthesized through intramolecular
[3+2] addition of in situ generated peroxycarbenium ions to C-C double bonds.
INTRODUCTION
Discovery of qinghaosu1 (artemisinin), a potent naturally-occurring antimalarial agent, has brought
entirely renewed interest to organic peroxides. To establish structure-activity relationships and to discover
new lead compounds for antimalarial drugs, a huge number of novel organic peroxides have been
designed and synthesized since the late 1970’s.
An issue of central importance in the synthesis of organic peroxides is the introduction of the peroxy
bond. To date, almost in all synthetic organic peroxides the peroxy bonds were taken from some
inorganic species that already contain O-O bond(s), such as 3O2, 1O2, and O3. Hydrogen peroxide (H2O2)
is also a readily available source for peroxy bonds, which has received more and more attention in recent
years because of the potential advantages in accessibility, handling, and cost.2
H
O
C
O
O
H
C
O
O
C
O
H
hydrogen
peroxide
hydroperoxides
organic peroxides
Figure 1. Incorporation of H2O2 into organic structures with one oxygen alkylated at a time.
This paper is dedicated to Professor Ei-ichi Negishi on the occasion of his 77th birthday

246
HETEROCYCLES, Vol. 86, No. 1, 2012
Incorporation of hydrogen peroxide into an organic framework is often achieved in a stepwise manner
(Figure 1), with one oxygen atom bonded to a carbon atom at a time through alkylation or ketalization.
Recently, we developed2t a PMA (phosphomolybdic acid) catalyzed transformation of ketones and ketals
into the corresponding gem-dihydroperoxyketals, which provided a facile way to complete the first step
(Figure 1). In efforts to complete the second step (viz., connecting another carbon atom to the
hydroperoxyl group) we noticed the Woerpel’s2p approach to 1,2-dioxolanes (also the original work3 of
Dussault, Figure 2). Although all their products were monocyclic, it seemed that application of such
reactions in an intramolecular manner would result in structurally more complex polycyclic peroxides.
Prompted by this thought, we carried out the work below.
R1
R2
O
R1
R2
OOH
+
R1
R2
SnCl4
O
SiMe3
+
OOH
R3O
R1
OOH
R2
Me3Si
Me3Si
(Dussault)
(Woerpel)
R3
R4
R1
R2
O
R1
R2
+
SnCl4
R1 O OSiEt3
R2 O SiEt3
O
OOSiEt3
R3
R4
Et3SiO
OSiEt3
O
HO
O
OH
O
O
O
O
O
O
+
X
X
X
2
X
3
4
1
a: X = C(CO2Me)2
b: X = O
Figure 2. The intermolecular additions of peroxycarbenium ions to alkenes giving monocyclic peroxides
developed by Dussault and Woerpel, and the main features of this work (conversion of 2 to 3 and 4).
RESULTS AND DISCUSSION
The synthesis merged with the condensation4 of dimethyl malonate (5) with the known5 aldehyde 6
(Scheme 1). The resulting ,-unsaturated species (7) was treated with vinyl Grignard reagent in the
presence of CuCl at –78 °C gave the expected Michael addition6 product 8 in 89% yield. The acidic
malonate CH proton was then removed with NaH to afford the corresponding carbanion, which reacted
with the commercially available 9 to yield 10. A Heck reaction was then performed under the
Pd(OAc)2/K2CO3/Ph3P/MeCN7 conditions. The resulting 11 was then converted into the corresponding
gem-dihydroperoxides 1a via reaction with H2O2 as reported previously2t with the aid of PMA.

HETEROCYCLES, Vol. 86, No. 1, 2012
247
HOAc
piperidine
CuCl
89%
O
O
CO2Me
O
O
H
+
CH2=CHMgBr
CH2Cl2
CO2Me

THF/ 78 °C
O
6
62%
MeO2C
CO2Me
7
5
Pd(OAc)2/PPh3
K2CO3/MeCN
O
O
O
O
NaH/THF
CO2Me
CO2Me
10
80 °C/36 h
92%
82%
Br
MeO2C
CO2Me
Br
8
Br
O
O
9
CO2Me
11
CO2Me
ref. 2t
HO
O
OH
Et3SiO
OSiEt3
O
Et3SiCl
O
O
imidazole
95%
CO2Me
CO2Me
DMF
91%
PMA/H2O2
CO2Me
CO2Me
1a
2a
O
O
SnCl4/CH2Cl2
3a
4a
(the less polar isomer, 32%)
(the more polar isomer, 14%)

8 °C/5 h
CO2Me
CO2Me
Et3SiO
O
OSiEt3
HO
O
OH
Et3SiCl
imidazole
O
O
O
2b
8 °C/5 h
DMF
87%
O
1b
SnCl4/CH2Cl2

O
2
O
1
3
1a
3
O
O
7a
O
7
5
4
H
6
4
5
O
O
2
H
1a
4b
1
7
+
6
nOe
4b
3b
O
O
7a
(with the atoms arbitrarily
numbered for comparison)
The less polar isomer
(22%)
The more polar isomer
(64%)
Scheme 1

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HETEROCYCLES, Vol. 86, No. 1, 2012
The hydroperoxide OH’s in 1a were silylated with Et3SiCl in the presence of imidazole to deliver the
bis-silylpoxyketal 2a in 91% yield. The key [3+2] cycloaddition was then examined at –78 °C in CH2Cl2
in the presence of SnCl4. After five hours’ reaction, the desired bridged peroxides, 3a (the less polar
isomer) and 4a (the more polar isomer), were isolated in 32% and 14% yields, respectively. The closely
related bis-silylpoxyketal 2b (derived in a similar manner by silylation of the known2t 1b) also underwent
facile [3+2] reaction under the same conditions, giving 3b (the less polar isomer) and 4b (the more polar
isomer) in 22% and 64% yield, respectively.
The products of the cycloadditions (3 and 4) are a pair of diastereomers in each case. Although the
relative configurations for 3a and 4a cannot be assigned with certainty, those for 3b and 4b are reliably
established with the aid of 2D NOESY experiment; a distinct nOe (the boxed structure on the bottom left
corner, Scheme 1) was observed for the polar isomer 4b.
Table 1. The in vitro activity against P. falciparum (NF54 strain).a,b
Peroxide
IC50 (ng/mL)
336
IC50 (M)
0.97
3a
4a
3b
4b
936
2.70
502
2.16
1516
6.53
Chloroquine
diphosphate
6.7
1.2
0.013
Artesunate
0.0030
a The in vitro antimalarial data were obtained as described previously
(ref. 8).
b Data shown are the values from n = 2–3 independent experiments.
The peroxides obtained were tested in vitro for their antimalarial activity. The results are shown in Table
1. The IC50’s were in the range of 0.97-6.53 M, with the less polar isomers somewhat more potent than
the more polar ones.
In summary, several 1,2-dioxolanes with the peroxy bond installed in a rigid spiro-bridge framework
were synthesized by using intramolecular [3+2] addition of in situ generated peroxycarbenium ions to
C-C double bonds. All products contain a fused benzene ring to serve as a built-in UV chromophore,
which may facilitate e.g., HPLC analysis in case of further biomedical investigations.

HETEROCYCLES, Vol. 86, No. 1, 2012
249
EXPERIMENTAL
The 1H NMR and 13C NMR spectra were recorded at ambient temperature using a Varian Mercury 300 or
a Bruke Avance 300 instrument (operating at 300 MHz for proton). The FTIR spectra were scanned with
a Nicolet Avatar 360 FT-IR. EIMS and EIHRMS were recorded with an HP 5989A and a Finnigan MAT
8430 mass spectrometer, respectively. The ESIMS and ESIHRMS were recorded with a PE Mariner
API-TOF and an APEX III (7.0 Tesla) FTMS mass spectrometer, respectively. Dry CH2Cl2 was obtained
by distillation over CaH2. Dry THF was distilled over Na/Ph2CO under argon before use. Degassed
MeCN was obtained by bubbling N2 into MeCN for 20 min. All other solvents and reagents were used as
received from commercial sources. PE = petroleum ether (chromatography solvent, bp 60−90 °C).
Dimethyl 2-(3-(2-methyl-1,3-dioxolan-2-yl)propylidene)malonate (7). Piperidine (0.2 mL, 2.0 mmol)
and glacial acetic acid (0.12 mL, 2.0 mmol) were added in turn to a solution of dimethyl malonate (3.90 g,
30 mmol) in dry CH2Cl2 (5 mL) stirred in an ice-water bath. After completion of the addition, the bath
was removed and the mixture was stirred at ambient temperature over night. When TLC showed
completion of the reaction, sat. aq. NH4Cl (10 mL) was added. The mixture was extracted with Et2O
(3×50 mL), washed with brine (3×15 mL), and dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation and column chromatography (1:6 EtOAc/PE) on silica gel gave 7 as a colorless oil
(1.6 g, 6.2 mmol, 62%): 1H NMR (300 MHz, CDCl3)  7.08 (t, J = 7.3 Hz, 1H), 4.00-3.87 (m, 4H), 3.84
(s, 3H), 3.78 (s, 3H), 2.42 (dt, J = 8.3, 7.3 Hz, 2H), 1.84 (t, J = 7.7 Hz, 2H), 1.32 (s, 3H). 13C NMR (75
MHz, CDCl3)  165.8, 164.3, 150.5, 127.5, 109.1, 64.6, 52.3, 52.2, 37.2, 24.5, 23.9; FT-IR (film) 2955,
2887, 1732, 1644, 1437, 1376, 1256, 1052, 863, 833 cm–1; ESI-MS m/z 281.0 ([M+Na]+); EI-HRMS
calcd for C12H18O6 (M+) 258.1103, found 258.1105.
Dimethyl 2-(5-(2-methyl-1,3-dioxolan-2-yl)pent-1-en-3-yl)malonate (8). CH2=CHMgBr (1.0 M, in
Et2O, 1.2 mL, 1.2 mmol) was added dropwise to a mixture of 7 (256 mg, 1.0 mmol) and CuCl (5.0 mg,
0.05 mmol) in dry THF (3 mL) stirred at –78 °C under N2 (balloon). After completion of the addition, the
mixture was stirred another 30 min at the same temperature, when TLC showed completion of the
reaction. sat. aq. NH4Cl (5 mL) was added. The mixture was extracted with Et2O (3×30 mL), washed
with brine (3×15 mL), and dried over anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (1:6 EtOAc/PE) on silica gel gave 8 as a colorless oil (236 mg, 0.89 mmol,
89%): 1H NMR (300 MHz, CDCl3)  5.63 (dt, J = 17.5, 9.6 Hz, 1H), 5.12 (d, J = 1.9 Hz, 1H), 5.07 (d, J =
2.6 Hz, 1H), 4.00-3.84 (m, 4H), 3.74 (s, 3H), 3.69 (s, 3H), 3.40 (d, J = 9.0 Hz, 2H), 2.76 (dq, J = 2.8, 9.6
Hz, 1H), 1.77-1.50 (m, 2H), 1.46-1.32 (m, 1H), 1.29 (s, 3H); 13C NMR (75 MHz, CDCl3)  168.6, 168.4,
137.6, 117.9, 109.7, 64.6, 64.5, 56.8, 52.4, 52.3, 44.1, 36.4, 26.6, 23.8; FT-IR (film) 2955, 2883, 1739,
1642, 1435, 1377, 1255, 1151, 1039, 924, 850 cm–1; ESI-MS m/z 309.0 ([M+Na]+); Anal. Calcd for

250
HETEROCYCLES, Vol. 86, No. 1, 2012
C14H22O6: C 58.73, H 7.74. Found: C 58.75, H 7.50.
Dimethyl 2-(2-bromobenzyl)-2-(5-(2-methyl-1,3-dioxolan-2-yl)pent-1-en-3-yl)malonate (10).
A
solution of the 2-bromobenzyl bromide 9 (525 mg, 2.10 mmol) in dry THF (1 mL) was added to a
mixture of 8 (200 mg, 0.70 mmol) and NaH (60% in mineral oil, 84 mg, 2.10 mmol, washed thrice with
petroleum ether before addition of THF) in dry THF (3 mL) stirred at ambient temperature already for 30
min. Stirring was then continued at the same temperature over night. When TLC showed completion of
the reaction, sat. aq. NH4Cl (5 mL) was added. The mixture was extracted with Et2O (3×50 mL), washed
with brine (2×15 mL), and dried over anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (1:5 EtOAc/PE) on silica gel gave 10 (260 mg, 0.57 mmol, 82%) as a
colorless oil: 1H NMR (300 MHz, CDCl3)  7.50 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.19 (d, J =
7.4 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.69 (dt, J = 16.9, 10.3 Hz, 1H), 5.19 (d, J = 2.2 Hz, 1H), 5.09 (d, J
= 1.7 Hz, 1H), 4.00-3.84 (m, 4H), 3.63 (s, 3H), 3.61 (s, 3H), 3.53 (d, J = 14.8 Hz, 1H), 3.38 (d, J = 14.8
Hz, 1H), 2.70 (t, J = 9.6 Hz, 1H), 1.92-1.66 (m, 2H), 1.56 (dt, J = 4.4, 13.1 Hz, 1H), 1.39-1.31 (m, 1H),
1.30 (s, 3H); 13C NMR (75 MHz, CDCl3)  170.5, 170.4, 137.2, 136.9, 132.5, 131.3, 128.0, 127.1, 126.2,
119.1, 109.8, 64.6, 64.5, 62.4, 52.2, 52.1, 50.4, 38.4, 37.3, 24.8, 23.8; FT-IR (film) 2981, 2880, 1732,
1474, 1435, 1377, 1248, 1045, 852, 751 cm–1; ESI-MS m/z 477.1 ([M+Na]+); MALDI-HRMS calcd for
C21H27O6BrNa ([M+Na]+) 477.08832, found 477.0893.
Dimethyl
3-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-4-methylene-3,4-dihydronaphthalene-2,2(1H)-
dicarboxylate (11). A solution of 10 (190 mg, 0.42 mmol), PPh3 (44 mg, 0.17 mmol), K2CO3 (300 mg,
2.52 mmol), and Pd(OAc)2 (14 mg, 0.06 mmol) in degassed MeCN (8 mL) was placed in liquid N2. The
resulting solid was evacuated with an oil pump and the vaccum was released with argon. The process was
repeated three time before the mixture was finally refluxed in a oil bath under argon for 36 h. The mixture
was cooled to ambient temperature. Et2O (50 mL) and water (20 mL) were added. The mixture was
extracted with extracted with Et2O (3×50 mL), washed with brine (2×20 mL), and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column chromatography (1:5 EtOAc/PE) on
silica gel gave 11 as a colorless oil (145 mg, 0.38 mmol, 92%): 1H NMR (300 MHz, CDCl3)  7.53 (d, J =
7.3 Hz, 1H), 7.24-7.08 (m, 3H), 5.56 (s, 1H), 5.05 (s, 1H), 4.00-3.80 (m, 4H), 3.78 (s, 3H), 3.60 (s, 3H),
3.57 (d, J = 17.2 Hz, 1H), 3.25 (d, J = 17.2 Hz, 2H), 1.49-1.82 (m, 3H), 1.38-1.22 (m, 1H), 1.21 (s, 3H);
13C NMR (75 MHz, CDCl3)  170.4, 170.3, 142.3, 133.1, 132.0, 128.8, 128.1, 126.4, 124.9, 112.4, 109.7,
64.5, 64.4, 58.4, 52.9, 52.8, 46.7, 36.7, 30.7, 23.6, 23.3; FT-IR (film) 2982, 2882, 1736, 1631, 1478, 1434,
1377, 1259, 1151, 1046, 948, 778, 736 cm–1; ESI-MS m/z 397.1 ([M+Na]+); MALDI-HRMS calcd For
C21H26O6Na ([M+Na]+) 397.16216, found 397.1635.
Dimethyl 3-(3,3-bis(triethylsilylperoxy)butyl)-4-methylene-3,4-dihydronaphthalene-2,2(1H)-

HETEROCYCLES, Vol. 86, No. 1, 2012
251
dicarboxylate (2a). A solution of 1a (150 mg, 0.40 mmol), Et3SiCl (202 L, 1.2 mmol) and imidazole
(103 mg, 1.52 mmol) in dry DMF (4 mL) was stirred at ambient temperature for 10 h. Et2O (50 mL) and
water (10 mL) were added. The mixture was extracted with extracted with Et2O (3×50 mL), washed with
water (2×20 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation and column chromatography (1:20 EtOAc/PE) on silica gel gave 11 as a colorless oil
1
(220 mg, 0.36 mmol, 91%): H NMR (300 MHz, CDCl3)  7.55 (d, J = 7.6 Hz, 1H ), 7.25-7.10 (m, 3H),
5.57 (s, 1H), 5.08 (s, 1H), 3.80 (s, 3H), 3.62 (s, 3H), 3.57 (d, J = 16.7 Hz, 1H), 3.35-3.318 (m, 2H),
1.94-1.68 (m, 2H), 1.67-1.47 (m, 1H), 1.25-1.37 (m, 1H), 1.23 (s, 3H), 0.98 (t, J = 8.0 Hz, 9H), 0.91 (t, J
13
= 8.0 Hz, 9H), 0.68 (q, J = 8.0 Hz, 6H), 0.59 (q, J = 8.0 Hz, 6H). C NMR (75 MHz, CDCl3)  170.4,
170.3, 142.2, 133.1, 132.0, 128.7, 128.0, 126.4, 125.0, 112.4, 110.5, 58.4, 52.9, 52.7, 46.7, 32.2, 30.8,
23.6, 18.7, 6.73, 6.66, 3.76, 3.67. FT-IR (film) 2954, 2878, 1742, 1456, 1434, 1233, 1280, 1140, 798, 733
cm–1; ESI-MS m/z 631.4 ([M+Na]+); ESI-HRMS calcd for C31H52O8Si2Na ([M+Na]+) 631.30929, found
631.31085.
Dimethyl
3-methyl-3,4,5,5a-tetrahydro-3,11b-methanonaphtho[1,2-c][1,2]dioxepine-6,6(7H)-
dicarboxylate (3a and 4a). A solution of SnCl4 in dry CH2Cl2 (1.0 M, 0.15 mL, 0.15 mmol) was added
to a solution of 2a (60 mg, 0.1 mmol) in CH2Cl2 (4 mL) stirred at –78 °C under argon (balloon). After
completion of the addition, stirring was continued at the same temperature for 5 h before the bath was
allowed to warm to ambient temperature over 1 h. When TLC showed completion of the reaction, Et2O
was added, followed by sat. aq. NaHCO3. The mixture was extracted with Et2O, washed in turn with
water, aq. sat. NaHCO3, and brine before being dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation and column chromatography (1:6 EtOAc/PE) on silica gel gave the less polar isomer
3a (11 mg, 0.032 mmol, 32%) and the more polar isomer 4a (5 mg, 0.014 mmol, 14%) as a colorless oils.
Data for 3a (the less polar isomer): 1H NMR (300 MHz, CDCl3)  7.21 (d, J = 8.8 Hz, 1H ), 7.11-7.01 (m,
2H), 6.94 (d, J = 7.3 Hz, 1H), 3.84 (s, 3H), 3.79 (d, J = 14.1 Hz, 1H), 3.76 (s, 3H), 3.68 (d, J = 8.5 Hz,
1H), 3.04 (d, J = 13.7 Hz, 1H), 2.78 (d, J = 7.8 Hz, 1H), 2.73 (d, J = 11.6 Hz, 1H), 2.59 (dt, J = 9.8, 2.1
Hz, 1H), 2.43-2.25 (m, 1H), 2.00 (dd, J = 15.0, 6.3 Hz, 1H), 1.72 (dd, J = 14.1, 6.7 Hz, 1H), 1.33 (s, 3H).
FT-IR (film) 2953, 2929, 1729, 1488, 1450, 1257, 1237, 1180, 1112, 997, 894, 766 cm–1; ESI-MS m/z
385.1 ([M+K]+); ESI-HRMS calcd for C19H22O6Na ([M+Na]+) 369.13086, found 369.13084.
Data for 4a (the more polar isomer): 1H NMR (300 MHz, CDCl3)  7.08 (d, J = 8.3 Hz, 1H ), 7.03 (d, J =
8.3 Hz, 1H), 6.94-6.84 (m, 2H), 3.83 (dd, J = 5.3, 10.1 Hz, 2H), 3.75 (s, 3H), 3.39 (s, 3H), 3.23 (d, J =
16.2 Hz, 1H), 2.83 (dd, J = 11.0, 2.7 Hz, 1H), 2.61 (d, J = 10.9 Hz, 1H), 2.23-2.05 (m, 1H), 2.02-1.91 (m,
1H), 1.71 (dd, J = 12.3, 6.0 Hz, 1H ), 1.52-1.41 (m, 1H), 1.35 (s, 3H). FT-IR (film) 2952, 2929, 1739,
1490, 1452, 1227, 1191, 1152, 893, 872, 759 cm–1; ESI-MS m/z 369.1 ([M+Na]+); ESI-HRMS calcd for

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HETEROCYCLES, Vol. 86, No. 1, 2012
C19H22O6Na ([M+Na]+) 369.13086, found 369.13086.
3,3,9,9-Tetraethyl-6-methyl-6-(2-(4-methyleneisochroman-3-yl)ethyl)-4,5,7,8-tetraoxa-3,9-disilaun-
decane (2b). The same procedure for conversion of 1a into 2a above was used (with 1b to replace 1a);
yield (chromatography with 1:100 EtOAc/PE): 87%.
1
Data for 2b (a colorless oil): H NMR (300 MHz, CDCl3)  7.69-7.60 (m, 1H), 7.27-7.18 (m, 2H),
7.97-6.06 (m, 1H), 5.62 (s, 1H), 5.08 (s, 1H), 4.87 (d, J = 15.2 Hz, 1H), 4.74 (d, J = 15.2 Hz, 1H), 4.28 (t,
J = 6.8 Hz, 1H), 2.07-1.80 (m, 4H), 1.36 (s, 3H), 0.97 (t, J = 8.2 Hz, 18H), 0.69 (q, J = 8.2 Hz, 12H). 13C
NMR (75 MHz, CDCl3)  141.6, 134.4, 131.4, 127.7, 126.9, 124.3, 123.9, 110.8, 107.1, 77.3, 65.6, 30.2,
27.2, 18.8, 6.8, 3.8; FT-IR (film) 2954, 2877, 1458, 1412, 1371, 1239, 1104, 1019, 798, 730 cm–1;
ESI-MS m/z 517.2 ([M+Na]+); ESI-HRMS calcd for C26H46O5Si2Na ([M+Na]+) 517.27760, found
517.27837.
(3R*,5aR,11bS*)-3-Methyl-4,5,5a,7-tetrahydro-3H-3,11b-methano[1,2]dioxepino[4,3-c]isochromene
(3b) and (3S*,5aR*,11bR*)-3-methyl-4,5,5a,7-tetrahydro-3H-3,11b-methano[1,2]dioxepino[4,3-c]-
isochromene (4b). The same procedure for conversion of 2a into 3a and 4a (but with 2b to replace 2a,
chromatography with 1:20 EtOAc/PE).
Data for 3b (the less polar isomer, a colorless oil, 22% from 2b): 1H NMR (300 MHz, CDCl3)  7.59 (dd,
J = 3.8, 5.6 Hz, 1H ), 7.29-7.20 (m, 2H), 7.00 (t, J = 4.2 Hz, 1H), 4.95 (d, J = 14.9 Hz, 1H), 4.88 (d, J =
14.9 Hz, 1H), 3.80 (d, J = 6.2 Hz, 1H), 2.93 (d, J = 11.7 Hz, 1H), 2.52-2.35 (m, 1H), 2.27 (d, J = 11.6 Hz,
1H), 1.95-1.82 (m, 1H), 1.76 (dd, J = 4.5, 10.4 Hz, 2H), 1.40 (s, 3H). 13C NMR (75 MHz, CDCl3)  135.3,
133.9, 127.8, 127.0, 123.8, 123.7, 84.3, 83.6, 74.8, 68.7, 54.7, 33.1, 24.7, 22.0. FT-IR (film) 2934, 2861,
1454, 1372, 1223, 1080, 1037, 855, 757 cm–1; ESI-MS m/z 255.0 ([M+Na]+); ESI-HRMS calcd for
C14H16O3Na ([M+Na]+) 255.09917, found 255.09921.
1
Data for 4b (the more polar isomer, a colorless oil, 64% from 2b): H NMR (300 MHz, CDCl3) 
7.72-7.61 (m, 1H ), 7.37-7.27 (m, 2H), 7.05 (t, J = 4.2 Hz, 1H), 4.85 (d, J = 14.8 Hz, 1H), 4.76 (d, J =
15.9 Hz, 1H), 3.73 (dd, J = 5.8, 11.1 Hz, 1H), 2.93 (dd, J = 2.8, 11.8 Hz, 1H), 2.34 (d, J = 11.6 Hz, 1H),
2.23-2.33 (m, 1H), 2.05-2.16 (m, 1H), 1.94 (dd, J = 6.7, 14.0 Hz, 1H), 1.65-1.80 (m, 1H), 1.46 (s, 3H).
13C NMR (75 MHz, CDCl3)  137.7, 128.8, 128.4, 127.28, 127.27, 124.4, 83.9, 80.9, 78.8, 68.1, 53.1,
35.6, 25.6, 21.2. FT-IR (film) 2941, 2851, 1493, 1447, 1376, 1297, 1213, 1108, 1038, 866, 756 cm–1;
ESI-MS m/z 255.0 ([M+Na]+); ESI-HRMS calcd for C14H16O3Na ([M+Na]+) 255.09917, found
255.09924.
ACKNOWLEDGEMENTS
This work was supported by the National Basic Research Program of China (the 973 Program,

HETEROCYCLES, Vol. 86, No. 1, 2012
253
2010CB833200), the National Natural Science Foundation of China (21172247, 21032002, 20921091,
20672129, 20621062, 20772143), and the Chinese Academy of Sciences.
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