Syntheses of (±)-thuriferic acid ethyl ester, its analogues and (±)-picropodophyllone

Article abstract of DOI:10.1016/j.tet.2005.03.069

(±)-Thuriferic acid ethyl ester, its analogues as well as (±)-picropodophyllone have been prepared. The synthetic strategy is based on the utility of vicinal dianions derived from α-aroylsuccinic esters.

Full text of DOI:10.1016/j.tet.2005.03.069

Tetrahedron 61 (2005) 5311–5321
Syntheses of (G)-thuriferic acid ethyl ester, its analogues
and (G)-picropodophyllone
*
Manat Pohmakotr, Taweechote Komutkul, Patoomratana Tuchinda, Samrarn Prabpai,
*
Palangpon Kongsaeree and Vichai Reutrakul
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Received 4 January 2005; revised 2 March 2005; accepted 18 March 2005
Available online 12 April 2005
Abstract—(G)-Thuriferic acid ethyl ester, its analogues as well as (G)-picropodophyllone have been prepared. The synthetic strategy is
based on the utility of vicinal dianions derived from a-aroylsuccinic esters.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ZnCl2. Compounds of type 34 have been used as useful
starting materials for the preparation of a-arylidene-g-
butyrolactones, which embodied all the necessary carbon
framework for the aryltetralone precursor of thuriferic acid
type lignans.5 Based on this highly versatile technique, we
herein report the preparation of thuriferic acid ethyl ester
(4a) and analogues as well as pricropodophyllone (2),3a,6 an
important precursor for many synthetic entries to podo-
phyllotoxin (Fig. 1).
Considerable research work on the isolation and synthesis of
lignan natural products and analogues such as podophyllo-
toxin and derivatives1 has been extensively investigated due
to their wide range of biological activities including
antineoplastic activity. Among these compounds, thuriferic
acid (1) isolated from the hexane extracts of Juniperus
thurifera leaves exhibits interesting cytotoxic activity.2 The
syntheses of thuriferic acid and derivatives, together with
2. Results and discussion
Starting from a-aroylsuccinic ester 5, vicinal dianion 6 was
generated by treatment with 2 equiv of lithium diisopropyl-
amide (LDA) in tetrahydrofuran (THF) at K78 8C for 1 h. It
was allowed to react with aromatic aldehydes (1.1 equiv) in
the presence of ZnCl2 (1 equiv) at K78 8C for 1 h, followed
by slowly warming up to reach room temperature overnight
to provide a-aroylparaconic esters 3 (50–60%) as diastereo-
meric mixtures of (3,4-trans),(4,5-cis)-isomer (TC-isomer),
(3,4-trans),(4,5-trans)-isomer (TT-isomer), (3,4-cis),(4,5-
trans)-isomer (CT-isomer) and (3,4-cis),(4,5-cis)-isomer
(CC-isomer). In each case, the TC-isomer was obtained as
the major isomer and could be separated from the other
diastereomers by recrystallisation (Scheme 1). Considering
a-aroylparaconic esters of type 3 as important starting
materials, our study towards the construction of aryltetra-
lone basic skeleton of thuriferic acid by acid-catalyzed
rearrangement of 3a employing SnCl4/CHCl3, concd
H2SO4/CHCl3 or P2O5/MeSO3H to provide 71d,6a,c was
undertaken. However, it was found that only 5–8% yields of
7 were obtained together with the unidentified products. The
low yield of aryltetralone 8 may be due to the fact that
Figure 1.
the precusor (G)-picropodophyllone (2) have been accom-
plished by several methods.3 In connection with our efforts
to utilize vicinal dianions derived from a-aroylsuccinates as
reagents for synthesis of g-butyrolactones and some lignan
natural products, we have recently reported a general
synthetic entry to a-aroylparaconic esters 3 by reacting the
vicinal dianion with aromatic aldehydes in the presence of
Keywords: a-Aroylparaconic ester; Picropodophyllone; a-Aroylsuccinic
ester; Vicinal dianion.
*
Corresponding authors. Tel.: C66 2 2015158; fax: C66 2 6445126;
e-mail addresses: scmpk@mahidol.ac.th; scvrt@mahidol.ac.th
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.069

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M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
Scheme 1.
enolization at 3-position of 3a occurs rapidly under the
attempted conditions. This avoids the intramolecular
electrophilic aromatic substitution of the initially formed
carbonium ion at the 5-carbon of 3a. To circumvent this
problem, the cyclisation of a-methylated a-aroylparaconic
ester 8a was studied. Thus, a-methylated g-lactone 8a was
prepared by treatment of the enolate anion derived from an
82:18 mixture of TC- and TT-isomers of 3a with methyl
iodide (NaH/THF/0 8C) to provide CC-8a7 (70% yield) and
CT-8a (10% yield) after chromatography. As expected, the
reaction of CC-8a with SnCl4 (10 equiv) in CHCl3 at 60 8C
for 6 h afforded aryltetralone 9 in 59% yield as a single
diastereomer after chromatography (Scheme 2). The (3,4-
trans),(4,5-trans) stereochemistry of 9 was established by a
series of NOE experiments. Thus, irradiation of H-5 signal
resulted in 9.8% enhancement of H-3 signal, but no
enhancement of H-4 signal was observed.
Scheme 3.
derivatives 4 after elimination. Therefore, the requisite a-
phenylsulfanylmethylparaconic ester 10a was prepared in
good yield from a-aroylparaconic ester TC-3a by employ-
ing NaH/THF/PhSCH2Cl/NaI at 0 8C to room temperature
overnight, followed by oxidation of the resulting 10a with
acetic acid/30% H2O2 (0 8C to rt, overnight).6 Compound
11a was obtained as a single diastereomer (CC-isomer). The
relative stereochemistry at the 4,5-position was assigned by
analysis of the coupling constant between H-4 and H-5
1
which appeared in the H NMR spectrum as doublets at d
4.88 and 6.16 (JZ6.9 Hz) ppm, respectively. The structure
of compound 11a was finally confirmed by X-ray crystallo-
graphy as shown in Figure 2.8 Similarly, the major isomers
CC-11b and CC-11c were prepared in good overall yields
starting from 3b (TC/TTZ82:18) and TC-3c, respectively.
Having compound 11a in hand, it was subjected to Lewis
acid-catalyzed rearrangement by reacting with SnCl4
(10 equiv) in CHCl3 at room temperature overnight. The
reaction afforded, presumably the intermediate 12a which
was treated immediately with diazabicycloundecane (DBU)
in THF at room temperature for 1 h to provide the required
thuriferic ethyl ester (4a) in 39% overall yield together with
the arylnapthalene 13a as the minor product in 6% yield. By
employing the same reaction sequence, 4b, 4c, 13b and 13c
Scheme 2.
This successful synthesis of aryltetralone 9 from compound
8 led us to propose a synthethic route to thuriferic acid ethyl
ester and its analogues. As shown in Scheme 3, it occurred
to us that Lewis acid-catalyzed rearrangement of compound
11 would provide compound 12 and then thuriferic acid

M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
5313
Kieselgel 60 F254, 0.5 mm) were used for column
chromatography and preparative TLC, respectively.
4.1.1. Preparation of diethyl a-(3,4-methylenedioxy-
benzoyl)succinate (5). By modification of the known pro-
cedure,9 a solution of piperonal (30.07 g, 200 mmol) in
methanol (100 mL) was added dropwise to a solution of
dimethylammonium chloride (32.74 g, 401 mmol) and
potassium cyanide (26.24 g, 402 mmol) in water (100 mL).
The resulting mixture was heated under reflux for 4 h. The
solvent was removed under reduced pressure, and water
(150 mL) was then added to the residue and extracted with
EtOAc (4!100 mL). The combined organic layers were
washed with saturated aqueous NaHSO3 (100 mL), water
(2!100 mL), brine and dried over anhydrous MgSO4.
Evaporation of solvent under reduced pressure gave a crude
product of 2-(N,N-dimethylamino)-2-(3,4-methylenedixoy-
phenyl)ethanenitrile, which was further used without
purification.
Figure 2. X-ray crystal structure of compound 11a.
were obtained in 49, 62, 4 and 1% yields, respectively. The
relative stereochemistries at C-4 and C-5 of these com-
pounds were assigned by comparing their coupling
constants at d 4.62–4.65 ppm (JtransZ4.0–4.1 Hz) with
those of compound 9.
A solution of the crude a-aminonitrile in THF (50 mL) was
slowly added to a THF (50 mL) solution of sodium ethoxide
[prepared by reacting Na metal (7.04 g, 305 mmol) with
absolute ethanol (145 mL)] at room temperature under an
argon atmosphere. After stirring at room temperature for
1 h, a solution of diethyl fumarate (52.70 g, 306 mmol) in
THF (50 mL) was added dropwise. The reaction mixture
was stirred at the same temperature overnight (15 h), then
diluted with water (200 mL) and extracted with EtOAc (3!
150 mL). The combined organic extracts were washed with
water (3!100 mL), brine and dried over anhydrous
MgSO4. Evaporation of solvent under reduced pressure
gave diethyl a-[1-N,N-dimethylamino-1-cyano-1-(3,4-
methylenedioxyphenyl)methyl]succinate of which was sub-
jected to hydrolysis in the next step.
Hydrolysis of the ester group of 4a with 6 M HCl in dioxane
under reflux for 15 h furnished (G)-picropodophyllone
(2)3a,6b–e in 43% yield after chromatography instead of the
expected (G)-thuriferic acid. The formation of 2 was
believed to occur via the acid-catalyzed lactonisation of the
initially formed thuriferic acid (1). (G)-Picropodophyllone
has been demonstrated to be a useful precursor for the
preparation of thuriferic acid (1).3a,b,d,e
3. Conclusion
A solution of CuSO4$5H2O (75.18 g, 301 mmol) in water
(80 mL) was added to a solution of the crude product in
ethanol (200 mL). The resulting mixture was heated under
reflux for 1 h. The reaction mixture was cooled to room
temperature, diluted with water (200 mL) and extracted
with EtOAc (3!150 mL). The combined extracts were
washed with water (3!100 mL), brine and dried over
anhydrous MgSO4. After removal of solvent under reduced
pressure, the crude product obtained was purified by column
chromatography (SiO2, 10–20% EtOAc in hexanes) to give
a yellow viscous liquid of diethyl a-(3,4-methylenedioxy-
benzoyl)succinate (5) (42.21 g, 66% yield). 1H NMR
(300 MHz, CDCl3): d 7.68 (dd, JZ8.1, 1.9 Hz, 1H, ArH),
7.49 (d, JZ1.9 Hz, 1H, ArH), 6.88 (d, JZ8.1 Hz, 1H, ArH),
6.05 (s, 2H, OCH2O), 4.76 (app t, JZ7.2 Hz, 1H,
COCHCO2Et), 4.18–4.09 (m, 4H, 2!CO2CH2CH3), 3.07
(dd, ABX-system, JZ17.3, 7.7 Hz, 1H, CHHCO2Et), 2.99
(dd, ABX-system, JZ17.3, 6.6 Hz, 1H, CHHCO2Et), 1.23
(t, JZ7.0 Hz, 3H, CO2CH2CH3), 1.18 (t, JZ7.0 Hz, 3H,
CO2CH2CH3). 13C NMR (75 MHz, CDCl3): d 192.0
(C]O), 171.2 (C]O), 168.7 (C]O), 152.3 (C–O), 148.2
(C–O), 130.6 (C), 125.5 (CH), 108.5 (CH), 107.9 (CH),
101.9 (OCH2O), 61.7 (OCH2), 60.9 (OCH2), 49.3 (CH),
33.3 (CH2), 14.0 (CH3), 13.8 (CH3). IR (neat): nmax 2984m,
2939w, 2908w, 1732s, 1681m, 1605m, 1505m, 1489m,
1444s, 1369m, 1353m, 1259s, 1177m, 1036s, 932m, 861m,
809m cmK1. MS: m/z (%) relative intensity 323 (MCC1,
In conclusion, we have described an efficient and general
route to (G)-thuriferic acid ethyl ester (4a) and analogues as
well as (G)-picropodophyllone (2) by exploiting a-aroyl-
paraconic esters 3 obtained from the reaction of vicinal
dianions derived from a-aroylsuccinic esters with aromatic
aldehydes. This method should find wide application in
synthesis of series of related aryltetralin derivatives.
4. Experimental
4.1. General
Melting points (uncorrected) were determined on a Bu¨chi
501 Melting Point Apparatus. IR spectra were recorded on a
Spectrum GX FT-IR system (Perkin Elmer) spectrometer.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Bruker DPX-300 spectrometer in CDCl3 with
TMS as an internal standard. Mass spectra were obtained on
a Thermo Finnigan Polaris Q mass spectrometer. High
resolution mass spectra were obtained on a Micromass
model VQ-TOF2 mass spectrometer. Elemental analyses
were determined on a Perkin Elmer Elemental Analyzer
2400 CHN. The X-ray crystallography was performed by
Kappa CCD. Silica gel 60H and silica gel plates (Merck,

5314
M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
35), 322 (MC, 14), 277 (10), 149 (100), 121 (2), 65 (6).
Anal. Calcd for C16H18O7: C, 59.63; H, 5.63. Found: C,
59.23; H, 5.63.
1.8 Hz, 1H, ArH), 6.94 (d, JZ8.3 Hz, 1H, ArH), 6.56 (s, 2H,
ArH), 6.09 (s, 2H, OCH2O), 5.92 (d, JZ7.8 Hz, 1H,
OCHAr), 5.01 (d, JZ3.7 Hz, 1H, COCHCO), 4.24 (dd, JZ
7.8, 3.7 Hz, 1H, CHCO2Et), 3.89–3.81 (m, 1H, CO2-
CHHCH3), 3.88 (s, 6H, 2!OCH3), 3.84 (s, 3H, OCH3),
3.79–3.63 (m, 1H, CO2CHHCH3), 0.90 (t, JZ7.2 Hz, 3H,
CO2CH2CH3). 13C NMR (75 MHz, CDCl3): d 188.9
(C]O), 170.4 (C]O), 169.5 (C]O), 153.2 (2!C–O),
153.1 (C–O), 148.4 (C–O), 138.2 (C–O), 130.4 (C), 129.4
(C), 127.2 (CH), 108.9 (CH), 108.1 (CH), 102.8 (2!CH),
102.1 (OCH2O), 81.2 (OCHAr), 61.4 (OCH2), 60.7 (OCH3),
56.2 (2!OCH3), 52.2 (CH), 50.2 (CH), 13.5 (CH3). IR
(nujol): nmax 1755s, 1734s, 1668s, 1602s, 1509m, 1456s,
1333s, 1287s, 1255s, 1232s, 1196m, 1154s, 1127s, 1040m,
1005m, 995m, 939m, 837m, 730m, 718m cmK1. MS: m/z
(%) relative intensity 472 (MC, 25), 399 (4), 295 (10), 283
(10), 282 (38), 250 (7), 249 (6), 237 (17), 236 (16), 203 (14),
196 (91), 195 (100), 191 (10), 149 (14), 121 (3), 67 (5).
Anal. Calcd for C24H24O10: C, 61.02; H, 5.12. Found: C,
60.88; H, 5.06.
4.2. Generation and reaction of the vicinal dianion 6 with
aromatic aldehydes
4.2.1. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(3,4,5-trimethoxyphenyl)-5-oxotetrahydrofuran-3-
carboxylate (3a). A solution of 5 (636.1 mg, 1.98 mmol) in
THF (1 mL) was added dropwise at K78 8C to a THF
solution of lithium diisopropylamide (LDA) under an argon
atmosphere [prepared by reacting diisopropylamine
(0.6 mL, 4.25 mmol) in THF (4 mL) with n-BuLi (1.49 M
in hexane, 2.8 mL, 4.17 mmol) at K78 8C for 30 min]. After
stirring at K78 8C for 1 h, a cooled (0 8C) mixture of 3,4,5-
trimethoxybenzaldehyde (433.9 mg, 2.21 mmol) in THF
(1 mL) and ZnCl2 (1 M in THF, 2.3 mL, 2.3 mmol) was
added dropwise to a solution of the vicinal dianion 6. The
resulting mixture was stirred at K78 8C for a further 1 h,
and then at 0 8C for 2 h, followed by slowly warming up to
room temperature overnight (15 h). It was quenched with
2 M HCl (4 mL), diluted with water (50 mL) and extracted
with EtOAc (3!50 mL). The combined organic layers were
washed with water, brine and dried over anhydrous Na2SO4.
After removal of solvent under reduced pressure, the crude
product obtained was purified by column chromatography
(SiO2, 30% EtOAc in hexanes) to give a pale yellow solid of
ethyl 4-(1,3-benzodioxol-5-carbonyl)-2-(3,4,5-trimethoxy-
phenyl)-5-oxotetrahydrofuran-3-carboxylate (3a) (523.6 mg,
56% yield) as a 67:3:25:5 mixture of TC/CC/TT/CT
Attempted separation of the other diastereomers from the
filtrate obtained after recrystallization of 3a was made by
preparative thin-layer chromatography (SiO2, 20% EtOAc
in hexanes; triple runs) to give a white solid of TC-3a (less
polar) and a yellow viscous liquid of TT-3a. 1H NMR
(300 MHz, CDCl3): d 7.78 (CT) and 7.72 (TT) (each dd, JZ
8.3, 1.7 Hz, 1H, ArH), 7.54 (d, JZ1.7 Hz, 1H, ArH of TT-
and CT-isomers), 6.93 (d, JZ8.3 Hz, 1H, ArH of TT- and
CT-isomers), 6.76 (CT) and 6.67 (TT) (each s, 2H, ArH),
6.09 (s, 2H, OCH2O of TT- and CT-isomers), 6.06 (CT) and
5.56 (TT) (each d, JZ9.5, 8.5 Hz, respectively, 1H,
OCHAr), 5.04 (d, JZ9.5 Hz, 1H, COCHCO of TT- and
CT-isomers), 4.26–4.09 (m, 1H, CHCO2Et of TT-isomer,
2H, CO2CH2CH3 of TT-isomers and 2H, CO2CH2CH3 of
CT-isomer), 3.89–3.86 (m, 9H, 3!OCH3 of TT- and CT-
isomers), 3.60 (app t, JZ9.2 Hz, CHCO2Et of CT-isomer),
1.20 (TT) and 1.01 (CT) (each t, JZ7.1 Hz, 3H,
CO2CH2CH3).
1
diastereomers. H NMR (300 MHz, CDCl3): d 7.48 (dd,
JZ8.2, 1.5 Hz, 1H, ArH of TC-isomer), 7.78 (br d, JZ
8.3 Hz, 1H, ArH of CT-isomer), 7.73 (dd, JZ8.2, 1.6 Hz,
1H, ArH of TT-isomer), 7.66 (br d, JZ9.4 Hz, 1H, ArH of
CC-isomer), 7.58 (TC) and 7.54 (TT and CT) (each d, JZ
1.5 Hz, 1H, ArH), 7.45 (br s, 1H, ArH of CC-isomer), 6.95
(TC), 6.93 (TT and CT) and 6.86 (CC) (each d, JZ8.2, 8.3,
8.6 Hz, respectively, 1H, ArH), 6.77 (CT), 6.68 (TT) and
6.56 (TC and CC) (each s, 2H, ArH), 6.09 (br s, 2H, OCH2O
of TC-, CC-, TT- and CT-isomers and 1H, OCHAr of CT-
isomer), 5.92 (TC), 5.74 (CC) and 5.57 (TT) (each d, JZ7.7,
8.4, 8.9 Hz, respectively, 1H, OCHAr), 5.05 (TT and CT),
5.01 (TC) and 4.48 (CC) (each d, JZ8.9, 3.7, 8.4 Hz,
respectively, 1H, COCHCO), 4.24 (dd, JZ7.7, 3.7 Hz, 1H,
CHCO2Et of TC-isomer), 4.20–4.02 (m, 1H, CHCO2Et of
TT-isomer, 2H, CO2CH2CH3 of TT-isomer, 2H, CO2CH2-
CH3 of CT-isomer and 1H, CHCO2Et of CC-isomer), 3.89–
3.79 (m, 9H, 3!OCH3 of TC-, CC-, TT- and CT-isomers,
and 1H, CO2CHHCH3 of TC-isomer) 3.78–3.56 (m, 1H,
CO2CHHCH3 of TC-isomer, 2H, CO2CH2CH3 of CC-
isomer and 1H, CHCO2Et of CT-isomer), 1.20 (TT), 1.09
(CT), 0.89 (TC) and 0.81 (CC) (each t, JZ7.1, 7.1, 7.2,
7.1 Hz, respectively, 3H, CO2CH2CH3). IR (CHCl3): nmax
3025m, 2941m, 2907m, 2843w, 1779s, 1733s, 1675s,
1596s, 1507s, 1490m, 1464s, 1446s, 1425m, 1379m,
1356m, 1334m, 1256s, 1185s, 1162s, 1130s, 1041s,
4.2.2. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(1,3-benzodioxol-5-yl)-5-oxotetrahydrofuran-3-car-
boxylate (3b). According to the general procedure as
described for compound 3a, the solution of the vicinal
dianion 6 (8.89 mmol) in THF (23 mL) was treated with a
THF (6 mL) solution of piperonal (2.0028 g, 13.34 mmol).
The crude product was purified by column chromatography
(SiO2, 20% EtOAc in hexanes) to give a pale yellow solid of
3b (1.8926 g, 50% yield) as a 85:0:13:2 mixture of TC/CC/
1
TT/CT diastereomers. H NMR (300 MHz, CDCl3): d 7.82
(dd, JZ8.2, 1.5 Hz, 1H, ArH of TC-isomer), 7.72 (br d, JZ
8.4 Hz, 1H, ArH of TT- and CT-isomers), 7.57 (d, JZ
1.5 Hz, 1H, ArH of TC-isomer), 7.54 (br s, 1H, ArH of TT-
and CT-isomers), 6.94 (TC) and 6.89 (TT and CT) (each d,
JZ8.2, 8.4 Hz, respectively, 1H, ArH), 6.84–6.76 (m, 3H,
ArH of TC-, TT- and CT-isomers), 6.09–5.96 (m, 2H,
OCH2O of TC-, TT- and CT-isomers and 1H, OCHAr of CT-
isomer), 5.89 (TC) and 5.51 (TT) (each d, JZ8.2, 8.8 Hz,
respectively, 1H, OCHAr), 5.04 (TC), 5.03 (TT) and 5.02
(CT) (each d, JZ5.9, 6.3, 9.1 Hz, respectively, 1H,
COCHCO), 4.34 (dd, JZ8.2, 5.9 Hz, 1H, CHCO2Et of
TC-isomer), 4.23–4.13 (m, 1H, CHCO2Et of TT-isomer,
2H, CO2CH2CH3 of TT-isomer and 2H, CO2CH2CH3 of
1003m, 936m, 852m, 833m, 810m cmK1
.
The pale yellow solid of 3a (diastereomeric mixture) was
recrystallized with EtOAc–hexanes to give a pure white
solid of TC-3a (mp 139–141 8C). 1H NMR (300 MHz,
CDCl3): d 7.83 (dd, JZ8.3, 1.8 Hz, 1H, ArH), 7.58 (d, JZ

M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
5315
CT-isomer), 3.95–3.75 (m, 2H, CO2CH2CH3 of TC-isomer),
3.67 (app t, JZ7.0 Hz, 1H, CHCO2Et of CT-isomer), 1.18
(TT), 0.99 (TC) and 0.89 (CT) (each t, JZ7.3, 7.2, 6.6 Hz,
respectively, 3H, CO2CH2CH3). IR (CHCl3): nmax 3029m,
2986m, 2904m, 1778s, 1735s, 1676s, 1605m, 1505s, 1490s,
1446s, 1376m, 1353m, 1255s, 1185m, 1162m, 1101m,
The pale yellow solid of 3c (diastereomeric mixture) was
recrystallized from EtOAc–hexanes to give a white solid of
1
TC-3c (mp 123–124 8C). H NMR (300 MHz, CDCl3): d
7.82 (dd, JZ8.2, 1.8 Hz, 1H, ArH), 7.57 (d, JZ1.8 Hz, 1H,
ArH), 7.26–7.22 (m, 2H, ArH), 6.95–6.87 (m, 3H, ArH),
6.08 (s, 2H, OCH2O), 5.93 (d, JZ8.3 Hz, 1H, OCHAr), 5.07
(d, JZ5.8 Hz, 1H, COCHCO), 4.36 (dd, JZ8.3, 5.8 Hz, 1H,
CHCO2Et), 3.89–3.78 (m, 1H, CO2CHHCH3), 3.81 (s, 3H,
OCH3), 3.76–3.65 (m, 1H, CO2CHHCH3), 0.93 (t, JZ
7.2 Hz, 3H, CO2CH2CH3). 13C NMR (75 MHz, CDCl3): d
189.2 (C]O), 170.7 (C]O), 169.2 (C]O), 160.0 (C–O),
153.0 (C–O), 148.4 (C–O), 129.8 (C), 127.3 (2!CH),
127.20 (CH), 127.1 (C), 113.8 (2!CH), 108.9 (CH), 108.1
(CH), 102.1 (OCH2O), 80.6 (OCHAr), 61.4 (OCH2), 55.3
(OCH3), 51.1 (CH), 49.9 (CH), 13.6 (CH3). IR (nujol): nmax
1769s, 1736s, 1726s, 1673s, 1613m, 1520m, 1505m, 1356s,
1245s, 1185m, 1160s, 1103s, 1032s, 981m, 937m, 875m,
856m, 820m, 812m, 724m cmK1. MS: m/z (%) relative
intensity 412 (MC, 3), 384 (10), 366 (4), 339 (5), 338 (8),
321 (6), 288 (14), 287 (8), 249 (25), 235 (13), 222 (22), 203
(34), 189 (7), 175 (9), 149 (68), 135 (100), 121 (18), 119 (6),
107 (6), 92 (3), 91 (6), 77 (12), 65 (11). Anal. Calcd for
C22H20O8: C, 64.07; H, 4.89. Found: C, 63.88; H, 4.84.
1041s, 937m, 810m cmK1
.
The pale yellow solid of the diastereomeric mixture of 3b
was recrystallized from EtOAc–hexanes to give a white
solid of TC-3b (mp 160–161 8C). 1H NMR (300 MHz,
CDCl3): d 7.81 (dd, JZ8.2, 1.8 Hz, 1H, ArH), 7.56 (d, JZ
1.8 Hz, 1H, ArH), 6.93 (d, JZ8.2 Hz, 1H, ArH), 6.79 (m,
3H, ArH), 6.07 (s, 2H, OCH2O), 5.98 and 5.97 (each d, JZ
1.4 Hz, 2H, OCH2O), 5.88 (d, JZ8.3 Hz, 1H, OCHAr), 5.04
(d, JZ5.7 Hz, 1H, COCHCO), 4.33 (dd, JZ8.3, 5.7 Hz, 1H,
CHCO2Et), 3.94–3.74 (m, 2H, CO2CH2CH3), 0.99 (t, JZ
7.2 Hz, 3H, CO2CH2CH3). 13C NMR (75 MHz, CDCl3): d
189.0 (C]O), 170.5 (C]O), 169.1 (C]O), 153.0 (C–O),
148.4 (C–O), 148.0 (C–O), 147.8 (C–O), 129.6 (C), 128.8
(C), 127.2 (CH), 119.7 (CH), 108.9 (CH), 108.2 (CH), 108.1
(CH), 106.3 (CH), 102.1 (OCH2O), 101.3 (OCH2O), 80.5
(OCHAr), 61.5 (OCH2), 51.1 (CH), 49.9 (CH), 13.6 (CH3).
IR (nujol): nmax 1779s, 1714s, 1664s, 1602m, 1505m,
1488m, 1448s, 1302 m, 1252s, 1190s, 1161s, 1113m,
1041m, 1030m, 1012m, 996m, 874m, 814m cmK1. MS: m/z
(%) relative intensity 426 (MC, 3), 382 (1), 352 (1), 326 (8),
308 (28), 291 (6), 276 (7), 249 (8), 231 (5), 227 (10), 225
(18), 209 (10), 204 (17), 203 (100), 202 (48), 149 (18), 121
(4), 105 (25), 77 (15). Anal. Calcd for C22H18O9: C, 61.97;
H, 4.26. Found: C, 61.55; H, 4.19.
4.3. Attempted preparation of ethyl 6,7-methylenedioxy-
1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-
tetrahydronaphthalene-3-carboxylate (7)
4.3.1. Using concentrated H2SO4. A solution of 3a
(402.2 mg, 0.85 mmol) as an 82:14:4 mixture of TC/TT/
CT diastereomers in CHCl3 (22 mL) was stirred in the
presence of concd H2SO4 (98%, 0.1 mL) at room tempera-
ture overnight (15 h). The crude product contained a small
4.2.3. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(4-methoxyphenyl)-5-oxotetrahydrofuran-3-carboxylate
(3c). According to the general procedure as described for
compound 3a, the solution of the vicinal dianion 6
(5.20 mmol) in THF (13 mL) was treated with a THF
(4 mL) solution of p-methoxybenzaldehyde (1.0655 g,
7.83 mmol). The crude product was purified by column
chromatography (SiO2, 20% EtOAc in hexanes) to give a
pale yellow solid of 3c (1.1261 g, 53% yield) as a 85:0:12:3
mixture of TC/CC/TT/CT diastereomers. 1H NMR
(300 MHz, CDCl3): d 7.83 (TC) and 7.73 (TT and CT)
(each dd, JZ8.2, 1.5, 8.1, 1.6 Hz, respectively, 1H, ArH),
7.58 (TC) and 7.55 (TT and CT) (each d, JZ1.5, 1.6 Hz,
respectively, 1H, ArH), 7.39 (br d, JZ8.5 Hz, 2H, ArH of
TT- and CT-isomers), 7.24 (m, 2H, ArH of TC-isomer),
6.96–6.89 (m, 3H, ArH of TC-, TT- and CT-isomers), 6.09
(s, 2H, OCH2O of TC-, TT- and CT-isomers), 6.08 (CT),
5.93 (TC) and 5.55 (TT) (each d, JZ8.6, 8.3, 8.9 Hz,
respectively, 1H, OCHAr), 5.07 (TC), 5.04 (TT) and 5.03
(CT) (each d, JZ5.7, 10.1, 9.0 Hz, respectively, 1H,
COCHCO), 4.36 (dd, JZ8.3, 6.2 Hz, 1H, CHCO2Et of
TC-isomer), 4.27–4.05 (m, 1H, CHCO2Et of TT-isomer, 2H,
CO2CH2CH3 of TT-isomer and 2H, CO2CH2CH3 of CT-
isomer), 3.89–3.79 (m, 1H, CO2CHHCH3 of TC-isomer and
3H, OCH3 of TC-, TT- and CT-isomers), 3.76–3.65 (m, 1H,
CO2CHHCH3 of TC-isomer and 1H, CHCO2Et of CT-
isomer), 1.17 (TT), 1.11 (CT) and 0.93 (TC) (each t, JZ7.2,
7.0, 7.2 Hz, respectively, 3H, CO2CH2CH3). IR (CHCl3):
nmax 3014m, 2978m, 2904m, 1778s, 1734s, 1676s, 1613m,
1516s, 1506m, 1489m, 1445s, 1381m, 1303m, 1287m,
1
amount of the expected product 7 as revealed by H NMR
spectrum. Attempted separation by preparative thin-layer
chromatography (SiO2, 50% EtOAc in hexanes) gave a
white solid of 7 [16.6 mg, 5% yield; mp 150–151 8C
(CH2Cl2), lit.6a,c,7 mp 152–153 8C (CH2Cl2)]. The 1H NMR
data were consistent with the literature. 1H NMR (300 MHz,
CDCl3): d 7.45 (s, 1H, ArH), 6.35 (s, 1H, ArH), 6.25 (s, 2H,
ArH), 5.95 and 5.93 (each br s, 2H, OCH2O), 4.41 (d, JZ
7.5 Hz, 1H, CHAr), 4.01–3.91 (m, 2H, CO2CH2CH3), 3.77
(s, 3H, OCH3), 3.72 (s, 6H, 2!OCH3), 3.27–3.20 (m, 1H,
CHCO2Et), 2.84 (dd, JZ17.0, 8.7 Hz, 1H, COCHH), 2.73
(dd, JZ17.0, 4.6 Hz, 1H, COCHH), 1.00 (t, JZ7.1 Hz, 3H,
CO2CH2CH3). IR (nujol): nmax 1728s, 1677s, 1615w,
1587m, 1501m, 1424m, 1328m, 1268s, 1233m, 1186s,
1124s, 1038m, 1012m, 995m, 930m, 846m cmK1. MS: m/z
(%) relative intensity 428 (MC, 59), 382 (4), 355 (100), 340
(9), 324 (25), 323 (25), 291 (9), 188 (29), 186 (21).
4.3.2. Using P2O5 in CH3SO3H.10 A solution of P2O5
(0.39 g) in CH3SO3H (3 mL) was added to a CH3SO3H
(0.9 mL) solution of 3a (183.2 mg, 0.39 mmol) as an
82:14:4 mixture of TC/TT/CT diastereomers at room
temperature under an argon atmosphere. After stirring at
room temperature overnight (15 h), the mixture was poured
onto crushed ice and extracted with EtOAc (3!20 mL).
The combined extracts were washed with saturated aqueous
NaHCO3 (3!20 mL), water (3!20 mL), brine and dried
over anhydrous Na2SO4. After removal of solvent under
reduced pressure, the crude product containing a small
amount of the expected product 7 was obtained as a revealed
1254s, 1178s, 1112m, 1040s, 937m, 851m, 810m cmK1
.

5316
M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
1
by H NMR spectrum. Purification was made by column
chromatography (SiO2, 30% EtOAc in hexanes) to give a
white solid of 7 (13.8 mg, 8% yield).
(C), 127.2 (CH), 110.3 (CH), 107.5 (CH), 102.6 (2!CH),
101.8 (OCH2O), 77.2 (OCHAr), 61.0 (C), 60.9 (OCH2),
60.7 (OCH3), 58.8 (CH), 56.1 (2!OCH3), 22.5 (CH3), 13.5
(CH3). IR (nujol): nmax 1784s, 1730s, 1660s, 1608s, 1597s,
1508s, 1428m, 1393m, 1376s, 1352s, 1333s, 1298s, 1283s,
1243s, 1194s, 1124s, 1096s, 1059m, 1042s, 1020s, 999s,
973m, 939m, 924m, 889m, 864m, 834m, 819m, 759m,
701m, 667m cmK1. MS: m/z (%) relative intensity 486
(MC, 16), 442 (14), 396 (2), 359 (7), 358 (7), 341 (6), 301
(7), 293 (21), 220 (4), 219 (10), 201 (17), 195 (8), 149 (100),
121 (10), 91 (2), 65 (6). HRMS (ESI-TOF) Calcd for
C25H27O10 (MCC1): 487.1604. Found 487.1605.
4.4. Preparation of a-methylated aryltetralone 9
4.4.1. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(3,4,5-trimethoxyphenyl)-4-methyl-5-oxotetrahydro-
furan-3-carboxylate (8a). Sodium hydride (80% dispersion
in oil, 37.5 g, 1.25 mmol) was washed with dry hexanes
(3 times) and suspended in THF (2 mL) at 0 8C under an
argon atmosphere. A THF (2 mL) solution of 3a (492.4 mg,
1.04 mmol) as an 82:18 mixture of TC/TT diastereomers
was added. The resulting suspension was stirred at 0 8C for
1 h, after which methyl iodide (0.14 mL, 2.24 mmol) was
added and the resulting mixture was slowly warmed up from
0 8C to room temperature overnight (15 h). The reaction
mixture was quenched with 0.5 M HCl (1 mL), diluted with
water (30 mL) and extracted with EtOAc (3!30 mL). The
combined organic layers were washed with 5% Na2S2O5,
water, brine and dried over anhydrous Na2SO4. After
removal of solvent under reduced pressure, the crude
product which consisted of an 80:20 mixture of CC/CT
diastereomers of 8a was purified by column chromato-
graphy (SiO2, 30% EtOAc in hexanes) to give two fractions
of product 8a.
4.4.2. Preparation of ethyl 2-methyl-6,7-methylenedioxy-
1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-
naphthalene-3-carboxylate (9). A solution of SnCl4 (1 M
in CHCl3, 13 mL, 13 mmol) was added to a CHCl3 (18 mL)
solution of CC-8a (594.6 mg, 1.22 mmol) at room tempera-
ture under an argon atmosphere. The reaction mixture was
heated at 60 8C for 6 h. After the mixture was allowed to
cool, the content was poured onto crushed ice and
partitioned with EtOAc (3!30 mL). The combined extracts
were washed with saturated aqueous NaHCO3 (3!20 mL),
water (3!20 mL), brine and dried over anhydrous Na2SO4.
After removal of solvent under reduced pressure, the crude
product obtained was purified by column chromatography
(SiO2, 30% EtOAc in hexanes) to give a white solid of the
pure isomer TT-9 [318.9 mg, 59% yield; mp 209–211 8C
(CH2Cl2-hexanes)]. 1H NMR (300 MHz, CDCl3): d 7.51 (d,
JZ1.2 Hz, 1H, ArH), 6.38 (s, 2H, ArH), 6.27 (s, 1H, ArH),
6.01–5.99 (m, 2H, OCH2O), 4.34 (d, JZ11.0 Hz, 1H,
CHAr), 4.06–3.91 (m, 2H, CO2CH2CH3), 3.86 (s, 3H,
OCH3), 3.83 (s, 6H, 2!OCH3), 3.07 (dd, JZ12.6, 11.0 Hz,
1H, CHCO2Et), 2.99–2.88 (m, 1H, COCHCH3), 1.26 (d, JZ
6.5 Hz, 3H, COCHCH3), 0.99 (t, JZ7.0 Hz, 3H, CO2CH2-
CH3). 13C NMR (75 MHz, CDCl3): d 195.9 (C]O), 172.3
(C]O), 153.3 (2!C–O), 152.2 (C–O), 147.2 (C–O), 141.6
(C), 137.2 (C–O), 136.6 (C), 126.5 (C), 108.3 (CH), 106.2
(CH), 105.9 (2!CH), 101.7 (OCH2O), 60.8 (OCH3), 60.5
(OCH2), 56.6 (CH), 56.1 (2!OCH3), 49.4 (CH), 44.3 (CH),
13.9 (CH3), 13.1 (CH3). IR (nujol): nmax 1727s, 1664s,
1610m, 1592s, 1499s, 1467s, 1430s, 1342m, 1305m, 1256s,
1181s, 1131s, 1035s, 1031s, 931m, 892m, 845m, 787m,
690m cmK1. MS: m/z (%) relative intensity 442 (MC, 52),
397 (2), 370 (23), 369 (100), 354 (12), 338 (19), 337 (14),
274 (7), 202 (7), 201 (45), 178 (8), 149 (4), 115 (3), 55 (2).
Anal. Calcd for C24H26O8: C, 65.15; H, 5.92. Found: C,
65.47; H, 6.04.
The less polar fraction (F1) was obtained as a white solid of
the pure diastereomer CT-8a [49 mg, 10% yield; mp 172–
174 8C (EtOAc–hexanes)]. H NMR (300 MHz, CDCl3): d
1
7.84 (dd, JZ8.2, 1.8 Hz, 1H, ArH), 7.59 (d, JZ1.8 Hz, 1H,
ArH), 6.88 (d, JZ8.2 Hz, 1H, ArH), 6.74 (s, 2H, ArH), 6.06
(s, 2H, OCH2O), 5.83 (d, JZ9.7 Hz, 1H, OCHAr), 4.27–
4.06 (m, 2H, CO2CH2CH3), 3.90 (s, 6H, 2!OCH3), 3.85 (s,
3H, OCH3), 3.15 (d, JZ9.7 Hz, 1H, CHCO2Et), 2.02 (s, 3H,
CH3), 1.23 (t, JZ7.2 Hz, 3H, CO2CH2CH3). 13C NMR
(75 MHz, CDCl3): d 193.4 (C]O), 173.5 (C]O), 168.7
(C]O), 153.2 (2!C–O), 151.9 (C–O), 147.8 (C–O), 138.3
(C–O), 133.1 (C), 129.5 (C), 126.2 (CH), 109.4 (CH), 107.9
(CH), 103.8 (2!CH), 101.9 (OCH2O), 80.6 (OCHAr), 62.1
(C), 61.0 (OCH2), 60.7 (OCH3), 60.4 (CH), 56.2 (2!
OCH3), 23.9 (CH3), 13.9 (CH3). IR (nujol): nmax 1770s,
1734s, 1681s, 1616m, 1598s, 1512s, 1493s, 1437m, 1424m,
1374s, 1349s, 1330s, 1281m, 1259s, 1241s, 1204s, 1172s,
1127s, 1101s, 1077m, 1040s, 1019s, 1004s, 973s, 936m,
886m, 868m, 837m, 700m, 686m cmK1. MS: m/z (%)
relative intensity 486 (MC, 7), 385 (25), 384 (79), 347 (11),
346 (46), 342 (25), 328 (6), 318 (9), 301 (24), 300 (100), 282
(59), 281 (23), 271 (14), 253 (11), 236 (52), 226 (10), 215
(12), 213 (14), 195 (25), 149 (35), 121 (9), 91 (2), 65 (6).
4.4.3. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(3,4,5-trimethoxyphenyl)-5-oxo-4-(phenylsulfanyl-
methyl)tetrahydrofuran-3-carboxylate (10a). Sodium
hydride (80% dispersion in oil, 45.7 mg, 1.52 mmol) was
washed with dry hexanes (3 times) and suspended in THF
(3 mL) at 0 8C under an argon atmosphere. A THF (4 mL)
solution of pure diastereomer TC-3a (589.8 mg, 1.25 mmol)
was added. The resulting reaction mixture was stirred at
0 8C for 1 h and a THF (1 mL) solution of chloromethyl
phenyl sulfide (396.8 mg, 2.5 mmol) was added, followed
by the addition of a solution of NaI (413.4 mg, 2.76 mmol)
in THF (3 mL). The reaction mixture was stirred at 0 8C and
slowly warmed up to room temperature overnight (15 h). It
was then quenched with 0.5 M HCl (1.5 mL), diluted with
The more polar fraction (F2) was obtained as a white solid
of the pure diastereomer CC-8a [352.1 mg, 70% yield; mp
160–162 8C (EtOAc–hexanes)]. 1H NMR (300 MHz,
CDCl3): d 7.84 (dd, JZ8.2, 1.7 Hz, 1H, ArH), 7.60 (d,
JZ1.7 Hz, 1H, ArH), 6.88 (d, JZ8.2 Hz, 1H, ArH), 6.57 (s,
2H, ArH), 6.05 (s, 2H, OCH2O), 5.76 (d, JZ5.8 Hz, 1H,
OCHAr), 3.85 (s, 6H, 2!OCH3), 3.83 (s, 3H, OCH3), 3.79–
3.67 (m, 2H, CO2CH2CH3), 3.62 (d, JZ5.8 Hz, 1H,
CHCO2Et), 1.93 (s, 3H, CH3), 0.85 (t, JZ7.2 Hz, 3H,
CO2CH2CH3). 13C NMR (75 MHz, CDCl3): d 194.9
(C]O), 173.0 (C]O), 169.5 (C]O), 153.2 (2!C–O),
151.7 (C–O), 147.5 (C–O), 137.9 (C–O), 129.6 (C), 128.8

M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
5317
1
water (30 mL) and extracted with EtOAc (3!30 mL). The
combined organic layers were washed with 5% Na2S2O5,
water, brine and dried over anhydrous Na2SO4. Filtration
followed by evaporation gave a crude product, which was
purified by column chromatography (SiO2, 30% EtOAc in
hexanes) to give a pale yellow viscous liquid of CC-10a
(448.3 mg, 60% yield). 1H NMR (300 MHz, CDCl3): d 7.85
(dd, JZ8.3, 1.8 Hz, 1H, ArH), 7.53 (d, JZ1.8 Hz, 1H,
ArH), 7.43–7.39 (m, 2H, SArH), 7.32–7.25 (m, 3H, SArH),
6.82 (d, JZ8.3 Hz, 1H, ArH), 6.39 (s, 2H, ArH), 6.03 (s, 2H,
OCH2O), 5.62 (d, JZ5.9 Hz, 1H, OCHAr), 3.98 (d, JZ
14.2 Hz, 1H, CHHSPh), 3.92 (d, JZ5.9 Hz, 1H, CHCO2Et),
3.83 (s, 6H, 2!OCH3), 3.81 (s, 3H, OCH3), 3.77–3.66 (m,
2H, CO2CH2CH3 and 1H, CHHSPh), 0.83 (t, JZ7.2 Hz,
3H, CO2CH2CH3). 13C NMR (75 MHz, CDCl3): d 192.0
(C]O), 171.3 (C]O), 169.4 (C]O), 153.1 (2!C–O),
151.7 (C–O), 147.5 (C–O), 137.9 (C–O), 134.1 (S–C), 131.8
(2!CH), 129.36 (C), 129.30 (2!CH), 129.1 (C), 127.9
(CH), 127.1 (CH), 110.2 (CH), 107.5 (CH), 102.5 (2!CH),
101.8 (OCH2O), 77.8 (OCHAr), 67.0 (C), 61.0 (OCH2),
60.8 (OCH3), 56.2 (2!OCH2), 55.1 (CH), 39.9 (SCH2),
13.5 (CH3). IR (nujol): nmax 1781s, 1725s, 1661m, 1594s,
1505s, 1487s, 1338s, 1242s, 1194s, 1162s, 1126s, 1036s,
931m, 863w, 820w, 746m, 722m, 695m cmK1. MS: m/z (%)
relative intensity 594 (MC, 6), 486 (3), 485 (8), 471 (3), 440
(6), 439 (24), 421 (9), 411 (5), 393 (4), 367 (5), 336 (5), 317
(15), 289 (13), 282 (3), 266 (9), 261 (8), 236 (7), 215 (4),
196 (13), 195 (24), 181 (3), 150 (51), 149 (100), 122 (6), 109
(2), 65 (6).
69% yield). H NMR (300 MHz, CDCl3): d 7.84 (dd, JZ
8.3, 1.8 Hz, 1H, ArH), 7.51 (d, JZ1.8 Hz, 1H, ArH), 7.39–
7.34 (m, 2H, SArH), 7.29–7.24 (m, 3H, SArH), 6.81 (d, JZ
8.3 Hz, 1H, ArH), 6.76 (d, JZ8.6 Hz, 1H, ArH), 6.69–6.67
(m, 2H, ArH), 6.02 (s, 2H, OCH2O), 5.94 (br s, 2H,
OCH2O), 5.62 (d, JZ5.9 Hz, 1H, OCHAr), 3.96 (d, JZ
14.1 Hz, 1H, CHHSPh), 3.90 (d, JZ5.9 Hz, 1H, CHCO2Et),
3.79–3.70 (m, 2H, CO2CH2CH3), 3.69 (d, JZ14.1 Hz, 1H,
CHHSPh), 0.89 (t, JZ7.2 Hz, 3H, CO2CH2CH3). 13C NMR
(75 MHz, CDCl3): d 192.0 (C]O), 171.3 (C]O), 169.2
(C]O), 151.7 (C–O), 147.7 (C–O), 147.6 (C–O), 147.5 (C–
O), 133.9 (S–C), 131.7 (2!CH), 129.2 (2!CH), 129.1 (C),
127.9 (CH), 127.4 (C), 127.1 (CH), 119.2 (CH), 110.2 (CH),
108.0 (CH), 107.5 (CH), 106.3 (CH), 101.8 (OCH2O), 101.2
(OCH2O), 77.7 (OCHAr), 66.9 (C), 60.9 (OCH2), 55.3
(CH), 40.0 (SCH2), 13.5 (CH3). IR (CHCl3): nmax 3030w,
2963w, 2902w, 1782s, 1737m, 1665m, 1606m, 1505s,
1489s, 1442s, 1376m, 1348m, 1256s, 1245s, 1159m,
1108m, 1041s, 937m, 866m, 813m cmK1. MS: m/z (%)
relative intensity 439 (MCK109, 13), 425 (4), 394 (3), 393
(14), 379 (3), 365 (4), 349 (3), 321 (4), 290 (3), 289 (8), 271
(9), 259 (4), 243 (11), 216 (3), 215 (5), 151 (37), 149 (100),
121 (10), 110 (2), 109 (2), 65 (8).
4.4.5. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(4-methoxyphenyl)-5-oxo-4-(phenylsulfanylmethyl)
tetrahydrofuran-3-carboxylate (10c). According to the
general procedure as described for compound 10a, a THF
(9 mL) solution of 3c (734.3 mg, 1.78 mmol; TC-isomer as
the major isomer and a trace amount of TT-isomer) was
added dropwise at 0 8C to the suspension of NaH (80%
dispersion in oil, 61.2 mg, 2.04 mmol) in THF (4 mL). After
stirring at 0 8C for 1 h, a THF (2 mL) solution of
chloromethyl phenyl sulfide (602.1 mg, 3.80 mmol mmol)
was added, followed by the addition of a solution of NaI
(602 mg, 4.02 mmol) in THF (6 mL). The reaction mixture
was stirred at 0 8C and slowly warmed up to room
temperature overnight (15 h). The crude product was
purified by column chromatography (SiO2, 20% EtOAc in
hexanes) to give a white solid of the pure diastereomer CC-
10c [724.1 mg, 76% yield; mp 140–141 8C (EtOAc–
4.4.4. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(1,3-benzodioxol-5-yl)-5-oxo-4-(phenylsulfanylmethyl)-
tetrahydrofuran-3-carboxylate (10b). According to the
general procedure as described for compound 10a, a THF
(10 mL) solution of 3b (1.3856 g, 3.25 mmol) as a 82:18
mixture of TC/TT diastereomers was added dropwise at 0 8C
to a suspension of NaH (80% dispersion in oil, 107 mg,
3.57 mmol) in THF (7 mL). After stirring at 0 8C for 1 h, a
THF (3 mL) solution of chloromethyl phenyl sulfide
(1.0315 g, 6.50 mmol) was added, followed by the addition
of a solution of NaI (1.0758 g, 7.18 mmol) in THF (7 mL).
The reaction mixture was stirred at 0 8C and slowly warmed
up to room temperature overnight (15 h). The crude product
was purified by column chromatography (SiO2, 20% EtOAc
in hexanes) to give two fractions of 10b.
1
hexanes)]. H NMR (300 MHz, CDCl3): d 7.84 (dd, JZ
8.3, 1.8 Hz, 1H, ArH), 7.52 (d, JZ1.8 Hz, 1H, ArH), 7.39–
7.34 (m, 2H, SArH), 7.29–7.24 (m, 3H, SArH), 7.14 (br d,
JZ8.8 Hz, 2H, ArH), 6.85 (br d, JZ8.8 Hz, 2H, ArH), 6.81
(d, JZ8.3 Hz, 1H, ArH), 6.02 (s, 2H, OCH2O), 5.69 (d, JZ
5.9 Hz, 1H, OCHAr), 3.97 (d, JZ14.0 Hz, 1H, CHHSPh),
3.93 (d, JZ5.9 Hz, 1H, CHCO2Et), 3.78 (s, 3H, OCH3),
3.74–3.61 (m, 2H, CO2CH2CH3), 3.71 (d, JZ14.0 Hz, 1H,
CHHSPh), 0.83 (t, JZ7.1 Hz, 3H, CO2CH2CH3). 13C NMR
(75 MHz, CDCl3): d 192.2 (C]O), 171.5 (C]O), 169.3
(C]O), 159.7 (C–O), 151.6 (C–O), 147.5 (C–O), 133.9
(S–C), 131.7 (2!CH), 129.3 (2!CH), 129.2 (C), 127.9
(CH), 127.1 (CH), 126.9 (2!CH), 125.7 (C), 113.6 (2!
CH), 110.2 (CH), 107.5 (CH), 101.7 (OCH2O), 77.8
(OCHAr), 66.9 (C), 60.9 (OCH2), 55.3 (CH), 55.2
(OCH3), 40.0 (SCH2), 13.4 (CH3). IR (nujol): nmax 1782s,
1724s, 1652m, 1602m, 1506m, 1487m, 1441s, 1340m,
1305m, 1259m, 1244s, 1199m, 1158m, 1112m, 1020m,
958m, 933m, 862m, 821m, 748m, 693m cmK1. MS: m/z (%)
relative intensity 535 (MCC1, 3), 489 (1), 426 (17), 425
(69), 411 (13), 397 (5), 381 (31), 380 (19), 379 (71), 365 (9),
351 (9), 335 (11), 307 (9), 289 (12), 271 (7), 257 (9), 243
The less polar fraction (F1) was obtained as a yellow viscous
liquid of 10b (103.3 mg, 6% yield) as a 70:30 mixture of
CT/TT diastereomers. H NMR (300 MHz, CDCl3): d 7.69
1
(dd, JZ9.1, 1.7 Hz, 1H, ArH of CT-isomer), 7.48–7.12 (m,
7H, ArH), 6.96–6.74 (m, 4H, ArH), 5.99 and 5.92 (s, 4H,
2!OCH2O of CT-isomer), 5.98 and 5.91 (s, 4H, 2!
OCH2O of TT-isomer), 5.74 (CT) and 5.28 (TT) (each d, JZ
9.4, 9.0 Hz, respectively, 1H, OCHAr), 4.29 and 3.55 (d, AB
system, JZ14.0 Hz, 2H, CH2SPh of CT-isomer), 4.19–3.92
(m, 2H, CO2CH2CH3), 3.99 (d, JZ9.4 Hz, 1H, CHCO2Et of
CT-isomer), 3.78 and 3.63 (d, AB system, JZ14.0 Hz, 2H,
CH2SPh of TT-isomer), 3.28 (d, JZ9.0 Hz, 1H, CHCO2Et
of TT-isomer), 1.22–1.12 (m, 3H, CO2CH2CH3 of TT-
isomer) 1.09 (t, JZ7.0 Hz, 3H, CO2CH2CH3 of CT-isomer).
The more polar fraction (F2) was obtained as a pale yellow
viscous liquid of the pure diastereomer CC-10b (1.2318 g,

5318
M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
(14), 242 (17), 241 (14), 229 (8), 150 (46), 149 (100), 136
(13), 135 (36), 122 (15), 110 (4), 109 (3), 65 (12).
(d, JZ8.3 Hz, 1H, ArH), 6.79 (d, JZ8.3 Hz, 1H, ArH), 6.12
(d, JZ6.7 Hz, 1H, OCHAr), 6.03 and 6.02 (each d, JZ
1.0 Hz, 2H, OCH2O), 5.96 and 5.95 (each d, JZ1.5 Hz, 2H,
OCH2O), 4.79 (d, JZ6.7 Hz, 1H, CHCO2Et), 4.15 (d, JZ
14.5 Hz, 1H, CHHSO2Ph), 3.82 (d, JZ14.5 Hz, 1H,
CHHSO2Ph), 3.74–3.55 (m, 2H, CO2CH2CH3), 0.86 (t,
JZ7.2 Hz, 3H, CO2CH2CH3). 13C NMR (75 MHz, CDCl3):
d 191.1 (C]O), 171.0 (C]O), 168.8 (C]O), 151.7 (C–O),
147.8 (C–O), 147.7 (C–O), 147.6 (C–O), 138.8 (SO2C),
134.6 (CH), 129.5 (2!CH), 128.8 (C), 128.0 (2!CH),
127.5 (C), 126.2 (CH), 119.7 (CH), 109.8 (CH), 108.0 (CH),
107.6 (CH), 106.7 (CH), 101.9 (OCH2O), 101.2 (OCH2O),
78.7 (OCHAr), 61.4 (C), 61.3 (OCH2), 58.7 (SO2CH2), 53.3
(CH), 13.4 (CH3). IR (CHCl3): nmax 3030m, 2987w, 2904m,
1787s, 1732s, 1673m, 1606m, 1505s, 1490s, 1448s, 1376m,
1326s, 1155s, 1108m, 1085m, 1041s, 937m, 867m, 809m,
687m cmK1. MS: m/z (%) relative intensity 580 (MC, 1),
440 (2), 439 (6), 411 (4), 393 (9), 365 (7), 349 (3), 321 (3),
289 (6), 243 (6), 237 (6), 236 (31), 216 (4), 190 (10), 150
(26), 149 (100), 121 (8), 78 (3), 77 (2), 65 (5). HRMS (ESI-
TOF) Calcd for C29H24O11SNa (MCCNa): 603.0937.
Found 603.0928.
4.4.6. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(3,4,5-trimethoxyphenyl)-5-oxo-4-(phenylsulfonyl-
methyl)tetrahydrofuran-3-carboxylate (11a). The pure
diastereomer CC-10a (164.8 mg, 0.28 mmol) was dissolved
in glacial acetic acid (1.5 mL) and cooled to 0 8C. 30%
Hydrogen peroxide (0.14 mL, 1.4 mmol) was then added
dropwise. The reaction mixture was stirred at 0 8C and
slowly warmed up to room temperature overnight (15 h).
The mixture was diluted with a mixture of water (2 mL) and
EtOAc (4 mL), neutralized with 10% NaOH at 0 8C and
then extracted with EtOAc (3!10 mL). The combined
organic layers were washed with 10% NaOH, water, 0.5 M
NH4Cl, brine and dried over anhydrous Na2SO4. After
removal of solvent under reduced pressure, the crude
product was purified by column chromatography (SiO2,
30% EtOAc in hexanes) to give a white solid of CC-11a
[113.4 mg, 65% yield; mp 162–164 8C (EtOAc–hexanes)].
1H NMR (300 MHz, CDCl3): d 7.85–7.82 (m, 2H,
SO2ArH), 7.71–7.65 (m, 1H, SO2ArH), 7.58–7.52 (m, 2H,
SO2ArH and 1H, ArH), 7.34 (d, JZ1.9 Hz, 1H, ArH), 6.81
(d, JZ8.2 Hz, 1H, ArH), 6.63 (s, 2H, ArH), 6.16 (d, JZ
6.9 Hz, 1H, OCHAr), 6.03 and 6.02 (each d, JZ1.1 Hz, 2H,
OCH2O), 4.88 (d, JZ6.9 Hz, 1H, CHCO2Et), 4.16 (d, JZ
14.6 Hz, 1H, CHHSO2Ph), 3.88 (s, 6H, 2!OCH3), 3.83 (s,
3H, OCH3), 3.82 (d, JZ14.6 Hz, 1H, CHHSO2Ph), 3.68–
3.48 (m, 2H, CO2CH2CH3), 0.79 (t, JZ7.2 Hz, 3H,
CO2CH2CH3). 13C NMR (75 MHz, CDCl3): d 190.9
(C]O), 171.1 (C]O), 168.9 (C]O), 153.1 (2!C–O),
151.7 (C–O), 147.7 (C–O), 138.8 (C–O), 137.9 (SO2C),
134.6 (CH), 129.5 (2!CH), 129.4 (C), 128.8 (C), 128.0
(2!CH), 126.0 (CH), 109.7 (CH), 107.6 (CH), 103.0 (2!
CH), 101.9 (OCH2O), 78.7 (OCHAr), 61.3 (OCH2), 61.1
(C), 60.7 (OCH3), 58.8 (SO2CH2), 56.2 (2!OCH3), 53.3
(CH), 13.3 (CH3). IR (nujol): nmax 1779s, 1719s, 1680s,
1610m, 1593m, 1511m, 1493s, 1449s, 1350s, 1336s, 1201s,
1160s, 1132s, 1106s, 1034m, 1000m, 951m, 930m, 866m,
828m, 797m, 762m, 720m, 691m cmK1. MS: m/z (%)
relative intensity 626 (MC, 16), 484 (4), 440 (4), 439 (4),
411 (5), 395 (5), 394 (11), 367 (4), 363 (7), 348 (7), 336 (7),
335 (9), 289 (14), 282 (20), 261 (7), 245 (9), 236 (21), 216
(4), 196 (11), 195 (20), 181 (4), 149 (100), 121 (12), 78 (7),
77 (7), 65 (9). HRMS (ESI-TOF) Calcd for C31H31O12S
(MCC1): 627.1536. Found 627.1516.
4.4.8. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(4-methoxyphenyl)-5-oxo-4-(phenylsulfonylmethyl)
tetrahydrofuran-3-carboxylate (11c). According to the
general procedure as described for compound 10a, the pure
diastereomer CC-10c (188.6 mg, 0.35 mmol) was dissolved
in glacial acetic acid (3 mL) and cooled to 0 8C. 30%
Hydrogen peroxide (0.18 mL, 1.8 mmol) was then added
dropwise. The reaction mixture was stirred at 0 8C and
slowly warmed up to room temperature overnight (15 h).
After usual work-up, the crude product was purified by
column chromatography (SiO2, 30% EtOAc in hexanes) to
give a white solid of CC-11c [163.7 mg, 83% yield; mp
167–168 8C (EtOAc–hexanes)]. 1H NMR (300 MHz,
CDCl3): d 7.82 (m, 2H, SO2ArH), 7.66 (m, 1H, SO2ArH),
7.58–7.50 (m, 2H, SO2ArH and 1H, ArH), 7.34 (d, JZ
1.3 Hz, 1H, ArH), 7.33 (br d, JZ9.0 Hz, 2H, ArH), 6.89 (br
d, JZ9.0 Hz, 2H, ArH), 6.81 (d, JZ8.3 Hz, 1H, ArH), 6.17
(d, JZ6.8 Hz, 1H, OCHAr), 6.03 and 6.02 (each d, JZ
1.0 Hz, 2H, OCH2O), 4.81 (d, JZ6.8 Hz, 1H, CHCO2Et),
4.16 (d, JZ14.8 Hz, 1H, CHHSO2Ph), 3.83 (d, JZ14.8 Hz,
1H, CHHSO2Ph), 3.80 (s, 3H, OCH3), 3.66–3.47 (m, 2H,
CO2CH2CH3), 0.80 (t, JZ7.1 Hz, 3H, CO2CH2CH3). 13C
NMR (75 MHz, CDCl3): d 191.3 (C]O), 171.2 (C]O),
168.9 (C]O), 159.9 (C–O), 151.7 (C–O), 147.6 (C–O),
139.0 (SO2C), 134.5 (CH), 129.5 (2!CH), 129.0 (C), 128.0
(2!CH), 127.4 (2!CH), 126.2 (CH), 125.9 (C), 113.6 (2!
CH), 109.8 (CH), 107.6 (CH), 101.9 (OCH2O), 78.8
(OCHAr), 61.5 (C), 61.2 (OCH2), 58.9 (SO2CH2), 55.3
(OCH3), 53.4 (C), 13.3 (CH3). IR (nujol): nmax 1789s,
1721s, 1652m, 1602m, 1584w, 1503m, 1487m, 1338s,
1306m, 1263s, 1245s, 1199m, 1152s, 1111m, 1086m,
1038m, 1019m, 959m, 927m, 862m, 821m, 757m, 710m,
689m cmK1. MS: m/z (%) relative intensity 567 (MCC1,
2), 566 (MC, 1), 425 (18), 397 (14), 381 (22), 380 (22), 379
(28), 351 (16), 335 (12), 307 (12), 303 (3), 275 (12), 230 (5),
229 (7), 223 (14), 222 (41), 203 (6), 151 (55), 149 (100), 137
(24), 135 (75), 121 (15), 77 (6), 65 (12). Anal. Calcd for
C29H26O10S: C, 61.48; H, 4.63. Found: C, 61.84; H, 4.69.
4.4.7. Preparation of ethyl 4-(1,3-benzodioxol-5-carbonyl)-
2-(1,3-benzodioxol-5-yl)-5-oxo-4-(phenylsulfonylmethyl)-
tetrahydrofuran-3-carboxylate (11b). According to the
general procedure as described for compound 10a, the pure
diastereomer CC-10b (814.1 mg, 1.48 mmol) was dissolved
in glacial acetic acid (10 mL) and cooled to 0 8C. 30%
Hydrogen peroxide (0.74 mL, 7.4 mmol) was then added
dropwise. The reaction mixture was stirred at 0 8C and
slowly warmed up to room temperature overnight (15 h).
After usual work-up, the crude product was purified by
column chromatography (SiO2, 30% EtOAc in hexanes) to
give a pale yellow viscous liquid of CC-11b (670.3 mg,
1
78% yield). H NMR (300 MHz, CDCl3): d 7.81 (d, JZ
7.4 Hz, 2H, SO2ArH), 7.66 (app t, JZ7.4 Hz, 1H, SO2ArH),
7.58–7.50 (m, 2H, SO2ArH and 1H, ArH), 7.34 (d, JZ
1.7 Hz, 1H, ArH), 6.88 (dd, JZ8.3, 1.7 Hz, 2H, ArH), 6.82

M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
5319
4.5. Preparation of thuriferic acid ethyl ester (4a) and
analogues 4b and 4c
1043s, 1012w, 950m, 865w cmK1. MS: m/z (%) relative
intensity 440 (MC, 100), 426 (53), 412 (2), 398 (7), 397
(27), 395 (7), 394 (9), 380 (3), 379 (8), 365 (10), 364 (27),
363 (64), 353 (11), 352 (6), 351 (9), 337 (14), 336 (13), 335
(15), 321 (16), 320 (12), 319 (25), 309 (8), 307 (8), 293 (9),
279 (8), 263 (7), 235 (5), 207 (4), 181 (5), 153 (8), 152 (7).
4.5.1. Preparation of ethyl 2-methylene-6,7-methylene-
dioxy-1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetra-
hydronaphthalene-3-carboxylate (4a). A solution of SnCl4
(1 M in CHCl3, 6.7 mL, 6.7 mmol) was added to a CHCl3
(10 mL) solution of CC-11a (424 mg, 0.67 mmol) at room
temperature under an argon atmosphere. The reaction
mixture was allowed to stir at room temperature overnight
(15 h). The mixture was poured onto crushed ice and
extracted with EtOAc (3!30 mL). The combined extracts
were washed with saturated aqueous NaHCO3 (3!20 mL),
water (3!20 mL), brine and dried over anhydrous Na2SO4.
After removal of solvent under reduced pressure, the crude
product was dissolved in THF (6 mL) under an argon
atmosphere and a THF (0.5 mL) solution of DBU (88.3 mg,
0.58 mmol) was then added. After stirring at room
temperature for 1 h, the reaction mixture was quenched
with 0.5 M HCl (1 mL), diluted with water (20 mL) and
extracted with EtOAc (3!20 mL). The combined organic
extracts were washed with water, brine and dried over
anhydrous Na2SO4. Filtration followed by evaporation gave
a crude product, which was purified by preparative thin-
layer chromatography (SiO2, 15% EtOAc in hexanes;
multiple runs) to give two bands; PLC1 and PLC2 of 4a
and 13a, respectively.
4.5.2. Preparation of ethyl 2-methylene-6,7-methylene-
dioxy-1-oxo-4-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-
naphthalene-3-carboxylate (4b). According to the general
procedure as described for compound 4a, a solution of
SnCl4 (1 M in CHCl3, 5.7 mL, 5.7 mmol) was added to a
CHCl3 (8.8 mL) solution of CC-11b (329.5 mg, 0.57 mmol)
and stirred at room temperature overnight (15 h). The crude
product obtained was dissolved in THF (2 mL) and then a
THF (0.5 mL) solution of DBU (80.2 mg, 0.53 mmol) was
added. The reaction mixture was stirred at room temperature
for 1 h. The crude product was purified by preparative thin-
layer chromatography (SiO2, 10% EtOAc in hexanes;
multiple runs) to give two bands; PLC1 and PLC2 of 4b
and 13b, respectively.
PLC1 (less polar) was obtained as a pale yellow viscous
liquid of 4b (109.2 mg, 49% yield). H NMR (300 MHz,
1
CDCl3): d 7.60 (s, 1H, ArH), 6.70 (d, JZ7.7 Hz, 1H, ArH),
6.53–6.48 (m, 3H, ArH), 6.33 (br s, 1H, C]CHH), 6.02 and
6.01 (each br s, 2H, OCH2O), 5.92 and 5.91 (each br s, 2H,
OCH2O), 5.32 (br s, 1H, C]CHH), 4.63 (d, JZ4.0 Hz, 1H,
CHAr), 4.07 (q, JZ7.3 Hz, 2H, CO2CH2CH3), 3.85 (d, JZ
4.0 Hz, 1H, CHCO2Et), 1.11 (t, JZ7.3 Hz, 3H, CO2CH2-
CH3). 13C NMR (75 MHz, CDCl3): d 184.1 (C]O), 171.4
(C]O), 152.8 (C–O), 147.89 (C–O), 147.86 (C–O), 146.6
(C–O), 139.8 (C), 138.2 (C), 135.3 (C), 127.5 (C), 125.6
(CH2), 121.6 (CH), 108.8 (CH), 108.5 (CH), 108.2 (CH),
106.7 (CH), 101.9 (OCH2O), 101.1 (OCH2O), 61.3 (OCH2),
55.8 (CH), 47.7 (CH), 13.9 (CH3). IR (CHCl3): nmax 3029m,
2928m, 2856m, 1727s, 1672m, 1614m, 1505s, 1481s,
1444m, 1387m, 1250s, 1183m, 1100w, 1041s, 939m,
864w cmK1. MS: m/z (%) relative intensity 394 (MC, 16),
348 (5), 322 (19), 321 (100), 293 (16), 291 (12), 263 (16),
235 (13), 233 (10), 205 (10), 177 (8), 176 (7), 149 (5).
HRMS (ESI-TOF) Calcd for C22H18O7Na (MCCNa):
417.0950. Found 417.0937.
PLC1 (less polar) was obtained as a pale yellow solid of 4a
[114.5 mg, 39% yield; mp 154–155 8C (CH2Cl2–hexanes)].
1H NMR (300 MHz, CDCl3): d 7.60 (s, 1H, ArH), 6.55 (s,
1H, ArH), 6.36 (br s, 1H, C]CHH), 6.25 (s, 2H, ArH), 6.03
(s, 2H, OCH2O), 5.36 (br s, 1H, C]CHH), 4.62 (d, JZ
4.1 Hz, 1H, CHAr), 4.07 (q, JZ7.2 Hz, 2H, CO2CH2CH3),
3.89 (d, JZ4.1 Hz, 1H, CHCO2Et), 3.81 (s, 3H, OCH3),
3.75 (s, 6H, 2!OCH3), 1.10 (t, JZ7.2 Hz, 3H, CO2CH2-
CH3). 13C NMR (75 MHz, CDCl3): d 184.1 (C]O), 171.4
(C]O), 153.2 (2!C–O), 152.8 (C–O), 147.9 (C–O), 139.7
(C), 138.4 (C–O), 137.0 (2!C), 127.4 (C), 125.6 (CH2),
108.8 (CH), 106.6 (CH), 105.3 (2!CH), 101.9 (OCH2O),
61.3 (OCH2), 60.7 (OCH3), 56.0 (2!OCH3), 55.5 (CH),
48.3 (CH), 13.9 (CH3). IR (nujol): nmax 1731s, 1660s, 1593s,
1500s, 1432s, 1337s, 1270s, 1159s, 1128s, 1095s, 1038s,
1012s, 936s, 897m, 844m, 809m, 694m cmK1. MS: m/z (%)
relative intensity 440 (MC, 32), 395 (2), 394 (6), 368 (25),
367 (100), 352 (3), 351 (5), 337 (6), 336 (16), 308 (7), 306
(4), 305 (5), 291 (4), 277 (3). Anal. Calcd for C24H24O8: C,
65.45; H, 5.49. Found: C, 65.19; H, 5.89.
PLC2 (more polar) was obtained as a yellow solid of 13b
(8.8 mg, 4% yield; mp 196–200 8C). H NMR (300 MHz,
1
CDCl3): d 7.48 (s, 1H, ArH), 6.87–6.75 (m, 4H, ArH), 6.02
and 6.01 (each br s, 2H, OCH2O), 6.00 and 5.99 (each br s,
2H, OCH2O), 5.25 (br s, 1H, ArOH), 4.08 (q, JZ7.1 Hz,
2H, CO2CH2CH3), 2.32 (s, 3H, CH3), 1.05 (t, JZ7.1 Hz,
3H, CO2CH2CH3). 13C NMR (75 MHz, CDCl3): d 169.5
(C]O), 148.0 (C–O), 147.9 (C–O), 147.8 (C–O), 147.2
(C–O), 146.9 (C–O), 132.0 (C), 129.1 (C), 128.9 (C), 123.9
(CH), 121.4 (C), 111.5 (C), 111.2 (CH), 107.9 (2!CH),
103.0 (CH), 101.2 (OCH2O), 101.0 (OCH2O), 98.1 (CH),
60.9 (OCH2), 13.8 (CH3), 12.7 (CH3). IR (CHCl3): nmax
3604w, 3027w, 2903w, 1721s, 1503s, 1490m, 1463s,
PLC2 (more polar) was obtained as a yellow solid of 13a
(18 mg, 6% yield; mp 163–164 8C). H NMR (300 MHz,
1
CDCl3): d 7.48 (s, 1H, ArH), 6.89 (s, 1H, ArH), 6.56 (s, 2H,
ArH), 6.01 (s, 2H, OCH2O), 5.35 (br s, 1H, ArOH), 4.05 (q,
JZ7.2 Hz, 2H, CO2CH2CH3), 3.91 (s, 3H, OCH3), 3.83 (s,
6H, 2!OCH3), 2.33 (s, 3H, CH3), 0.99 (t, JZ7.2 Hz, 3H,
CO2CH2CH3). 13C NMR (75 MHz, CDCl3):d 169.7
(C]O), 152.7 (2!C–O), 148.1 (C–O), 148.0 (C–O),
147.9 (C–O), 137.2 (C–O), 133.9 (C), 131.5 (C), 129.3
(C), 128.7 (C), 121.4 (C), 111.6 (C), 107.7 (2!CH), 102.9
(CH), 101.2 (OCH2O), 98.2 (CH), 61.0 (OCH2), 60.9
(OCH3), 56.1 (2!OCH3), 13.8 (CH3), 12.6 (CH3). IR
(CHCl3): nmax 3604w, 3014w, 2964w, 2939w, 2906w,
1717s, 1583s, 1503m, 1463s, 1414m, 1369s, 1353s, 1129s,
1351m, 1137w, 1114w, 1042s, 949m, 865w, 818w cmK1
.
MS: m/z (%) relative intensity 394 (MC, 100), 366 (26), 349
(23), 348 (40), 320 (17), 319 (33), 318 (48), 293 (16), 291
(40), 290 (36), 263 (13), 262 (14), 261 (11), 233 (12), 205
(13), 177 (12), 175 (11), 165 (7), 151 (8), 150 (4), 88 (6).

5320
M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
4.5.3. Preparation of ethyl 2-methylene-6,7-methylene-
dioxy-1-oxo-4-(4-methoxyphenyl)-1,2,3,4-tetrahydro-
naphthalene-3-carboxylate (4c). According to the general
procedure as described for compound 4a, a solution of
SnCl4 (1 M in CHCl3, 2.9 mL, 2.9 mmol) was added to a
CHCl3 (4.5 mL) solution of CC-11c (163.7 mg, 0.29 mmol)
and stirred at room temperature overnight (15 h). The crude
product obtained was dissolved in THF (3 mL) and then a
THF (0.5 mL) solution of DBU (41.7 mg, 0.27 mmol) was
added. The reaction mixture was stirred at room temperature
for 1 h. The crude product was purified by preparative thin-
layer chromatography (SiO2, 10% EtOAc in hexanes;
multiple runs) to give two bands; PLC1 and PLC2 of 4c
and 13c, respectively.
and CHCOO). 13C NMR (75 MHz, CDCl3): d 193.4
(C]O), 175.5 (C]O), 153.8 (C–O), 153.7 (2!C–O),
148.4 (C–O), 139.5 (C), 137.9 (C–O), 137.2 (C), 127.2 (C),
109.4 (CH), 106.0 (CH), 104.6 (2!CH), 102.2 (OCH2O),
70.4 (OCH2), 60.7 (OCH3), 56.1 (2!OCH3), 46.6 (CH),
43.4 (CH), 43.3 (CH). IR (CHCl3): nmax 3025m, 2937m,
1778s, 1670s, 1615s, 1591s, 1505s, 1481s, 1257s, 1131s,
1040s, 1023s, 1002m, 939m, 892w cmK1. MS: m/z (%)
relative intensity 412 (MC, 8), 369 (25), 368 (100), 367
(24), 354 (30), 353 (76), 339 (8), 337 (8), 325 (10), 293 (15),
278 (15), 263 (10), 237 (10), 235 (11), 207 (15), 202 (19),
201 (30), 194 (10), 189 (5), 181 (7), 168 (8), 154 (10), 153
(13), 152 (14), 105 (14), 104 (21), 91 (20), 78 (21), 77 (10),
76 (9), 51 (6). Anal. Calcd for C22H20O8: C, 64.08; H, 4.89.
Found: C, 64.50; H, 5.12. HRMS (ESI-TOF) Calcd for
C22H20O8Na (MCCNa): 435.1056. Found 435.1042.
PLC1 (less polar) was obtained as a white solid of 4c
[67.9 mg, 62% yield; mp 215–217 8C (Et2O–hexanes)]. H
1
NMR (300 MHz, CDCl3): d 7.59 (s, 1H, ArH), 6.95 (br d,
JZ8.7 Hz, 2H, ArH), 6.79 (br d, JZ8.7 Hz, 2H, ArH), 6.51
(s, 1H, ArH), 6.32 (br s, 1H, C]CHH), 6.00 and 5.99 (each
d, JZ1.2 Hz, 2H, OCH2O), 5.29 (br s, 1H, C]CHH), 4.65
(d, JZ4.1 Hz, 1H, CHAr), 4.10–4.00 (m, 2H, CO2CH2-
CH3), 3.86 (d, JZ4.1 Hz, 1H, CHCO2Et), 3.76 (s, 3H,
OCH3), 1.09 (t, JZ7.2 Hz, 3H, CO2CH2CH3). 13C NMR
(75 MHz, CDCl3): d 184.3 (C]O), 171.5 (C]O), 158.5
(C–O), 152.7 (C–O), 147.7 (C–O), 140.2 (C), 138.3 (C),
133.4 (C), 129.2 (2!CH), 127.5 (C), 125.5 (CH2), 113.9
(2!CH), 108.8 (CH), 106.6 (CH), 101.8 (OCH2O), 61.2
(OCH2), 55.8 (CH), 55.1 (OCH3), 47.3 (CH), 13.9 (CH3). IR
(CHCl3): nmax 3027w, 3009w, 2929w, 2855w, 1727s,
1676w, 1612m, 1512s, 1480s, 1464w, 1380w, 1251s,
1179m, 1039s, 939w, 841w cmK1. MS: m/z (%) relative
intensity 380 (MC, 25), 349 (6), 334 (6), 308 (21), 307
(100), 306 (26), 279 (19), 277 (5), 276 (5), 249 (11), 221 (6),
189 (3), 178 (3). HRMS (ESI-TOF) Calcd for C22H20O6Na
(MCCNa): 403.1158. Found 403.1125.
Acknowledgements
We thank the Thailand Research Fund for financial supports
(BRG/22/2544 to M. P. and TRF4780020 to P. K.), as well
as the award of a Senior Research Scholar to V. R. Thanks
are also made to the Higher Education Development
Project: Postgraduate Education and Research Program in
Chemistry for support.
References and notes
1. (a) Ayres, D. C.; Loike, J. D. Lignans: Chemical, Biological
and Clinical Properties; Cambirdge University Press:
Cambridge, 1990. (b) Canel, C.; Moraes, R. M.; Dayan,
F. E.; Ferreirfa, D. Phytochemistry 2000, 54, 115–120.
(c) Ward, R. S. Synthesis 1992, 719–730. (d) Peterson, J. R.;
Do, H. D.; Rogers, R. D. Synthesis 1991, 275–277 and
references cited. (e) Stahelin, H. F.; von Wartburg, A. Cancer
Res. 1991, 51, 5–15. (f) Ward, R. S. Nat. Prod. Rep. 1999, 16,
75–96. (g) Ward, R. S. Nat. Prod. Rep. 1997, 14, 43–74.
(h) Ward, R. S. Nat. Prod. Rep. 1995, 12, 183–205.
PLC2 (more polar) was obtained as a yellow viscous liquid
of 13c (0.9 mg, 1% yield). H NMR (300 MHz, CDCl3): d
1
7.49 (s, 1H, ArH), 7.23 (d, JZ8.5 Hz, 2H, ArH), 6.95 (d,
JZ8.5 Hz, 2H, ArH), 6.81 (s, 1H, ArH), 5.99 (s, 2H,
OCH2O), 5.05 (br s, 1H, ArOH), 4.01 (q, JZ7.1 Hz, 2H,
CO2CH2CH3), 3.86 (s, 3H, OCH3), 2.34 (s, 3H, CH3), 0.97
(t, JZ7.1 Hz, 3H, CO2CH2CH3).
´
2. (a) San Feliciano, A.; Lopez, J. L.; Medarde, M.; Miguel del
Corral, J. M.; de Pascual-Teresa, B.; Puebla, P. Tetrahedron
1988, 44, 7255–7260. (b) San Feliciano, A.; Medarde, M.;
´
Lopez, J. L.; Puebla, P.; Miguel del Corral, J. M.; Barrero,
A. F. Phytochemistry 1989, 28, 2863–2866. (c) San Feliciano,
´
A.; Miguel del Corral, J. M.; Lopez, J. L.; de Pascual-Teresa,
B. Phytochemistry 1992, 31, 1713–1717.
4.5.4. Preparation of (G)-picropodophyllone (2). A
solution of thuriferic acid ethyl ester (4a) (25.5 mg,
0.06 mmol) in dioxane (0.8 mL) containing HCl (6 M,
0.3 mL) was heated under reflux for 15 h. After removal of
dioxane under reduced pressure, water (10 mL) was added
to the residue and extracted with EtOAc (3!10 mL). The
combined organic layers were washed with water, brine and
dried over anhydrous Na2SO4. After removal of solvent
under reduced pressure, the crude product was purified by
column chromatography (SiO2, 30% EtOAc in hexanes) to
give a white solid of (G)-picropodophyllone (2) [10.6 mg,
43% yield; mp 182–183 8C (MeOH): the spectral data were
3. (a) Ogiku, T.; Yoshida, S.; Kuroda, T.; Takahashi, M.;
Ohmizu, H.; Iwasaki, T. Bull. Chem. Soc. Jpn. 1992, 65,
¨
3495–3497. (b) Hofert, P. H.; Matusch, R. Helv. Chim. Acta
1994, 77, 771–777. (c) Miguel del Corral, J. M.; Gordaliza,
´ ´
M.; Lopez, J. L.; del Olmo, E.; Castro, M. A.; Lopez, M. L.
´
Helv. Chim. Acta 1995, 78, 1793–1796. (d) Lopez-Perez, J. L.;
´
´
del Olmo, E.; de Pascual-Teresa, B.; Merino, M.; Martın, S.;
San Feliciano, A. Tetrahedron 1995, 51, 6343–6348.
´ ´
(e) Lopez-Perez, J. L.; del Olmo, E.; de Pascual-Teresa, B.;
Merino, M.; San Feliciano, A. Tetrahedron 1996, 52,
´
4903–4910. (f) Madrigal, B.; Puebla, P.; Ramos, A. C.; Pelaez,
´
R.; Gravalos, D.; Caballero, E.; Medarde, M. Bioorg. Med.
´
Chem. 2002, 10, 303–312. (g) Ramos, A. C.; Pelaez, R.;
´
Lopez, J. L.; Caballero, E.; Medarde, M.; San Feliciano, A.
1
identical to those reported in the literature6b,d–f. H NMR
(300 MHz, CDCl3): d 7.50 (s, 1H, ArH), 6.69 (s, 1H, ArH),
6.24 (s, 2H, ArH), 6.05 and 6.04 (each d, JZ1.1 Hz, 2H,
OCH2O), 4.76 (d, JZ9.2 Hz, 1H, OCHH), 4.69 (s, 1H,
CHAr), 4.38–4.33 (m, 1H, OCHH), 3.80 (s, 3H, OCH3),
3.76 (s, 6H, 2!OCH3), 3.31 and 3.29 (each br s, 2H, CHCO

M. Pohmakotr et al. / Tetrahedron 61 (2005) 5311–5321
5321
Tetrahedron 2001, 57, 3963–3977. (h) Madrigal, B.; Puebla,
´
P.; Pelaez, R.; Caballero, E.; Medarde, M. J. Org. Chem. 2003,
68, 854–864.
8. X-ray crystal structure analysis of compound 11a. Crystal
data for 11a: C31H30O12S, MWZ626.63, triclinic, space group
˚
˚
˚
P1, aZ10.0515 (4) A, bZ10.7450 (2) A, cZ15.2055 (5) A,
4. This type of lactones has been used as versatile starting
materials for the preparation of aryltetralone precursors for
podophyllotoxin, see: (a) Gensler, W. J.; Gastonis, C. D.
J. Org. Chem. 1966, 31, 3224–3227. (b) Kaneko, T.; Wong, H.
Tetrahedron Lett. 1987, 28, 517–520.
aZ109.525 (2)8, bZ100.379 (2)8, gZ94.111 (2)8, VZ
3
1506.99 (8) A , ZZ2, DcalcZ1.381 mg/m3. A total of 6064
˚
unique reflections (4888 observed, jFojO4s/jFoj) was
measured at room temperature from a 0.20!0.15!0.10 mm3
colorless crystal using graphite monochromated Mo Ka
5. Pohmakotr, M.; Sampaongoen, L.; Issaree, A.; Tuchinda, P.;
Reutrakul, V. Tetrahedron Lett. 2003, 44, 6717–6720.
6. (a) Gensler, W. J.; Samour, C. M.; Wang, S. Y.; Johnson, F.
J. Am. Chem. Soc. 1960, 82, 1714–1727. (b) Kende, A. S.;
Liebeskind, L. S.; Mills, J. E.; Rutledge, P. S.; Curran, D. P.
J. Am. Chem. Soc. 1977, 99, 7082–7083. (c) Murphy, W. S.;
Wattanasin, S. J. Chem. Soc., Perkin Trans. 1 1982, 271–276.
(d) Andrews, R. C.; Teague, S. J.; Meyers, A. I. J. Am. Chem.
Soc. 1988, 110, 7854–7858. (e) Yoshida, S.; Yamanaka, T.;
Miyake, T.; Moritani, Y.; Ohmizu, H.; Iwasaki, T. Tetrahedron
1997, 53, 9585–9598.
˚
radiation (lZ0.71073 A) on a Bruker–Nonius kappaCCD
diffractometer. The crystal structure was solved by direct
methods using SIR-97, and then all atoms except hydrogen
atoms were refined anisotropically on F2 using SHELXL-97 to
give a final R-factor of 0.0773 and wRZ0.2378 (all data).
Atomic coordinates, bond lengths, bond angles, and thermal
parameters have been deposited with the Cambridge Crystallo-
graphic Data Center, 12 Union Road, Cambridge CB2 1EZ,
England (CCDC 254984).
9. (a) Reutrakul, V.; Nimgirawath, S.; Panichanun, S.; Ratana-
nukul, P. Chem. Lett. 1979, 399–400. (b) Bu¨chi, G.; Liang, H.;
Wu¨est, H. Tetrahedron Lett. 1978, 2763–2764.
7. The relative stereochemistry of CC-8a was established by the
NOE experiments as shown below.
10. Eaton, P. E.; Carlson, G. R.; Lee, J. T. J. Org. Chem. 1973, 33,
4071–4073.