Regiospecific substitution of the carbon-boron bond of tris(4-methylfuran-3-yl)boroxine: A model ring C→BC→ABC approach towards eudesmanolides

Article abstract of DOI:10.1016/S0040-4020(01)00654-8

A synthetic study of eudesmanolides was performed utilizing a Suzuki coupling reaction of tris(4-methylfuran-3-yl)boroxine (6) as the pivotal step. The other key reactions involved Friedel-Crafts acylation, Wacker-Tsuji reaction and aldol condensation. In this Ring C→BC→ABC approach, a model compound 3 towards the synthesis of eudesmanolides 11,13-dihydrotubiferin (1) and artogallin (2) was realized. In another model study, the five-membered analog 4 was also obtained.

Full text of DOI:10.1016/S0040-4020(01)00654-8

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 6935±6940
Regiospeci®c substitution of the carbon±boron bond of tris-
ꢀ4-methylfuran-3-yl)boroxine: a model ring C!BC!ABC
approach towards eudesmanolidesq
Chung-Yan Yick and Henry N. C. Wongp
Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People's Republic of China
Dedicated to Dr Douglas Lloyd of the University of St. Andrews on the occasion of his 80th birthday
Received 20 April 2001; revised 29 May 2001; accepted 14 June 2001
AbstractÐA synthetic study of eudesmanolides was performed utilizing a Suzuki coupling reaction of tris/4-methylfuran-3-yl)boroxine /6)
as the pivotal step. The other key reactions involved Friedel±Crafts acylation, Wacker±Tsuji reaction and aldol condensation. In this Ring
C!BC!ABC approach, a model compound 3 towards the synthesis of eudesmanolides 11,13-dihydrotubiferin /1) and artogallin /2) was
realized. In another model study, the ®ve-membered analog 4 was also obtained. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
An organosilicon±organoboron protocol directed to the
synthesis of 3,4-disubstituted furans was recently estab-
lished in our laboratory.1,2 The same method was subse-
quently extended to the realization of polysubstituted
furans.3 Herein, we would like to report the application
of this strategy as a pivotal step in the synthetic study of
eudesmanolides, e.g. 11,13-dihydrotubiferin /1)4 and
artogallin /2).5 Our initial target molecule is furan 3 because
2. Results and discussion
the oxidative conversion of furans to butanolides is well
documented.6 By employing a model Ring C!BC!ABC
As depicted in Scheme 1, the title compound tris/4-methyl-
furan-3-yl)boroxine /6) was prepared from 3-methyl-4-
approach, the construction of 3 as well as its related
compound 4 utilizing the title compound tris/3-methyl-
furan-4-yl)boroxine /5) as a precursor is delineated below.
trimethylsilylfuran /5),1f which in turn, was synthesized
through Diels±Alder reaction between trimethylsilyl-1-
propyne and 4-phenyloxazole8 after extrusion of benzo-
It is noteworthy that a compound structurally similar to
nitrile.1f The Suzuki coupling of boroxine 6 with ethyl
4 was recently used to synthesize the cyathin core of
4-bromo-3-methoxycrotonate /7)9 was not trivial due
primarily to the unexpected formation of the self-coupling
product 4,40-dimethyl-3,30-bifuran /8). After much experi-
mentation, we were able to obtain the desired product 9 in
60% yield, together with 20% yield of 8, by employing
palladium bis/dibenzylideneacetone) as catalyst through a
slow addition of 6 to 7. With 9 /Ring C) in hand, we then
proceeded to the formation of Ring B.
diterpenes erinacine and scabronine.7
The methyl enol ether moiety of 9 was ®rst converted with
p-TsOH´H2O in aqueous EtOH, providing the b-ketoester
10 in 87% yield /Scheme 2). Methylation of 10 then led to
the methyl-substituted ketoester 11 in 75% yield. Consecu-
tive alkylation of 11 was also achieved through the use of
KO-t-Bu as base. In this way, a butenyl group as well as an
allyl group were introduced, affording the dialkylation
products 12 and 13, respectively /Scheme 2).
q Taken in part from the Ph.D. thesis of C.-Y. Y., The Chinese University of
Hong Kong, 1999.
Keywords: aldol reactions; Friedel±Crafts reactions; furans; Suzuki reac-
tions; terpenes and terpenoids.
p
Corresponding author. Tel.: 1852-2609-6329; fax: 1852-2603-5057;
e-mail: hncwong@cuhk.edu.hk
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00654-8

6936
C.-Y. Yick, H. N. C. Wong / Tetrahedron 57 +2001) 6935±6940
Scheme 1.
all the resulting tri¯uoroacetate to hydroxycyclohexenone
16. The hydroxy group of 16 was oxidized to a carbonyl
group with Dess±Martin periodinane10 to give the diketone
18 in 90% yield. Oxidation of the terminal double bond was
expected to lead to a methyl ketone on the side-chain.
However, to suppress the possible oxidation of the
enolizable methylene group /C-4) of the cyclohexenone
ring /vide infra), the C-5 carbonyl was selectively protected
with ethylene glycol to afford 20. Due to the crowding
around C-7 and the lower reactivity arising from the
conjugation with the furan ring, the C-5 carbonyl reacted
preferentially while the C-7 carbonyl remained intact. This
1
route is supported by H NMR spectral data of 20 because
the H-2 of the furan ring shows a slightly down-®eld absorp-
tion11 at d 7.36 because of the deshielding effect of the C-7
carbonyl group. Wacker-Tsuji oxidation12 of 20 was then
carried out to afford the diketone 22 in 87% yield. Our ®rst
target molecule 3 was eventually obtained through an aldol
cyclization reaction of 22 with pyrrolidine in benzene as
solvent /Scheme 3). The use of KO-t-Bu as base was
found to only lead to a dismal yield of 3. The successful
conversion of 22 to 3 was presumably due to the formation
of an enamine at the less sterically demanding carbonyl
Scheme 2.
Since b-ketoacid is vulnerable to decarboxylation, ketoester
12 was ®rstly reduced to hydroxyester 14 by NaBH4.
Saponi®cation of 14 with NaOH was followed immediately
without further puri®cation by a Friedel±Crafts acylation
/Scheme 3). Tri¯uoroacetic anhydride was found to be
effective in promoting the cyclization, providing the cyclo-
hexenone /Ring B). Treatment of the resulting product with
an aqueous 1 M NaOH was, however, needed to hydrolyze
1
group. The H NMR spectrum of compound 3 exhibits
absorptions of the alkene proton and the furan proton at d
6.18and 7.26, respectively, as two sharp singlets, and the
two isolated methylene protons appear as two doublets at d
2.71 and 2.84 with Jˆ16.8Hz because of geminal coupling.
It is anticipated that a similar entry resembling that for
the model synthesis of 3 will in due course provide key
Scheme 3.

C.-Y. Yick, H. N. C. Wong / Tetrahedron 57 +2001) 6935±6940
6937
solution of BCl3 /1.0 M) in CH2Cl2 /5 mL) under N2 at
2788C. After stirring for 6 h, the reaction was quenched
with 0.5 M Na2CO3 /5 mL) and the mixture was extracted
with Et2O /3£50 mL). The organic extract was dried
/MgSO4) and evaporated. The crude product was chromato-
graphed on silica gel /200 g, hexanes±Et2O, 2:1) to give 6
1
/292 mg, 90%) as colorless crystals, mp 130±1318C. H
Scheme 4.
NMR /CDCl3) d 2.25 /s, 9H), 7.21 /s, 3H), 7.90 /d, Jˆ
1.0 Hz, 3H); 13C NMR /CDCl3) d 10.0, 123.8, 140.5,
154.6; MS /EI) m/z 324 /M1). Anal. Calcd for
C15H15B3O6: C, 55.66; H, 4.67. Found: C, 55.45; H, 4.58.
intermediates for the synthesis of the tricyclic sesquiter-
penoids 11,13-dihydrotubiferin /1) and artogallin /2).
In order to widen the synthetic scope of our route for
the realization of 3, compound 13 was also subjected to a
similar procedure as illustrated also in Scheme 3. As can be
seen, reduction of 13 gave alcohol 15, which was cyclized
through the same saponi®cation±Friedel±Crafts acylation±
hydrolysis of tri¯uoroacetate steps to provide 17. Oxidation
of 17 to 19 was followed by the protection of the less
hindered and more reactive C-5 carbonyl /vide supra),
leading to the monoketone 21. A Wacker±Tsuji reaction
was carried out for 21, from which the diketone 23 was
obtained in 88% yield. In contrary to 22, KO-t-Bu was
found to be effective in the aldol reaction. In this manner,
23 was smoothly cyclized to 4 in 79% yield. The structure of
4 is supported by its 1H NMR spectrum that reveals
characteristic alkene and furan absorptions at d 6.01 and
7.36, respectively. The 13C NMR spectrum of 4 shows a
quaternary signal at d 206.9 that corresponds to the enone
carbonyl carbon.
3.1.3. 4,40-Dimethyl-3,30-bifuran ꢀ8) and ethyl 4-ꢀ4-
methylfuran-3-yl)-3-methoxycrotonate ꢀ9). To a re¯uxing
mixture of 7 /4 g, 18mmol), 2 M aq. K 3PO4 /30 mL) and
Pd/dba)2 /0.5 g, 0.9 mmol) in THF /60 mL) was added a
solution of 6 /2 g, 6 mmol) in THF /60 mL) under N2 over
2 h. After addition, the mixture was re¯uxed for a further
1 h. After ®ltration, THF was evaporated under reduced
pressure. The aqueous residue was extracted with Et2O
/4£50 mL) and the organic extract was dried /MgSO4).
After evaporation, the residue was chromatographed on a
silica gel column /100 g, hexanes±EtOAc, 50:1) to afford 8
/290 mg, 20%) as colorless crystals, mp 43.5±448C and 9
/2.4 g, 60%) as a pale yellow oil.
Compound 8: 1H NMR /CDCl3) d 2.06 /d, Jˆ1.2 Hz, 6H),
7.28/s, 2H), 7.47 /d, Jˆ1.2 Hz, 2H); 13C NMR /CDCl3) d
9.4, 117.7, 119.5, 139.7, 140.0; MS m/z 162 /M1); HRMS
/EI) Calcd for C10H10O2: 162.0680. Found: 162.0677.
1
An attempt was also initiated in the hope of oxidizing the
terminal double bond of 19 by a Wacker±Tsuji reaction in
the presence of the enolizable C-4 methylene group
/Scheme 4). However, only over-oxidized product 24 was
Compound 9: H NMR /CDCl3) d 1.27 /t, Jˆ7.2 Hz, 3H),
1.97 /d, Jˆ1.2 Hz, 3H), 3.62 /s, 3H), 3.88 /d, Jˆ0.6 Hz,
2H), 4.14 /q, Jˆ7.2 Hz, 2H), 5.05 /s, 1H), 7.12 /s, 1H),
7.24 /s, 1H); 13C NMR /CDCl3) d 8.1, 14.3, 25.7, 55.5,
59.5, 90.9, 120.3, 121.0, 139.1, 140.5, 167.3, 173.5; MS
/EI) m/z 224 /M1); HRMS /FAB) Calcd for C12H17O4
/MH1): 225.1127. Found: 225. 1132.
1
isolated. The H NMR spectrum of 24 shows clearly the
absence of the signal corresponding to the two protons at
C-4, and its 13C NMR spectrum expectedly exhibits four
carbonyl carbon absorptions.
3.1.4. Ethyl 4-ꢀ4-methylfuran-3-yl)acetoacetate ꢀ10). To a
solution of 9 /2.1 g, 10 mmol) in EtOH±H2O /2:1) /200 mL)
was added a catalytic amount of p-TsOH´H2O. The mixture
was re¯uxed for 6 h. EtOH was removed under reduced
pressure and the aqueous residue was extracted with Et2O
/4£60 mL). After drying /MgSO4) and evaporation, the
crude product was subjected to ¯ash column chroma-
tography on silica gel /100 g, hexanes±EtOAc, 10:1) to
afford 10 /1.8g, 87%) as a pale yellow oil. 1H NMR
/CDCl3) d 1.25 /t, Jˆ7.2 Hz, 3H), 1.90 /s, 3H), 3.46 /s,
2H), 3.59 /s, 2H), 4.16 /q, Jˆ7.2 Hz, 2H), 7.18/s, 1H),
7.31 /s, 1H); 13C NMR /CDCl3) d 7.7, 13.8, 37.8, 47.8,
61.2, 117.3, 119.8, 139.8, 140.9, 166.9, 199.8; MS /EI)
m/z 210 /M1); HRMS /EI) Calcd for C11H14O4 /M1)
210.0892. Found: 210.0887.
The avenue for the successful synthesis of compounds 3 and
4 will serve as a model pathway in our future quest for the
sesquiterpenoid eudesmanolides.
3. Experimental
3.1. Data for compounds
3.1.1. 4-Methyl-3-trimethylsilylfuran ꢀ5).1f A sealed tube
containing trimethylsilyl-1-propyne /10 g, 90 mmol),
4-phenyloxazole8 /12.9 g, 90 mmol) and anhydrous DBU
/1.5 g, 10 mmol) was heated at 3008C for 7 days to give a
dark brown mixture. Vacuum distillation /bath temperature
30±608C/65±80 pa) of the resulting mixture gave a color-
less liquid, which was ¯ash chromatographed on silica gel
/100 g, hexanes) to afford 5 as a colorless oil /11 g, 80%).
1H NMR /CDCl3) d 0.17 /s, 9H), 1.99 /d, Jˆ0.7 Hz, 3H),
7.16 /s, 2H); MS /EI) m/z 154 /M1). Anal. Calcd for
C8H14OSi: C, 62.30; H, 8.69. Found: C, 62.86; H, 9.03.
3.1.5. Ethyl 2-methyl-4-ꢀ4-methylfuran-3-yl)acetoacetate
ꢀ11). To a solution of 10 /1.5 g, 7.1 mmol) in anhydrous
THF /15 mL) at 08C was added KO-t-Bu /800 mg,
7.1 mmol). The mixture was allowed to stir for 30 min.
MeI /0.5 mL, 8.5 mmol) was then added. White precipitate
appeared immediately. After stirring for a further 1 h, the
precipitate was ®ltered off with Celite. The ®ltration cake
was washed with Et2O /100 mL), and the ®ltrate was dried
3.1.2. Trisꢀ4-methylfuran-3-yl)boroxine ꢀ6).1f To a solu-
tion of 5 /462 mg, 3 mmol) in CH2Cl2 /100 mL) was added a

6938
C.-Y. Yick, H. N. C. Wong / Tetrahedron 57 +2001) 6935±6940
/MgSO4) and evaporated. The residue was chromato-
graphed on a silica gel column /80 g, hexanes±EtOAc,
15:1) to afford 11 /1.2 g, 75%) as a pale yellow oil. H
NMR /CDCl3) d 1.26 /t, Jˆ7.2 Hz, 3H), 1.34 /d, Jˆ
7.2 Hz, 3H), 1.90 /d, Jˆ0.9 Hz, 3H), 3.62 /s, 2H), 3.64 /q,
Jˆ7.2 hz, 1H), 4.17 /q, Jˆ7.2 Hz, 2H), 7.19 /s, 1H), 7.31 /s,
1H); 13C NMR /CDCl3) d 7.9, 12.9, 14.0, 36.7, 51.6, 61.4,
117.4, 120.0, 139.9, 141.1, 170.3, 202.8; MS /EI) m/z 224
/M1). Anal. Calcd for C12H16O4: C, 64.27; H, 7.19. Found:
C, 64.30; H, 6.87.
3.1.9. Ethyl 2-methyl-2-ꢀprop-2-en-1-yl)-3-hydroxy-4-ꢀ4-
methylfuran-3-yl)butanoate ꢀ15). Similar to the prepa-
ration of 14, compound 15 was prepared from 13 /260
mg, 1 mmol) in EtOH /10 mL) and NaBH4 /42 mg,
1 mmol). Column chromatography on silica gel /20 g,
hexanes±EtOAc, 10:1) afforded 15 /240 mg, 92%) as a
1
1
colorless oil. H NMR /CDCl3) d 1.21 /s, 3H), 1.27 /t,
Jˆ7.2 Hz, 3H), 1.94 /d, Jˆ1.2 Hz, 3H), 2.30±2.38/m,
2H), 2.48±2.61 /m, 3H), 3.78±3.81 /m, 1H), 4.14 /q, Jˆ
7.2 Hz, 2H), 5.07 /s, 1H), 5.12 /dd, Jˆ6.0, 1.8Hz, 1H),
5.69±5.75 /m, 1H), 7.17 /s, 1H), 7.28/s, 1H); 13C NMR
/CDCl3) d 8.2, 14.2, 17.0, 25.8, 40.7, 50.6, 60.7, 74.9, 118.5,
120.0, 121.7, 133.3, 139.6, 140.5, 176.0; MS /EI) m/z 266
/M1); HRMS /EI) Calcd for C15H23O4 /MH1): 267.1591.
Found: 267.1592.
3.1.6. Ethyl 2-methyl-2-ꢀbut-3-en-1-yl)-4-ꢀ4-methyl-
furan-3-yl)acetoacetate ꢀ12). Similar to the preparation
of 11, compound 12 was prepared from 11 /1.2 g,
5.4 mmol) in anhydrous THF /15 mL), KO-t-Bu /670 mg,
5.9 mmol) and 4-iodobut-1-ene /1.1 g, 5.9 mmol). Column
chromatography on silica gel /80 g, hexane±EtOAc, 30:1)
3.1.10. 3,6-Dimethyl-6-ꢀbut-3-en-1-yl)-4,5,6,7-tetrahydro-
5-hydroxybenzo[b]furan-7ꢀ6H)-one ꢀ16). To a solution of
14 /900 mg, 3.2 mmol) in MeOH /20 mL) was added slowly
an aqueous solution of 2 M NaOH /5 mL). The mixture was
then re¯uxed for 10 h. After that H2O /10 mL) was added
and the resulting mixture was washed with CH2Cl2 /10 mL).
The aqueous layer was acidi®ed with 3N HCl until the pH
reached 1. It was then extracted with CH2Cl2 /5£10 mL).
The combined organic extract was dried /MgSO4) and
evaporated under reduced pressure. The residue was re-
dissolved in anhydrous CH2Cl2 /20 mL). Tri¯uoroacetic
anhydride /1.3 mL, 9.6 mmol) was slowly added. After
stirring for 4 h, 1 M NaOH solution /15 mL) was added.
The mixture was allowed to stir for a further 4 h, the organic
layer was separated and the aqueous layer was extracted
with CH2Cl2 /3£20 mL). The combined organic extract
was dried /MgSO4) and evaporated. The residue was
puri®ed by column chromatography on silica gel /30 g,
hexanes±EtOAc, 1:1) to afford 16 /300 mg, 40%) as a
viscous yellow oil. Compound 16 shows very complex
1H- and 13C NMR spectra due to the presence of a pair of
diastereomers. The structure of 16 was con®rmed after its
oxidation to 18. MS /EI) m/z 234 /M1); HRMS /EI) Calcd
for C14H18O3 /M1): 234.1256. Found: 234.1256.
1
afforded 12 /900 mg, 60%) as a colorless oil. H NMR
/CDCl3) d 1.24 /t, Jˆ7.2 Hz, 3H), 1.39 /s, 3H), 1.88 /s,
3H), 1.92±2.06 /m, 4H), 3.53 /s, 2H), 4.17 /q, Jˆ7.2 Hz,
2H), 4.93±5.04 /m, 2H), 5.70±5.81 /m, 1H), 7.16 /d, Jˆ
1.2 Hz, 1H), 7.25 /s, 1H); 13C NMR /CDCl3) d 8.0, 13.9,
18.9, 28.4, 33.1, 34.1, 59.1, 61.3, 115.0, 117.6, 120.0,
137.4, 139.5, 140.8, 172.7, 204.2; MS /EI) m/z 279
/MH1); HRMS /EI) Calcd for C16H22O4 /M1): 278.1518.
Found: 278.1515.
3.1.7. Ethyl 2-methyl-2-ꢀprop-2-en-1-yl)-4-ꢀ4-methyl-
furan-3-yl)acetoacetate ꢀ13). Similar to the preparation
of 11, compound 13 was prepared from 11 /1.2 g,
5.4 mmol) in anhydrous THF /15 mL), KO-t-Bu /670 mg,
5.9 mmol) and allyl iodide /0.5 mL, 5.9 mmol). Column
chromatography on silica gel /80 g, hexanes±EtOAc,
1
30:1) afforded 13 /855 mg, 60%). H NMR /CDCl3) d
1.25 /t, Jˆ7.2 Hz, 3H), 1.39 /s, 3H), 1.89 /d, Jˆ0.3 Hz,
3H), 2.56 /dd, Jˆ14.1, 7.5 Hz, 1H), 2.69 /dd, Jˆ14.1,
7.5 Hz, 1H), 3.50 /d, Jˆ18.0 Hz, 1H), 3.57 /d, Jˆ18.0 Hz,
1H), 4.19 /dq, Jˆ7.2, 1.2 Hz, 2H), 5.08/s, 1H), 5.13 /dd,
Jˆ6.0, 1.2 Hz, 1H), 5.61±5.70 /m, 1H), 7.18/s, 1H), 7.26
/s, 1H); 13C NMR /CDCl3) d 8.0, 13.9, 19.1, 33.3, 39.5,
59.1, 61.4, 117.6, 119.1, 120.0, 132.4, 139.5, 140.8, 172.3,
203.9; MS /EI) m/z 264 /M1); HRMS /EI) Calcd for
C15H20O4 /M1): 264.1362. Found: 264.1361.
3.1.11. 3,6-Dimethyl-6-ꢀprop-2-en-1-yl)-4,5,6,7-tetrahydro-
5-hydroxybenzo[b]furan-7ꢀ6H)-one ꢀ17). Similar to the
preparation of 16, compound 17 was prepared from 15
/900 mg, 3.4 mmol) and was obtained /300 mg, 40%)
after column chromatography on silica gel /30 g,
3.1.8. Ethyl 2-methyl-2-ꢀbut-3-en-1-yl)-3-hydroxy-4-ꢀ4-
methylfuran-3-yl)butanoate ꢀ14). To a stirred solution of
12 /280 mg, 1 mmol) in EtOH /10 mL) at 08C was added
NaBH4 /42 mg, 1 mmol). After stirring for 30 min, the
reaction was quenched with saturated NH4Cl /5 mL).
EtOH was removed under reduced pressure and the aqueous
residue was extracted with Et2O /5£5 mL). The ethereal
extract was dried /MgSO4) and evaporated. Column
chromatography of the residue on silica gel /20 g,
hexanes±EtOAc 10:1) gave 14 /253 mg, 89%) as a colorless
oil. 1H NMR /CDCl3) d 1.23 /s, 3H), 1.28/t, Jˆ7.2 Hz, 3H),
1.62±1.68/m, 1H), 1.82±1.92 /m, 1H), 1.97 /d, Jˆ0.9 Hz,
3H), 2.08±2.11 /m, 1H), 2.29±2.41 /m, 2H), 2.54±2.60 /m,
1H), 3.81±3.86 /m, 1H), 4.18 /q, Jˆ7.2 Hz, 2H), 4.94±5.06
/m, 2H), 5.74±5.83 /m, 1H), 7.18 /s, 1H), 7.29 /s, 1H); 13C
NMR /CDCl3) d 8.2, 14.2, 16.5, 25.8, 28.8, 31.3, 35.6, 50.5,
60.7, 114.8, 119.9, 121.7, 138.0, 139.6, 140.5, 176.3; MS
/FAB) m/z 281 /MH1); HRMS /EI) Calcd for C16H24O4
/M1): 280.1675. Found: 280.1676.
1
hexanes±EtOAc, 1:1). The H- and 13C NMR spectra of
17 are again very complex and its structure was con®rmed
after its oxidation to 19. MS /EI) m/z 221 /MH1); HRMS
/EI) Calcd for C13H16O3 /M1): 220.1099. Found: 220.1100.
3.1.12. 3,6-Dimethyl-6-ꢀbut-3-en-1-yl)-4,5,6,7-tetrahydro-
benzo[b]furan-5ꢀ4H),7ꢀ6H)-dione ꢀ18). To a stirred solu-
tion of 16 /240 mg, 1 mmol) in CH2Cl2 /5 mL) was added
Dess±Martin periodinane10 /636 mg, 1.5 mmol) and the
mixture was stirred for 10 min at room temperature under
N2. After the addition of sat. aq. NaHCO3 solution /10 mL),
the organic layer was separated and the aqueous layer was
extracted with Et2O /3£10 mL). The combined organic
solution was dried /MgSO4) and evaporated to give a resi-
due which was chromatographed on a silica gel column
/30 g, hexanes±EtOAc, 3:1) to give 18 /220 mg, 90%) as
1
a light yellow oil. H NMR /CDCl3) d 1.37 /s, 3H), 1.90±

C.-Y. Yick, H. N. C. Wong / Tetrahedron 57 +2001) 6935±6940
6939
2.01 /m, 4H), 2.04 /d, Jˆ0.9 Hz, 3H), 3.59 /d, Jˆ20.7 Hz,
1H), 3.67 /d, Jˆ20.7 Hz, 1H), 4.89±4.96 /m, 2H), 5.64±
5.77 /m, 1H), 7.50 /d, Jˆ0.9 Hz, 1H); 13C NMR /CDCl3)
d 7.6, 19.0, 29.0, 35.5, 36.0, 62.1, 115.2, 120.7, 132.8,
137.2, 145.9, 146.1, 185.3, 205.8; MS /EI) m/z 232 /M1).
Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C,
72.22; H, 7.02.
was allowed to stir for 3 h. Then it was poured into 3N HCl
/3 mL) and the mixture was extracted with EtOAc
/5£10 mL). The combined extract was washed successively
with sat. aq. NaHCO3 /10 mL) and brine /10 mL).
After drying /MgSO4) and evaporation, the residue was
chromatographed on silica gel /20 g, hexanes±EtOAc 1:1)
to give 22 /184 mg, 87%) as colorless crystals, mp 161±
1
162.58C. H NMR /CDCl3) d 1.10 /s, 3H), 1.80±2.03 /m,
3.1.13. 3,6-Dimethyl-6-ꢀprop-2-en-1-yl)-4,5,6,7-tetrahydro-
benzo[b]furan-5ꢀ4H),7ꢀ6H)-dione ꢀ19). Similar to the
preparation of 18, compound 19 was prepared from 17
/220 mg, 1 mmol) and Dess±Martin periodinane /635 mg,
1.5 mmol). Column chromatography on silica gel /30 g,
hexanes±EtOAc, 3:1) gave 19 /200 mg, 92%) as a light
2H), 1.95 /s, 3H), 2.06 /s, 3H), 2.34±2.45 /m, 1H), 2.51±
2.63 /m, 1H), 2.78/d, Jˆ17.1 Hz, 1H), 2.97 /d, Jˆ17.1 Hz,
1H), 3.91±4.08/m, 4H), 7.32 /s, 1H); 13C NMR /CDCl3) d
7.5, 12.9, 27.7, 29.6, 29.8, 38.3, 54.9, 65.0, 65.5, 113.6,
120.8, 134.5, 144.8, 146.0, 187.5, 207.9; MS /EI) m/z 292
/M1); Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found:
C, 65.57; H, 6.77.
1
yellow oil. H NMR /CDCl3) d 1.30 /s, 3H), 2.00 /s, 3H),
2.48/dd, Jˆ13.8, 7.2 Hz, 1H), 2.57 /dd, Jˆ13.8, 7.2 Hz,
1H), 3.57 /s, 2H), 4.97±5.06 /m, 2H), 5.52±5.61 /m, 1H),
7.46 /d, Jˆ1.2 Hz, 1H); 13C NMR /CDCl3) d 7.6, 8.3, 5.8,
41.5, 62.3, 119.2, 120.7, 132.0, 133.0, 142.0, 146.0, 184.9,
205.3; MS /EI) m/z 219 /MH1). Anal. Calcd for C13H14O3:
C, 71.54; H, 6.46. Found: C, 71.52; H, 6.03.
3.1.17. 3,6-Dimethyl-6-ꢀ2-oxoprop-1-yl)-5,5-ꢀ1,3-dioxolan-
2-yl)-4,5,6,7-tetrahydrobenzo[b]furan-5ꢀ4H),7ꢀ6H)-dione
ꢀ23). Similar to the preparation of 22, compound 23 was
prepared from 21 /180 mg, 0.7 mmol), PdCl2 /12 mg,
0.07 mmol) and CuCl /69 mg, 0.7 mmol) in DMF±H2O
/7:1) /5 mL). Chromatography on silica gel /20 g,
hexanes±EtOAc, 1:1) afforded 23 /169 mg, 88%) as color-
3.1.14. 3,6-Dimethyl-6-ꢀbut-3-en-1-yl)-5,5-ꢀ1,3-dioxolan-
2-yl)-4,5,6,7-tetrahydrobenzo[b]furan-5ꢀ4H),7ꢀ6H)-dione
ꢀ20). A solution of 18 /220 mg, 0.9 mmol), ethylene glycol
/0.1 mL, 1.8mmol) and a catalyst amount of p-TsOH´H2O
in anhydrous C6H6 /20 mL) was heated to re¯ux with a
Dean±Stark trap for 24 h. The mixture was diluted with
Et2O /20 mL) and washed successively with sat. aq.
NaHCO3 /10 mL) and brine /10 mL). After drying
/MgSO4) and evaporation, the residue was chromato-
graphed on silica gel /30 g, hexanes±EtOAc, 3:1) to afford
1
less crystals, mp 148±1498C. H NMR /CDCl3) d 1.34 /s,
3H), 1.99 /d, Jˆ1.2 Hz, 3H), 2.06 /s, 3H), 2.49 /d, Jˆ
13.5 Hz, 1H), 2.81 /d, Jˆ18Hz, 1H), 2.89 /d, Jˆ18Hz,
1H), 2.92 /d, Jˆ13.5 Hz, 1H), 3.87±4.02 /m, 4H), 7.42 /d,
Jˆ1.2 Hz, 1H); 13C NMR /CDCl3) d 7.7, 21.2, 29.7, 31.2,
45.8, 56.9, 64.9, 65.1, 113.0, 121.0, 134.9, 145.6, 186.4,
207.3; MS /EI) m/z 278/M 1); Anal. Calcd for C15H18O5:
C, 64.72; H, 6.52. Found: C, 64.07; H, 6.63.
1
20 /215 mg, 82%) as a colorless oil. H NMR /CDCl3) d
3.1.18. 3,5a-Dimethyl-5,5-ꢀ1,3-dioxolan-2-yl)-4,5,5a,6,7,8-
hexahydronaphtho[1,2-b]furan-8ꢀ7H)-one ꢀ3). A solution
of 22 /180 mg, 0.6 mmol) and pyrrolidine /0.05 mL, 0.6
mmol) in anhydrous C6H6 /20 mL) was re¯uxed with a
Dean±Stark trap for 12 h. The mixture was then diluted
with Et2O /20 mL) and washed successively with 3N HCl
/10 mL), H2O /10 mL) and brine /10 mL). After drying
/MgSO4) and evaporation, the residue was chromato-
graphed on silica gel /20 g, hexanes±EtOAc, 1:1) to afford
3 /115 mg, 70%) as a colorless oil. 1H NMR /CDCl3) d 1.36
/s, 3H), 1.76±1.83 /m, 1H), 1.97 /s, 3H), 2.25±2.36 /m, 1H),
2.51±2.57 /m, 2H), 2.71 /d, Jˆ16.8Hz, 1H), 2.84 /d, Jˆ
16.8Hz, 1H), 3.94±4.11 /m, 4H), 6.18/s, 1H), 7.26 /s, 1H);
13C NMR /CDCl3) d 7.8, 20.4, 26.0, 29.6, 33.3, 43.1, 65.5,
65.8, 112.4, 116.5, 121.4, 126.8, 142.9, 146.2, 150.2, 198.2;
MS /EI) m/z 274 /M1); HRMS /EI) Calcd for C16H18O4
/M1): 274.1205. Found: 274.1201.
1.17 /s, 3H), 1.63±1.71 /m, 1H), 1.79±1.96 /m, 2H), 1.98/d,
Jˆ1.2 Hz, 3H), 2.12±2.19 /m, 1H), 2.76 /d, Jˆ16.8Hz,
1H), 2.97 /d, Jˆ16.8Hz, 1H), 3.93±4.10 /m, 4H), 4.87±
5.00 /m, 2H), 5.66±5.79 /m, 1H), 7.36 /d, Jˆ0.9 Hz, 1H);
13C NMR /CDCl3) d 7.7, 12.4, 28.4, 34.1, 56.0, 65.1, 65.8,
114.0, 114.4, 120.8, 134.1, 138.3, 144.7, 146.3, 187.8; MS
/EI) m/z 276 /M1); Anal. Calcd for C16H20O4: C, 69.55; H,
7.30. Found: C, 69.28; H, 7.49.
3.1.15. 3,6-Dimethyl-6-ꢀprop-2-en-1-yl)-5,5-ꢀ1,3-dioxolan-
2-yl)-4,5,6,7-tetrahydrobenzo[b]furan-5ꢀ4H),7ꢀ6H)-dione
ꢀ21). Similar to the preparation of 20, compound 21 was
prepared from 19 /220 mg, 1 mmol), ethylene glycol
/0.1 mL, 1.8mmol) and a catalytic amount of p-TsOH´H2O.
Chromatography on a silica gel column /30 g, hexanes±
EtOAc 3:1) afforded 21 /215 mg, 81%) as a colorless oil.
1H NMR /CDCl3) d 1.15 /s, 3H), 2.00 /s, 3H), 2.41±2.50
/m, 2H), 2.88 /d, Jˆ17.1 Hz, 1H), 2.94 /d, Jˆ17.1 Hz, 1H),
3.95±4.09 /m, 4H), 4.94±5.01 /m, 2H), 5.74±5.83 /m, 1H),
7.37 /s, 1H); 13C NMR /CDCl3) d 7.6, 13.9, 30.0, 38.9, 55.9,
65.0, 65.6, 113.6, 117.0, 120.7, 133.8, 134.1, 144.7, 146.3,
187.4; MS /EI) m/z 262 /M1); Anal. Calcd for C15H18O4: C,
68.69; H, 6.92; C, 68.30; H, 6.95.
3.1.19. 3,5a-Dimethyl-5,5-ꢀ1,3-dioxolan-2-yl)-4,5,5a,6-
tetrahydroindeno[4,5-b]furan-7-one ꢀ4). To a solution of
23 /140 mg, 0.5 mL) in anhydrous THF /5 mL) was added
KO-t-Bu /67 mg, 0.6 mmol) at 08C. The mixture was
allowed to stir for 1 h. It was then poured into H2O
/10 mL) and extracted with EtOAc /3£10 mL). The
combined extract was washed with dil. aq. NH4Cl /5 mL)
and brine /5 mL). After drying /MgSO4) and evaporation,
the residue was chromatographed on silica gel /15 g,
hexanes±EtOAc, 1:1) to afford 4 /104 mg, 79%) as colorless
crystals, mp 138±138.58C. 1H NMR /CDCl3) d 1.39 /s, 3H),
2.00 /s, 3H), 2.09 /d, Jˆ17.1 Hz, 1H), 2.70 /d, Jˆ17.4 Hz,
1H), 2.73 /d, Jˆ17.1 Hz, 1H), 2.86 /d, Jˆ17.1 Hz, 1H),
3.1.16. 3,6-Dimethyl-6-ꢀ3-oxobut-1-yl)-5,5-ꢀ1,3-dioxolan-
2-yl)-4,5,6,7-tetrahydrobenzo[b]furan-5ꢀ4H),7ꢀ6H)-dione
ꢀ22). To a solution of PdCl2 /12 mg, 0.07 mmol) and CuCl
/69 mg, 0.7 mmol) in DMF±H2O /7:1) /5 mL) under an
atmosphere of O2 was added 20 /200 mg, 0.7 mmol) in
the same solvent mixture /5 mL) over 30 min. The mixture

6940
C.-Y. Yick, H. N. C. Wong / Tetrahedron 57 +2001) 6935±6940
3.98±4.14 /m, 4H), 6.01 /s, 1H), 7.36 /s, 1H); 13C NMR
/CDCl3) d 7.9, 25.4, 30.0, 43.7, 50.6, 65.4, 65.6, 111.6,
118.1, 121.6, 128.4, 144.1, 145.1, 164.7, 206.9; MS /EI)
m/z 260 /M1); Anal. Calcd for C15H16O4: C, 69.22; H,
6.20. Found: C, 68.86; H, 6.39.
Chem. 1996, 68, 723. /c) Ye, X.-S.; Yu, P.; Wong, H. N. C.
Liebigs Ann. Chem. 1997, 459.
3. Wong, M. K.; Leung, C. Y.; Wong, H. N. C. Tetrahedron
1997, 53, 3497.
4. Bohlmann, F.; Zdero, C. Phytochemistry 1982, 21, 647.
5. San Feliciano, A.; Medarde, M.; Poza, M. T.; Miguel, J. M.
Phytochemistry 1986, 25, 1757.
Acknowledgements
6. Inter alia, see /a) Ishii, H.; Tozyo, T.; Minato, H. J. Chem. Soc.
+C) 1966, 1545. /b) Kido, F.; Tsutsumi, K.; Maruta, R.;
Yoshikoshi, A. J. Am. Chem. Soc. 1979, 101, 6420.
7. Wright, D. L.; Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.;
Frey, D. A. Org. Lett. 1999, 1, 1535.
The work described in this article was substantially
supported by a grant from the Research Grants Council of
the Hong Kong Special Administrative Region, China
/Project CUHK 450/95P). H. N. C. W. wishes to thank the
Croucher Foundation /Hong Kong) for a Croucher Senior
Research Fellowship /1999±2000).
8. /a) Bredereck, H.; Gompper, R. Chem. Ber. 1954, 87, 700.
/b) Hutton, J.; Potts, B.; Southern, P. F. Synth. Commun.
1979, 9, 789.
9. /a) Smissman, E. E.; Voldeng, A. N. J. Org. Chem. 1964, 29,
3161. /b) Weinreb, S. M.; Auerbach, J. J. Am. Chem. Soc.
1975, 97, 2503. /c) Hopf, H.; Natsias, K. Liebigs Ann.
Chem. 1988, 705.
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