Total synthesis of bulbophylol-B

Article abstract of DOI:10.1021/np800226n

The first total synthesis of bulbophylol-B (1) has been achieved with the longest linear sequence of 12 steps and an overall yield of 17.9% via a new and practical approach to construct the dihydrodibenz[b,f]oxepin skeleton employing Wittig, selective reduction, and intramolecular Ullmann reactions as key steps.

Full text of DOI:10.1021/np800226n

1938
J. Nat. Prod. 2008, 71, 1938–1941
Total Synthesis of Bulbophylol-B
Jinshun Lin,† Weige Zhang,*,† Nan Jiang,† Zeyu Niu,† Kai Bao,† Liang Zhang,† Dailin Liu,‡ Chao Pan,† and Xinsheng Yao*,‡
School of Pharmaceutical Engineering, Shenyang Pharmaceutical UniVersity, Shenyang 110016, People’s Republic of China, and The Research
Institute of Traditional Chinese Medicines and Natural Products, Jinan UniVersity, Guangzhou 510632, People’s Republic of China
ReceiVed April 9, 2008
The first total synthesis of bulbophylol-B (1) has been achieved with the longest linear sequence of 12 steps and an
overall yield of 17.9% via a new and practical approach to construct the dihydrodibenz[b,f]oxepin skeleton employing
Wittig, selective reduction, and intramolecular Ullmann reactions as key steps.
Dihydrodibenz[b,f]oxepins are a set of rare natural products
present in plants such as Bauhinia purpurea Linn, Bauhinia
Variegata Linn, and Juncus effusus Linn, most of which exhibit
interesting and useful biological activities.1-3 Bulbophylol-B (1),
a natural polyoxygenated dihydrodibenz[b,f]oxepin isolated from
Bulbophyllum kwangtungense Schltr (Orchidaceae) by Wu and co-
workers, demonstrated significant cytotoxicity against human
epithelial carcinoma (HeLa) and human erythromyeloblastoid
leukemia (K562) cell lines.4 Kitanaka et al. indicated that bulbo-
phylol-B exhibited a potent inhibitory effect on nitric oxide (NO)
production and radical-scavenging activity.5 In our laboratory, 1
was also obtained from Bulbophyllum odoratissimum Lindl, a folk
herb used for the treatment of phthisis and rheumatism in the
southern part of China.6 Although several methods for construction
of the dihydrodibenz[b,f]oxepin skeleton have been reported,7,8 to
the best of our knowledge, total synthesis of dihydrodibenz[b-
,f]oxepin natural products, including 1, has never been documented.
Our continued interest in searching for new antitumor agents and
understanding their structure-activity relationships prompted us
to develop a reliable and efficient synthetic route to bulbophylol-
B.
Conversion of 3-hydroxybenzaldehyde to the benzyltriphenyl-
phosphonium salt (3) was achieved in a five-step reaction sequence.
Bromination of 3-hydroxybenzaldehyde (11) provided 12,10 which
was protected with a benzyl group to give 13. Reduction of 13
with NaBH4 in THF/MeOH (1:1) at 0 °C gave the corresponding
phenylmethanol (14), which was treated with phosphorus tribromide
to furnish benzyl bromide 15. Treatment of 15 with triphenylphos-
phine in toluene under reflux provided 3, which was used directly
in the next step (Scheme 3).
Having prepared intermediates 2 and 3, we focused our attention
on synthesis of the target molecule (1). Wittig reaction of aldehyde
2 with benzyltriphenylphosphonium salt 3 (1.1 equiv) by treating
with n-BuLi (1.1 equiv) in THF at -78 °C afforded a mixture of
trans- and cis-stilbene 16 in an approximate 6:4 ratio, in 78% yield.
Then deprotection of 16 with tetrabutylammonium fluoride (1.1
equiv) gave 17 in near quantitative yield (Scheme 4).
Since catalytic hydrogenation had been proved to be an efficient
and convenient process for the conversion of stilbenes to dihy-
drostilbenes,11 we treated stilbene 17 under H2 using Pd/C or Raney
Ni as catalyst in solvents such as EtOAc and MeOH. However,
the main product was 5-(3-hydroxyphenethyl)-7-methoxybenzo-
[d][1,3]dioxol-4-ol, a natural dihydrostilbene reported previously,12
and no 18 was found in the reaction mixture. This result illustrated
that the carbon-bromine bond of 17 was sensitive under these
conditions and had been cleaved via catalytic hydrogenolysis.
Therefore, other reduction systems, such as Zn/HCl,13 NaBH4/
NiCl2,14 and TsNHNH2/NaOAc15 were tested, and the latter was
found to be the most efficient agent. The solution of stilbene 17,
4-methylbenzenesulfonohydrazide (5.0 equiv), and anhydrous so-
dium acetate (2.0 equiv) in EtOH was refluxed under N2 for 2 h to
provide the desired dihydrostilbene 18 in 95% yield. Under these
conditions, the double bond of 17 was reduced with a high degree
of selectivity, while the aromatic benzyl ether and aromatic halide
bonds remained unaffected.
The strategy for the synthesis of bulbophylol-B (1) involved the
Wittig reaction, selective reduction of a carbon-carbon double
bond, and intramolecular Ullmann diaryl ether forming reaction as
the key steps for construction of the dihydrodibenz[b,f]oxepin
skeleton, while the retro-synthetic analysis of the target molecule
led to substituted benzaldehyde 2 and benzyltriphenyl-phosphonium
salt 3 (Scheme 1).
Synthesis of 2 commenced with the commercially available
benzene-1,2,3-triol 4, which was converted to ketone 5.9 Monom-
ethylation of p-OH was achieved by treating 5 with (CH3O)2SO2
under basic conditions to give compound 6. Treatment of 6 with
CH2Cl2 and K2CO3 in DMF afforded 7. Baeyer-Villiger oxidation
of 7 with m-CPBA in the presence of Na2HPO4 gave the
corresponding ester (8), which was hydrolyzed to furnish phenol
9. Vilsmeier reaction of 9 by treatment with dimethylformamide
(DMF) and phosphorus oxychloride gave the corresponding sali-
cylaldehyde 10, which was then protected with the triisopropyllsilyl
(TIPS) group by the usual method to give the intermediate 2
(Scheme 2).
Compared with palladium-catalyzed O-arylations16 or SNAr-
based reactions on aryl fluorides,17 the Ullmann reaction is a more
common method for forming biaryl-ether linkages. Attempted
synthesis of 19 was carried out in pyridine at 130-140 °C by
employing Cu, Cu2O, CuCl, or CuBr as a catalyst, in the presence
of K2CO3 or NaH as a base, but the reaction did not go to
completion and/or a complex mixture was obtained. In 2002,
Olivera18 and co-workers reported that a soluble copper(I) complex,
CuBr·DMS, promoted intramolecular Ullmann biaryl-ether cou-
pling in good yields (74-87%).
Following the procedure described above, the premixed solution
of dihydrostilbene 18, CuBr ·DMS (2.0 equiv), and NaH (1.1 equiv)
in anhydrous pyridine was heated under N2 at 120 °C for 6 h to
give dihydrodibenzoxepin 19 in 89% yield. The excellent yield
obtained was due probably to the high catalytic efficiency of the
copper(I) bromide-dimethylsulfide complex and the stability of
the dihydrostilbene substrate under Ullmann reaction conditions.
* Corresponding authors. Tel: +86 24 23986422. Fax: +86 24 23986393.
E-mail: zhangweige2000@sina.com. Tel: +86 20 85221559. Fax: +86 20
85225849. E-mail: yaoxinsheng@tom.com.
† Shenyang Pharmaceutical University.
‡ Jinan University.
10.1021/np800226n CCC: $40.75
2008 American Chemical Society and American Society of Pharmacognosy
Published on Web 10/30/2008

Notes
Journal of Natural Products, 2008, Vol. 71, No. 11 1939
Scheme 1
Scheme 2a
a Reagents and conditions: (a) (CH3CO)2O (1.1 equiv), H2SO4, reflux (90%); (b) (CH3O)2SO2 (0.6 equiv), K2CO3 (1.2 equiv), CH3COCH3, reflux; (c) CH2Cl2 (2
equiv), K2CO3 (1.5 equiv), DMF, 90 °C (59% from 5); (d) m-CPBA (5.0 equiv), Na2HPO4, (1.3 equiv), CH2Cl2, 0 °C, then reflux; (e) KOH (1.1 equiv), H2O, RT
(78%) (from 7); (f) POCl3 (4.0 equiv), DMF (8.7 equiv), 0 °C, then 75 °C (79%); (g) TIPS-Cl (1.0 equiv), imidazole (2.5 equiv), THF, reflux (89%).
Scheme 3a
a Reagents and conditions: (h) Br2 (1.0 equiv) CCl4, 0 °C (76%); (i) BnCl (1.1 equiv), K2CO3 (1.5 equiv) DMF, 80 °C (98%); (j) NaBH4 (0.5 equiv), THF/MeOH,
0 °C (98%); (k) PBr3 (0.4 equiv), THF, 0 °C to reflux (95%); (l) PPh3 (1.0 equiv), toluene, reflux (90%).
Scheme 4a
a Reagents and conditions: (m) n-BuLi (1.1 equiv), THF, then 2 (1.0 equiv), -78 °C (78%); (n) TBAF (1.1 equiv), THF, RT (98%); (o) Ts-NHNH2 (5.0 equiv),
NaOAc (2.0 equiv), EtOH, reflux (95%); (p) CuBr· DMS (2.0 equiv), NaH (1.1 equiv), Py, 120 °C (89%); (q) H2, 10% Pd/C, EtOH, RT (95%).
Cleavage of the benzyl protecting group of 19 via hydrogenolysis
in the presence of Pd/C gave 1 in near quantitative yield. Synthetic
1 was identical in all respects (1H NMR, 13C NMR, MS) with
natural bulbophylol-B (Scheme 4).
In summary, we have completed an efficient total synthesis of
bulbophylol-B (1) from commercially available benzene-1,2,3-triol
and 3-hydroxybenzaldehyde with the longest linear sequence of
12 steps and an overall yield of 17.9%. This is the first example of
the total synthesis of a dihydrodibenz[b,f]oxepin natural product.
Further, we have developed a new and practical approach to
construct the dihydrodibenz[b,f]oxepin skeleton employing Wittig,
selective reduction, and intramolecular Ullmann reactions as key
steps. Compared with reported methods, the main advantages of
the present procedure are higher yields and milder conditions.
Experimental Section
General Experimental Procedures. Melting points were determined
1
using a hot-stage microscope and are uncorrected. H and 13C NMR
spectra were taken in CDCl3 solution on Bruker ARX-300 or Bruker
ARX-600 spectrometers with TMS as the internal reference (Bruker
BioSciences). Mass spectra were obtained using a Micromass Quattro
micro API mass spectrometer (Waters Corp, Milford, MA). Elemental
analyses (C and H) were performed at Jilin University (Changchun,
China). Thin-layer chromatography was performed on GF254 silica
gel plates (0.25 mm layer, Qingdao Ocean Chemicals), and the plates

1940 Journal of Natural Products, 2008, Vol. 71, No. 11
Notes
were examined under UV light at 254 nm. Column chromatography
was run on silica gel (200-300 mesh) from Qingdao Ocean Chemicals
(Qingdao, China). Unless otherwise noted, all materials were obtained
from commercially available sources and were used without further
purification.
× CH), 1.11 (18H, s, 6 × CH3); EIMS m/z [M]+ 309 (11), 174 (11),
131 (100), 103 (63).
2-Bromo-5-hydroxybenzaldehyde (12). Br2 (4.2 mL, 82 mmol) was
added dropwise over 15 min to a solution of 3-hydroxbenzaldehyde
11 (10.0 g, 82 mmol) in CCl4 (250 mL) kept at 25 °C. The reaction
mixture was stirred for 2 h at room temperature, after which H2O (350
mL) and CH2Cl2 (350 mL) were added. The organic layer was separated
and dried, and the solvent was removed in Vacuo to afford 12 (6.26 g,
2,3,4-Trihydroxyacetophenone (5). Equimolar quantities of pyro-
gallol (4) (2.5 g, 19.8 mmol) and Ac2O (1.9 mL, 19.8 mmol) were
refluxed with a drop of concentrated H2SO4 for 1 h. The mixture was
cooled and poured into 10 mL of H2O containing 2 mL of EtOH. Two
drops of concentrated HCl was added, and the solution was refluxed
for 45 min to decompose excess Ac2O. The reaction mixture was
concentrated in Vacuo and the residue crystallized from n-hexane/
EtOAc, yielding 5 as a yellow, crystalline solid (3.0 g, 90%): mp
76%) as a white solid: mp 134-136 °C (lit.20 mp 135-136 °C); H
1
NMR (300 MHz, CDCl3) δ 10.29 (1H, s, ArCHO), 7.53 (1H, d, J )
9.0 Hz, Ar-H2), 7.40 (1H, d, J ) 3.0 Hz, Ar-H5), 7.01 (1H, dd, J )
9.0 Hz, 3.0 Hz, Ar-H3). Anal. Calcd for C7H5BrO2: C, 41.82; H, 2.51.
Found: C, 41.66; H, 2.46.
9
1
171-173 °C. (lit. mp 169-172 °C); H NMR (300 MHz, CDCl3) δ
12.73 (1H, s, OH), 7.30 (1H, d, J ) 8.9 Hz, Ar-H6), 6.53 (1H, d, J )
8.9 Hz, Ar-H5), 5.84 (1H, s, OH), 5.44 (1H, s, OH), 2.57 (3H, s,
COCH3).
2-Bromo-5-benzyloxybenzaldehyde (13). A mixture of 12 (8.0 g,
39.9 mmol), 1-(chloromethyl)benzene (4.9 mL, 41.9 mmol), and
anhydrous K2CO3 (8.3 g, 59.9 mmol) in DMF (50 mL) was stirred at
80 °C for 2 h, cooled to room temperature, and then poured into H2O
(200 mL). The solid was filtered and washed, and the filtrate was
extracted with EtOAc, brined, dried over anhydrous Na2SO4, and
concentrated in Vacuo to give 13 (11.3 g, 98%) as a pale yellow solid:
2,3-Dihydroxy-4-methoxyacetophenone (6). A solution of 5 (5.0
g, 29.8 mmol) and K2CO3 (4.9 g, 35.5 mol) in 200 mL of acetone was
stirred at room temperature for 45 min. Then (CH3O)2SO2 (1.6 mL,
16.4 mmol) was added dropwise over 1.5 h. The reaction mixture was
refluxed for 6 h and then cooled to room temperature. After filtration
and concentration, the resulting residue was used directly in the next
step.
4-Methoxy-2,3-methylenedioxyacetophenone (7). To a solution of
6 (5.4 g, 29.8 mmol) in DMF (30 mL) were added CH2Cl2 (9.5 mL,
59.5 mmol) and K2CO3 (6.2 g, 44.6 mmol). The reaction mixture was
stirred under reflux for 6 h at 90 °C. After filtration, the solvent was
removed in Vacuo to afford a black solid, which was subjected to flash
column chromatography (n-hexane/EtOAc, 5:1) to yield 7 as a white
solid (4.7 g, two steps total yield 59%): mp 99-100 °C (lit.19 mp
100-101 °C); 1H NMR (300 MHz, CDCl3) δ 7.44 (1H, d, J ) 9.1 Hz,
Ar-H6), 6.59 (1H, d, J ) 9.1 Hz, Ar-H5), 6.11 (2H, s, OCH2O), 3.96
(1H, s, OCH3), 2.56 (3H, s, COCH3).
4-Methoxy-2,3-methylenedioxyphenyl Acetate (8). To a suspension
of 7 (5.0 g, 25.5 mmol) and anhydrous Na2HPO4 (4.7 g, 33.2 mmol)
in CH2Cl2 (50 mL) was added m-CPBA (85%, 23.4 g, 127.5 mmol),
in portions and in an ice-water bath, and the mixture was stirred at
room temperature for 1 h. The resulting mixture was refluxed overnight,
then cooled and filtered. The filter cake was washed with CH2Cl2 (3 ×
30 mL). Evaporation of the solvent in Vacuo gave a residue, which
was directly used in the next reaction.
mp 44-46 °C (lit.21 mp 43-45 °C); H NMR (300 MHz, CDCl3) δ
1
10.30 (1H, s, ArCHO), 7.50-7.55 (2H, m, Ar-H2/H5), 7.34-7.44 (5H,
m, 5 × Ar-H), 7.10 (1H, dd, J ) 9.0 Hz, 3.0 Hz, Ar-H3), 5.09 (2H, s,
ArOCH2Ph). Anal. Calcd for C14H11BrO2: C, 57.36; H, 3.81. Found:
C, 57.39; H, 3.85.
2-Bromo-5-benzyloxybenzyl Alcohol (14). NaBH4 (65.0 mg, 1.7
mmol) was added, in portions, to 13 (1.0 g, 3.5 mmol) in 10 mL of
CH3OH/THF (1:1) in an ice-water bath for 30 min. The solvent was
evaporated. Then 1 M HCl was poured into the mixture, which was
then extracted with CH2Cl2, brined, dried (Na2SO4), and concentrated
1
in Vacuo to afford 14 (1.0 g, 98%) as white solid: mp 88-90 °C; H
NMR (300 MHz, CDCl3) δ 7.33-7.43 (6H, m, 5 × Ar-H, Ar-H6),
7.15 (1H, d, J ) 3.0 Hz, Ar-H2), 6.79 (1H, dd, J ) 8.7 Hz, 3.0 Hz,
Ar-H3), 5.07 (2H, s, ArOCH2Ph), 4.71 (2H, s, CH2OH); EIMS m/z
[M]+ 292 (3), 293 (3), 91 (100), 89 (6), 77 (5), 66 (5). Anal. Calcd for
C14H13BrO2: C, 57.36; H, 4.47. Found: C, 57.26; H, 4.43.
2-Bromo-5-benzyloxybenzyl Bromide (15). To a solution of 14
(2.0 g, 6.8 mmol) in 20 mL of anhydrous THF was added PBr3 (0.7 g,
2.7 mmol) in anhydrous THF (3.0 mL) at a rate maintaining reflux.
After heating and stirring for an additional 4 h under N2, the mixture
was cooled and poured into H2O and extracted with EtOAc. The organic
layer was washed successively with a saturated NaHCO3 solution, H2O,
and brine, then dried over anhydrous Na2SO4. The solvent was removed
4-Methoxy-2,3-methylenedioxyphenol (9). KOH (1.4 g, 25 mmol)
in H2O (10 mL) was added to the crude 8 (5.5 g, 25.8 mmol) in MeOH
(20 mL), and the mixture was stirred for 2 h at room temperature. The
mixture was concentrated to 10 mL and acidified with 2 M HCl (5
mL). The aqueous layer was extracted with CHCl3 (3 × 20 mL), washed
with H2O (2 × 20 mL) and brine (20 mL), dried over anhydrous
Na2SO4, and concentrated. The residue was purified by column
chromatography (CC) (n-hexane/EtOAc, 3:1) to give 9 (4.38 g; two
steps total yield 78%) as a white solid: mp 103-105 °C (lit.12 mp
1
in Vacuo to give 15 (2.3 g, 95%) as a white solid: mp 64-65 °C; H
NMR (300 MHz, CDCl3) δ 7.37-7.46 (6H, m, 5 × Ar-H, Ar-H6),
7.08 (1H, d, J ) 3.0 Hz, Ar-H2), 6.80 (1H, dd, J ) 8.7 Hz, 3.0 Hz,
Ar-H3), 5.04 (2H, s, ArOCH2Ph), 4.55 (2H, s, CH2Br); EIMS m/z [M]+
358 (2), 356 (4), 275 (3), 156 (3), 91 (100), 77 (10). Anal. Calcd for
C14H12Br2O: C, 47.23; H, 3.40. Found: C, 47.20; H, 3.45.
Benzyltriphenyphosphonium Salt (3). The mixture of 15 (10.0 g,
36.4 mmol) and triphenylphosphine (9.5 g, 36.4 mmol) in anhydrous
toluene was refluxed for 8 h, then cooled and filtered. The filter cake
was washed with toluene and dried to afford 3 (17.6 g, 90%) as a white
solid.
1
100-101 °C); H NMR (300 MHz, CDCl3) δ 6.43 (1H, s, H-6), 6.42
(1H, s, H-5), 5.99 (2H, s, OCH2O), 4.48 (1H, s, OH), 3.85 (1H, s,
OCH3).
2-Hydroxy-3,4-methylenedioxy-5-methoxybenzaldehyde (10). POCl3
(5.5 mL, 59.5 mmol) was added dropwise to DMF (10 mL, 129.4 mmol)
over 15 min at 5 °C, then stirred at room temperature for 20 min
followed by addition of 9 (2.5 g, 14.9 mmol) in portions. The mixture
was slowly heated to 75 °C and then stirred at this temperature for
2 h. The resulting mixture was cooled to 5 °C and poured into H2O
(50 mL). After filtration, the filter cake was purified by CC (n-hexane/
CHCl3, 1:1) to give 10 (2.3 g, 79%) as a white solid: mp 181-182 °C
1-(2-Triisopropylsilaneoxy-3,4-methylenedioxy-5-methoxyphenyl)-
2-(2-bromo-5-benzyloxy)ethene (16). To a suspension of 3 (2.0 g,
3.7 mmol) in anhydrous THF (15 mL) at -78 °C was added n-BuLi
(1.6 mL of a 2.5 M solution in hexane; 4.1 mmol). The resulting red
solution was stirred under N2 for 1 h. Then a solution of 2 (1.2 g, 3.7
mmol) in anhydrous THF (5 mL) was added dropwise over 30 min.
The reaction mixture was stirred for an additional 2 h under N2, then
stirred for 2 h at room temperature. The reaction was quenched with
saturated aqueous NH4Cl. Then the mixture was extracted with CH2Cl2,
and the combined organic layer was washed with brine and dried
(Na2SO4). The solvent was removed in Vacuo to afford a crude product,
which was separated by flash chromatography (n-hexane/EtOAc, 20:
(lit.12 mp 179-180 °C); H NMR (300 MHz, CDCl3) δ 10.83 (1H,
1
CHO), 9.73 (1H, s, OH), 6.75 (1H, s, Ar-H), 6.18 (2H, s, OCH2O),
3.93 (3H, s, OCH3).
2-Triisopropylsilyoxy-3,4-methylenedioxy-5-methoxybenzalde-
hyde (2). Imidazole (1.9 g, 28.4 mmol) was added to a solution of 10
(2.0 g, 11.4 mmol) and triisopropylchlorosilane (2.4 mL, 11.4 mmol)
in anhydrous THF (20 mL). The mixture was stirred for 4 h, diluted
with 5% NaHCO3 (10 mL), extracted with EtOAc (3 × 20 mL), dried,
and concentrated in Vacuo. The residue was purified by CC (n-hexane/
EtOAc, 10:1) to give 2 (3.4 g, 89%) as a white solid: mp 28-30 °C;
1H NMR (300 MHz, CDCl3) δ 10.33 (1H, s, CHO), 7.07 (1H, s, Ar-
H6), 6.05 (2H, s, OCH2O), 3.88 (3H, s, OCH3), 1.29-1.37 (3H, m, 3
1
1) to yield 16 (1.7 g, 78%, mixture of Z/E isomers) as a clear oil: H
NMR (300 MHz, CDCl3) Z/E δ 7.30-7.46 (6H, m, 5 × Ar-H, Ar-
H3′), 6.87/6.90 (1H, d, J ) 3.0 Hz, Ar-H4′), 6.82/6.77 (1H, d, J ) 12
Hz, CHd), 6.72 (1H, d, J ) 3.0 Hz, Ar-H6′), 6.54/6.77 (1H, d, J ) 12
Hz, CHd), 6.18/6.80 (1H, s, Ar-H6), 5.91/5.96 (2H, s, OCH2O), 4.80/
5.04 (2H, s, ArOCH2Ph), 3.42/3.93 (3H, s, OCH3), 1.26-1.36 (3H, m,
3 × CH),1.22 (18H, s, 6 × CH3); EIMS m/z [M]+ 287 (2), 174 (10),
133 (99), 103 (75), 89 (16), 75 (100).

Notes
1-(2-Hydroxy-3,4-methylenedioxy-5-methoxyphenyl)-2-(2-bromo-
Journal of Natural Products, 2008, Vol. 71, No. 11 1941
C-4), 136.1 (C, C-4a), 134.6 (C, C-3), 133.0 (C, C-9), 126.7 (C, C-11a),
121.9 (C, C-7), 116.5 (C, C-9a), 113.7 (C, C-6), 107.7 (C, C-1), 102.1
(C, OCH2O), 56.9 (C, OCH3), 30.6 (C, C-11), 29.7 (C, C-10); EIMS
m/z [M]+ 286 (100), 265 (10), 228 (16), 213 (13), 185 (11), 128 (10),
77 (11). Anal. Calcd for C16H14O5: C, 67.13; H, 4.93. Found: C, 67.05;
H, 4.98.
5-benzyloxy)ethene (17). To a stirred solution of 16 (1.0 g, 1.7 mmol)
in THF (5 mL) was added TBAF (46.2 mg, 1.8 mmol). The reaction
mixture was stirred for 30 min at room temperature, then diluted with
EtOAc and washed with 0.5 M HCl, and the organic layer was extracted
with EtOAc. The combined organic layer was washed with H2O and
brine, then dried (Na2SO4) and concentrated in Vacuo to give 17 (0.8
1
Acknowledgment. We are grateful to Shenyang Personnel Bureau
and Shenyang Science and Technology Bureau for their financial
support of this research.
g, 98%) as a clear oil: H NMR (300 MHz, CDCl3) Z/E δ 7.29-7.46
(6H, m, 5 × Ar-H, Ar-H3′), 6.82/7.14 (1H, d, J ) 3.0 Hz, Ar-H6′),
6.74/6.77 (1H, d, J ) 3.0 Hz, Ar-H4′), 6.69/6.70 (H, br s, CHdCH),
6.21 (1H, s, Ar-H6), 5.97/6.02 (2H, s, OCH2O), 4.57/4.82 (2H, s,
ArOCH2Ph), 3.57/3.91 (3H, s, OCH3); EIMS m/z [M]+ 378 (2), 376
(20), 285 (23), 181 (17), 111 (16), 97 (28). 91(100). Anal. Calcd for
C23H19BrO5: C, 60.67; H, 4.21. Found: C, 60.57; H, 4.15.
Supporting Information Available: Copies of proton and carbon
NMR spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1-(2-Hydroxy-3,4-methylenedioxy-5-methoxyphenyl)-2-(2-bromo-
5-benzyloxy)ethane (18). NaOAc (0.9 g, 11 mmol) and p-tolysulfo-
nylhydrazide (0.9 g, 4.4 mmol) were added to a solution of 17 (1.0 g,
2.2 mmol) in EtOH (10 mL), and the mixture was refluxed for 2 h
under N2. Then the solution was worked up using Et2O, saturated
aqueous NaHCO3, and brine and dried over MgSO4, and the solvent
was removed in Vacuo. The residue was purified by CC (n-hexane/
EtOAc, 4:1) to give 18 (1.0 g, 95%) as a white solid: mp 139-142
°C; 1H NMR (300 MHz, CDCl3) δ 7.34-7.55 (6H, m, 5 × Ar-H, Ar-
H3′), 6.83 (1H, d, J ) 3.0 Hz, Ar-H6′), 6.68 (1H, dd, J ) 8.7, 3.0 Hz,
Ar-H4′), 6.24 (1H, s, Ar-H6), 5.93 (2H, s, OCH2O), 4.99 (2H, s,
ArOCH2Ph), 3.80 (3H, s, OCH3), 2.93 (2H, d, J ) 8.1 Hz, CH2), 2.84
(2H, d, J ) 8.1 Hz, CH2); EIMS m/z [M]+ 358 (2), 356 (4), 354 (2),
156 (3), 91 (100), 77 (10). Anal. Calcd for C23H21BrO5: C, 60.41; H,
4.63. Found: C, 60.35; H, 4.60.
References and Notes
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1993, 34, 1182–1184.
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C. W.O. Patent 2,005,090,337, 2005.
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Sims and Bulbophyllum ororatissimumLindl. Ph.D. Thesis, Shenyang
Pharmaceutical University, Shenyang, China, 2004, p 125.
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Org. Chem. 2004, 69, 2920–2928.
2-Methoxy-3,4-methylenedioxy-8-benzyloxy-10,11-dihydrodibenz-
[b,f]oxepin (19). NaH (95% in oil dispersion, 64.0 mg, 2.4 mmol) was
added to a stirred solution of 18 (1.0 g, 2.2 mmol) and CuBr·Me2S
(99%, 0.8 g, 4.4 mmol) in anhydrous pyridine (10 mL) under N2 at
ambient temperature. After stirring for 15 min, the reaction mixture
was heated at 120 °C for 5.5 h. The mixture was allowed to cool, poured
into 1.37 M HCl (10 mL), and extracted with CH2Cl2 (5 × 10 mL).
The organic layer was washed with 0.31 M CuSO4 (1 × 5 mL) and
dried (Na2SO4), and the solvent removed in Vacuo. The residue was
purified by CC (n-hexane/EtOAc, 8:1) to give 19 (0.7 g, 89%) as a
white solid: mp 148-150 °C; 1H NMR (600 MHz, CDCl3) δ 7.37-7.42
(5H, m, 5 × Ar-H), 7.26 (1H, d, J ) 3.0 Hz, Ar-H9), 6.83 (1H, d, J
) 8.7 Hz, Ar-H6), 6.70 (1H, dd, J ) 8.7, 3.0 Hz, Ar-H7), 6.24 (1H,
s, Ar-H1), 5.95 (2H, s, OCH2O), 4.99 (2H, s, ArOCH2Ph), 3.80 (3H,
s, OCH3), 2.92-2.95 (2H, m, CH2), 2.81-2.85 (2H, m, CH2); EIMS
m/z [M]+ 377 (6), 347 (2), 283 (8), 271 (11), 181 (24), 91 (100). Anal.
Calcd for C23H20O5: C, 73.39; H, 5.36. Found: C, 73.32; H, 5.40.
2-Methoxy-3,4-methylenedioxy-8-hydroxy-10,11-dihydrodibenz-
[b,f]oxepin (1, bulbophylol-B). A solution of 19 (1.0 g, 2.7 mmol) in
EtOAc (20 mL) was stirred in the presence of 10% Pd-C (50 mg)
under H2 at room temperature for 12 h. The catalyst was removed by
filtration and washed with EtOAc. The filtrate was concentrated in
Vacuo to give 1 (0.7 g, 95%) as a light yellow power: mp 106-108
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1
°C; H NMR (300 MHz, CDCl3) δ 7.06 (1H, d, J ) 4.8 Hz, Ar-H9),
6.61 (2H, br s, Ar-H6, H7), 6.25 (1H, s, Ar-H1), 6.0 (2H, s, OCH2O),
3.84 (3H, s, OCH3), 3.05 (4H, br s, CH2CH2); 13C NMR (75 MHz,
CDCl3) δ 151.8 (C, C-8), 151.0 (C, C-5a), 139.7 (C, C-2), 139.2 (C,
NP800226N