Total synthesis of ailanthoidol and precursor XH14 by stille coupling

Article abstract of DOI:10.1021/jo020653t

Ailanthoidol 1, which can be isolated from Chinese herbal medicine, is achieved in which the longest linear sequence is only six steps in 48% overall yield from commercially available 5-bromo-2-hydroxy-3-methoxybenzaldehyde. The key transformations in the

Full text of DOI:10.1021/jo020653t

analogues from the readily available 5-bromo-7-methoxy-
2-bromobenzofuran (5) by Stille coupling.
Tota l Syn th esis of Aila n th oid ol a n d
P r ecu r sor XH14 by Stille Cou p lin g
The Pd-catalyzed cross-coupling reaction is well-known
in a wide variety of transmetalation reagents including
Sn, Mg, Zn, B, Al, Zr, and Cu.7 Perhaps the easiest route
to 1 would have been to couple dibromobenzofuran, bro-
mophenol, and bromopropenol by Pd-catalyzed reaction.
In previous projects8 we have achieved such couplings
by treating a mixture of two aryl bromides with a bis-
(trialkyltin) in the presence of a palladium catalyst. The
reaction proceeds via in situ conversion of one aryl bro-
mide to the corresponding stannane followed by coup-
ling of the latter with the other benzofuranyl bromide.
In the beginning of our synthesis, the commercial avail-
ability of 5-bromo-2-hydroxy-3-methoxybenzaldehyde
prompted us to prepare dibromobenzofuran 5 from this
compound. It was anticipated that 5 was smoothly
prepared as shown in Scheme 1. In the case of 5 and the
known 1-benzyloxy-4-bromo-2-methoxybenzene,9 how-
ever, the palladium-catalyzed reaction with (Me3Sn)2 to
give 2-arylbenzofuran 7 was unsuccessful. The major
product was biphenyl, the product from the homocoupling
of 4-bromomethoxylbenzoxylbenzene. Consequently we
sought to first convert bromobenzene into a stannane in
a separate step, which proceeded smoothly to provide
arylstannane 6. Although we did not know yet the
chemoselectivity of the two different bromo substituents
in 5, we did run the Sonogashira reactions with tetrahy-
dropyranoxypropyne and 5 to give only 2-acetyleneben-
zofuran. Similarly, we would anticipate that the reactiv-
ity of the furan ring in 5 could also undergo the Stille
coupling faster than that of the benzene ring. Fortu-
nately, with dibromide 5 and stannane 6 in hand,
palladium-catalyzed cross coupling gave the regioselec-
tive 2-arylbenzofuran 7 in excellent yield (96%). The
resultant benzofuran 7 was then transformed into ail-
anthoidol in two steps. Briefly, this involved Stille
coupling of stannylpropenol and 7, followed by removal
of the benzyl protecting group with TiCl4, but in low yield
(5% yield over two steps). The low isolated yield might
be caused because the free hydroxy group of stannylpro-
penol made this compound more hydrophilic than that
of the protected stannyl alcohol. Also, the allyl alcohol 8
was very unstable under acid and neutral conditions
during isolation.
Shun-Yu Lin, Chih-Lung Chen, and Yean-J ang Lee*
Department of Chemistry, National Changhua University of
Education, Changhua 50058, Taiwan
leeyj@cc.ncue.edu.tw
Received October 15, 2002
Abstr a ct: Ailanthoidol 1, which can be isolated from
Chinese herbal medicine, is achieved in which the longest
linear sequence is only six steps in 48% overall yield from
commercially available 5-bromo-2-hydroxy-3-methoxyben-
zaldehyde. The key transformations in the synthesis are the
Stille coupling reactions of benzofuranyl bromide with
stannanyl compounds. This synthetic strategy can be modi-
fied to give access to a variety of different ailanthoidol and
XH14 analogues.
Studies on the constituents of plants of Zanthoxylum
ailanthoidos1 and Salvia miltiorrhiza Bunge (Danshen),2
which are used in Chinese traditional herbal medicines,
showed a number of them with pharmacological interest.3
Ailanthoidol (1) and XH14 (2) were isolated from the
chloroform-soluble fraction of stem woods of Zanthoxylum
ailanthoidos and the aqueous extracts of Danshen,
respectively. Recently, during a synthesis of the phyto-
toxin, Garcifuran B,4 we became aware of the facile
conversion of o-hydroxybenzaldehydes to benzofurans
and the proceeding of Stille5 coupling of bromobenzo-
furans and stannanes to arylbenzofuran skeleton. There-
fore, ailanthoidol (1) and XH14 (2) are ideal targets for
the application of these reactions. Although 1 and 2 have
been synthesized by several groups,6 they were achieved
with very time-consuming and complicated synthetic
approaches. To overcome these technical difficulties, we
report our studies on the synthesis of ailanthoidol
With the aim of developing a successful route to 1, an
alternative method of construction was examined (Scheme
1). Coupling of the benzofuranyl bromide 7 with stanna-
nyl ester proceeded readily in dioxane by Pd(0)-catalysis
to give the known6e 9 in excellent 92% yield. According
to the procedure of Lutjens and Scammells, it involved
removal of the benzyl protecting group with TiCl4 fol-
lowed by DIBAL or LiAlH4 reduction of the ester to afford
1 in the highest 95% yield (over two steps). Melting point
and 1H and 13C NMR spectra of the synthetic product
* Corresponding author. Fax +886-4-7211190.
(1) Sheen, W. S.; Tsai, I. L.; Teng, C. M.; Chen, I. S. Phytocheminstry
1994, 36, 213.
(2) Yang, Z.; Hon, M. H.; Chui, K. Y.; Xu, H. M.; Lee, C. M.; Cui, Y.
X.; Wong, H. N. C.; Poon, C. D.; Fung, B. M. Tetrahedron Lett. 1991,
32, 2061.
(3) (a) Kao, C. L.; Chern, J . W. Tetrahedron Lett. 2001, 42, 1111.
(b) Kao, C. L.; Chern, J . W. J . Org. Chem. 2002, 67, 6772 and references
therein. (c) Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H.
N. C. J . Org. Chem. 1992, 57, 7248. (d) Scammells, P. J .; Baker, S. P.;
Beauglehole, A. R. Bioorg. Med. Chem. 1998, 8, 1517.
(4) Kelly, T. R.; Szabados, A.; Lee, Y. J . J . Org. Chem. 1997, 62,
428.
(5) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813.
(6) (a) See ref 1c. (b) Bates, R. W.; Rama-Devi, T. Synlett 1995, 1151.
(c) Hutchinson, S. A.; Luetjens, H.; Scammells, P. J . Bioorg. Med.
Chem. Lett. 1997, 7, 3081. (d) Fuganti, C.; Serra, S. Tetrahedron Lett.
1998, 39, 5609. (e) Lutjens, H.; Scammells, P. J . Tetrahedron Lett.
1998, 39, 6581. (f) See refs 3a and 3b.
(7) Tseng, T. H.; Tsheng, Y. M.; Lee, Y. J .; Hsu, H. L. J . Chin. Chem.
Soc. 2000, 47, 1165 and references therein.
(8) Kelly, T. R.; Lee, Y. J .; Mears, R. J . J . Org. Chem. 1997, 62,
2774.
(9) Riegel, B.; Wittcoff, H. J . Am. Chem. Soc. 1946, 68, 1913.
10.1021/jo020653t CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/25/2003
2968
J . Org. Chem. 2003, 68, 2968-2971

SCHEME 1. Syn th esis of Aila n th oid ol (1)
SCHEME 2. Syn th esis of P r ecu r sor XH14
are in agreement with those reported for the naturally
derived material.1,2b
Exp er im en ta l Section 10
5-Br om o-7-m eth oxy-2-br om oben zofu r a n (5). Nitrobenzo-
furan 4 (0.80 g, 3.0 mmol) was placed together with PBr3 (5 mL)
into a 25-mL round-bottomed flask under a nitrogen atmosphere.
The mixture was then heated to 175 °C (oil bath temperature)
with stirring under nitrogen flux and maintained at that
temperature for 5 h. The flask was removed from the oil bath
and allowed to cool to ambient temperature. The a dark-brown
suspension was neutralized with NaHCO3 until pH 8, followed
by extraction with CH2Cl2 (3 × 100 mL). The organic layer was
concentrated and the crude product was subjected to column
It is worth noting that our synthetic strategy can be
employed in the formal synthesis of XH14. The synthesis
of precusor XH14 12a was achieved by using a closely
related strategy that utilized the Stille coupling condi-
tions described above. Alcohol 8 was converted to acetoxy
compound 11. Subsequent catalytic hydrogenation ef-
fected simultaneous debenzylation and reduction of the
alkene in 98% yield (Scheme 2). On the other hand, the
Sonogashira reaction can be employed to couple the key
bromobenzofuran 7 and protected propargyl alcohol,
especially acetoxy, to provide 13 in 62∼83% yield,
respectively. The precursor 13a was smoothly carried out
with Pd on carbon under 1 atm of H2 to generate 12a in
93% yield. Finally, it suggests that the key precursor 12a
can undergo the regioselective 3-position formylation by
using a Gatterman-Adams reaction3c,6c to achieve XH14.
In conclusion, a concise route to ailanthoidol 1 has been
achieved in which the longest linear sequence is only six
steps from commercially available materials in 48%
overall yield. This synthesis is high yielding and easily
modified to give access to a variety of different ailan-
thoidol and XH14 analogues. In addition, it demonstrated
the usefulness of the Stille coupling reaction for 2-aryl-
benzofuran synthesis. The preparation of theses com-
pounds is currently underway and their biological ac-
tivities will be investigated to evaluate the efficacy of
these compounds as antitumor agents.
chromatography (SiO2
(0.66 g, 74%) as white solid: mp 82-84 °C; H NMR (CDCl3) δ
3.93 (s, 3H), 6.58 (s, 1H), 6.81 and 7.14 (d, J ) 1.6 Hz, 2H); 13
, CH2Cl2/ether 1/1) to yield dibromide 5
1
C
NMR (CDCl3) δ 56.2, 108.0, 109.9, 114.8, 116.5, 129.1, 131.1,
143.8, 144.7; HRMS (FAB) calcd for C9H6O2Br2 (M+) 303.8735,
found 303.8730. Anal. Calcd for C9H6O2Br2: C, 35.33; H, 1.98;
O, 10.46. Found: C, 35.17; H, 1.68; O, 10.76.
(4-Ben zyloxy-3-m eth oxyp h en yl)tr im eth ylsta n n a n e (6).
A mixture of the known 1-benzyloxy-4-bromo-2-methoxybenzene9
(0.60 g, 2.1 mmol), hexamethyl ditin (0.60 mL, 3.1 mmol), and
freshly prepared tetrakis(triphenylphosphine)palladium(0)4 (0.12
g, 5 mol %) in 5 mL of dioxane was placed into a sealable tube
equipped with a small magnetic stir bar. The tube was degassed
by three cycles of evacuation and refilling with N2 and sealed
under vacuum. The vertical tube was partly immersed in an oil
bath heated to 105 °C. The solution was heated under reflux
for 2 h. After cooling, the reaction mixture was filtered and the
(10) For general experimental procedures, see: Lee, J . M.; Tseng,
T. H.; Lee, Y. J . Synthesis 2001, 15, 2247. Elemental analyses were
performed on a Heracus CHN-OS Rapid spectrometer in the Taichung
Instrumentation Center, National Science Council, Taiwan.
J . Org. Chem, Vol. 68, No. 7, 2003 2969

filtrate evaporated. The residue was subjected to flash column
chromatography (Al2O3, cyclohexane) to give 6 (0.77 g, 100%)
as a colorless oil:1H NMR (CDCl3) δ 0.28 (s, 9H), 3.93 (s, 3H),
5.17 (s, 2H), 6.89-7.47 (m, 8H); 13C NMR (CDCl3) δ -9.4, 56.1,
70.8, 113.9, 118.8, 127.2, 127.7, 128.5, 133.7, 137.3, 148.6, 149.4;
HRMS (EI) calcd for C17H22O2Sn (M+) 378.0642, found 378.0637.
2-(4-Ben zyloxy-3-m eth oxyp h en yl)-5-br om o-7-m eth oxy-
ben zofu r a n (7). Dibromide 5 (2.50 g, 8.2 mmol), tetrakis-
(triphenylphosphine)palladium(0) (0.95 g, 10 mol %), and stan-
nane 6 (3.41 g, 9.0 mmol) were introduced to a sealable tube
containing anhydrous dioxane (10 mL) and the reaction mixture
was degassed. The tube was sealed and heated for 5 h at 145
°C, and after cooling the solution was filtered and evaporated
in vacuo. The filtrate residue was subjected to flash chromatog-
raphy (SiO2, CH2Cl2/ether 1/3) to provide the desired 7 (3.47 g,
96%) as a white solid: mp 156-158 °C; 1H NMR (CDCl3) δ 3.98
and 4.01 (s, 6H), 5.20 (s, 2H), 6.79 (s, 1H), 6.88 (d, J ) 1.6 Hz,
1H), 6.92 (d, J ) 8.9 Hz, 1H), 7.28 (d, J ) 1.6 Hz, 1H), 7.33-
7.47 (m, 7H); 13C NMR (CDCl3) δ 56.1, 56.2, 70.9, 99.8, 108.6,
109.9, 113.8, 115.6, 115.9, 118.2, 123.2, 127.2, 127.9, 128.6, 132.2,
136.7, 142.7, 145.4, 149.0, 149.7, 157.1; HRMS (FAB) calcd for
C23H19O4Br (M+) 438.0467, found 438.0464.
7.70 (d, J ) 16.0 Hz, 1H), 8.07 (s, 1H); 13C NMR [(CD3)2CO] δ
14.8, 56.6, 56.6, 60.9, 100.1, 106.5, 109.4, 115.5, 116.6, 118.0,
119.5, 123.0, 129.5, 131.9, 132.6, 146.1, 146.6, 148.9, 148.9, 158.4,
167.5.
(E)-2-(4-Hyd r oxy-3-m eth oxyp h en yl)-5-(3-h yd r oxyp r op e-
n yl)-7-m eth oxyben zofu r a n (1). DIBAL (8.2 mL of a 1 M
solution in hexane, 8.2 mmol) was added to a solution of 10 (0.76
g, 2.1 mmol) in THF (50 mL) at -78 °C. The mixture was stirred
for 2 h, then quenched with saturated aqueous Na2SO4‚10H2O
(5 mL) and allowed to warm to room temperature. When a
gelatinous mixture formed it was diluted with CH2Cl2 and
MeOH. The mixture was filtered, washing with ethyl acetate
and MeOH. The solvent was evaporated and the residue was
subjected to flash chromatography (SiO2, CH2Cl2) to afford 1
(0.64 g, 95%) as a white solid: mp 199-201 °C (lit.1 mp 199-
1
201 °C); H NMR (DMSO) δ 3.87 and 3.97 (s, 6H), 4.13 (d, J )
4.7 Hz, 2H), 5.59 (s, 1H), 6.31 (dt, J ) 15.8, 5.0 Hz, 1H), 6.57 (d,
J ) 15.8 Hz, 1H), 6.86 (d, J ) 8.2 Hz, 1H), 6.90 (s, 1H), 7.03 (d,
J ) 1.4 Hz, 1H), 7.10 (s, 1H), 7.29 (dd, J ) 8.2, 1.4 Hz, 1H), 7.33
(s, 1H); 13C NMR (CDCl3 + DMSO) δ 55.8, 55.8, 61.8, 100.3,
104.4, 108.6, 111.0, 115.9, 118.1, 121.3, 129.4, 129.4, 131.0, 133.2,
142.7, 144.7, 147.7, 148.0, 156.4.
(E)-2-(4-Ben zyloxy-3-m eth oxyp h en yl)-5-(3-h yd r oxyp r o-
p en yl)-7-m eth oxyben zofu r a n (8). This allyl alcohol 8 was
prepared, using the above procedure, from 7 (0.50 g, 1.1 mmol)
and (E)-2-(tri-n-butylstannyl)propenol5 (0.48 g, 1.4 mmol) with
catalyst Pd(0) (0.13 g, 10 mol %) in dioxane (5 mL) under reflux
for 4 h at 145 °C. The product was isolated in 36% yield (0.17 g,
0.4 mmol) after flash chromatography (SiO2, CH2Cl2/cyclohexane
(E)-2-(4-Ben zyloxy-3-m et h oxyp h en yl)-5-(3-a cet oxyp r o-
p en yl)-7-m eth oxyben zofu r a n (11). A mixture of 8 (0.50 g, 1.2
mmol) and pyridine (0.15 mL, 1.8 mmol) in CH2Cl2 (25 mL) was
added to acetyl chloride (0.13 mL, 1.8 mmol), and the solution
was stirred at ambient temperature for 20 min. The solvent was
removed in vacuo, and the residue was chromatographed on a
silica gel column (CH2Cl2) to give 11 (0.53 g, 96%) as a white
1
1/1) as a white solid: mp 159-160 °C; H NMR (CDCl3) δ 1.72
1
solid: mp 160-161.5 °C; H NMR (CDCl3) δ 2.13 (s, 3H), 4.00
(br s, 1H), 3.89 and 3.95 (s, 6H), 4.24 (d, J ) 5.4 Hz, 2H), 5.10
(s, 2H), 6.21 (dt, J ) 15.7, 5.4 Hz, 1H), 6.57 (d, J ) 15.7 Hz,
1H), 6.74 (s, 1H), 6.75 (s, 1H), 6.83 (d, J ) 8.2 Hz, 1H), 7.03 (s,
and 4.06 (s, 6H), 4.76 (dd, J ) 6.6, 0.8 Hz, 2H), 5.20 (s, 2H),
6.28 (dt, J ) 15.8, 6.6 Hz, 1H), 6.73 (d, J ) 15.8 Hz, 1H), 6.85
(s, 1H), 6.90 (dd, J ) 8.1, 1.5 Hz, 1H), 6.96 (d, J ) 1.5 Hz, 1H),
7.16 (d, J ) 1.3 Hz, 1H), 7.29-7.50 (m, 7H); 13C NMR (CDCl3)
δ 20.8, 55.7, 55.8, 64.9, 70.6, 100.3, 104.2, 108.3, 111.8, 113.5,
117.7, 121.7, 123.3, 127.1, 127.7, 128.3, 130.9, 132.0, 134.6, 136.5,
143.6, 144.8, 148.5, 149.4, 156.3, 170.6. MS (EI+) m/z (%) 458
(M+, 30), 459 (M + 1, 8), 368 (22), 367 (100), 91 (18); HRMS
(EI) calcd for C28H26O6 (M+) 458.1729, found 458.1732.
1
1H), 7.22-7.38 (m, 7H); H NMR [(CD3)2CO] δ 3.83 (t, J ) 5.4
Hz, 1H), 3.92 and 4.03 (s, 6H), 4.23 (t, J ) 5.3 Hz, 2H), 5.17 (s,
2H), 6.37 (dt, J ) 15.8, 5.3 Hz, 1H), 6.65 (d, J ) 15.8 Hz, 1H),
7.01 (d, J ) 1.4 Hz, 1H), 7.11 (s, 1H), 7.13 (d, J ) 8.2 Hz, 1H),
7.17 (d, J ) 1.2 Hz, 1H), 7.35-7.49 (m, 7H); 13C NMR (CDCl3)
δ 56.0, 56.1, 63.8, 70.9, 100.5, 104.5, 108.6, 111.7, 113.8, 118.0,
123.6, 127.3, 127.3, 127.9, 128.5, 131.2, 131.7, 132.7, 136.8, 143.7,
145.0, 148.7, 149.7, 156.6; HRMS (EI) calcd for C26H24O5 (M+)
416.1624, found 416.1615.
2-(4-Hyd r oxy-3-m eth oxyp h en yl)-5-(3-a cetoxyp r op yl)-7-
m eth oxyben zofu r a n (12a ). Compound 11 (0.28 g, 0.6 mmol)
was dissolved in THF (15 mL). Acetic acid (glacial, 2.0 mL) and
palladium on carbon (10%, 0.13 g) were added and the reaction
was placed with shaking in Parr-Shaker equipment under 1 atm
of H2. After stirring for 8 h at ambient temperature, the reaction
mixture was filtered and evaporated to provide a colorless oil.
Column chromatography with CH2Cl2/ether/hexane (1/1/1) as an
eluent gave pure 12a (0.22 g, 98%) as a white solid: mp 79-80
°C (lit.3c mp 80-80.5 °C); 1H NMR [(CD3)2CO] δ 1.97 (m, 2H),
2.01 (s, 3H), 2.73 (t, J ) 6.4 Hz, 2H), 3.94 and 4.00 (s, 6H), 4.06
(t, J ) 6.6 Hz, 2H), 6.76 (d, J ) 1.3 Hz, 1H), 6.95 (d, J ) 8.2 Hz,
1H), 6.98 (d, J ) 1.3 Hz, 1H), 7.02 (s, 1H), 7.41 (dd, J ) 8.2, 2.0
Hz, 1H), 7.47 (d, J ) 2.0 Hz, 1H), 8.05 (s, 1H); 13C NMR [(CD3)2-
CO] δ 21.0, 31.7, 33.1, 56.4, 56.5, 64.3, 100.9, 108.3, 109.2, 113.1,
116.5, 119.2, 123.4, 132.3, 138.3, 142.3, 146.0, 148.6, 148.9, 157.5,
171.2; HRMS (EI) calcd for C21H22O6 (M+) 370.1416, found
370.1422.
(E)-2-(4-Ben zyloxy-3-m eth oxyp h en yl)-5-(ca r beth oxyeth -
ylen e)-7-m eth oxyben zofu r a n (9). Into a sealable tube were
introduced bromide 7 (1.80 g, 4.1 mmol), (E)-3-(tri-n-butylstan-
nyl)propenoic acid ethyl ester5 (1.91 g, 4.9 mmol), freshly
prepared tetrakis(triphenylphosphine)palladium(0) (0.47 g, 10
mol %), and anhydrous dioxane (10 mL). The tube was sealed
and heated at 140 °C for 5 h. After cooling, the solution was
filtered, the filtrate was evaporated in vacuo, and the residue
was subjected to flash chromatography (SiO2, CH2Cl2/cyclohex-
ane 1/1). The known6e ester 9 (1.73 g, 92%) was isolated as a
white solid: mp 142-144 °C; 1H NMR [(CD3)2CO] δ 1.28 (t, J )
7.1 Hz, 3H), 3.92 and 4.07 (s, 6H), 4.20 (q, J ) 7.1 Hz, 2H), 5.15
(s, 2H), 6.52 (d, J ) 16.0 Hz, 1H), 7.12 (d, J ) 8.3 Hz, 1H), 7.15
(s, 1H), 7.26 (d, J ) 1.4 Hz, 1H), 7.31-7.52 (m, 8H), 7.72 (d, J
) 16.0 Hz, 1H); 13C NMR [(CD3)2CO] δ 14.8, 56.5, 56.7, 60.8,
71.5, 101.7, 106.5, 109.8, 115.1, 115.6, 118.1, 118.8, 124.3, 128.7,
128.9, 129.4, 131.9, 132.5, 138.4, 146.1, 146.1, 146.6, 150.5, 151.3,
158.1, 167.4; HRMS (EI) calcd for C28H26O6 (M+) 458.1729, found
458.1731. Anal. Calcd for C28H26O6: C, 73.35; H, 5.72; O, 20.94.
Found: C, 73.16; H, 5.52; O, 20.75.
Gen er a l Con d ition s for th e Son oga sh ir a Rea ction . 2-(4-
Be n zyloxy-3-m e t h oxyp h e n yl)-5-(3-a ce t oxyp r op yn yl)-7-
m eth oxyben zofu r a n (13a ). A mixture of bromobenzofuran 7
(0.40 g, 0.9 mmol), tetrakis(triphenylphosphine)palladium(0)
(0.11 g, 10 mol %), CuI (0.33 g, 20 mol %), and acetoxy propyne
(0.13 g, 1.4 mmol) was introduced to a sealable tube containing
anhydrous Et3N (5 mL) and the reaction mixture was degassed.
The tube was sealed and heated for 5 h at 90 °C, and after
cooling, the solution was filtered and evaporated in vacuo. The
filtrate residue was subjected to flash chromatography (SiO2,
CH2Cl2/ether 1/3) to provide the desired 13a (0.27 g, 66%) as a
white solid: mp 149-151 °C; 1H NMR (CDCl3) δ 2.14 (s, 3H),
3.99 and 4.01 (s, 6H), 4.93 (s, 2H), 5.19 (s, 2H), 6.83 and 6.87 (s,
2H), 6.93 (d, J ) 8.8 Hz, 1H), 7.30-7.47 (m, 8H); 13C NMR
(CDCl3) δ 20.8, 52.9, 56.1, 56.2, 71.0, 81.2, 87.0, 100.2, 108.7,
109.9, 113.9, 117.1, 117.4, 118.1, 123.3, 127.3, 127.9, 128.6, 130.9,
(E)-2-(4-Hyd r oxy-3-m eth oxyp h en yl)-5-(ca r beth oxyeth yl-
en e)-7-m eth oxyben zofu r a n (10). To a solution of 9 (1.25 g,
2.7 mmol) in CH2Cl2 (25 mL) was added TiCl4 (0.33 mL, 3.0
mmol) dropwise at ambient temperature. The reaction was
monitored by TLC and quenched by treatment with MeOH. The
solvent was removed and the residue was subjected to flash
chromatography (SiO2, CH2Cl2) to give 10 (1.00 g, 100%) as a
1
white solid: mp 149-151 °C (lit.3a,b mp 149-151 °C); H NMR
[(CD3)2CO] δ 1.27 (t, J ) 7.1 Hz, 3H), 3.93 and 4.07 (s, 6H), 4.20
(q, J ) 7.1 Hz, 2H), 6.52 (d, J ) 16.0 Hz, 1H), 6.94 (d, J ) 8.2
Hz, 1H), 7.07 (s, 1H), 7.24 (d, J ) 1.4 Hz, 1H), 7.41 (dd, J ) 8.2,
2.0 Hz, 1H), 7.43 (d, J ) 1.4 Hz, 1H), 7.47 (d, J ) 2.0 Hz, 1H),
2970 J . Org. Chem., Vol. 68, No. 7, 2003

136.7, 144.0, 144.7, 148.9, 149.8, 157.1, 170.3; HRMS (EI) calcd
for C28H24O6 (M+) 456.1573, found 456.1577.
(CDCl3) δ 56.1, 56.2, 58.0, 62.0, 71.0, 71.7, 83.3, 87.0, 100.2,
108.7, 109.8, 113.9, 117.2, 117.7, 118.1, 123.4, 127.3, 127.8, 127.9,
128.1, 128.4, 128.6, 130.9, 136.8, 137.5, 144.0, 144.7, 148.9, 149.8,
157.0; HRMS (EI) calcd for C33H28O5 (M+) 504.1937, found
504.1934.
2-(4-Ben zyloxy-3-m eth oxyp h en yl)-5-(3-tetr a h yd r op yr a -
n oxyp r op yn yl)-7-m eth oxyben zofu r a n (13b). The 13b was
prepared, using the general procedure, from 7 (0.62 g, 1.4 mmol)
and tetrahydropyranoxypropyne (0.30 g, 2.1 mmol). The product
13b was isolated in 82% yield (0.58 g, 1.2 mmol) as a white
Ack n ow led gm en t. We thank the National Science
Council of the Republic of China for financial support
(Research Grant NSC 90-2113-M-018-008). We also
acknowledge with appreciation the NSC-supported
HRMS spectrometry facility (Department of Chemistry,
Chung-Hsing University) for providing high-resolution
mass spectra.
1
solid: mp 169-171 °C; H NMR (CDCl3) δ 1.54-1.85 (m, 6H),
3.61 and 3.90 (m, 2H), 3.99 and 4.02 (s, 6H), 4.52 (ABq, J )
15.8, 4.7 Hz, 2H), 4.93 (t, J ) 3.3 Hz, 1H), 5.20 (s, 2H), 6.84 (s,
1H), 6.86 (d, J ) 1.3 Hz, 1H), 6.93 (d, J ) 8.9 Hz, 1H), 7.27-
7.47 (m, 8H); 13C NMR (CDCl3) δ 19.1, 25.4, 30.3, 54.8, 56.1,
56.2, 62.0, 71.0, 83.4, 86.4, 96.8, 100.2, 108.7, 109.9, 113.9, 117.3,
118.1, 123.4, 127.3, 128.0, 130.9, 136.8, 144.0, 144.7, 148.9, 149.8,
157.0.
2-(4-Ben zyloxy-3-m eth oxyp h en yl)-5-(3-ben zyloxyp r op y-
n yl)-7-m eth oxyben zofu r a n (13c). From 7 (0.25 g, 5.7 × 10-1
mmol) and benzyloxypropyne (0.12 g, 8.5 × 10-1 mmol), 13c was
obtained in 62% (0.18 g, 3.5 × 10-1 mmol) yield as a white
solid: mp 122-125 °C; 1H NMR (CDCl3) δ 3.99 and 4.03 (s, 6H),
4.43 and 4.71 (s, 4H), 5.20 (s, 2H), 6.85 (s, 2H), 6.88 (d, J ) 1.2
Hz, 1H), 6.94 (d, J ) 8.9 Hz, 1H), 7.30-7.48 (m, 13H); 13C NMR
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic char-
acterization and 1H and 13C NMR spectra of the compounds
described in the text. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O020653T
J . Org. Chem, Vol. 68, No. 7, 2003 2971