A convenient synthesis of naturally occurring benzofuran ailanthoidol

Article abstract of DOI:10.1016/S0040-4039(00)02163-8

A convenient method for the synthesis of ailanthoidol starting from vanillin is provided using trimethylsilyldiazomethane lithium salt to generate a diphenylacetylene and subsequent oxymercuration cyclization of the resulting alkyne with mercury acetate in acetic acid as key steps.

Full text of DOI:10.1016/S0040-4039(00)02163-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1111–1113
A convenient synthesis of naturally occurring benzofuran
ailanthoidol
Chai-Lin Kao and Ji-Wang Chern*
School of Pharmacy, College of Medicine, National Taiwan University No. 1, Section 1, Jen-Ai Road, Taipei 100, Taiwan
Received 15 September 2000; revised 15 November 2000; accepted 22 November 2000
Abstract—A convenient method for the synthesis of ailanthoidol starting from vanillin is provided using trimethylsilyldia-
zomethane lithium salt to generate a diphenylacetylene and subsequent oxymercuration cyclization of the resulting alkyne with
mercury acetate in acetic acid as key steps. © 2001 Elsevier Science Ltd. All rights reserved.
involve the coupling of ortho-halophenols with alkynes
via an organometallic reaction with concomitant
cyclization of the resulting diphenylacetylene skeleton.
However, to explore the structure–activity relationship,
a variety of analogs are required and a wide diversity of
available starting materials is critical to synthesize
analogs for biological studies. Therefore, an efficient
and practical approach for the synthesis of versatile
analogs is needed. We reasoned that the dipheny-
lacetylene skeleton would be suitable by coupling the
appropriate diphenyl ketone with the lithium salt of
trimethylsilyldiazomethane.8 Subsequently, the resulting
diphenylacetylene would undergo facile intramolecular
solvomercuration with mercury acetate to afford the
corresponding benzofuran skeleton.9 Herein, we de-
velop a convenient approach for the synthesis of ailan-
thoidol starting from vanillin.
Ailanthoidol 1, a neolignan with a 2-arylbenzofuran
skeleton, was isolated from the Chinese herbal medicine
Zanthoxylum ailanthoides. It has been reported that
neolignans and lignans possess a variety of biological
activities, such as anticancer,1 antiviral,2 immunosup-
pressive,3 antioxidant,4 antifungal5 and antifeedant
activities.6 However, due to the limited amounts of
compound 1, its biological activity has not yet been
established.
Although there are several approaches available in the
Our strategy starts with the bromination of vanillin
with bromine in acetic acid to give 3-bromo-4-hydroxy-
literature7 for the preparation of compound 1, most
Scheme 1.
Keywords: ailanthoidol; benzofuran; trimethylsilyldiazomethane lithium salt; oxymercuration.
* Corresponding author. Fax: 886-2-23934221; e-mail: chern@jwc.mc.ntu.edu.tw
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02163-8

1112
C.-L. Kao, J.-W. Chern / Tetrahedron Letters 42 (2001) 1111–1113
without further purification and treated with NaBH4
5-methylbenzaldehyde 3. Methylation of compound 3
with methyl iodide in the presence of tetrabutyl-
ammonium iodide (TBNI) as catalyst10 produces the
3-bromo-4,5-dimethoxybenzaldehyde 4, which was
treated with 2,2-dimethyl-1,3-propanediol to afford 1-
bromo-2,3-dimethoxy-5-(5%,5%-dimethyl-1%,3%-dioxan-2%-
yl)benzene 5 in 58% yield (Scheme 1). However, direct
methylation of 3 with methyl iodide under various
conditions, such as K2CO3/MeI in ethanol, KOH/MeI
in methanol, KOH/MeI in DMF, or NaH/MeI in
DMF, was unsuccessful.
in THF to afford compound 1112 in 85% yield.
The dioxane moiety of 11 was deprotected in a mix-
ture of acetone and hydrochloric acid to furnish 2-(4-
benzyloxy-3-methoxyphenyl)-7-methoxybenzo[b]furan-
5-carboxaldehyde 12 in 92% yield. Unfortunately,
hydrogenation of 12 with Pd–C/H2 gave an unexpected
compound 14 by reduction of the aldehyde group
instead of the desired product 13 (Scheme 3). Alterna-
tively, compound 11 was debenzylated with Pd–C/H2
and subsequently deacetylated in a mixture of acetone
and 6N HCl to afford the desired product 13 in 70%
yield.
Nevertheless, compound 5 was obtained in 71% yield
starting from 2 without any further purification of the
intermediates. Compound 5 was then treated with n-
butyl lithium and coupled with 4-benzyloxy-3-methoxy-
benzaldehyde 6 to give 1-(p-benzyloxy-m-methoxy-
phenyl)-1-(2,3-dimethoxy-5-(5%,5%-dimethyl-1%,3%-dioxan-
2%-yl)phenyl carbinol 7 in 77% yield accompanied with a
trace amount of the debrominated product of com-
pound 5 (Scheme 2).
Finally, elongation of the side chain at the 5-position
of 13 via a Wittig reaction gave 2-(p-hydroxy-m-meth-
oxyphenyl)-7-methoxy-5-(carbethoxy-1-propen-1-yl)-
benzo[b]furan 1513 which was treated with DIBAL-H to
afford the target compound 1 in 77% yield (Scheme 4).
In summary, a total synthesis of ailanthoidol was
achieved in 12 steps with a 17% overall yield from
vanillin 2. This investigation provides a practical
approach toward the synthesis of ailanthoidol. Its
analogs can also be simply synthesized either by func-
tionalization at the 5-position of 13 or by using a
variety of vanillin analogs as starting material. The
mercurial intermediate 10 is considered to be a very
useful intermediate for the preparation of analogs by
the direct replacement of the mercurial moiety with
different functional groups. Using this strategy, the
synthesis of other neolignans and lignans is currently
under active investigation in our laboratory.
Subsequent oxidation of the resulting carbinol 7 with
manganese oxide furnished the corresponding ketone 8
in 96% yield. Compound 8 was then treated with
trimethylsilyl diazomethane lithium salt to give the
corresponding alkyne 9 via a Covlin rearrangement11
in 97% yield. Compound 9 was treated with mercury
acetate in acetic acid and then quenched with satu-
rated sodium chloride solution to yield 2-(p-benzyl-
oxy - m - methoxyphenyl) - 3 - chloromercurio - 5 - (5%,5%-
dimethyl-1%,3%-dioxan-2%-yl)-7-methoxybenzofuran 10.
The chloromercurial intermediate 10 was isolated
Scheme 2.

C.-L. Kao, J.-W. Chern / Tetrahedron Letters 42 (2001) 1111–1113
1113
Scheme 3.
Scheme 4.
Acknowledgements
8. (a) Shioiri, T.; Aoyama, T. J. Synth. Org. Chem. Jpn. 1996,
54, 918–928; (b) Ito, Y.; Shioiri, T.; Aoyama, T. Synlett
1997, 1163–1164.
9. Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984,
106, 4218–4227.
We thank the National Science Council of the Republic
of China for the financial support of this work (NSC
89-2314-002-135).
10. McKillop, A.; Fiand, J.-C.; Hug, R. P. Tetrahedron 1974,
30, 1379–1382.
11. Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans.
1 1977, 1379–1382.
References
1. Sheen, W.-S.; Tsai, I.-L.; Teng, C.-M.; Chen, I.-S. Phyto-
chemistry 1994, 36, 213–215.
12. Compound 11: mp 160–162°C; 1H NMR (CDCl3, 400
MHz) l 0.80 (s, 3 H), 1.33 (s, 3 H), 3.67 (d, J=11 Hz, 2
H), 3.79 (d, J=11 Hz, 2 H), 3.97 (s, 3 H), 4.05 (s, 3 H),
5.17 (s, 2 H), 5.44 (s, 1 H), 6.85 (s, 1 H), 6.91 (d, J=8 Hz,
1 H), 6.98 (s, 1 H), 7.30 (s, 2 H), 7.34–7.39 (m, 4 H), 7.44
(d, J=8 Hz, 2 H); 13C NMR (CDCl3, 100 MHz) l 22.4,
23.6, 30.7, 56.5, 56.7, 71.5, 78.2, 101.2, 102.6, 104.9, 109.2,
111.6, 114.5, 118.5, 124.3, 127.8, 128.4, 129.0, 131.3, 134.9,
137.3, 144.6, 145.5, 149.2, 150.3, 157.0. Anal. calcd for
C29H30O6: C, 73.40; H, 6.37. Found: C, 73.37; H, 6.37.
13. The E-olefin geometry was confirmed by the coupling
constant (J=16 Hz) of two vinylic protons. Compound 15:
mp 149–151°C; 1H NMR (CDCl3, 400 MHz) l 1.33 (t, J=7
Hz, 3 H), 3.95 (s, 3 H), 4.03 (s, 3 H), 4.26 (q, J=7 Hz, 2
H), 5.90 (s, 1 H, exchangeable), 6.38 (d, J=16 Hz, 1 H),
6.81 (s, 1 H), 6.92 (s, 1 H), 6.96 (d, J=8 Hz, 1 H), 7.27
(s, 1 H), 7.32 (d, J=2 Hz, 1 H), 7.37 (dd, J=2, 8 Hz, 1
H), 7.72 (d, J=16 Hz, 1 H); 13C NMR (CDCl3, 100 MHz)
l 14.8, 56.5, 56.6, 60.9, 100.6, 105.6, 108.1, 114.9, 115.3,
117.3, 117.4, 119.5, 122.9, 131.0, 131.9, 145.6, 145.9, 147.1,
147.3, 157.8, 167.7. Anal. calcd for C21H20O6: C, 68.47; H,
5.47. Found: C, 68.63; H, 5.52.
2. (a) Tsai, I.-L.; Hsien, C.-F.; Duh, C.-Y. Phytochemistry
1998, 48, 1371–1375; (b) Jenab, M.; Thompson, L. U.
Carcinogenesis 1996, 17, 1343–1348; (c) Thompson, L. U.;
Rickard, S. E.; Orcheson, L. J.; Seidl, M. M. Carcinogenesis
1996, 17, 1373–1376; (d) Thompson, L. U.; Seidl, M. M.;
Rickard, S. E.; Orcheson, L. J.; Fong, H. H. S. Nutr. Cancer
1996, 26, 159–165.
3. Iwasaki, T.; Kondo, K.; Kuroda, T.; Moritani, Y.; Yama-
gata, S.; Sugiura, M.; Kikkawa, H.; Kaminuma, O.;
Ikezawa, K. J. Med. Chem. 1996, 39, 2696–2704.
4. (a) Gordaliza, M.; Faircloth, G. T.; Castro, M.; Corral, J.
M.; Lopez-Vazquez, M.; Feliciano, A. S. J. Med. Chem.
1996, 39, 2865–2868; (b) Gordaliza, M.; Castro, M.; Corral,
J. M.; Lopez-Vazquez, M.; Feliciano, A. S.; Faircloth, G.
T. Bioorg. Med. Chem. Lett. 1997, 7, 2781–2786.
5. Lu, H.; Liu, G.-T. Planta Med. 1992, 58, 311–313.
6. Zacchino, S.; Rodriguez, G.; Pezzenati, G.; Orellana, G.
J. Nat. Prod. 1997, 60, 659–662.
7. (a) Bates, R. W.; Rama-Devi, T. Synlett 1995, 1151–1152;
(b) Lutjens, H.; Scammells, P. J. Tetrahedron Lett. 1998,
39, 6581–6584; (c) Fuganti, C.; Serra, S. Tetrahedron Lett.
1998, 39, 5609–5610.
.