A concise and efficient synthesis of salvinal from isoeugenol via a phenoxenium ion intermediate

Article abstract of DOI:10.1016/j.tetlet.2006.10.131

In this letter, we describe how salvinal can be efficiently synthesized from isoeugenol via a phenoxenium ion intermediate by four steps in 23% over all total yield.

Full text of DOI:10.1016/j.tetlet.2006.10.131

Tetrahedron Letters 47 (2006) 9195–9197
A concise and efficient synthesis of salvinal from isoeugenol
via a phenoxenium ion intermediate
Eng-Chi Wang,a Yung-Shung Weinb and Yueh-Hsiung Kuob,c,d,
*
aFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
bDepartment of Chemistry, National Taiwan University, Taipei 106, Taiwan
cAgricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan
dCollege of Pharmacy, China Medical University, Taichung 404, Taiwan
Received 26 January 2006; revised 26 October 2006; accepted 27 October 2006
Abstract—In this letter, we describe how salvinal can be efficiently synthesized from isoeugenol via a phenoxenium ion intermediate
by four steps in 23% over all total yield.
Ó 2006 Elsevier Ltd. All rights reserved.
Salvinal, a naturally occurring neolignan, was firstly iso-
lated from Salvia mitorrhiza Burge (Danshen), a Chinese
medicinal plant, and was found as a novel adenosine A1
receptor ligand.1 The aqueous extract of this plant has
been popularly used as folk medicine for treatment of
angina pectoris, acute myocardial infarction, etc. in
China.2 In addition, chloroform extract of this plant
exhibits cytotoxic activities against various cell lines
derived from human carcinomas.3 Recently, the detailed
molecular action mechanism of salvinal has been
clarified as a microtubule inhibitor, similar to the effect
of colchicines.4 For further animal studies and other
biological interesting purposes, a larger amount of
salvinal is required. Thus, there is an urgent need to
develop a concise and efficient synthetic method for pro-
ducing salvinal is urgent. After carefully examining the
published methods for the synthesis of salvinal reported
by Yang et al.,1a Hutchison et al.,5 Kao and Chern,6 and
our previous study,7 we found that some common draw-
backs still exist including multiple synthetic steps, low
over all total yield and tedious reaction conditions. We
herein report an improved strategy for the synthesis of
salvinal starting from isoeugenol in four steps with good
over all total yield (Scheme 1).
Oxidation coupling of isoeugenol was carried out by the
hypervalent iodine reagent, iodobenzene diaceate (IDA)
reported by Juhasz et al.,8 to give 2,3-dihydrobenzofuran
O
H
PtO2/H2
PhI(OAc)2
DDQ (2.0 eq)
OH
OH
O
CH3OH
95%
O
HO
1,4-dioxane
reflux, 24 h
83%
CH2Cl2
OCH3
OCH3
OCH3
OCH3
OCH3
40%
3
2
1
CHO
SeO2, EtOH
HO
HO
OH
OH
reflux, 24 h
72%
O
OCH3
O
OCH3
OCH3
OCH3
5
4
Scheme 1. The synthesis of salvinal from isoeugenol.
Keywords: Isoeugenol; Iodobenzene diacetate; Oxidative coupling; Salvinal.
*
Corresponding author. E-mail: yhkuo@ntu.edu.tw
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.131

9196
E.-C. Wang et al. / Tetrahedron Letters 47 (2006) 9195–9197
O
H
OH
O
OCH3
OCH3
3
O
DDQ (1.0 eq)
H
OH
O
CHO
OH
O
dioxane
H
O
OCH3
OH
OCH3
reflux, 12 h
OCH3
O
OCH3
OCH3
91%
2
2-1
OCH3
3-1
Scheme 2. Compound 2 was oxidized by 1–3 equiv of DDQ.
(2) in 40% yield. When 2 was reacted with 2 equiv of 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) in refluxing
1,4-dioxane, benzofuran (3)9 was produced through
dehydrogenation and allylic oxidation in one-pot within
24 h, giving a yield of 83%. At the same reaction condi-
tion, when 2 was treated with 1 equiv DDQ, it gave com-
pound 2–110 in a yield of 91% through allylic oxidation
and no product from dehydrogenation reaction was
isolated. Furthermore when 3 equiv of DDQ was used
instead to carry out the reaction, compound 3–111 was
obtained in 77% yield. These reactions described above
can be summarized as follows (Scheme 2).
References and notes
1. (a) Yang, Z.; Hon, P. M.; Chui, K. Y.; Xu, Z. L.; Chang,
H. M.; Lee, C. M.; Cui, Y. X.; Wong, H. N. C.; Poon, C.
D.; Fung, B. M. Tetrahedron Lett. 1991, 32, 2061–2064;
(b) Scammells, P. J.; Baker, S. P.; Beauglehole, A. R.
Bioorg. Med. Chem. 1998, 6, 1517–1524.
2. Chen, W. Z. Acta Pharm. Sinica 1984, 19, 876–880.
3. Wu, W. L.; Chang, W. L.; Chen, C. F. Am. J. Chin. Med.
1991, 19, 207–216.
4. Chang, J. Y.; Chang, C. Y.; Kuo, C. C.; Chen, L. T.;
Wein, Y. S.; Kuo, Y. H. Mol. Pharmacol. 2004, 65, 77–84.
5. Hutchinson, S. A.; Luetjens, H.; Scammells, P. J. Bioorg.
Med. Chem. Lett 1997, 7, 3081–3084.
6. Kao, C.-L.; Chern, J.-W. J. Org. Chem. 2002, 67, 6772–
6787.
7. Kuo, Y.-H.; Wu, C.-H. J. Nat. Prod. 1996, 59, 625–628.
8. Juhasz, L.; Kurti, L.; Antus, S. J. Nat. Prod. 2000, 63,
866–870.
9. Synthesis of 3: To a stirred solution of 2 (2.12 g,
6.43 mmol) in 1,4-dioxane (50 mL) was added DDQ
(3.24 g, 14.27 mmol) and heated to the reflux for 24 h.
After usual work-up process and column chromatographic
From this result, we have successfully improved the
previous study reported by Iliefski et al.12 They reported
that the allylic oxidation of arylpropene with DDQ can
only be worked slowly at the condition of appropriate
amount of water at room temperature. We also found
that the arylpropene functionality was more easily oxi-
dized to arylpropenal than that of oxidation of aryl-
dihydrofuran to arylfuran in compound 2. The other
oxidant and dehydrogenating reagent, selenium oxide
was limited for lower yield in this reaction due to the
poor solubility in dioxane compared to DDQ which
can be soluble and reacted efficiently. The reduction of
a,b-unsaturated aldehyde moiety in benzofuran (3)
was smoothly achieved by Adam’s catalyst (PtO2/H2)
to afford compound 4 in a yield of 95%.13 Finally, the
methyl group at 3-position of alcoholic benzofuran (4)
was successfully oxidized by selenium oxide in refluxing
ethanol to give the title compound, salvinal (5) in 72%
yield.14
purification process (EtOAc/n-hexane = 1/8), pure
3
(1.81 g, 83%) was obtained as colorless crystal, mp 221–
222 °C. IR (KBr) cmꢀ1, mmax: 2949, 2811, 2727, 1674,
1616, 1513, 1214, 1128, 972. 1H NMR (CDCl3, 300 MHz):
d 2.40 (3H, s, CH3–C-3), 3.95 (3H, s, OCH3–C-30), 4.03
(3H, s, OCH3–C-7), 5.85 (1H, br s, OH), 6.70 (1H, dd,
J = 15.9, 7.6 Hz, H-200), 6.97 (1H, s, H-20), 6.99 (1H, d,
J = 8.0 Hz, H-50), 7.26–7.30 (3H, m, H-4, H-6, H-60), 7.55
(1H, d, J = 15.9 Hz, H-100), 9.68 (1H, d, J = 7.6 Hz, H-300).
13C NMR (CDCl3, 75 MHz): d 9.5, 56.1, 105.6, 109.4,
110.1, 113.8, 114.6, 120.8, 123.0, 127.4, 129.6, 133.5, 144.6,
145.4, 146.2, 146.7, 153.9, 193.6. EI-MS m/z (%) (70 eV):
338 (M+, 100), 326 (21), 310 (100), 295 (14), 267 (15), 151
(13), 137 (14), 69 (17), 57 (19). HRMS (EI, m/z): Calcd for
C20H18O5: 338.1154. Found: 338.1141.
In conclusion, in our process compound 2 was oxidized
and dehydrogenated by DDQ in refluxing 1,4-dioxane in
one-pot to give compound 3 in high yield and in a short
reaction time which is an advantage. In addition, effec-
tive oxidation of allylic methyl carbon, at 3-position of
benzofuran (4) by inexpensive selenium oxide is also
an advantage. Thus, we have successfully established a
concise and efficient synthesis for salvinal in four steps
and in 23% over all total yield.
10. Compound 2-1 was obtained as colorless crystal, mp 177–
178 °C. IR (KBr) cmꢀ1, mmax: 3486, 2821, 2734, 1684,
1620, 1133, 821. 1H NMR (CDCl3, 300 MHz): d 1.40 (3H,
d, J = 6.8 Hz, CH3–C-3), 3.50 (1H, m, H-3), 5.18 (1H, d,
J = 7.9 Hz, H-2), 5.66 (1H, s, OH), 6.60 (1H, dd, J = 15.8,
7.6 Hz, H-200), 6.87 (1H, d, J = 8.1 Hz, H-50), 6.89 (1H, s,
H-20), 6.93 (1H, d, J = 8.1 Hz, H-60), 6.99 (1H, s, H-6),
7.02 (1H, s, H-4), 7.41 (1H, d, J = 15.8 Hz, H-100), 9.64
(1H, d, J = 7.6 Hz, H-300). 13C NMR (CDCl3, 75 MHz): d
17.7, 45.1, 55.9, 56.0, 94.5, 108.9, 111.8, 114.3, 117.3,
119.9, 126.3, 128.1, 131.2, 134.0, 144.6, 146.0, 146.7, 150.6,
153.2, 193.6. EI-MS m/z (%) (70 eV): 340 (100), 325 (7),
203 (7), 151 (8), 137 (15), 97 (15), 83 (16), 71 (18), 57 (30).
HRMS (EI, m/z): Calcd for C20H20O5: 340.1311. Found:
340.1300.
Acknowledgement
The financial support from National Science Council of
ROC is gratefully acknowledged.

E.-C. Wang et al. / Tetrahedron Letters 47 (2006) 9195–9197
9197
11. Compound 3-1 was obtained as colorless crystal, mp 234–
235 °C, IR (KBr) cmꢀ1, mmax: 3488, 2854, 2734, 1680,
1619, 1513, 1279, 1027. 1H NMR (CDCl3, 300 MHz): d
4.01 (3H, s, OCH3), 4.06 (3H, s, OCH3), 6.02 (1H, s, OH),
6.75 (1H, dd, J = 15.9, 7.7 Hz, H-200), 7.07 (1H, d,
J = 8.0 Hz, H-50), 7.09 (1H, J = 1.8 Hz, H-20), 7.37 (1H,
d, J = 1.9 Hz, H-6), 7.41 (1H, dd, J = 8.0, 1.8 H, H-60),
7.58 (1H, d, J = 15.9 Hz, H-100), 8.05 (1H, d, J = 1.9 Hz,
H-4), 9.72 (1H, d, J = 7.7 Hz, –CHO-300), 10.30 (1H, s,
CHO-3). 13C NMR (CDCl3, 75 MHz): d 55.9, 56.2, 107.0,
112.4, 115.3, 116.0, 116.2, 118.5, 123.1, 127.4, 128.4, 132.3,
143.7, 145.0. 148.2, 150.4, 153.8, 165.7, 186.6, 194.3. EI-
MS m/z (%) (70 eV): 352 (M+, 100), 323 (40), 296 (15), 281
(20), 253 (33), 181 (18), 152 (23). HRMS (EI, m/z): Calcd
for C20H16O6: 352.0947. Found: 352.0939.
165–166 °C. IR (KBr) cmꢀ1, mmax: 3431, 2851, 1602,
1516, 1455, 1386, 1222, 1052, 793. 1H NMR (CDCl3,
300 MHz): d 1.95 (2H, m, H-200), 2.38 (3H, s, CH3–C-3),
2.79 (2H, t, J = 7.9 Hz, H-100), 3.71 (2H, t, J = 6.5 Hz, H-
300), 3.96 (3H, s, OCH3–C-30), 4.01 (3H, s, OCH3–C-7),
5.73 (1H, br, OH–C-40), 6.63 (1H, d, J = 2.0 Hz, H-6),
6.91 (1H, d, J = 2.0 Hz, H-20), 6.98 (1H, d, J = 8.2 Hz, H-
50), 7.26 (1H, dd, J = 8.2, 2.0 Hz, H-60), 7.30 (1H, d,
J = 2.0 Hz, H-4). 13C NMR (CDCl3, 75 MHz): d 9.6, 32.6,
34.8, 56.1, 62.4, 107.4, 109.5, 110.8, 114.5, 120.6, 123.8,
133.0, 136.9, 144.7, 145.7, 146.6, 151.4. EI-MS m/z (%)
(70 eV): 342 (M+, 5), 340 (100), 324 (37), 312 (26), 297
(19), 284 (20), 148 (13), 97 (16), 91 (18), 69 (23), 57 (28);
HRMS (EI, m/z): Calcd for C20H22O5: 342.1467. Found:
342.1481.
12. Iliefski, T.; Li, S.; Lundquist, K. Tetrahedron Lett. 1998,
39, 2413–2416.
14. Synthesis of 5: To a stirred solution of 4 (0.64 g,
1.87 mmol) in EtOH (20 mL) was added SeO2 (0.42 g,
3.74 mmol) and heated to reflux for 12 h. Then, the
reaction mixture was cooled to room temperature and was
filtered through Celite 545R. After concentration in vacuo,
the resulting residue was subjected to silica gel chromato-
graphic column (EtOAc/n-hexane = 1/5). Pure 5 (0.48 g,
72%) was obtained as colorless crystal, mp 173–174 °C.
13. Reduction of 3 to prepare 4: To a stirred solution
of 3 (1.33 g, 3.93 mmol) in MeOH (20 mL) was added
10% PtO2/H2O (96.3 mg) and bubbled H2 at room
temperature for 6 h. The reaction was monitored by
TLC until the starting material was completely con-
sumed. After usual work-up and column chromatographic
1
purification process (EtOAc/n-hexane = 2/5), pure
4
The spectral data of H NMR, 13C NMR, EI-MS are all
(1.28 g, 95%) was obtained as colorless crystal, mp
coincident to the reported salvinal.