168 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 168$
Total Synthesis of (2)-Kadsurenin M$
Wang Ming Yi, Wu An Xin and Pan Xin Fu*
Department of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P.R. China
The first total synthesis of racemic kadsurenin M was accomplished starting from vanillin via a key intermediate 3,4-dimethoxy-
cinnamyl 4-formyl-2-methoxyphenyl ether.
Kadsurenin M, (7S,8S) 1, a natural neolignan derivative,%
has been isolated from the aerial part of Piper kadsura
(Choisy) Ohwi,1 a Chinese traditional drug used for the
treatment of in¯ammation and rheumatic conditions. Its
structure was characterized upon the basis of spectral data.
In continuation of our research work on the total synthesis
of bioactive natural neolignans, we report here the ®rst total
synthesis of racemic kadsurenin M.
Experimental
Melting points were measured on
a micro-melting point
apparatus and are uncorrected. Mass spectra were recorded on a
ZAB-HS spectrometer, 1H- and 13C-NMR spectra on a Bruker
AM-400 instrument in CDCl3 with Me4Si as internal standard
and IR spectra on a FT-170 SX spectrometer. Elemental analyses
were performed on a Carlo Erba-1106 instrument. All compounds
were puri®ed by ¯ash chromatography on silica gel H (200±300
mesh; Qingdo Marine Chemical Factory), eluting with solvent
mixtures of light petroleum (bp 60±90 8C), acetone and chloroform.
3,4-Dimethoxycinnamyl 4-Formyl-2-methoxyphenyl Ether 4.ÐTo
a solution of vanillin 2 (1.06 g, 7 mmol) in anhydrous ethanol
(20 ml) was added in portions sodium (0.16 g, 7 mmol) at room
temperature. The mixture was stirred for 1 h, and subsequently the
solvent was removed under reduced pressure to aord the sodium
The synthetic route is depicted in Scheme 1. Unstable 3,4-
dimethoxycinnamyl chloride 3, readily available in 62.3%
yield from vanillin 2 by sequential methylation, conden-
sation, selective reduction2 and chlorination,3 was coupled
with the sodium salt of vanillin in N,N-dimethylformamide
(DMF) at room temperature to give compound 4 as colour-
less crystals in 60% yield. This method for the preparation
of the cinnamyl phenyl ether 4 may also be useful for
the syntheses of many other benzofuranoid neolignan
precursors.
salt of vanillin in nearly quantitative yield. To
a solution of
the sodium salt of vanillin in DMF (10 ml) was added dropwise a
solution of 3 (1.5 g, 7.1 mmol) in DMF. The mixture was stirred at
room temperature for 24 h, after which the solvent was evaporated
under vacuum and the residue was extracted with Et2O. Standard
ethereal work-up and ¯ash chromatography gave a yellowish solid
(1.5 g) which was crystallized from Et2O to provide 4 (1.3 g, 60%)
1
as colourless needles: mp 125.5±126.5 8C; ꢀmax/cm (KBr) 3002±
2884 (CH, aliphatic), 1680 (CHO), 1586, 1511, 1463, 1421, 1396,
1339, 1264, 1235, 1159, 1137, 1026, 968, 862, 811; ꢁH 3.88, 3.90, 3.95
(3 s, 3Â 3 H, 3ÂOMe), 4.85 (d, J 6.0 Hz, 2 H, CH1CH0CH2), 6.33
(m, 1 H, CH1CH0CH2), 6.69 (d, J 16 Hz, 1 H, CH1CH0CH2),
6.81±7.46 (m, ArH), 9.86 (s, CHO); m/z (EIMS) 328 (M+,
10%), 300 (9), 177 (100), 146 (20) (Found: C, 69.42; H,
6.31. C19H20O5 requires C, 69.50; H, 6.14%).
rac-Kadsurenin M 1.ÐAn anti-pressure glass pipe charged with
a solution of 4 (164 mg, 0.5 mmol) in diethylaniline (2 ml) was
sealed and then heated at 180 8C for 12 h, cooled and diluted with
Et2O (20 ml). The solution was washed with 2 M HCl and H2O,
dried and evaporated to a residue. Puri®cation by ¯ash chromatog-
raphy gave a yellowish oil (66 mg). Crystallization from Et2O
yielded pure rac-kadsurenin M 1 (60 mg, 36.6%): mp 117±118 8C
1
(lit.,5 119±120 8C);
ꢀ
max/cm
(KBr) 3059±2951 (CH, aliphatic),
1682 (CHO), 1592, 1517, 1488, 1462, 1422, 1394, 1325, 1291, 1163,
1077, 1027, 943, 897; ꢁH 1.43 (d, 3 H, J 6.6 Hz, 9-H), 3.57 (dq, 1 H,
J 9.3 Hz, 6.6 Hz, 8-H), 3.88 (s, 3 H, 3-OMe), 3.89 (s, 3 H, 4-OMe),
3.95 (s, 3 H, 3'-OMe), 5.27 (d, 1 H, J 9.3 Hz, 7-H), 6.87 (d, 1 H, J
9.0 Hz, 5-H), 6.95 (d, 1 H, J 9.0 Hz, 6-H), 6.97 (s, 1 H, 2-H), 7.35
(s, 1 H, 6'-H), 7.38 (s, 1 H, 2'-H), 9.85 (s, 1 H, 7'-H); ꢁC 131.5
(C-1), 110.9 (C-2), 149.3 (C-3), 149.5 (C-4), 111.8 (C-5), 119.2 (C-6),
94.6 (C-7), 44.8 (C-8), 17.8 (C-9), 153.3 (C-1'), 109.5 (C-2'), 133.6
(C-3'), 144.9 (C-4'), 131.7 (C-5'), 120.0 (C-6'), 190.6 (C-7'), 55.9
(C-3,4), 56.1 (C-3'); m/z (EIMS) 328 (M+, 100%), 313 (18), 297 (9),
253 (12), 225 (10), 161 (10), 151 (20), 149 (21), 137 (7) (Found:
C, 69.50; H, 6.24. C19H20O5 requires C, 69.50; H, 6.14%).
Scheme 1 Reagents: i, Me2SO4, 33% NaOH; ii, HO2CCH2CO2Et,
Pyr; iii, LiAlH4^AlCl3 (3:1), Et2O; iv, SO2Cl2, Pyr, CH2Cl2; v, sodium
salt of vanillin, DMF; vi, PhNEt2
Compound 1 was prepared by heating a sealed pipe
charged with a solution of 4 in N,N-diethylaniline at 180 8C
in 40% yield. The thermal reaction involved a Claisen
rearrangement followed by an abnormal Claisen rearrange-
ment.4 trans-2-Aryl-3-methylbenzofuran 1 was the major
product and the corresponding cis isomer was not observed
on TLC, owing to its very low content. The experiment
result is consistent with the high stereospeci®city of
associated with abnormal Claisen rearrangements. The
spectral data for 1 were identical with those reported.1
We thank Dr Cui Yu-Xin for obtaining NMR spectra.
Received, 3rd September 1997; Accepted, 28th October 1997
Paper E/7/06443H
References
1 Y. Ma, G. Q. Han and Y. Y. Wang, Yaoxue Xuebao, 1993, 28,
370.
2 P. Y. Ding and D. Q. Yu, Zhongguo Yaowu Huaxue Zazhi, 1995,
5, 59.
3 E. Siegfried, J. H. Drewer; Alda, A. L. Robin and J. U. Ursula,
Phytochemistry, 1984, 23, 1313.
4 G. F. Schmid, H. J. Hansen and H. Schmid, Helv. Chim. Acta,
1972, 55, 1625.
5 F. S. El-Feraly, S. F. Cheatham, C. D. Huord and W. S. Li,
Phytochemistry, 1982, 21, 1133±1135.
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
%Systematic name: (2S,3S)-2-(3,4-dimethoxyphenyl)-7-methoxy-3-
methyl-2,3-dihydrobenzo[b]furan-5-carbaldehyde.
Yi, Wang Ming
