Total Synthesis of (2)-Kadsurenin M$WangMingYi,Wu An Xin and Pan Xin Fu*Department of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University,Lanzhou 730000, P.R. ChinaThe 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 thetreatment of inammation and rheumatic conditions.Itsstructure was characterized upon the basis of spectral data.In continuation of our research work on the total synthesisof bioactive natural neolignans, we report here the rst totalsynthesis of racemic kadsurenin M.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 coupledwith 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 preparationof the cinnamyl phenyl ether 4 may also be useful forthe syntheses of many other benzofuranoid neolignanprecursors.Compound 1 was prepared by heating a sealed pipecharged with a solution of 4 in N,N-diethylaniline at 180 8Cin 40% yield. The thermal reaction involved a Claisenrearrangement followed by an abnormal Claisen rearrange-ment.4 trans-2-Aryl-3-methylbenzofuran 1 was the majorproduct and the corresponding cis isomer was not observedon TLC, owing to its very low content.The experimentresult is consistent with the high stereospecicity ofassociated with abnormal Claisen rearrangements. Thespectral data for 1 were identical with those reported.1ExperimentalMelting points were measured on a micro-melting pointapparatus and are uncorrected.Mass spectra were recorded on aZAB-HS spectrometer, 1H- and 13C-NMR spectra on a BrukerAM-400 instrument in CDCl3 with Me4Si as internal standardand IR spectra on a FT-170 SX spectrometer. Elemental analyseswere performed on a Carlo Erba-1106 instrument. All compoundswere puried by ash chromatography on silica gel H (200¡Ó300mesh; Qingdo Marine Chemical Factory), eluting with solventmixtures of light petroleum (bp 60¡Ó90 8C), acetone and chloroform.3,4-Dimethoxycinnamyl 4-Formyl-2-methoxyphenyl Ether 4.Toa 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 roomtemperature.The mixture was stirred for 1 h, and subsequently thesolvent was removed under reduced pressure to aord the sodiumsalt of vanillin in nearly quantitative yield. To a solution ofthe sodium salt of vanillin in DMF (10 ml) was added dropwise asolution of 3 (1.5 g, 7.1 mmol) in DMF. The mixture was stirred atroom temperature for 24 h, after which the solvent was evaporatedunder vacuum and the residue was extracted with Et2O.Standardethereal work-up and ash chromatography gave a yellowish solid(1.5 g) which was crystallized from Et2O to provide 4 (1.3 g, 60%)as colourless needles: mp 125.5¡Ó126.5 8C; max/cm£¾1 (KBr) 3002¡Ó2884 (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, 33 H, 3OMe), 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¡Ó7.46 (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.An anti-pressure glass pipe charged witha solution of 4 (164 mg, 0.5 mmol) in diethylaniline (2 ml) wassealed and then heated at 180 8C for 12 h, cooled and diluted withEt2O (20 ml). The solution was washed with 2 M HCl and H2O,dried and evaporated to a residue. Purication by ash chromatog-raphy gave a yellowish oil (66 mg).Crystallization from Et2Oyielded pure rac-kadsurenin M 1 (60 mg, 36.6%): mp 117¡Ó118 8C(lit.,5 119¡Ó120 8C); max/cm£¾1 (KBr) 3059¡Ó2951 (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, J9.0 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%).We thank Dr Cui Yu-Xin for obtaining NMR spectra.Received, 3rd September 1997; Accepted, 28th October 1997Paper E/7/06443HReferences1 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¡Ó1135.J. Chem. Research (S),1998, 168$Scheme 1 Reagents: i, Me2SO4, 33% NaOH; ii, HO2CCH2CO2Et,Pyr; iii, LiAlH4^AlCl3 (3:1), Et2O; iv, SO2Cl2, Pyr, CH2Cl2; v, sodiumsalt of vanillin, DMF; vi, PhNEt2$This is a Short Paper as dened 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.*To receive any correspondence.168 J. CHEM. RESEARCH (S), 1998