A Convenient Synthesis of (±)-3-Methoxybenzodioxane-4,9,9′-triol Neolignan, and Methyl Ethers of Isoamericanol A and Isoamericanin A

Abstract

The (2)-3-methoxybenzodioxane-4,9,9'-triol neolignan 9, and methyl ethers of isoamericanol A 8 and isoamericanin A 7 were synthesized from the readily available materials caffeic acid and ferulic acid, using a coupling reaction as a key step.Isoamericanol A, isoamericanin A and (2)-3-methoxybenzodioxane-4,9,9'-triol neolignan are three neolignans isolated from phytocaccaceae and Juniperns chinesis 1,2 and were assigned structure 7 H H H , 8 H H H and 9 respectively through spectral studies. In the literature it is reported that natural products containing the 1,4-benzodioxane ring have cytotoxic and hepatoprotective, 3 and other biological activity associated with the 1,4-benzodioxane group, 4 but no syntheses of these particular natural products have been reported.In order to study methods of construction of the 1,4-benzodioxane ring and the structure±activity relationship, we developed a facile synthetic route to (2)-3-methoxybenzodioxane-4,9,9'-triol neolignan 9, and methyl ethers of isoamericanol A 7 and isoamericanin A 8, in which use of silver carbonate as the oxidizing agent resulted in higher regioselectivity (ca. 30:1) than that obtained with silver oxide (ca. 20 :1) by Merlini et al. 5 As shown in Scheme 1, 3-(3,4-dihydroxy)phenylprop-2-enoate 5 and ferulic alcohol 3 were synthesized from the starting materials caeic acid and ferulic acid based on an earlier report, 3 then compounds 3 and 5 were converted into key intermediate 6 by a coupling reaction, which was then reduced with LiAlH 4 ±AlCl 3 (3 :1) to aord alcohol 7. Then 7 was hydrogenated to get the target compound 9 and was oxidized with MnO 2 ±SiO 2 to obtain compound 8. ExperimentalMelting points were measured on a Ko¯er apparatus and were uncorrected. Mass spectra were recorded on a ZAB-HS spectrometer. Elemental analyses were performed on a Carlo-Erba 1106 instrument. IR spectra were recorded on a Nicolet 170 SXFT-IR spectrometer. 1 H NMR spectra were recorded on a Bruker Ac-80 J. Chem. Research (S), 1999, 100±1016Scheme 1 Reagents and conditions: i: CH 3 OH, H 2 SO 4 , reflux; ii; LiAlH 4 , AlCl 3 room temp.; iii, Ag 2 CO 3 , acetone±benzene (1: 2), room temp.; iv, MnO 2 ±SiO 2 , CH 2 Cl 2 room temp.; v: H 2 , Pd/C (10%) and AM-400 instrument. Chemical shifts are referenced to Me 4 Si on the d scale. J values are in Hz. Standard¯ash chromatography was employed to purify the crude reaction mixture using ca. 200 H300 mesh silica gel under positive nitrogen pressure.

First Syntheses of (±)‐Butesuperins A and B

“…Biomimetic oxidative coupling has been successfully employed in the syntheses of 1,4‐benzodioxane lignan natural products . A number of oxidants have been examined for the regio‐ and stereoselective construction of 1,4‐benzodioxane systems via oxidative coupling including AgO, Ag 2 CO 3 , TiO 2 , AgNO 3, K 3 Fe(CN) 6, and horseradish peroxidase with hydrogen peroxide . As a part of our ongoing efforts to protect public health from illegal dietary supplements, we report herein the syntheses of butesuperins A ( 1 ) and B ( 2 ) by utilizing biomimetic oxidative coupling as a key step.…”

“…We next sought to screen a number of oxidants that could be used for this type of oxidative coupling. Oxidative coupling with Ag 2 CO 3 generated butesuperin A ( 1 ) in moderate yields (Table , entries 5 and 6) . However, this oxidative coupling failed when TiO 2 , AgNO 3, AgOAc, Na 2 Cr 2 O 7 , I 2 , CuO, or ZnO was used as the oxidant.…”

“…The reaction was also attempted in several other solvents to improve the yield and selectivity, but in vein ( Table 1, entries 3 and 4). 12 However, this oxidative coupling failed when TiO 2 , 13 AgNO 3, 14 AgOAc, Na 2 Cr 2 O 7 , I 2 , CuO, or ZnO was used as the oxidant. Oxidative coupling with Ag 2 CO 3 generated butesuperin A (1) in moderate yields (Table 1, entries 5 and 6).…”

The Stereoselective Synthesis of Neolignans

“…155 The use of 10 as the diphenol precursor was less efficient. Ag 2 CO 3 mediated oxidative coupling of 10 and 2 afforded 234 and 235 (R = CO 2 Me) in 40% yield (234:235 = 1:30) 156,157 and coupling with K 3 Fe(CN) 6 gave exclusively 234 in 31% yield. 158 Reduction of the ester group of 234 and 235 provided 228 and 229 in 82% and 75% yield, respectively.…”

“…Oxidation of the allylic alcohol then furnished 230 and 231 in 60% and 80% yield, respectively (Scheme 52). [156][157][158] No explanation was provided by the authors for the different regioselectivity in the cross-coupling induced by silver and by iron salts. However, one possible explanation might be as follows: basic silver salts suspended in aprotic organic solvents slowly deprotonates the phenol groups prior to the electron abstraction.…”