Synthesis of Isoeuparin and Isotubaic Acid

Abstract

The compounds containing the benzofuran moiety are widely distributed in nature. They are used as versatile intermediates in organic and natural product synthesis. They have also shown a range of biologically activities. Among these, isoeuparin (1) was isolated from the roots of Tagetes patula and isotubaic acid (2) (rotenic acid) was obtained from the natural insecticide rotenone as a degradation product (Figure 1). The synthetic approaches to isoeuparin and isotubaic acid had been reported. We have used these known reactions in the synthesis of isoeuparin derivatives, but these reactions produce the expected products in low yield. The necessity for overcoming this problem has prompted a search for new routes for the synthesis of isoeuparin (1) and isotubaic acid (2). We have interest in the rhodium(II)-catalyzed reaction of iodonium ylides with several substrates. Recently, we have tried rhodium(II)-catalyzed reactions of iodonium ylides with electron-deficient and conjugated alkynes. These reactions provided tetrahydrobenzofuran derivatives 3-6 in moderate yields (Scheme 1). As an application of these methodologies, we describe herein an efficient total synthesis of isoeuparin (1) and isotubaic acid (2) starting from 6. Our synthetic strategy of isoeuparin (1) and isotubaic acid (2) is depicted in Scheme 2. The crucial starting material 6 was readily prepared in 53% yield from the iodonium ylide and 2-methyl-1-buten-3-yne in the presence of 1 mol % of Rh2(Opiv)4. 8 The reaction of 6 with methyl carbonate using excess NaH in the presence of a catalytic amount of KH in THF gave 7 in 96% yield. Oxidation of 7 with DDQ in refluxing 1,4-dioxane afforded aromatic compound 8 in 46% yield. Support for the structural assignment of 8 comes from spectroscopic analysis. The H NMR spectrum of 8 shows the expected two aromatic protons at δ 7.73 (d, J = 8.8 Hz) and δ 6.96 (d, J = 8.8 Hz). Conversion of 8 to isoeuparin (1) was accomplished by hydrolysis and the subsequent addition of MeLi. Reaction of 8 with 2.5 M NaOH in refluxing methanol gave acid 9 in 97% yield, which was treated with excess MeLi (4 eq) in toluene at 50 C for 4 h to afford 1 in 65% yield. The spectroscopic properties of our synthetic material 1 agreed well with those reported in the literature. Conversion of 9 to isotubaic acid (2) was carried out by catalytic hydrogenation. Hydrogenation of 9 at 20 psi H2 for 10 min in ethyl acetate afforded 2 in 88% yield. The spectral data of our synthetic material 2 agreed well with those reported in the literature. In conclusion, we have described here the synthesis of isoeuparin (1) and isotubaic acid (2) starting from tetrahydrobenzofuran 6. These synthetic approaches are expected to be widely used in the total synthesis of other natural products containing the benzofuran moiety.