Highly Effective Total Synthesis of Benzofuran Natural Product Egonol

Abstract

Benzo[b]furan natural products isolated from the Styracaceae family such as Styrax japonicum, S. formosanus, S. obassia, S. macranthus and S. officinalis show variety of biological activities including insecticidal, fungicidal, antimicrobial, antisweet, antiproliferative, cytotoxic and antioxidant properties. Egonol, 5-(3-hydroxypropyl)-7-methoxy-2-(3,4-methylenedioxyphenyl)benzofuran, was first isolated in 1915 from the seed oil of Styrax japonicum and first synthesized by Kawai condensing an o-hydroxybenzaldehyde with an α-chlorophenylacetic acid and known to be an effective pyrethrum synergist. A number of total synthesis of egonol have been reported by using Sonogashira coupling, Lewis acid induced dehydrocyclization, dienylacetylene coupling with carbene complex, and palladium-catalyzed cross-coupling reaction. We report herein the most effective total synthesis of egonol (1, Figure 1) in 5 steps with 74% overall yield from vanillin by using Sonogashira coupling reaction. Vanillin (2) reacted with I2/Ag2SO4 in EtOH at room temperature to give iodovanillin 3 in 80% yield (Scheme 1). Sonogashira coupling of 3 with 3,4-methylenedioxyphenylacetylene (4), which was easily prepared from piperonal via Colvin rearrangement, by using Pd(PPh3)4/CuI/Et3N in DMF yielded benzofuran 5 in 95% yield through successive coupling and cyclization in one-step. Sonogashira coupling reactions were very sensitive to the haloaryl substituents as shown in Scheme 2. Bromovanillin 8 was not reactive with acetylene 4 in Sonogashira coupling reaction, and Wittig coupled bromide 9 and iodide 10 were also not reactive with 4 in coupling reaction, which indicated that the reaction sequences were very important in egonol synthesis and Sonogashira coupling should be done before Wittig reaction. Wittig reaction of 5 with (carbethoxymethylene)triphenylphosphorane produced carbethoxyethenylbenzofuran 6 in 99% yield, which was reduced to 7 in 99% yield by H2/PdC. Direct reduction of conjugated ester 6 to egonol 1 was performed by using LiAlH4 or LiBH4 as shown in Scheme 3. Partially reduced alcohol 11 with egonol and some other byproducts were formed in both cases and it was not easy to separate egonol from the alcohol 11 by column chromatography. Finally, reduction of ester 7 with DIBAL-H gave egonol (1) in 99% yield. Khan isolated a new egonol derivative, 5-(3-propanoyloxypropyl)-7-methoxy-2-(3,4-methylenedioxyphenyl)benzofuran (12), from Styrax obassia (Scheme 4). The newly found benzofuran 12 was easily prepared from our synthetic egonol 1 by esterification with propanoic acid using DCC in 99% yield and confirmed by NMR data with literature. In conclusion, the 5 steps reaction procedures including iodination, Sonogashira coupling, Wittig reaction, hydrogenation and metal hydride reduction produced egonol in