Two-step Biocatalytic Resolution of rac-Primary Alcohol for Obtaining Each Isomeric Intermediate of Xanthorrhizol

From many kinds of natural products, interesting compounds have been extracted for human health and exhibited various biological activities, such as anticancer, antifungal, antioxidant, etc. They have been used as either raw mixtures or modified single ingredients for increased effectiveness. In addition, natural products have been used as lead compounds for new drug discovery programs. Phenolic sesquiterpene compounds have attracted much interest for their broad biological activities. Among them, xanthorrhizol has been investigated in the search for new biological activities. It was first isolated by Kochendoerfer from rhizomes of Curcuma xanthorrhiza Roxb. and exhibited antibacterial and antifungal activities. It has one chiral center, thus (R)and (S)-isomer can be generated as in Figure 1. Antibacterial activity is shown by (R)-xanthorrhizol which is a naturally occurring isomer. Owing to its broad pharmacological activities, several research groups have synthesized it as racemic or an enantiomerically pure compound. Of these, 3-methoxy-4-methyl acetophenone was employed as starting material and reacted with the corresponding homoprenyl bromide. Meyers et al. asymmetrically synthesized (S)-xanthorrhizol and analogues employing oxazolines as a chiral auxiliary. On the other hand, there is a report concerning chemoenzymatic transformation. In this report, they used baker’s yeast to reduce α,β-unsaturated aldehyde asymmetrically. Additionally, other reports were published to synthesize similar structures, such as curcuphenol and heliannuol D. Recently, Serra S. reported a result about resolution of substituted 2-aryl-propanols. This report is a comprehensive study about resolution of various substrates with lipases and includes a xanthorrhizol intermediate analogue. In spite of these reports, there is no one which gave both enantiomers as a pure state. Thus, we focused on the development of a method obtaining both enantiomers using a biocatalyst. As reported previously in patent, the primary alcohol 2, 2-(3-methoxy-4-methylphenyl)propan-1ol, was selected as a substrate for resolution as Figure 1. In order to prepare it, the commercially available compound 3, methyl 3-methoxy-3-methyl benzoate, was transformed to 2 through 3-steps as Scheme 1. The compound 3 was reacted with the Grignard reagent, CH3MgBr in THF, to give the carbinol 4. The compound 4 was carefully dehydrated to give 5 under the concentrated sulfuric acidic condition, otherwise transformed to the indane cyclic structure. Lastly, the resulting double bond was hydroborated with boraneSMe2 complex and oxidized with alkaline H2O2 to give the compound 2. To obtain the optically pure each isomer of the compound 2, we used hydrolysis or esterification reaction, which is dependent on the substrate physical property. At first, to get a suitable enzyme for this reaction, various enzymes were screened and their results are shown in Table 1. For hydrolysis, the compound 2 was acetylated as the substrate as Scheme 2. Its reaction condition was under pH 7