Synthesis of Two Phenolic, Bioactive Compounds, 1 & 2

Saturday, February 13, 2016
Derek Dimas, Del Mar College, Corpus Christi, TX
Background: Several bioactive compounds including 1 (4-Methoxy-1,3-benzodioxol-5-yl)(phenyl)methanone and 2(-)(S)-(4-Methoxy-1,3-benzodioxol-5-yl)(phenyl)methanol have been isolated from roots of Lindera fruticosa and Securidaca inappendiculata, shrubs endemic to Brazil. These compounds have been evaluated for inhibitory effects on acyl-CoA:cholesterol acyltransferase activity as well as in vitro oxidation of low-density lipoprotein. Our objective was to synthesize both bioactive phenolic compounds 1 and 2. Methods: Starting with the commercially available catechol, 3-methoxy-benzene-1,2 diol (3), a series of steps were taken to reach the desired compounds 1 and 2.  By way of literature methods, the ortho-catecholic hydroxyl groups of 3 were protected using a methenyl group.  A subsequent Vilsmeir-Haack formylation was done, resulting in the addition of an aldehydic group in the requisite position.  With the aldehydic intermediate in hand, a Grignard Reaction was done (phenyl magnesium bromide) to add a phenyl group resulting in a racemic mixture of +2.  Oxidation of +2 provided benzophenone 1.  Asymmetric reduction of +2 provided 1.  Results: Overall, yields of 1 and 2 were modest, and the optical purity of 2 will be determined by polarimetry.  At the time of this writing an alternative and shorter route to 1is being explored. We will provide 1H NMR and IR data to support the structural designations.  Polarimetric data will be provided as well to determine the optical purity of 1.  We also will attempt to have MS (mass spectral) data for each significant compound. Conclusions: We have demonstrated the utility of the Vilsmeir-Haack fomylation process, as well as other common reactions found in the synthetic organic chemists’ arsenal. Compound 1 has been produced by way of oxidation of +2.  Our current objective is to produce 1 directly by conducting a benzoylation procedure directly upon 4-methoxy-1,3-benzo-dioxole-5-carbaldehyde.  The latter compound is a formal intermediate in the existing synthesis.  If this proves successful, the number of steps needed to produce 2 and 1 will be reduced from by four and five steps, respectively, to three and four steps respectively.  Synthesis of bioactive compounds such as these from commercially available chemicals may lead to medical therapies without the destruction of endemic plants and habitats.