Synthesis of hydroquinone dihydroisocoumarins: Application of the contrasteric aromatic Claisen rearrangement

Natural products based on a dihydroisocoumarin scaffold typically possess a resorcinol motif due to their biosynthesis. Utilizing the contrasteric aromatic Claisen rearrangement, the total syntheses of butryoisocoumarin A and 5-hydroxymellein, along with four hydroquinone-derived analogues of dihydroisocoumarin natural products, are presented. The synthetic routes were designed in a step-economical manner while accessing structures with various substitution patterns (i.e., different aromatic substitution patterns, primary, secondary, and tertiary alcohols, and either γ- or δ-lactones). In total, only 17 total steps were required for the synthesis of the six targeted compounds. This opportunity for molecular mutation of the positioning of the phenols in the compounds, relative to their position in the natural products, opens the door to new structural scaffolds for use in total synthesis and medicinal chemistry lead discovery efforts.