Regioselectivity Study of Contrasteric Aromatic Claisen Rearrangements and Their Utilization in the Total Syntheses of 5-Hydroxymellein and Botyroisocoumarin A

In this study, we present data on the regioselectivity of aromatic Claisen rearrangements with <i>meta</i>-substituted benzenes. A variety of gentisic acid, tetralin, and <i>m</i>-salicylamide derivatives were synthesized to test the potential of an internal base to direct the regioselectivity of <i>ortho</i>-alkylation. A key mechanistic insight hinges on a reversible [3,3]-sigmatropic rearrangement step, supported by ¹H NMR studies of the isomerization of a <i>Z</i> to <i>E</i> crotyl group. This evidence supports the potential for the keto-enol tautomerization step of the aromatic Claisen rearrangement to be the rate-determining step. A ¹³C NMR study shows that this kinetic insight can be used to direct regioselectivity by correlating the carbonyl carbon shifts of salicylamides to the regioselectivity of the associated aromatic Claisen rearrangement. Systems with rigid, in-plane bases, especially <i>meta</i>-lactone carbonyls, are highly regioselective for the contrasteric position. The utility of this regioselectivity was used in 4-step syntheses of 5-hydroxymellein and botyroisocoumarin A.