Development of a Hypervalent Iodine Promoted One Step Formation of Tri- and Tetrasubstituted Cyclobutanes with Defined Relative and Absolute Configuration
Final Report Abstract
The α-alkylation of ketones with alcohols using hydrogen borrowing chemistry has emerged as a powerful tool for C–C-bond formation. This concept is based on a transition metal catalyst oxidizing the alcohol to a carbonyl compound which then condenses with the ketone to give an enone intermediate. Subsequent reduction of the formed condensation product by the catalyst with the “borrowed” hydrogen from the alcohol gives the corresponding alkylated ketone. Contributions of the Donohoe group to this field made use of the sterically demanding pentamethyl phenyl group (Ph*) to prevent overreduction of the ketone moiety. Furthermore, the Br2-mediated retro-Friedel-Crafts acylation of the Ph* group allows for the synthesis of different carboxylic acid derivatives. In this context, a new cascade reaction was developed, imbedding a vinyl cyclopropane rearrangement in the described sequence. Starting from cyclopropyl-substituted secondary alcohols, the enone intermediate formed after condensation contains a vinyl cyclopropane motif that undergoes a ring-expansion to give cyclopentanes with high trans-diastereoselectivity as the final product. Interestingly, mechanistic studies with independently synthesized reaction intermediates revealed that this rearrangement is not promoted by the transition metal catalyst, but the result of a radical process initiated by a single electron transfer. This new method tolerates a wide variety of substitution patterns on the cyclopropyl alcohol and allows for the efficient construction of complex bicyclic carbon skeletons with up to four continuous stereocenters.
