Catalytic Asymmetric Synthesis and Applications of Stereogenic β'-Methyl Enones and β,β'-Dimethyl Ketones

The "Magic Methyl" effect has received tremendous interest in medicinal chemistry due to the significant pharmacological and physical modification of properties that have been observed upon introducing a methyl group, especially, a stereogenic methyl group into potential chiral drug candidates. The prevalence of stereogenic β-methyl ketone structural motifs in bioactive compounds and natural products has long motivated the development of enantioselective strategies toward their synthesis. Herein, we have rationally designed a Rh-catalyzed asymmetric monohydrogenation of readily-available β'-methylene conjugated enones with high efficiency and remarkable site-selectivity and enantioselectivity control for the practical construction of enantioenriched β'-methyl unsaturated enones that are difficult to access by other methods. Control experiments revealed that the conjugated C=C bond in β'-methylene conjugated enones plays a significant role in enhancing the reactivity of monohydrogenation. This methodology is applicable for the preparation of chiral β,β'-dimethyl ketones through consecutive double asymmetric hydrogenation of β,β'-dimethylene ketones. Detailed mechanistic investigation and DFT studies further provided strong support for a unique processive catalysis pathway for double asymmetric hydrogenation. The synthetic utilities have been demonstrated in the concise synthesis of several key intermediates for bioactive molecules, asymmetric total synthesis of natural products (S)-(+)-ar-Turmerone and (S)-(+)-dihydro-ar-Turmerone, and two C₂-symmetric chiral spirocyclic diol frameworks.