Streamlined Catalytic Enantioselective Synthesis of α-Substituted β,γ-Unsaturated Ketones and Either of the Corresponding Tertiary Homoallylic Alcohol Diastereomers
Juan del Pozo, Shaochen Zhang, Filippo Romiti, Shibo Xu, Ryan P. Conger, Amir H. Hoveyda
Abstract
A widely applicable, practical, and scalable strategy for efficient and enantioselective synthesis of β,γ-unsaturated ketones that contain an α-stereogenic center is disclosed. Accordingly, aryl, heteroaryl, alkynyl, alkenyl, allyl, or alkyl ketones that contain an α-stereogenic carbon with an alkyl, an aryl, a benzyloxy, or a siloxy moiety can be generated from readily available starting materials and by the use of commercially available chiral ligands in 52-96% yield and 93:7 to >99:1 enantiomeric ratio. To develop the new method, conditions were identified so that high enantioselectivity would be attained and the resulting α-substituted NH-ketimines, wherein there is strong C═N → B(pin) coordination, would not epimerize before conversion to the derived ketone by hydrolysis. It is demonstrated that the ketone products can be converted to an assortment of homoallylic tertiary alcohols in 70-96% yield and 92:8 to >98:2 dr-in either diastereomeric form-by reactions with alkyl-, aryl-, heteroaryl-, allyl-, vinyl-, alkynyl-, or propargyl-metal reagents. The utility of the approach is highlighted through transformations that furnish other desirable derivatives and a concise synthesis route affording more than a gram of a major fragment of anti-HIV agents rubriflordilactones A and B and a specific stereoisomeric analogue.