Synthesis of β-Hydroxylactams via Co-Catalyzed Alkylative Aldol Cyclization

Significance

Reported here is an intramolecular variant of highly diastereoselective Co-catalyzed alkylative aldol cyclizations of α,β-unsaturated amides with tethered ketones using trialkylalumi­num (R₃Al) reagents to give substituted piperidi­nones. This process leads to β-hydroxylactams containing three contiguous stereocenters with high diastereoselectivity. This reaction using Ni(acac)₂ as catalyst and R₃Al as reductant gives the normal reductive aldol product preferentially over alkylative aldol product, a reaction which is not explained. A possible catalytic cycle and rationale of stereochemical outcome based on a ­Zimmerman-Traxler-type transition state was discussed as shown.