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.

Comment

The reported reaction provides useful chiral piperidone building blocks for further asymmetric transformations. The scope of the reaction was fairly well studied. Reaction with R^¹ = EDGs worked better than those containing EWGs. This is the first report of conjugate addition of R₃Al reagents to α,β-unsaturated amides (Ni- and Cu-catalyzed addition of R₃Al to enones or enals is known: L. Bagnell et al. Aust. J. Chem. 1975, 28, 801; A. Alexakis et al. Chem. Commun. 2005, 2843; K. Li et al. Angew. Chem. Int. Ed. 2006, 45, 7600). Previously reported by this group are inter- and ­intramolecular Co-catalyzed reductive aldol reactions with Et₂Zn as the stoichiometric reductant (H. W. Lam et al. Org. Lett. 2007, 9, 4367; H. W. Lam et al. Org. Lett. 2006, 8, 3729). The simplicity of the procedure and the readily available starting materials bode well for further exploration of this method.