Asymmetric three- and [2 + 1]-component conjugate addition reactions for the stereoselective synthesis of polysubstituted piperidinones†
The efficiency and stereoselectivity of the conjugate addition of lithium (Z)- or (E)-β-amino ester enolates, generated by lithium amide conjugate addition to an α,β-unsaturated ester or deprotonation of a β-amino ester, respectively, to a range of α,β-unsaturated acceptors has been investigated. Deprotonation of a β-amino ester with LDA, followed by conjugate addition to a chiral α,β-unsaturated oxazolidinone gives high 2,3-anti selectivity (∼90% d.e.), with hydrogenolysis and purification to homogeneity generating stereodefined trisubstituted piperidinones as single stereoisomers. Asymmetric three-component couplings of α,β-unsaturated esters and alkylidene malonates initiated by lithium amide conjugate addition proceeds with high levels of 2,3-anti stereoselectivity, with hydrogenolysis giving tetrasubstituted piperidinones.