UC Santa Barbara

The stereoselective functionalization of pyridines remains a powerful strategy for the synthesis of biologically and synthetically valuable heterocycles. In this work, we have developed an efficient method for the direct enantio- and diastereoselective conjugate addition of 2-alkylpyridines to α-, β-unsaturated esters, mediated by chiral lithium amides. Under optimized conditions, this transformation delivers products bearing two adjacent stereocenters with excellent levels of both enantioselectivity and diastereoselectivity. Notably, the methodology also enables the independent installation of either the α- or β-stereocenter with high enantiomeric control, demonstrating its flexibility in accessing stereochemically diverse pyridine derivatives.The absolute configuration of the α- and β-stereocenters was confirmed by single-crystal X-ray diffraction of a representative N-methylated salt, providing a reference for the stereochemical assignment of the substrates. The synthetic utility of the method was further showcased through one-pot applications that exploit the in situ-generated enolate for secondary transformations, including alkylation, aldol condensation, and α-oxidation, thereby enabling the construction of up to four stereocenters in a single sequence.