A general method to assemble multi-substituted chiral piperidines was developed, inspired by the biosynthesis of piperidine natural products. In biosynthesis, Δ¹-piperideine 4 plays a key role as a common intermediate giving rise to a variety of piperidine-based natural alkaloids. Nature uses L-lysine as a building block, enzymatically transforming it into a δ-amino carbonyl intermediate 3 as the precursor to cyclize into Δ¹-piperideine 4. We envisioned that such a process could be accomplished by a vinylogous type Mannich reaction if a functionalized dienolate was employed. A stereoselective three-component vinylogous Mannich-type reaction (VMR) of 1,3-bis-trimethylsily enol ether 7 was therefore investigated and was found to give cyclized chiral dihydropyridinone compound 9 as an adduct. Like Δ¹-piperideine in biosynthesis, the chiral 2,3-dihydropyridinone compound 9 from VMR is a versatile intermediate for building a variety of new chiral piperidine compounds. The method was showcased by concise two-step approaches in the synthesis of the bioactive natural alkaloids (+)-241D; (−)-241D and isosolenopsin A. Furthermore, when properly functionalized substrate aldehyde 24 was employed, the corresponding dihydropyridinone adduct 25 cyclized to form a second piperidine ring, leading to a chiral polyfunctional quinolizidine enaminone 27. This versatile intermediate was used to prepare a variety of new chiral quinolizidine compounds, including natural alkaloid (−)-epimyrtine.