Asymmetric Synthesis of Piperidine via N-Sulfinyl Ketimines

Significance

2,4,6-Trisubstituted piperidines were synthesized via a 5-step sequence in overall moderate to good yield and excellent stereoselectivity. A Michael addition to an α,β-unsaturated ketone by an N-sulfinyl metalloenamine (formed in situ by deprotonation of the corresponding ketimine with LDA followed by transmetallation with ZnBr₂) afforded the addition product in good yield and excellent diastereoselectivity. Reduction using L-selectride, followed by DMP oxidation resulted in a syn-5-amino-ketone, while the anti-product was obtained using NaBH₄/Ti(OEt)₄ as a reductant. After cleavage of the N-tert-butylsulfinyl group using HCl, the aminoketone was readily converted into 2,4,6-trisubstituted piperidine in high diastereoselectivity using DIBAL-H.