The Brønsted Acid‐Catalyzed, Enantioselective Aza‐Diels–Alder Reaction for the Direct Synthesis of Chiral Piperidones

We disclose herein the first enantioselective aza‐Diels–Alder reaction of β‐alkyl‐substituted vinylketene silyl‐O,O‐acetals and imines furnishing a broad range of optically highly enriched 4‐alkyl‐substituted 2‐piperidones. As a catalyst for this one‐pot reaction we employed a chiral phosphoric acid which effects a vinylogous Mannich reaction directly followed by ring‐closure to the lactam. Subsequent fully diastereoselective transformations including hydrogenation, enolate alkylation, and lactam alkylation/reduction processes converted the cycloadducts into various highly substituted piperidines of great utility for the synthesis of natural products and medicinally active compounds. All into one product: A phosphoric acid‐catalyzed 3‐component aza‐Diels–Alder reaction of β‐alkyl‐vinylketene silyl‐O,O‐acetals 1 with in situ‐generated imines furnished 4‐alkyl‐substituted 2‐piperidones 2 as major products in good yields and excellent enantioselectivity. Subsequent conversion of 2 into various highly substituted piperidines was accomplished with high flexibility and full control of stereoselectivity (PMP=para‐methoxyphenyl; TBS=tert‐butyldimethylsilyl).