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

• Published in: Chemistry : a European journal Vol. 23; no. 3; pp. 513 - 518
• Main Authors: Weilbeer, Claudia, Sickert, Marcel, Naumov, Sergei, Schneider, Christoph
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 12.01.2017; Wiley Subscription Services, Inc
• Subjects: Alkylation; asymmetric synthesis; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; aza-Diels–Alder reaction; Biological Products - chemical synthesis; Biological Products - chemistry; Catalysis; Chemistry; Chemistry, Multidisciplinary; Crystallography, X-Ray; Cycloaddition Reaction; Hydrogenation; Molecular Conformation; organocatalysis; Phosphoric Acids - chemistry; Physical Sciences; piperidones; Piperidones - chemical synthesis; Piperidones - chemistry; Science & Technology; silylketene acetals; Stereoisomerism; ASYMMETRIC CATALYSIS; VINYLOGOUS MANNICH REACTION; ALDIMINES; INDOLIZIDINE-BASED ALKALOIDS; SILICON LEWIS-ACID; BRASSARDS DIENE; MICHAEL REACTIONS; IMINO DIENOPHILES; ESTER IMINES; organocatalysis; DANISHEFSKY DIENE; piperidones; silylketene acetals; asymmetric synthesis; aza-Diels-Alder reaction
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201604356

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).