Efficient Enantiomeric Synthesis of Pyrrolidine and Piperidine Alkaloids from Tobacco

• Published in: Journal of organic chemistry Vol. 66; no. 19; pp. 6305 - 6312
• Main Authors: Felpin, Girard, Sandrine, Vo-Thanh, Giang, Robins, Richard J, Villiéras, Jean, Lebreton, Jacques
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21.09.2001
• Subjects: Alkaloids - chemical synthesis; Alkaloids - isolation & purification; Magnetic Resonance Spectroscopy; Molecular Conformation; Nicotiana - chemistry; Piperidines - chemistry; Piperidines - isolation & purification; Plants, Toxic; Pyrrolidines - chemistry; Pyrrolidines - isolation & purification
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo010386b

An enantiomeric synthesis of six piperidine and pyrrolidine alkaloids, (S)-nornicotine 1, (S)-nicotine 2, (S)-anatabine 3, (S)-N-methylanatabine 4, (S)-anabasine 5, and (S)-N-methylanabasine 6, known as natural products in tobacco, was established from a common chiral homoallylic (S)-3-(1-azido-but-3-enyl)-pyridine 15. An intramolecular hydroboration−cycloalkylation of the homoallylic azide intermediate 15 served as the key step in the pyrrolidine ring formation. A ring closing metathesis reaction (RCM) of a diethylenic amine intermediate (S)-allyl-(1-pyridin-3-yl-but-3-enyl)-carbamic acid benzyl ester 20 served as the key step in the piperidine ring formation. From the commercially available 3-pyridinecarboxaldehyde 13, a short and convenient enantiomeric synthesis of tobacco alkaloids is described:  (S)-nornicotine 1 (5 steps, with an overall yield of 70%), (S)-nicotine 2 (6 steps, 65%), (S)-anatabine 3 (8 steps, 30%), (S)-N-methylanatabine 4 (8 steps, 25%), (S)-anabasine 5 (8 steps, 35%), and (S)-N-methylanabasine 6 (8 steps, 25%).