Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines

• Published in: Journal of the American Chemical Society Vol. 138; no. 13; pp. 4338 - 4341
• Main Authors: Kubota, Koji, Watanabe, Yuta, Hayama, Keiichi, Ito, Hajime
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.04.2016; Amer Chemical Soc
• Subjects: Antidepressive Agents - chemical synthesis; Antidepressive Agents - chemistry; Antidepressive Agents - pharmacology; Catalysis; Chemistry; Chemistry, Multidisciplinary; Dihydropyridines - chemistry; Molecular Structure; Paroxetine - chemical synthesis; Paroxetine - chemistry; Paroxetine - pharmacology; Physical Sciences; Piperidines - chemical synthesis; Piperidines - chemistry; Pyridines - chemistry; Science & Technology; Stereoisomerism; CATALYZED HYDROBORATION; HETEROCYCLES; EFFICIENT ROUTE; BORONIC ESTERS; ALDEHYDES; AMINE; BORYLATION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.6b01375

We have developed a novel approach for the synthesis of enantio­enriched 3-boryl-tetrahydro­pyridines via the Cu­(I)-catalyzed regio-, diastereo-, and enantio­selective proto­borylation of 1,2-dihydro­pyridines, which were obtained by the partial reduction of the pyridine derivatives. This dearomatization/enantio­selective borylation stepwise strategy provides facile access to chiral piperidines together with the stereo­specific transformation of a stereo­genic C–B bond from readily available starting materials. Furthermore, the utility of this method is demonstrated for the concise synthesis of the antidepressant drug (−)-paroxetine. A theoretical study of the reaction mechanism is also described.