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Shiomi S, Sugahara E, Ishikawa H. Efficient Organocatalytic Construction of C4-Alkyl Substituted Piperidines and Their Application to the Synthesis of (+)-α-Skytanthine. Chemistry. 2015;21(42):14758-63doi: 10.1002/chem.201503117.
Shiomi, S., Sugahara, E., & Ishikawa, H. (2015). Efficient Organocatalytic Construction of C4-Alkyl Substituted Piperidines and Their Application to the Synthesis of (+)-α-Skytanthine. Chemistry (Weinheim an der Bergstrasse, Germany), 21(42), 14758-63. https://doi.org/10.1002/chem.201503117
Shiomi, Shinya, et al. "Efficient Organocatalytic Construction of C4-Alkyl Substituted Piperidines and Their Application to the Synthesis of (+)-α-Skytanthine." Chemistry (Weinheim an der Bergstrasse, Germany) vol. 21,42 (2015): 14758-63. doi: https://doi.org/10.1002/chem.201503117
Shiomi S, Sugahara E, Ishikawa H. Efficient Organocatalytic Construction of C4-Alkyl Substituted Piperidines and Their Application to the Synthesis of (+)-α-Skytanthine. Chemistry. 2015 Oct 12;21(42):14758-63. doi: 10.1002/chem.201503117. Epub 2015 Sep 03. PMID: 26333476.
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Chemistry. 2015 Oct 12;21(42):14758-63. doi: 10.1002/chem.201503117. Epub 2015 Sep 03.

Efficient Organocatalytic Construction of C4-Alkyl Substituted Piperidines and Their Application to the Synthesis of (+)-α-Skytanthine.

Chemistry (Weinheim an der Bergstrasse, Germany)

Shinya Shiomi, Erika Sugahara, Hayato Ishikawa

Affiliations

  1. Department of Chemistry, Graduate School of Science and Technology , Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto 860-8555 (Japan), Fax: (+81)?96-342-3397 http://www.sci.kumamoto-u.ac.jp/?ishikawa/ishikawa-lab/Top.html.
  2. Department of Chemistry, Graduate School of Science and Technology , Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto 860-8555 (Japan), Fax: (+81)?96-342-3397 http://www.sci.kumamoto-u.ac.jp/?ishikawa/ishikawa-lab/Top.html. [email protected].

PMID: 26333476 DOI: 10.1002/chem.201503117

Abstract

Chiral piperidines which contain an alkyl group at C4 positions are one of the important architectures because it is appeared in several natural products. An efficient protocol for the preparation of C4-alkyl substituted chiral piperidines using secondary amine catalyzed formal aza [3+3] cycloaddition reaction with aliphatic α,β-unsaturated aldehydes and thiomalonamate derivatives is reported. In our reaction system, thiomalonamate is an excellent nucleophile and the addition of suitable acid and its amount is an important factor for the acceleration effect in organocatalytic reaction. Furthermore, water and MeOH also have an acceleration effect. These efforts lead to only 0.1 mol % catalyst loading in multigram scale synthesis for suitable reaction time. In addition, the efficient enantioselective total synthesis of (+)-α-skytanthine by using our developed reaction as key step was achieved in total 15 % yield. All carbon and nitrogen units were introduced by one step with high enantioselectivity.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords: cycloaddition; organocatalysis; piperidine synthesis; thiomalonamate; α-skytanthine

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