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

Shinya Shiomi, Erika Sugahara, Hayato Ishikawa

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

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 0.1mol 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. An efficient protocol for the preparation of C4-alkyl substituted chiral piperidines using a secondary amine catalyzed formal aza [3+3] cycloaddition reaction with aliphatic α,β-unsaturated aldehydes and thiomalonamate derivatives is described. In addition, the enantioselective total synthesis of (+)-α-skytanthine using this developed reaction as key step was achieved in total 15% yield. All carbon and nitrogen units were introduced by one step with high enantioselectivity.

Original languageEnglish
Pages (from-to)14758-14763
Number of pages6
JournalChemistry - A European Journal
Volume21
Issue number42
DOIs
Publication statusPublished - 2015 Oct 1
Externally publishedYes

Keywords

  • cycloaddition
  • organocatalysis
  • piperidine synthesis
  • thiomalonamate
  • α-skytanthine

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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