General Approach to Enantiopure 1-Aminopyrrolizidines: Application to the Asymmetric Synthesis of the Loline Alkaloids

J Org Chem. 2023 Jul 7;88(13):8093-8098. doi: 10.1021/acs.joc.3c00047. Epub 2023 Jun 13.

Abstract

The synthesis of a range of loline alkaloids is reported. The C(7) and C(7a) stereogenic centers for the targets were formed by the established conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-benzyloxypent-2-enoate, ensuing enolate oxidation to give an α-hydroxy-β-amino ester, and then formal exchange of the resultant amino and hydroxyl functionalities (via the intermediacy of the corresponding aziridinium ion) to give an α-amino-β-hydroxy ester. Subsequent transformation gave a 3-hydroxyprolinal derivative which was converted to the corresponding N-tert-butylsulfinylimine. Mannich-type reaction with the enolate derived from O-Boc protected methyl glycolate then formed the remaining C(1) and C(2) stereogenic centers for the targets. The 2,7-ether bridge was formed by a displacement reaction, completing construction of the loline alkaloid core. Facile manipulations then gave a range of loline alkaloids, including loline itself.

MeSH terms

  • Alkaloids*
  • Oxidation-Reduction
  • Pyrrolizidine Alkaloids*
  • Stereoisomerism

Substances

  • loline
  • 1-aminopyrrolizidine
  • Alkaloids
  • Pyrrolizidine Alkaloids