Addition of ester enolates to N-alkyl-2-fluoropyridinium salts: total synthesis of (+/-)-20-deoxycamptothecin and (+)-camptothecin

J Org Chem. 2002 Oct 18;67(21):7465-74. doi: 10.1021/jo026173j.

Abstract

Several 4-substituted dihydropyridones or 2-pyridones have been prepared by nucleophilic addition of alpha-(methylsulfanyl)ester enolates to N-alkyl-2-fluoropyridinium salts, followed by acid hydrolysis or oxidation with concomitant hydrolysis, of the intermediate 2-fluoro-1,4-dihydropyridine adducts, respectively. Addition of the enolate derived from isopropyl alpha-(methylsulfanyl)butyrate to N-(quinolylmethyl)-2-fluoropyridinium triflate 21 followed by DDQ treatment gave pyridone 29, from which (+/-)-20-deoxycamptothecin (31), a known precursor of camptothecin, was synthesized by a radical cyclization-desulfurization, with subsequent elaboration of the lactone E ring by chemoselective reduction. A similar sequence starting from the enolate of a chiral 2-hydroxybutyric acid derivative (33) provides access to natural (+)-camptothecin (37).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemical synthesis*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Camptothecin / analogs & derivatives*
  • Camptothecin / chemical synthesis*
  • Camptothecin / chemistry*
  • Esters
  • Indicators and Reagents
  • Models, Molecular
  • Molecular Conformation
  • Pyridinium Compounds*
  • Stereoisomerism

Substances

  • Antineoplastic Agents, Phytogenic
  • Esters
  • Indicators and Reagents
  • Pyridinium Compounds
  • Camptothecin