Asymmetric sulfonium ylide mediated cyclopropanation: Stereocontrolled synthesis of (+)-LY354740

VK Aggarwal*, E Grange

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

73 Citations (Scopus)

Abstract

The reaction of ester-stabilized suffonium ylides with cyclopentenone to give (+)-5 ((1S,5R,6S)-ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate), an important precursor to the pharmacologically important compound (+)LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)(2), ethyl diazoacetate, 60 degrees C and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo- and enantioselectivity. Under catalytic conditions, closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide-mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95% ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has be en applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.

Original languageEnglish
Pages (from-to)568-575
Number of pages8
JournalChemistry - A European Journal
Volume12
Issue number2
DOIs
Publication statusPublished - 23 Dec 2006

Keywords

  • asymmetric synthesis
  • cyclopropanation
  • diastereoselectivity
  • LY354740
  • sulfur ylides
  • METABOTROPIC GLUTAMATE RECEPTORS
  • IN-SITU GENERATION
  • (+)-2-AMINOBICYCLO<3.1.0>HEXANE-2,6-DICARBOXYLIC ACID LY354740
  • PHARMACOLOGICAL CHARACTERIZATION
  • SULFUR YLIDES
  • CARBONYL-COMPOUNDS
  • AGONIST LY354740
  • DIAZO-COMPOUNDS
  • AMINO-ACIDS
  • POTENT

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