Neighboring amide participation in the Fenton oxidation of a sulfide to sulfoxide, vinyl sulfide and ketone relevant to oxidation of methionine thioether side chains in peptides

Olivier Mozziconacci, Ganga Viswanathan Bhagavathy, Takuhei Yamamoto, George S. Wilson, Richard S Glass, Christian Schöneich

Research output: Contribution to journalArticle

Abstract

Oxidation of Met affects the stability of proteins, and was identified as a step in the beta amyloid-dependent pathogenesis of Alzheimer's disease. One-electron oxidation of Met is facilitated through stabilization of sulfide radical cations with electron-rich heteroatoms. The formation of such 2-center-3-electron bonds, formed between sulfide radical cations and amides, leads to pronounced product selectivity during biologically relevant oxidation conditions. Conformationally constrained methionine analogs embedded within a norbornane framework, i.e., 2,6-endo, endo- and 2,6-exo, endo-pyrrolidine amide thiomethyl bicyclo[2.2.1]heptanes were synthesized. Oxidation of both methionine analogs in the Fenton oxidation yielded some sulfoxide. In addition, the oxidation of the endo, endo-derivative generated a vinyl sulfide while the exo, endo-derivative was converted into a ketone, indicating a selective influence of a sulfur-oxygen 2-center-3-electron bond on product formation. Mechanistic details of product formation were investigated through the incorporation of stable isotopes.

Original languageEnglish (US)
Pages (from-to)7770-7789
Number of pages20
JournalTetrahedron
Volume72
Issue number48
DOIs
StatePublished - Dec 1 2016

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Keywords

  • Conformationally constrained sulfide
  • Fenton oxidation
  • methionine
  • Neighboring group effect
  • Sulfide radical cation
  • Two center–three electron (2c–3e) bond

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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