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 journalArticlepeer-review

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 - 2016

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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