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Keywords:

  • NMR;
  • 1H;
  • 13C;
  • methylnaltrexone;
  • remisporine;
  • coniothyrione;
  • ring contraction;
  • benzyl-benzilic acid rearrangement

A contracted ring degradation product, WYE-120318 (compound 2), was discovered during the development phase for methylnaltrexone bromide (compound 1) drug substance. The compound was isolated by high-performance liquid chromatography fractionation, and its structure was determined by spectroscopic data analyses. WYE-120318 is formed from methylnaltrexone through a benzyl-benzilic acid type rearrangement reaction to yield an α-hydroxy-cyclopentanecarboxylic acid substructure. The proposed structure and the formation mechanism are confirmed by the synthesis of WYE-120318 from methylnaltrexone (compound 1).

A similar benzyl-benzilic acid type rearrangement reaction can be envisioned as the biological origin of remisporine A (compound 3), a naturally occurring cyclopentadienyl compound that autocatalytically dimerizes to remisporine B (compound 4). The structure of remisporine A was deduced from its dimer 4. Coniothyione (compound 5) can be considered as the first example of a stable natural product bearing the remisporine A skeleton. However, the regiochemistry of the chlorosubstitution in the coniothyrione structure needs to be revised to compound 6 on the basis of the nuclear magnetic resonance data and biogenesis analysis. Copyright © 2012 John Wiley & Sons, Ltd.