WYE-120318, a ring contraction product of methylnaltrexone, and structure revision of coniothyrione

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. 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, and its structure was determined by spectroscopic data analyses. Remisporine A (compound 3) is envisioned as a naturally occurring ring contraction compound that autocatalytically dimerizes to 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 chlorosubstituent needs to be revised to compound 6.