title: WYE-120318, a ring contraction product of methylnaltrexone, and structure revision of coniothyrione.
abstract: 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.
authors.affiliation: Structure Elucidation Group, Pfizer Worldwide Research and Development, 445 East Point Road, Groton, CT 06340, USA. fangming.kong@pfizer.com
authors.forename: Fangming
authors.initials: F
authors.lastname: Kong
authors.forename: Tianmin
authors.initials: T
authors.lastname: Zhu
authors.forename: Weitao
authors.initials: W
authors.lastname: Pan
authors.forename: Russ
authors.initials: R
authors.lastname: Tsao
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Pagano
authors.forename: Bao
authors.initials: B
authors.lastname: Nguyen
authors.forename: Brian
authors.initials: B
authors.lastname: Marquez
mesh_terms: D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002867:Chromones / Q000737:chemistry*; D019281:Dimerization; D009682:Magnetic Resonance Spectroscopy; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D002867:Chromones; D000644:Quaternary Ammonium Compounds; C580618:WYE-120318; C519757:coniothyrione; C032257:methylnaltrexone; D009271:Naltrexone