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.

Application of 1,n-ADEQUATE and Modified Variants to Structure Elucidation and Spectral Assignment Problems

“…44 The structure was determined using a combination of HSQC/HMBC data to locate the chloro substituent at the 3-position as shown by 12 based on the absence of a correlation from the methine singlet to the C1 carbonyl. More recently in a study by Kong et al, 45 based on empirical carbon chemical shift arguments, it was proposed that the location of the chloro substituent should be at the 4-position as shown by 13 rather than the 3-position as originally reported. That study was reported without the acquisition of any new NMR data.…”

Rare Chromones from a Fungal Mutant of the Marine-Derived Penicillium purpurogenum G59

“…Cyclopentachromones (CPCs), the tricyclic cyclopentabenzopyan-9-one derivatives, are relatively rare in nature. Only a few in this family has so far been reported from fungi, including coniochaetones A–D [ 1 , 2 , 3 ] and E–I [ 4 ], coniothyrione [ 5 , 6 ], diaportheones A–B [ 7 ], preussochromones D–F [ 8 ], cryptosporioptide [ 9 ], and remisporine A [ 10 ]. Remisporine B is a unique CPC dimer resulting from a spontaneous Diels-Alder reaction of remisporine A [ 10 ].…”

Coniothyrione: anatomy of a structure revision

“…Recently, a revision of the chloro substitution in the structure of coniothyrione based on the analysis of previously published data was reported (Fig. ) . The reported investigation and interpretation piqued our interest and led us to rigorously explore the basis of this new structure proposal.…”

“…The original structure, 1 , was chosen on the basis of the absence of what was believed to be a key 3 J CH HMBC correlation from the proton assigned as H4 to C1 . As pointed out in the work of Kong et al ., the bond angle between these two atoms is ~70°. This dihedral angle suggests that the 3 J CH coupling would be expected to be small on the basis of a Karplus‐like angular dependence on the coupling constant thus leaving the utility of this negative evidence questionable.…”

“…One of the main tenets of the updated structural proposal was an argument based on an empirical analysis of the 13 C chemical shifts reported in the original communication . Upon further investigation, we discovered that analysis of the 13 C NMR chemical shifts of this structure class was not straightforward and that an empirical approach to their analysis for the regiochemical assignment of the structure of coniothyrione may not be reliable.…”