Thiol-trapping natural products under the lens of the cysteamine assay: friends, foes, or simply alternatively reversible ligands?

The literature on thia-Michael acceptors is vast and can be cherry-picked to show either that these compounds pollute chemical libraries displaying unselective binding and propensity to toxicity, or, alternatively, that the thiol-trapping reaction is highly selective and critical for bioactivity. Since the energy of the carbon\u2013sulfur bond (ca 60\ua0kcal/mole) is similar to the one of the \u3c0-component of a carbon\u2013carbon double bond, all thia-Michael additions are, in principle, reversible, and basically thermodynamically driven by the difference in energy between an S\u2013H and a C\u2013H bond. However, the rate of the backward reaction can vary dramatically, depending on mesomeric effects, strain, and steric considerations that can substantially lower the kinetic barrier to the forward and backward reactions, while the position of the equilibrium is strongly affected by steric effects. As a result, a pulsed, transient binding reminiscent of a non-covalent interaction can take place. We describe how an NMR assay to identify transient Michael acceptors was serendipitously discovered during an investigation on the migraine-inducing toxic constituents of the headache tree [Umbellularia californica (Hook. & Arn.) Nutt.], and summarize how the assay can also be used to locate thia-Michael acceptor sites in complex natural products, to comparatively evaluate thiol affinity in multi-electrophilic compounds, and to rate mixtures of acceptors according to their reactivity with thiol groups

Genepolide, a sesterpene gamma-lactone with a novel carbon skeleton from mountain wormwood (Artemisia umbelliformis)

The sesterpene γ-lactone genepolide (5) has been isolated from a Swiss horticultural variety of mountain wormwood (Artemisia umbelliformis) developed as a thujones-free alternative to native Western Alps wormwoods for the production of liqueurs. Genepolide is the formal Diels-Alder adduct of the exomethylene-γ-lactone costunolide (2) and the diene myrcene (6), two poorly reactive partners in cycloaddition reactions, and its structure was elucidated through a combination of spectroscopic methods. An investigation on the thermal stability of mixtures of 2 and 6, as well as considerations on the sensitivity of 2 to Br0nsted and Lewis acids, suggests that 5 is a genuine natural product and that the Swiss chemotype of A. umbelliformis contains Diels-Alderase enzymatic activity that is lacking in native mountain wormwoods from Western Alps. Remarkable differences in thermal and acid-catalyzed reactions of the cyclodecadiene moiety of 2 and 5 suggest that quaternarization at C-11 has far-reaching effects on the reactivity of their homoconjugated medium-sized diene system. The wide occurrence of this structural motif in sesquiterpenoids makes this issue worth a systematic investigation

A sesterpene lactone from Artemisia umbelliformis Lam.

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A sesterterpene lactone from Artemisia umbelliformis Lam.

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