Model tetraenal 9b underwent intramolecular Diels-Alder cycloaddition in CHCl at -10 °C under catalysis by the bulky Lewis acid B(CF) to deliver as major components the cis-fused angularly-methylated octahydronaphthalene products, which are formed through the alternative exo orientations of the reacting moieties. One of these diastereomers features the relative and absolute configuration present in the core of nahuoic acid A, a natural product that acts as a cofactor-competitive inhibitor of the lysine methyl transferase SETD8. By contrast, catalysis of the reaction by MeAlCl at -40 °C selectively afforded the trans-fused isomer resulting from the Re-endo orientation.

The natural product tripartin has been reported to inhibit the N-methyl-lysine histone demethylase KDM4A. A synthesis of tripartin starting from 3,5-dimethoxyphenylacrylic acid was developed, and the enantiomers were separated by chiral HPLC. We observed that both tripartin enantiomers manifested an apparent increase in H3K9me3 levels when dosed in cells, as measured by western blot analysis. Thus, there is no enantiomeric discrimination toward this natural product in terms of its effects on cellular histone methylation status. Interestingly, tripartin did not inhibit isolated KDM4A-E under our assay conditions (IC >100 μm). Tripartin analogues with a dichloromethylcarbinol group derived from the indanone scaffold were synthesized and found to be inactive against isolated recombinant KDM4 enzymes and in cell-based assays. Although the precise cellular mode of action of tripartin is unclear, our evidence suggests that it may affect histone methylation status via a mechanism other than direct inhibition of the KDM4 histone demethylases.

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Inspired on the biogenetic proposal of an intramolecular Diels-Alder (IMDA) cycloaddition, the total synthesis of natural product nahuoic acid A, a cofactor-competitive inhibitor of the epigenetic enzyme lysine methyl transferase...