Total synthesis of nahuoic acid A via a putative biogenetic intramolecular Diels-Alder (IMDA) reaction.

ABSTRACT: Inspired by 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 SETD8, has been carried out. A non-conjugated pentaenal precursor was synthesized with high levels of stereoselectivity at seven stereogenic centers and with the appropriate control of double bond geometries. Although the IMDA reaction of the non-conjugated pentaenal using Me2AlCl for catalysis at -40 °C selectively afforded the trans-fused diastereomer corresponding to the Re-endo mode of cycloaddition, under thermal reaction conditions it gave rise to a mixture of diastereomers, that preferentially formed through the exo mode, including the cis-fused angularly-methylated octahydronaphthalene diastereomer precursor of nahuoic acid A. The natural product could be obtained upon oxidation and overall deprotection of the hydroxyl groups present in the Si-exo IMDA diastereomer.

SUBMITTER: Guillade L 

PROVIDER: S-EPMC8612404 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature