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Updated: Oct 10, 2025

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides
Published on: May 26, 2019
Total synthesis of nahuoic acid A via a putative biogenetic intramolecular Diels-Alder (IMDA) reaction
Lucía Guillade1, Paula Mora1, Pedro Villar1
1Departamento de Química Orgánica, Facultade de Química, CINBIO, IIS Galicia Sur, Universidade de Vigo 36310 Vigo Spain qolera@uvigo.es rar@uvigo.es.
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.
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