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 MeAlCl for catalysis at -40 °C selectively afforded the -fused diastereomer corresponding to the mode of cycloaddition, under thermal reaction conditions it gave rise to a mixture of diastereomers, that preferentially formed through the mode, including the -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 IMDA diastereomer.
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Total synthesis of nahuoic acid A a putative biogenetic intramolecular Diels-Alder (IMDA) reaction.
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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 MeAlCl for catalysis at -40 °C selectively afforded the -fused diastereomer corresponding to the mode of cycloaddition, under thermal reaction conditions it gave rise to a mixture of diastereomers, that preferentially formed through the mode, including the -fused angularly-methylated octahydronaphthalene diastereomer precursor of nahuoic acid A.
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