Studies towards the Total Synthesis of Amycolamicin: A Chiral Auxiliary-Based Diels-Alder Approach towards the Decalin Core

The stereoselective synthesis of (1S,2S,5R)-5-((4-methoxybenzyl)oxy)-2-methyl-8-methylene-1,2,4a,5,6,7,8,8a-octahy-dronaphthalene-1-carboxylic acid (2) is described, which comprises the bicyclic core structure of the natural product amycolamicin (1). The bicyclic ring-system was established via an intramolecular Diels-Alder reaction of a triene carrying a SuperQuat chiral auxiliary. The latter could be readily removed by methanolysis in excellent yield, which allowed for effective conversion of a hydroxy group at C(1) into the methylene group present in the natural product. The intramolecular Diels-Alder reaction could also be performed with a triene incorporating a classical, phenylalanine-derived Evans auxiliary, but the removal of the latter from the initial Diels-Alder product was hampered by competing attack of nucleophiles on the endocyclic carbonyl group in the oxazolidinone ring. Acid 2 could be converted into an acyl cyanide that features as a key advanced intermediate in one of the three total syntheses of amycolamicin reported to date.ISSN:1434-193XISSN:1099-069