Hetero diels-alder synthesis of 3-hydroxypyridines: Access to the nosiheptide core

The 1-azadiene hetero Diels-Alder reaction of silylated enol oximes with alkynes was investigated and was optimized to furnish 2,5,6-trisubstituted 3-hydroxypyridines in high yields in one simple operation. Importantly, monosubstituted alkynyl ketones were found to lead to the formation of the 6-isomer with exceptional regioselectivity (> 95:5). This methodology was applied to a scaleable synthesis of the core structure of the potent antibiotic nosiheptide. Protecting groups were optimized, which led to a racemization-free seven-step synthesis of the key building block.