Regioselective Synthesis of Functionalized 3-Hydroxypyridines

Significance

Reported is a general and flexible synthetic route to structurally diverse 2,5,6-trisubstituted 3-hydroxypyridines, involving a hetero-­Diels-Alder reaction of azadienes with internal alkynes as the key step. Use of readily accessible silylated oximes 2 (with EWG on N-1) was necessary to increase the reactivity of the 1-azadienes (D. L. Boger, A. M. Kasper J. Am. Chem. Soc. 1989, 111, 1517; D. L. Boger et al. J. Am. Chem. Soc. 1991, 113, 1713), and allowed facile deprotection of the hydroxypyridine intermediate B. Increased stability, but decreased reactivity, was observed with sterically encumbered 1-azadienes (X = OTES). Good to excellent yields were obtained with electron-deficient alkynes, although electron-rich alkynes were inert under the reaction conditions. The reaction was found to be highly regioselective. Cycloaddition using a thiazolyl alkyne afforded a functionalized pyridine building block of nosiheptide, a peptidic antibiotic, as part of a seven-step synthesis.