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.

Comment

The 3-hydroxypyridine framework is found in a variety of natural products, including enzyme co-factors (A. C. Eliot, J. F. Kirsch Annu. Rev. Biochem. 2004, 73, 383), the thiopeptide antibiotic nosiheptide (C. Pascard, A. Ducruix, J. Lunel, T. Prangé J. Am. Chem. Soc. 1977, 99, 6418), and the bipyridinic antibiotics Caerulomycin B and C (G. Quéguiner and co-workers J. Org. Chem. 2002, 67, 3272). Application of the reported chemistry to the facile and regioselective two-step construction of a key 3-hydroxypyridine intermediate (en route to the nosiheptide building block) using simple reagents and reliable reactions is a marked improvement over the previously reported cumbersome synthesis of a structurally similar intermediate (K. Umemura et al. Tetrahedron Lett. 1997, 38, 3539).