Expeditious Microwave-Assisted Synthesis of 5‑Alkoxyoxazoles from α‑Triflyloxy Esters and Nitriles

A rapid and general access to diversely substituted 5-alkoxyoxazoles <b>2</b> (i.e., R¹, R² = alkyl, phenyl) from easily accessible α-triflyloxy/hydroxy esters <b>1</b> and nitriles with good yields (41–76%) is reported. The versatility of the cyclization is shown for a range of substrates with high selectivity toward triflates over mesylates and proved to be compatible with sensitive functional groups. As an illustration of this transformation, the first synthesis of the recently isolated hydroxypyridine methyl multijuguinate <b>4</b> was achieved in four steps through a hetero Diels–Alder reaction of the 5-alkoxyoxazole and acrylic acid, followed by a protodecarboxylation reaction

Thermally Controlled Decarboxylative [4 + 2] Cycloaddition between Alkoxyoxazoles and Acrylic Acid: Expedient Access to 3‑Hydroxypyridines

A modified Kondrat’eva cycloaddition involving an unprecedented thermally controlled metal-free decarboxylative aromatization affords an expedient access to natural 3-hydroxypyridine/piperidine systems

Metal-Free Decarboxylative Hetero-Diels–Alder Synthesis of 3‑Hydroxypyridines: A Rapid Access to <i>N</i>‑Fused Bicyclic Hydroxypiperidine Scaffolds

A complete experimental and theoretical study of the thermally controlled metal-free decarboxylative hetero-Diels–Alder (HDA) reaction of 5-alkoxyoxazoles with acrylic acid is reported. This strategy offers a new entry to valuable 2,6-difunctionalized 3-hydroxypyridines from readily available 2- and 4-disubstituted 5-alkoxyoxazoles. The reaction conditions proved compatible with, among others, ketone, amide, ester, ether, and nitrile groups. The broad functional group tolerance of the protocol allows a rapid and versatile access to both hydroxyindolizidine and hydroxyquinolizidine derivatives via a pyridine dearomatization strategy

Kondrat’eva Ligation: Diels–Alder-Based Irreversible Reaction for Bioconjugation

Diversification of existing chemoselective ligations is required to efficiently access complex and well-defined biomolecular assemblies with unique and valuable properties. The development and bioconjugation applications of a novel Diels–Alder-based irreversible site-specific ligation are reported. The strategy is based on a Kondrat’eva cycloaddition between bioinert and readily functionalizable 5-alkoxyoxazoles and maleimides that readily react together under mild and easily tunable reaction conditions to afford a fully stable pyridine scaffold. The potential of this novel bioconjugation is demonstrated through the preparation of fluorescent conjugates of biomolecules and a novel Förster resonance energy transfer (FRET)-based probe suitable for the in vivo detection and imaging of urokinase-like plasminogen activator (uPA), which is a key protease involved in cancer invasion and metastasis