Divergent Pathway for the Solid-Phase Conversion of Aromatic Acetylenes to Carboxylic Acids, α-Ketocarboxylic Acids, and Methyl Ketones

Abstract

An efficient divergent pathway for the selective and quantitative solid-phase conversion of aromatic acetylenes to the corresponding carboxylic acids, alpha-keto-carboxylic acids, and methyl ketones is presented. A range of aromatic trimethylsilyl-protected acetylene building blocks was synthesized in excellent yields using a Sonogashira cross-coupling protocol and used in solid-phase synthesis on PEGA resin. Dependent on the selection of conditions, the same solid-supported alkyne could be quantitatively converted to an aromatic carboxylic acid, an aromatic alpha-ketocarboxylic acid, or an aromatic methyl ketone. The conversion to carboxylic acid involved an OsO4/NaIO4/HMTA-mediated oxidative cleavage of the silyl-deprotected alkyne to provide the aromatic carboxylate in excellent yield. The alpha-ketocarboxylic acids were obtained by direct treatment of the trimethylsilyl-protected alkyne with OsO4/NMO/HMTA, while the ketones were obtained by simple acid-mediated hydration of the alkyne using aqueous TFA. In general, all products were obtained in excellent purities, typically above 90%. In addition, it was shown that the alkyne-containing building blocks could easily be incorporated into resin-bound peptides and after chemoselective conversion of the alkyne the new functional groups could be used for further derivatization into peptidomimetic compounds.