N-Alkenylation of hydroxamic acid derivatives with ethynyl benziodoxolone to synthesize cis-enamides through vinyl benziodoxolones.

The stereoselective synthesis of cis-β-N-alkoxyamidevinyl benziodoxolones (cis-β-N-RO-amide-VBXs) from O-alkyl hydroxamic acids in the presence of an ethynyl benziodoxolone-acetonitrile complex (EBX-MeCN) is reported herein. The reaction was performed under mild conditions including an aqueous solvent, a mild base, and room temperature. The reaction tolerated various O-alkyl hydroxamic acids derived from carboxylic acids, such as amino acids, pharmaceuticals, and natural products. Vinyl dideuterated cis-β-N-MeO-amide-VBXs were also synthesized using deuterium oxide as the deuterium source. Valine-derived cis-β-N-MeO-amide-VBX was stereospecifically derivatized to hydroxamic acid-derived cis-enamides without the loss of stereoselectivity or reduction in the deuterium/hydrogen ratio.