Synthesis of four isotopically labeled forms of a proteasome inhibitor, bortezomib

[D-2](1R)-3-methyl-l-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)aminolpropyl]-aminolbutyl] boronic acid ([D-2]bortezomib), a proteasome inhibitor, was synthesized in 11 steps from isobutyryl chloride. Key steps in the synthesis included formation of the isobutyryl boronic acid via Grignard reaction and preparation of the chiral chloride using Matteson reaction. [C-13(9)]bortezomib, [[D-5]bortezomib, and [D-1]bortezomib were similarly synthesized from appropriate labeled precursors. Copyright (C) 2007 John Wiley & Sons, Ltd.