Proteasome inhibition by a totally synthetic β-lactam related to salinosporamide A and omuralide

A new and effective proteasome inhibitor, β-lactam 3, has been accessed enantioselectively by multistep synthesis from the readily prepared intermediates 7 and 8 which were joined by a [2 + 2]-cycloaddition reaction to form the spiro β-lactam 9 stereoselectively. The intermediate 9 was converted to 3 in seven steps and 30% overall yield. The β-lactam 3 is stable for many days in water at pH 7, in contrast to the natural β-lactones salinosporamide A (1) and omuralide (2). In common with 1 and 2, the β-lactam 3 effectively inhibits the mammalian proteasome. Copyright © 2005 American Chemical Society.