A convergent synthesis of SylA was developed and consists
of the synthesis of a fully functionalized macrocycle, which
is subsequently coupled with a urea moiety. For cyclization,
ring-closing metathesis of a conformationally preorganized
precursor was employed. The established synthetic route was then applied to the synthesis of SylA derivatives by
using various peptidic side chains for decoration of the SylA macrocycle. The resulting collection of SylA analogues was tested for proteasome inhibition, revealing PEGylated SylA derivatives as the most potent proteasome inhibitors.