A Bioinspired Synthesis of (±)-Rubrobramide, (±)-Flavipucine, and (±)-Isoflavipucine

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α-bromo-β-ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,β-epoxy-γ-lactam. Furthermore, the absolute configuration of naturally occurring (+)-rubrobramide was determined by vibrational circular dichroism. (±)-Flavipucine and (±)-isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α-bromo-β-ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)-flavipucine, which was converted into (±)-isoflavipucine by thermal isomerization.