Syntheses of Naturally Occurring Lactams by the Use of Darzens Reaction

This paper describes racemic syntheses of naturally occurring lactams, epolactaene, berkeleyamide D, rubrobramide, flavipucine, and isoflavipucine. The key step is a regioselective Darzens reaction between glyoxals and alpha-bromo-beta-ketoamides. (+/-)-Epolactaene was synthesized by a Darzens reaction between methylglyoxal and a-bromo-beta-ketoamide. The synthesis of (+/-) berkeleyamide D was accomplished in only four steps from the reported starting material. The key features of this synthesis include the construction of a spirocyclic ring system by a C-acylation reaction followed by an intramolecular spirocyclization via an epoxide-opening reaction. Following optical resolution by chiral HPLC, the absolute configurations of both enantiomers of berkeleyamide D were determined by the vibrational circular dichroism exciton chirality method. The construction of the core tricyclic ring system of (+)-rubrobramide was achieved by a cascade reaction in a single step from an alpha,beta-epoxy-gamma-lactam. The alpha,beta-epoxy-gamma-lactam was prepared by the Darzens reaction. The absolute configuration of naturally occurring (+)-rubrobramide was determined by vibrational circular dichroism exciton chirality method. (+/-)-Flavipucine and isoflavipucine were synthesized from an epoxyketone, which was prepared by reaction of isobutylglyoxal with a protected alpha-bromo-beta-ketoamide. Removal of the protective groups in the epoxy ketone, and formation of the pyridone ring gave (+/-)-flavipucine, which was converted into isoflavipucine by thermal isomerization.