Multienzymatic Synthesis of γ‐Lactam Building Blocks from Unsaturated Esters and Hydroxylamine

Abstract

The assembly of enzymatic cascades and multi-step reaction sequences represents an attractive alternative to traditional synthetic-organic approaches. The biocatalytic reaction mediators offer not only mild conditions and permit the use of environmentally benign reagents, but the high compatibility of different enzymes promises more streamlined reaction setups. In this study, a triple-enzymatic strategy was developed that enables the direct conversion of γ,δ-unsaturated esters to N-hydroxy-γ-lactame building blocks. Hereby, a lipase-catalyzed hydroxylaminolysis generates hydroxamic acid intermediates that are subsequently aerobically activated by horseradish peroxidase and glucose oxidase to cyclize in an intramolecular nitroso ene reaction. Utilizing the hydroxyl­aminolysis/ene-cyclization sequence for the preparation of an aza-spirocyclic lactam, the multi-enzymatic methodology was successfully employed in the synthesis of key intermediates en route to alkaloids of the Cephalotaxus family.