No abstract

Nature provides an inexhaustible diversity of small organic molecules with beautiful molecular architectures that have strong and selective inhibitory activities. However, this tremendous biomedical potential often remains inaccessible, as the structural complexity of natural products can render their synthetic preparation extremely challenging. This problem is addressable by harnessing the biocatalytic procedures evolved by nature. In this work, we present an enzymatic total synthesis of ikarugamycin. The use of an iterative PKS/NRPS machinery and two reductases has allowed the construction of 15 carbon-carbon and 2 carbon-nitrogen bonds in a biocatalytic one-pot reaction. By scaling-up this method we demonstrate the applicability of biocatalytic approaches for the ex vivo synthesis of complex natural products.

All roads lead to Rome: The biosynthesis of the leporins in Aspergillus sp. involves an unprecedented pericyclic reaction cascade. The enzyme LepI directs the periselectivity of a [4+2] cycloaddition towards a hetero-Diels-Alder reaction outcome to give the leporin molecular scaffold. The Diels-Alder side product is morphed into the leporin core structure by a LepI-catalyzed retro-Claisen rearrangement, culminating in efficient kinetic side product recycling.