An Artificial In Vitro Metabolism to Angiopterlactone B Inspired by Traditional Retrosynthesis

Nature's way to construct highly complex molecular entities as part of biosynthetic pathways is unmatched by any chemical synthesis. Yet, relying on a cascade of native enzymatic transformations to achieve a certain target structure, biosynthesis is also significantly limited in its scope. In this study, non‐natural biocatalytic modules, a peroxidase‐mediated Achmatowicz rearrangement and a dehydrogenase‐catalyzed borrowing‐hydrogen‐type isomerization were successfully incorporated into an artificial metabolism, combining the benefits of traditional retrosynthesis with the elegance and efficacy of biosynthetic networks. In a highly streamlined process, the total synthesis of tricyclic angiopterlactone B was achieved in two steps operating entirely in an aqueous environment while relying mainly on enzymes as key reaction mediators. Biocatalytic cascades, combining the selectivity of biological systems with the elegance of chemical synthesis, offer an exceptional opportunity for the preparation of complex molecular structures. By integrating native and abiotic enzyme modules in a metabolism‐like network, a five‐enzyme cascade coupled with a carbonate‐induced dimerization step yielded the tricyclic natural product angiopterlactone B in a two‐step process.