Polycyclic diterpenes exhibit many important biological activities, but de novo synthetic access to these molecules is highly challenging because of their structural complexity. Semisynthetic access has also been limited by the lack of chemical tools for scaffold modifications. We report a chemoenzymatic platform to access highly oxidized diterpenes by a hybrid oxidative approach that strategically combines chemical and enzymatic oxidation methods. This approach allows for selective oxidations of previously inaccessible sites on the parent carbocycles and enables abiotic skeletal rearrangements to additional underlying architectures. We synthesized a total of nine complex natural products with rich oxygenation patterns and skeletal diversity in 10 steps or less from ent-steviol.

Direct functionalization of C-H bond is rapidly becoming an indispensible tool in chemical synthesis. However, due to the ubiquity of C-H bonds, achieving site-selective functionalization remains an arduous task, especially on advanced synthetic intermediates or natural products. In contrast, Nature has evolved a multitude of enzymes capable of performing this task with extraordinary selectivity, and the use of these enzymes in organic synthesis may provide a viable solution to contemporary challenges in site-selective functionalization of complex molecules. This review covers recent applications of enzymatic C-H functionalization strategies in natural product synthesis, both in the context of key building block preparation and late-stage functionalization of advanced synthetic intermediates.

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Methoxyl group is the most abundant functional group of lignin, which affects the property, reactivity, and application of lignin. Efficient demethylation is always of interest to the area of lignin...

A combination of genomic and metabolomic approaches recently resulted in the identification of a nonribosomal tetrapeptide tambromycin, which possesses promising antiproliferative activity and several unusual structural features, including a densely substituted indole, a methyloxazoline ring, and an unusual pyrrolidine-containing amino acid called tambroline. In this work, we identify a concise synthetic route to access tambromycin, which relies on the strategic use of biocatalytic and chemocatalytic C-H functionalization methods to prepare two key precursors to the natural product in an efficient and scalable manner. The success of our study highlights the benefits of applying the principles of biocatalytic retrosynthesis as well as C-H functionalization logic to the synthesis of complex molecular scaffolds.