Enzyme Library-enabled Chemoenzymatic Tropolone Synthesis

Enzymes can offer an enticing tool for building complex chemical scaffolds through succinct routes and under mild conditions. Yet, the common application of biocatalysts in organic synthesis is often hampered by unpredictable substrate scope and scalability challenges, deterring the planning of biocatalytic steps at the retrosynthetic planning stage. Herein, we detail a method using a sequence similarity network to curate a library of non-heme iron (NHI)-dependent enzymes capable of performing complexity generating biocatalytic transformations. In the course of this study, we probed the substrate scope of TropC-like enzymes to furnish a range of beta-hydroxytropolone products. The potential to access diverse scaffolds was investigated and a variety of tropolone-containing molecules were prepared on milligram-scale. Furthermore, chemoenzymatically generated tropolones were transformed through a variety of chemistries to achieve the total synthesis of stipitaldehyde, an abbreviated formal synthesis of deoxyepolone B, and additional tropolone building blocks with a high density of functional handles. This work lays the foundation for using NHI enzymes in retrosynthetic planning of complex molecules and natural product analogues.