Chemomimetic Biocatalysis for Enantioselective Synthesis of Cycloheptanoid Scaffolds
Final Report Abstract
In the original DFG application, I proposed the synthesis of cycloheptanoids through directed evolution of hemeproteins. However, I did not found an competent enzymes with the disired initial activity, therefore this research plan was suspended. Alternatively, I continued to work on directed evolution of hemeproteins for other non-natural trasformations. During the funding period of the DFG, I have completed one project which is primary amination of C(sp3)–H bonds. Primary amination of C(sp3)–H bonds remains unprecedented in both biosynthesis and synthetic chemistry. In this project, a set of new-to-nature enzymes were developed to enable this transformation, providing an unprecedented approach to accessing primary aliphatic amines with high chemoselectivity, regioselectivity, and enantioselectivity. Directed evolution of genetically-encoded cytochrome P411 enzymes generated variants that selectively functionalize benzylic and allylic C–H bonds, affording a broad scope of enantioenriched primary amines. This biocatalytic process is efficient and selective (up to 3930 TTN and 96% ee), and can be performed on preparative scale. Considering the fundamental roles of primary amines in the biological world and the natural occurrence and biocompatibility of hydroxylamine derivatives, it’s anticipated that these new, fully genetically-encoded enzymes will provide a starting point to extend or even reformulate currently mapped nitrogen metabolism. Such activities may already exist in nature, whose vast catalytic capabilities have only been partially explored. Further elucidation of the catalytic mechanism and characterization of the key intermediate would be valuable to generalize this process and inspire the design of corresponding small-molecule catalysts. Additionally, this enzymatic method should be of great commercial interest, considering the prevalence of primary amines in pharmaceuticals and the lack of efficient and direct methods to directly synthesize primary amines from hydrocarbons. Caltech has issued a provisional patent for this project.
Publications
- Enantioselective Aminohydroxylation of Styrenyl Olefins Catalyzed by an Engineered Hemoprotein. Angew. Chem, Int. Ed. 2019, 58, 3138–3142
Cho, I.; Prier, C. K.; Jia, Z.-J.; Zhang, R. K.; Görbe, T.; Arnold, F. H.
(See online at https://doi.org/10.1002/anie.201812968)
