New to Nature C–C Bond Forming Cyclases: Pushing the Boundaries of Ring Forming Reactions

Citation

Wackelin, Daniel Joseph (2024) New to Nature C–C Bond Forming Cyclases: Pushing the Boundaries of Ring Forming Reactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/26ag-8c56. https://resolver.caltech.edu/CaltechTHESIS:09022023-064950039

Abstract

Biocatalysts have shown themselves to be extremely powerful for the synthesis of pharmaceuticals, fragrances, and fine chemicals, providing products with high yields and selectivities. Recently, new-to-nature biocatalysis has received increased attention, allowing for the benefits of biocatalysis to be applied to reactions that were previously the sole domain of chemocatalysts. Engineers have begun to develop enzymes that catalyze new-to-nature C–C bond forming cyclisation reactions, which are quite powerful due to their ability to build the carbon skeleton of molecules. Despite this, this class of enzymes is limited in scope. This thesis details the expansion of C–C bond forming cyclases, including expanding the scope of cytochrome P411 cyclopropanation and an intramolecular C–H functionalization strategy for the synthesis of diverse rings. Chapter 1 introduces biocatalysis and its recent applications, especially as they apply to new-to-nature C–C bond forming cyclisation reactions. Chapter 2 shows the development of a cytochrome P411 that catalyzes the enantio- and diastero-specific synthesis of 1,2,3-polysubstituted cyclopropanes. Using directed evolution, this carbene transferase was evolved to react with internal alkenes and build two C–C bonds, expanding the scope and specificity of cyclopropanation reactions. Chapter 3 describes the expansion of this biocatalytic system toward the synthesis of stereoconvergent products, enabling more efficient synthesis from non-diasteropure starting materials. Chapter 4 details the evolution of a cytochrome P411 to perform an intramolecular C–H functionalization using diazo compounds, making a variety of differently sized rings with different molecular geometries. In summary, this work addresses the need for expansion of new-to-nature C–C bond forming cyclisation reactions and provides a guide for expanding new-to-nature reactions to their full potential.

Thesis Files