Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Miller, Scott
Abstract
Metal-catalyzed nitrene transfer remains one of the most powerful methods to introduce nitrogen into minimally functionalized organic frameworks. In recent years, there have been significant advances in the development of catalytic systems to achieve these transformations selectively in increasingly complex environments. Despite this, full site- and stereocontrol remains challenging in many cases. This work describes our contributions to the field of selective metal-catalyzed nitrene transfer, which involve the use of peptide- based environments surrounding the catalytic metal. Chapter 1 places this work in a larger context, introduces the topics of homogeneous catalysis and nitrene transfer, and discusses methods to enable selective reactions, such as hydrogen-bond-driven catalysis and metallopeptide catalysis. Chapter 2 chronicles the development of a new set of chiral bisoxazoline ligandsderived from the dehydration of serine-containing peptides. We applied these ligands in the site-selective copper-catalyzed aziridination of substituted 1,3-dienes, our model system for polyene natural products. We showed a significant enhancement of the inherent site-selectivity, and used control experiments to support our hypothesis that this site-selectivity was driven by hydrogen-bond interactions between the peptide-based ligand and an amide directing group present in the 1,3-diene substrate. Chapter 3 describes the genesis of a new class of chiral dirhodium(II) complexes based on β-turn-containing tetrameric aspartyl peptides. We demonstrated the modularity and ease of synthesis of this platform through the preparation of a library of 40 new catalysts. Also detailed is the characterization of our optimized catalyst via NMR and X-ray crystallographic studies, presenting the first reported crystal structure of a peptidic dirhodium(II) aspartate complex. This solid-state structure revealed a number of interesting structural insights, including a fourfold symmetry, and can serve as an inspiration for potential modifications to enhance selectivity. The application of the dirhodium(II) metallopeptide library in enantioselective benzylic C(sp3)–H amination is showcased in Chapter 4. Through optimization of the ligand, we were able to achieve levels of enantioselectivity at or above the state of the art, and addressed a number of challenges that exist with previously reported catalyst systems. In addition, we observed a heretofore unknown transformation for dirhodium(II) involving nitrene insertion into N-alkylamide C(sp3)-H bonds to form 1,1-diamines. Control studies showed that it is plausible that the catalyst undergoes self-amination through this same mechanism under the reaction conditions. Ultimately, in this work we unveil two new ligand classes that address a number of selectivity challenges in metal-catalyzed nitrene transfer. Their ease of synthesis and modularity, together with our discussion on important structural and mechanistic elements, provides a foundation for the development of next-generation bisoxazoline ligands and dirhodium(II) metallopeptides and their application in nitrene transfer and beyond.
Recommended Citation
van den Heuvel, Naudin, "Peptidic Environments for Site- and Enantioselective Nitrene Transfer" (2023). Yale Graduate School of Arts and Sciences Dissertations. 986.
https://elischolar.library.yale.edu/gsas_dissertations/986
