Non-heme iron C-H oxidation: tolerance of nitrogen-containing motifs with application to amino-acid and peptide oxidation

Direct oxidation of C-H bonds using non-heme iron catalysis has proven to be a highly useful transformation since its development in recent years. The ability to directly install oxygen into a hydrocarbon framework negates the need for pre-oxidized materials, and allows for quick and efficient access to more diverse and complex molecules; in some cases, access to motifs that would not otherwise be accessible is possible. Furthermore, ligation at the iron center with a tetra-dentate amine complex containing two adjacent, equatorial active sites on the metal has allowed for synthetically useful levels of reactivity, with the added benefit of predictable selectivity and even directing group effects. In addition, the PDP ligand framework has been shown amenable to various steric and electronic modifications, allowing for tuning of reactivity and selectivity. Key limitations are still prevalent in the methodology, however, including lack of an enantioselective variant, and little/no tolerance of certain common functional groups including amines and most aromatic rings. This work describes development of novel substrate protection methods to address the functional group tolerance of nitrogen-containing substrates, with further application to oxidation of amino-acids and small peptides. Due to inherent catalyst reactivity and reaction conditions, highly complex molecules with a variety of functional groups remain challenging for C-H oxidation, a process that is highly desired in academic and industrial settings alike. The inherent ligation capabilities of nitrogen to iron (exemplified by the tetra-amine PDP ligand) obviate the difficulty in tolerating a substrate containing any variety of amine motifs. Novel protection strategies using various electron-withdrawing group on nitrogen were developed which prevent this ligation, and allow for productive oxidation at distal sites on the molecule. Due to the abundance of various classes of amines, different protective group strategies were developed, depending on which type of amine was present. Application of these protective schemes was then applied to amino-acid and peptide settings. An added benefit of an ester moiety adjacent to the amine allowed for simple nitrosulfonyl protection, whereby oxidation of aliphatic side chain residues was possible. In other cases, certain residues were found to be oxidatively stable. In dipeptide settings, selectivity trends were studied between various residues, and it was also found that residue position (N- vs. C- terminus) greatly affected reactivity trends. Overall this process has been shown to greatly surpass current state of the art methods for amino-acid and peptide oxidation/diversification, and increases the synthetic potential for development of pharmaceuticals of this variety.

Name thesis:degree_name

M.S.

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2013

Author dc:creator

• Snapper, Gregory

Contributors dc:contributor

• White, M. Christina

• C-H Oxidation
• Non-Heme Iron
• Peptide Oxidation
• Alkaloid C-H Oxidation

Statement dc:rights

• Copyright 2013 Gregory Snapper

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/45655

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/45655