| Peptides are attractive scaffolds for catalysts, due not only to the modularity of their side chains, but also to the inherent functionality of their backbones, which has the potential to engage substrates through non-covalent interactions such as hydrogen bonding. As such, the Miller group has developed numerous catalysts that can mediate transformations such as acylation, phosphorylation, bromination, and epoxidation, with high levels both of reactivity and of enantioselectivity. The selectivity in such reactions is controlled by the particular amino acid sequence of the peptide. Therefore one challenge in the development of such catalysts is to identify sequences that can induce the desired selectivity, be it regio-, enantio-, or chemoselectivity. The catalytic activity typically stems from a specific functional group that is installed in the peptide because of its ability to mediate a particular chemical reaction. As such, it is a separate challenge to expand the scope of peptide catalysts by exploring new functional groups that can be incorporated into peptide scaffolds and used to catalyze a desired reaction.;The dioxirane is a three-membered cyclic peroxide that may be prepared by the reaction of a ketone with a variety of nucleophilic oxidants. This highly reactive functional group, which can be further activated by proximal electron-withdrawing groups, can effect a wide range of electrophilic oxidations, including epoxidation and C--H oxidation. In the course of the oxidation reaction, the dioxirane is converted back into the parent ketone, thus allowing the ketone to be used catalytically in conjunction with a stoichiometric oxidant. Furthermore, the reaction can be rendered enantioselective, if the ketone is embedded in a suitable chiral scaffold. This dissertation describes the synthesis of a fluorinated ketone that can be embedded in a peptide scaffold, then converted to the dioxirane in situ and used to epoxidize alkenes in high yield and good enantioselectivity.;The oxaziridine is the mono-nitrogenated analog of the dioxirane. These oxidants typically have higher thermal stability relative to dioxiranes, but may also be activated by adjacent electron-withdrawing groups. In particular, fluorinated oxaziridines can be powerful enough to mediate oxidation reactions as challenging as C--H oxidation. Here, the evaluation of peptide-embedded trifluoro-methyl oxaziridines for their ability to effect C--H oxidation is described.;In addition to metal free oxidation methods, organometallic complexes are known to catalyze myriad oxidation reactions. It is also known that ligand motifs can be incorporated into peptides and used to position metal ions at fixed positions in peptide and protein sequences. In this dissertation, various ligand motifs have been incorporated into peptide sequences and investigated, in conjunction with different transition metals, as catalysts for the oxidation of organic substrates. In particular, peptide complexes of ruthenium have been shown to oxidize benzylic C--H bonds at room temperature. Furthermore, peptide complexes of both ruthenium and copper have been shown to oxidize various alcohols, including the glycopeptide natural product teicoplanin-A 22.;The Miller group has previously shown that peptides containing aspartic acid can serve as efficient catalysts for hydrogen-bond directed epoxidation of alkenes via the intermediacy of the peracid. Here, the methodology has been applied to an advanced indole intermediate in the total synthesis of the natural products cyclopiamine B and ent-citrinalin B. The substrate, which is predominantly converted to the undesired diastereomer in the reaction with conventional oxidants, is converted to the desired diastereomer in high yield under the influence of a variety of aspartate-containing catalysts. The oxidation, which thought to be directed by hydrogen bonding, tolerates the presence of an oxidation-prone chromene moiety, which is not oxidized appreciably by the peptide catalysts.;Finally, the aspartic peracid system has also been applied in the Baeyer--Villiger oxidation of cyclic ketones to the corresponding lactones. The peptide sequence, which was discovered through a combinatorial on-bead screening approach, is thought to engage the substrates through hydrogen bonding and is capable to reversing the regioselectivity with respect to m-CPBA. Furthermore, the catalyst is stereoselective, forming the products in moderate to excellent enantiomeric excesses. |
