Unnatural amino acid derived fragments are present in a multitude of pharmaceuticals and biologically relevant molecules including complex peptides. Current preparative methods focus almost entirely on the enantioselective synthesis of the α-amino acid and rely on traditional condensative amide bond formation for peptide synthesis. Herein we report the development and application of a two-step protocol for the synthesis of unnatural α-alkyl α-amino amides, featuring enantioselective aza-Henry additions that feed directly into Umpolung Amide Synthesis (UmAS). The first and second enantioselective additions of bromonitromethane to N-Boc alkyl imines are reported. In the first, a known cinchona alkaloid-derived phase-transfer catalyst was leveraged to provide β-amino-α-bromonitroalkanes in high enantiopurity. The second method employs a bifunctional bis(amidine) catalyst to obtain the same β-amino-α-bromonitroalkanes with increased scope (access to both enantiomers) and in improved yield. In a separate study, mechanistic insight led to the development of UmAS utilizing N-iodosuccinimide (NIS) as a substoichiometric promoter, providing access to α-amino amides as a single diastereomer using fully enantioselective and catalytic methods. This two-step peptide synthesis protocol was applied to the synthesis of a fluorinated analogue of the natural product feglymycin, a tridecapeptide featuring nine arylglycine residues. Additionally, a protocol for the one-pot oxidative amidation of primary nitroalkanes was developed.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-10262016-111459 |
| Date | 26 October 2016 |
| Creators | Schwieter, Kenneth E. |
| Contributors | Jeffrey N. Johnston, Ph.D., Gary A. Sulikowski, Ph.D., Nathan D. Schley, Ph.D., Robert H. Carnahan, Ph.D. |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-10262016-111459/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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