Dissertation
The Aziridine-Mediated Ligation and Efforts Towards a General Synthesis of N-terminal Aziridinyl Peptides
Doctor of Philosophy (PhD), Washington State University
01/2013
Handle:
https://hdl.handle.net/2376/5047
Abstract
Herein is described the Aziridine-Mediated Ligation's discovery, conceptual development, and the efforts to develop a general synthetic method for the synthesis of unprotected peptide chains terminated in an aziridine. The Aziridine Mediated Ligation is a chemical ligation of a C-terminal thioacid and N-terminal aziridinyl peptide in the presence of active copper(II) ion. The process was demonstrated to be chemoselective for the desired reaction in the presence of a wide array of other free functional groups under denaturing aqueous conditions. It is proposed that the copper(II) activates the C-terminal thioacid, creating a water-stable "active ester" which shows an enhanced reactivity for aziridines over a typical amine.
The scope of the Aziridine-Mediated Ligation is limited because of the difficulties synthesizing and isolating unprotected aziridinyl peptides from aqueous media. A thorough examination of known protecting groups led to the discovery of a photo-released precursor to the aziridine coupling partner, which readily participates in the Aziridine-Mediated Ligation. The photolysis by-products appear to be inert to the Aziridine-Mediated Ligation as well. The stability of the aziridinyl peptide derivatives to harsh aqueous acidic conditions has also been established, providing a proof-of-principle that this method will be compatible with standard 9-fluoronylmethoxycarbonyl (Fmoc)-based solid phase peptide synthesis techniques. Also noteworthy is the use of a photo-deprotection of an aziridine, which was previously unreported and may find applications to total chemical synthesis of natural products as well the studies of enzyme mechanisms.
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Details
- Title
- The Aziridine-Mediated Ligation and Efforts Towards a General Synthesis of N-terminal Aziridinyl Peptides
- Creators
- Frank Brock Dyer
- Contributors
- Philip P Garner (Advisor)Robert C Ronald (Committee Member)Gregory J Crouch (Committee Member)Jonel P Saludes (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Chemistry, Department of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 315
- Identifiers
- 99900581537001842
- Language
- English
- Resource Type
- Dissertation