Open Access Dissertation
Date of Award
DEVELOPMENT AND APPLICATIONS OF THIOACIDS IN PEPTIDE CHEMISTRY AND EXPLORATION OF METHODS TOWARD THE STEREOCHEMICAL ELUCIDATION AND SYNTHESIS OF VIRGINEONE
Advisor: David Crich
Degree: Doctor of Philosophy
This dissertation describes investigations toward the development of methods for the synthesis of peptidyl thioacids and thioesters, with particular emphasis on applications in peptide chemistry, and the exploration of methods toward the assignment of the relative and absolute configuration of virgineone and its total synthesis.
The first part of chapter one introduces the general characteristics and reactivity of thioacids, and describes their potential for application to the chemical synthesis of peptides and proteins. The second part of chapter one overviews the solution and solid-phase synthesis of peptidyl thioacids and thioesters. The last section of chapter one reviews the importance of tetramic acid containing natural products, and the various methods for their formation, and continues with an overview of stereoselective methods for â-mannosylation, such as are required for the total synthesis of virgineone, a novel glycosylated tetramic acid containing natural product.
The second chapter describes studies focused on the development of a methodology for the synthesis of amino and peptidyl thioacids based on the cleavage of the 9-fluorenylmethyl (Fm) group from 9-fluorenlylmethyl thioesters. Subsequently, the formation of native amide bonds in the reaction between C-terminal peptidyl thioacids and electron deficient N-terminal 2,4-dinitrobenzenesulfonamides is presented.
In chapter three, building on the method for the solution-phase synthesis of amino and peptidyl thioacids described in chapter two, the development of a 9-fluorenlylmethyl thioester based linker, N-[9-(tritylthiomethyl)-9H-fluoren-2-yl]succinamic acid is described. The use of this linker for the synthesis of peptidyl thioacids on solid support employing Boc-SPPS is then demonstrated.
In chapter four, continuing the theme of the development of the chemistry of thioacids, a method for the in situ generation of thioacids by the regioselective ring opening of â-thiolactones is set out. To further explore this concept, investigations were conducted on the ring-opening of various â-thiolactones with soft aromatic thiolates to form thiocarboxylates, with subsequent trapping in-situ by Mukaiyama's reagent or Sanger's reagent in presence of an amine to form amide bonds.
In chapter five, studies toward the assignment of configuration and the total synthesis of vigineone are described. A practical synthetic route to various stereoisomers of virgineone is elaborated.
In chapter six, overall conclusions of the dissertation are presentated, while in chapter seven, the experimental procedures and characterization data for the synthesized compounds are documented.
Sana, Kasinath, "Development And Applications Of Thioacids In Peptide Chemistry And Exploration Of Methods Toward The Stereochemical Elucidation And Synthesis Of Virgineone" (2010). Wayne State University Dissertations. Paper 185.