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Improved Gram-Scale Procedure for MIBA-Catalyzed Direct Amidation and Its Application to the Preparation of alpha and beta Peptides Open Access


Other title
Direct Amidation
alpha and beta Peptides
Type of item
Degree grantor
University of Alberta
Author or creator
Fatemi, Solmaz
Supervisor and department
Hall, Dennis (Department of Chemistry)
Examining committee member and department
Lowary, Todd L. (Department of Chemistry)
Xu, Yunjie (Department of Chemistry)
Department of Chemistry

Date accepted
Graduation date
Master of Science
Degree level
Direct condensation between a carboxylic acid and amine must overcome the initial formation of a thermodynamically stable and unreactive carboxylate-ammonium salt, providing the amide product only at very high temperatures (over 160 oC) that are incompatible with many functionalized molecules. Currently, the most popular industrial methods of amide synthesis rely on activation of a carboxylic acid (using a coupling reagent such as a carbodiimide) and subsequent coupling of the activated species with an amine. These methodologies suffer from inherent drawbacks such as low yields, racemization, degradation and difficult purification, thus making them expensive and wasteful. To address these challenges, numerous mild coupling reagents and methods have been developed that not only are high yielding, but that potentially help to prevent racemization of neighbouring stereogenic centres. The development of a mild and general direct amidation reaction is of great interest in organic synthesis and process chemistry. In the past decade, the use of boronic acids has emerged as a very useful and versatile tool for direct amidation at low temperatures. Driven by this goal, Hall and coworkers discovered the exceptional ability of ortho-iodophenylboronic acid as a recoverable catalyst for direct amidations under mild and waste-free conditions at room temperature. A drawback of the initial optimal procedure is that the reactant concentrations must be low and a fairly large amount of molecular sieves is required to drive the reaction, which limits large-scale applications. The objectives of this research are firstly, to optimize the direct amidation reaction conditions to develop a scalable and “greener” process, secondly, to explore superior catalysts in order to expand the reaction scope, thirdly, to investigate proper additives to improve the efficiency of this direct amidation reaction. Chapter Two describes the details of optimization of this methodology and the applications in multigram syntheses of amides and dipeptides. As a result, the E factor in the newly optimized conditions is almost 10 times higher. Currently, there are no general catalytic methods to access dipeptides directly from amino acids in a simple, green, and atom-economical fashion at low temperature. The subsequent application of our methodology in dipeptide syntheses was also investigated and discussed in Chapter Three. The optimization of the catalytic direct dipeptide synthesis and the substrate scope is discussed in detail. Both catalysts and substrates were optimized to perform direct peptide synthesis catalytically using doubly protected amino acids (alpha-phthalimido amino acids or alpha-azido carboxylic acids) as C-terminal amino acids with C-protected alpha-amino esters as N-terminal amino acids.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
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