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Title: Synthetic approaches towards conformationally constrained amino acids
Author: Walke, Amol Ashok
ISNI:       0000 0004 2703 7081
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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This thesis describes research undertaken on the synthesis of conformationally constrained analogues of phenylalanine. The work is introduced by an overview of the significance of conformationally constrained amino acids in chemical biology. An example of how a potent and selective conformationally constrained tryptophan was designed and synthesized is provided. This section also reviews constrained phenylalanine analogues, detailing the influence of their constraints on their stereochemistry. The introductory Chapter ends with the description of an investigation into the use of a conformationally constrained phenylalanine analogue, Tic, in the development of potent bioactive peptides, and a discussion of the potential applications of higher homologues of Tic. The second Chapter commences with a short discussion about asymmetric synthesis and chiral resolution, followed by an example which illustrates these concepts. This is followed by a discussion on the work done in the modification and optimization of the Gibson synthesis of the amino acid Sic, which gave multigram quantities of this amino acid. Attempts to resolve racemic Sic were unsuccessful. The next Chapter begins with an introduction to aromatic C-H bond activation and a discussion of conventional Heck and oxidative Heck methodologies used in C-C bond formation. The syntheses of three novel cyclization substrates with varying degrees of electron densities in their aromatic rings are documented. Attempts to achieve intramolecular cyclization of these molecules via the Fujiwara addition method, the Gaunt oxidative Heck method and the Glorius oxidative Heck method, are described. The fourth Chapter introduces the concept of aromatic C-H bond activation via chelation assistance. A concise survey of different functional groups that are commonly used as ortho-directing groups via chelation with organometallic catalysts is presented along with an example that illustrates how this methodology has been used to synthesize potentially bioactive compounds. This is followed by a description of the synthesis of a new potential cyclization substrate with a ketone as a directing group. Attempts to achieve an intramolecular cyclization of this substrate using different [Ru] and [Rh] catalysts were unsuccessful. Chapter five begins with a brief summary of the use of gold catalysts for C-C bond formation via aromatic C-H activation. Four new substrates with potential for cyclization with varying degrees of electron densities in their aromatic rings were synthesized. Intramolecular cyclization of these substrates using Au(III) and Au(I) catalysts proved to be unsuccessful. Finally, Chapter six contains the experimental details that support the results described and discussed in Chapters 2-5.
Supervisor: Gibson, Sue Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral