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.