Solution and Solid Phase Synthesis of Unusual a-Amino Acids From

Non-proteinogenic amino acids have also ken used extensively as probes of
biochemical rnechanisms. By incorporating amino acids that are confonnationaily
restrïcted, isotopically labeled or chernically modified into peptides or proteins, insight
may be gained into the mechanism of enzymatic action or binding properties of the
enzyme. Rationally designed inhibitors may then be developed. Isotopically labeled
substrates can also be used to study biosynthetic pathways in order to elucidate the
mechanistic details and various steps involved in those pathways. Recent advances in
protein engineering use a codon that codes for a transfer RNA containing an unusual
amino acid, thus allowing the incorporation of unusual amino acids directly into large
proteins."
The other factor goveming the increased interest in arnino acids is the remarkable
gro wth in as ymrnetric organic s ynthesis. Amino acids, as compounds natu rd1 y
incorporating both chirality and functionality, have been intrinsically involved in the
development of as yrnmetrïc s ynthesis as both substrates and targets? The proteinogenic
amino acids provide a cheap source of starting materials usually available in both
enantiomenc foms. and can be used as chiral auxiliaries,6 reagents7 and substrates.'
The research presented in this thesis has concentrated on expanding the synthetic
use of the 2,6,7-trioxabicyclo[2.2.2]0ctane protecting group for the a-carboxylate group
in arnino acids that was pioneered earlier in this laboratory9 The use of this group in the
synthesis of unusual amino acids will be described.
The volume of Iiterature relevant to arnino acid synthesis is immense and a
comprehensive review is beyond the scope of this thesis. However, a comparatively brief
review of classical routes for the synthesis of both racernic and optically active amino