A linker approach to heterocyclic amino acids

Polypeptide Nucleic Acids, PNAs, are analogues of DNA and have the potential to bind to DNA by base-pairing and hence act as therapeutic agents. Amino acids carrying heterocycles in their side-chains are valid targets as natural products and as components of these potential therapeutic agents (PNAs) for use in living organisms. The aim of this investigation was to synthesise a range of heterocyclic amino acids, that could be used in the formation of PNAs. The proteinogenic amino acids, serine and cysteine and the unnatural amino acids, homocysteine, 2,3-diaminopropionic acid and 2,4-diaminobutyric acid, have been used in the formation of said heterocyclic amino acids via a C–X bond (where X=C, S, O or N) in a linker chain. It was decided to approach the synthesis of heterocyclic amino acids by way of a linker approach, joining the ready-formed heterocycle with an amino acid. Once the amino acids had been suitably protected several different methods were attempted in order to form heterocyclic amino acids. To form a carbon–carbon (X=C) bond in the linker chain, radical and organocuprate conjugate addition reactions and hydroboration and metathesis coupling were attempted. The formation of a linker containing a carbon–heteroatom bond (X=S, O or N) was investigated using a substitution approach. [Continues.]