The development of a facile and general method for the preparation of enone derived alpha-amino acids is described. The key step involves a Horner-Wadsworth-Emmons reaction between an aspartic acid derived beta-keto phosphonate ester and a range of aldehydes resulting in the formation of highly functionalised alpha-amino acids in good yields. An efficient two-stage deprotection process using mild conditions was developed to give the parent alpha-amino acids. Application of this methodology has produced a novel fluorescent alpha-amino acid that has potential as a biological marker.

The first stereoselective synthesis of 2,6-trans-6-substituted-4-oxo-L-pipecolic acids using a tandem reductive amination/6-endo-trig cyclisation process is described. The sequential reduction and cyclisation mediated by sodium cyanoborohydride allowed the preparation of a series of highly functionalised 6-alkyl and 6-aryl analogues.

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-L-pipecolic acids to the corresponding 4-hydroxy-L-pipecolic acids was also performed.

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