Synthesis of novel heterocyclic α-amino acids

Berthelot, Didier (2001). Synthesis of novel heterocyclic α-amino acids. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00004a80

Abstract

This thesis describes the incorporation of heterocycles as part of an α-amino acid side-chain. Two methods were adopted. The first involved the alkylation of a pseudoephedrine glycinamide enolate using haloalkanes. The method was validated by making the naturally occurring amino acid phenylalanine. Subsequently naphthyl-, pyridyl-, biphenyl- and isoxazolyl- groups were successfully incorporated into the amino acid side chain. The enantiomeric excess of the product amino acids was found to be moderate (10-87%) due to poor diastereoselectivity in the key alkylation step. Moreover, the strict experimental conditions required for the alkylation reaction were found to be difficult to reproduce. Attempts to apply this enolate anion strategy to the incorporation of nucleic acid bases utilising an analogous purine electrophile failed, the reaction leading only to elimination.

Thus, amino acids that carry a nucleic acid base in the side chain were synthesised by an alternative method. In this, N-(2-iodoethyl)- and N-(3-iodopropyl)-pyrimidines and purines underwent stereoselective conjugate radical addition with an optically active oxazolidinone acceptor derived from (R)-S-methylcysteine to give syn-adducts. Hydrolysis of the oxazolidinone adducts followed by deprotection afforded the desired amino acids carrying pyrimidine- (thymine, uracil) and purine- (adenine, guanine) containing side chains. The enantiomeric excesses, which reflect the diastereoselectivity of the radical addition step, were found to be between 85 and 89%.