A simple approach to several tripeptides consisting of two terminal glycine fragments and a central pipecolic acid derivative was found via a multicomponent reaction starting from tetrahydropyridines. The protected peptides 2a-g were formed in high yields and with different substitution patterns of the central heterocyclic amino acid. In cases where chiral imines were used the target compounds were obtained with remarkable diastereoselectivity. The influence of different substituents attached to the pipecolic acid fragment on N-terminal amide isomerism was investigated using X-ray crystallography and NMR spectroscopic methods.
Several derivatives of homopipecolic acid are prepared by α‐amino alkylation of malonic acid with cyclic imines 6 and 7. These are prepared on a large scale and with different substitution patterns. The β‐amino acids 8 and 9 were formed in high yield and with remarkable diastereoselectivity if chiral imines are used as starting materials. The diastereoselectivity of the amino alkylation leading to homopipecolic acid analogues is compared to those of thiazolidineacetic acids by epimerisation experiments. A method for resolution of the obtained racemic β‐amino acids by diastereomeric salt formation is described. The β‐amino acids 9 and 15 were converted into their corresponding carbacepham analogues 14 and isopenam 16. The isopenam endo‐16 was selectively epimerised by mild basic treatment of the N/S‐acetal to give an exo‐configured precursor of isopenicillin G.
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