Switching the stereochemical outcome of 6-endo-trig cyclizations; synthesis of 2,6-cis-6-substituted 4-oxopipecolic acids.

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-6-substituted-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.