The synthesis of diastereomeric 4-methyl-4-phenylpipecolic acids and their derivatives is described. Investigation by double resonance proton spectroscopy revealed that the conformational preference of substituents attached to the piperidine ring depends upon the hybridization of the piperidine nitrogen. In the free amino acids or leucinamide dipeptides, the C-2 carboxyl group is equatorial. Introduction of a carbamyl moiety on the piperidine nitrogen induces a change in the piperidine ring conformation such that the C-2 carboxyl group is axial, despite a cis-diaxial interaction with the C-4 substituent. The inverted conformational preference of the C-2 and C-4 groups in the tert-butyloxycarbonyl and unprotected derivatives is attributed to a severe steric interaction between the partially sp2 hybridized NCO moiety in the carbamate group and an equatorial C-2 carboxyl group. The X-ray crystal structures of both cis-and trans-N-[(tert-butyloxy)carbonyl]-4-methyl-4-phenylpipecolic acids corroborate the solution spectroscopic studies and the concept of pseudoallylic strain in substituted piperidine carbamates. In addition, comparison of the two crystallographically determined structures indicates that hydrogen bonding to the carbonyl of the carbamate produces delocalization into the N-C bond resulting in a shorter bond and more planar piperidyl nitrogen. The conformational preference afforded by pseudoallylic strain indicates that substituted pipecolic acids can be employed in the design of conformationally restricted peptide analogues.