A method for constraining short peptides (<20 residues) of arbitrary sequence to an alpha-helical conformation (similar to 100% helical in H2O at 25 degrees C) is presented. Glutamine residues at positions i and i + 7 of the peptides were tethered with an alkanediyl chain between the side chain nitrogen atoms. Peptides containing this tether were readily synthesized on the solid phase by amide formation between an alpha,omega-diaminoallcane and the side chain carboxylates of glutamate residues. The resulting cyclic peptides were studied by NMR and CD and were found to adopt an alpha-helical conformation in aqueous solution. The alpha-helix was thermally stable to greater than or equal to 40 degrees C. Corresponding untethered control peptides with N-methylglutamine at the i and i + 7 positions lacked helicity under the same conditions. Analogous peptides were also prepared for comparison using the thiolysine cross-linking method described previously [Jackson, D. Y.; King, D. S.; Chmielewski, J.; Singh, S.; Schultz, P. G. J. Am Chem. Soc. 1991, 113, 9391-9392].