Many dipeptide boronic acids of the type H(2)N-X-Y-B(OH)(2) are potent protease inhibitors. Interest in these compounds as drugs for cancer, diabetes, and other diseases is growing. Because of the great mutual B-N affinity, cyclization through the N- and B-termini, forming six-membered rings, is a common occurrence at neutral pH and higher where the terminal amino group is unprotonated. Here we report the discovery that when X, the N-terminal amino acid, contains a side chain having a functional group with boron affinity and suitable geometry, additional cyclization in the form of bidentate intramolecular chelation or "autochelation" may occur, predominantly at mid pH. NMR studies of two compounds, l-Aspartyl-l-boroProline (Asp-boroPro) and l-Histidyl-l-boroProline (His-boroPro), are reported here from pH 0.5 to pH 12 by (1)H, (15)N, (13)C, and (11)B NMR. Both of these previously unreported autochelates contain two fused six-membered rings, cis-proline, chiral boron, and -NH(2)(+) protons in slow exchange with water, even at 25 degrees C and pH as high as 4. Using microscopic acid-base equilibrium constants, we show that at high pH (>8 for Asp-boroPro and >10 for His-boroPro) hydroxide competes with the side chains for boron, reducing the chelates from bidentate to monodentate. At low pH (<0.5), proton competition for N-terminal nitrogens causes both compounds to become noncyclic. High chelate stability causes a reduction of the apparent acidic dissociation constant of the protonated N-terminal amino group greater than eight units. In the His-boroPro autochelate, imidazolate anion is produced at the extraordinarily low pH value of approximately 9.