Coupling reagent dependent regioselectivity in the synthesis of lysine dipeptides

Participation of either the N(e) or N(α) of L-methyl lysinate (2) in peptide bond formation could be selectively achieved by the use of either isobutyl chloroformate (method A) or N,N,-bis(2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl) (method B), respectively. The amidation performed according to method A gives high yields of the dipeptides 3a-e, irrespective of the amino acids used. In method B, N(α) amidation is highly preferred especially with bulky amino acids, yielding 4a, 4c and 4e. The less bulky 4b and 4d gave B 4.5 and 20 regioselection N(α)/N(e) amidation ratios. A mechanistical rationalization for these selectivities is discussed.