Coupling reagent dependent regioselectivity in the synthesis of lysine dipeptides

Participation of either the N-epsilon or N-alpha of L-methyl lysinate (2) i n peptide bond formation could be selectively achieved by the use of either isobutyl chloroformate (method A) or N,N,-bis(2-oxo-3-oxazolidinyl) phosph inic chloride (BOP-Cl) (method B), respectively. The amidation performed ac cording to method A gives high yields of the dipeptides 3a-e, irrespective of the amino acids used. In method B, Na amidation is highly preferred espe cially with bulky amino acids, yielding 4a, 4c and 4e. The less bulky 4b an d 4d gave 4.5 and 20 regioselection N-alpha/N-epsilon amidation ratios. A m echanistical rationalization for these selectivities is discussed.