N,N'‐bis(2‐oxo‐3‐oxazolidinyl) phosphinic chloride (BOP‐Cl); a superb reagent for coupling at and with iminoacid residues

Abstract

Analytically pure dipeptides containing two iminoacids [Pro, MeAla, MePhe, MeVal and SPip (γ‐thiapipecolinic acid)] were prepared with BOP‐Cl [N,N]‐bis(2‐oxo‐3‐oxazolidinyl) phosphinic chloride] at normal temperature (0° — r.t.) in high yields (80–100%) and with excellent optical purity (below noise limit in 1H n.m.r.). Maximum yields were obtained with Zervas' preactivation procedure, using, for example, an excess of BOP‐Cl followed by the addition of (an equal excess of) the aminocomponent. Racemization suppressors (HOBt, imidazole, etc.) are of no use in these difficult couplings. Z‐Me Val‐Me Val‐OBut (yield: 89%, without racemization (!)) and Z‐SPip‐SPip‐OMe (yield: 96%, less than 5% stereomutation) were prepared for the first time, whereas all other coupling reagents have failed. Peptide acids with N‐methylaminoacids as the COOH‐terminal residues were coupled with excellent yields (70–90%), but unfortunately chiral integrity could not be preserved. Pronounced chiral induction was observed during the preparation of Z‐Pro‐MePhe‐MeAla‐OBut, and an influence of the penultimate protecting group was detected. In contrast, Z‐MeVal‐MeVal‐MeVal‐MeVal‐OBut was formed with probably only 5% stereomutation (yield: 52%). Some side reactions with BOP‐Cl are observed: e.g. symmetrical anhydride and DKP formation.