Synthesis of Cyclosporine. Part II. Synthesis of Boc‐D‐Ala‐MeLeu‐MeLeu‐MeVal‐OH, a part of the peptide sequence of cyclosporine, by different strategic ways and synthesis of its isomers Boc‐D‐Ala‐MeLeu‐D‐MeLeu‐MeVal‐OH, Boc‐D‐MeLeu‐DMeVal‐OH, and Boc‐D‐Ala‐MeLeu‐MeLeu‐D‐MeVal‐OH as reference compounds

Abstract

AbstractBoc‐D‐Ala‐MeLeu‐MeLeu‐MeVal‐OH (DLLL) and its isomers DLDL, DLDD and DLLD were synthesized using several different strategic approaches and a modification of the mixed pivalic anhydride method for carboxyl activation. Alternatively, the tert‐butoxy‐carbonyl (Boc) or benzyloxycarbonyl (Z) amino‐protecting groups and the benzyloxy (OBzl) or tert‐butoxy (OtBu) carboxyl‐protecting groups were used to protect the reacting peptides. By monitoring the reaction temperature, it was possible to synthesize, starting from the tripeptide DLL as peptide model, either the tetrapeptide DLLL (−20°) or the tetrapeptide DLDL (+20°), selectively. Using 1H‐NMR spectroscopy to follow the mixed pivalic anhydride formation of the DLL‐ and DLD‐tripeptides, it could be shown that anhydride formation is strongly dependent on the temperature. It is slow at −20° (several hours) and fast at +20° (20 to 40min). The isomerization of the DLL‐anhydride to the more stable DLD‐anhydride can be reduced to a minimum by working at −20°, while this isomerization proceeds to near completion at +20°.