SYNTHESIS OF PEPTIDES MEDIATED BY KOBT

Coupling of Fmoc-amino acid chlorides can be mediated by the potassium salt of 1-hydroxybenzotriazole (KOBt), the reaction being carried out in an organic medium. The use of a base like NaHCO3/Na2CO3 or DIEA/NM M/pyridine is not necessary. Coupling is fast and racemization free; t he work-up, isolation of the product and scale-up are easy. The pentap eptide sequence of Fmoc-[Leu]enkephalin was thus synthesized in the so lution phase on a 5 mmol scale without isolation of any intermediate. Acylation of C-protected N-methylamino acid esters by Fmoc-N-methylami no acid chlorides by this procedure is also feasible, as demonstrated by the synthesis of cyclosporin A fragments 4-7 and 8-11. The peptides obtained in high yields were crystalline solids, unlike earlier repor ts in which they were obtained mostly as oily or foamy intermediates. They showed spectral properties identical with those of the authentic compounds. (C) Munksgaard 1994.