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.