Abstract

The synthesis of two Aib-containing cyclic octapeptides, cyclo(Leu-Aib-Phe-Aib-Gly-Aib-Phe-Aib) (1) and cyclo(Gly-Aib-Aib-Val-Aib-Leu-Aib-Phe) (2), and a cyclic heptapeptide cyclo(Gly-Aib-Val-Aib-Leu-Aib-Phe) (3), is described. The linear precursors of 1–3 were prepared using solution-phase techniques, and the cyclisation was also accomplished in solution. Among the coupling reagents examined in the final macrolactamisation step, PyAOP, HATU and DEPC/DEPBT efficiently yielded cyclised products. However, the success of the cyclisation was found to be dependent on the coupling reagent used. The two octapeptides 1 and 2 were obtained in much better yields (up to 63%) than the cycloheptapeptide 3 (30–37%). In addition, crystal-state conformational analysis of 2 was performed by X-ray crystallography. Six intramolecular hydrogen bonds stabilise the structure characterised by two consecutive type II /I β-turns, two consecutive type II/III β-turns, one γ -turn, and one inverse γ -turn.