Synthesis of the Marine Sponge Cycloheptapeptide Stylopeptide 11

The solution-phase synthesis of the marine sponge stylopeptide 1 ( 2 ), cyclo-(Leu-Ile-Phe-Ser-Pro-Ile-Pro), was conveniently accomplished using N -terminal Fmoc- and C -terminal tert -butyl ester protection with tert -butyl ether side-chain blocking for serine. Peptide bond formation for each step except for the final cyclization was effected with diethyl phosphorocyanidate to give the linear heptapeptide in 19% yield. Both TBTU ( 4 ) or BOP-Cl ( 5 ) were used to cyclize the heptapeptide and resulted in 67% and 13% yields of stylopeptide 1 ( 2 ), respectively. Peptide 2 was obtained in 11% overall yield based on the TBTU cyclization procedure. The general approach represents a useful improvement in the synthesis of such cyclic peptides. The synthetic stylopeptide 1 ( 2 ) proved to be identical with the natural product.