Exploring Solution-Phase Cyclization and Sulfamyl Safety-Catch Resin Strategies for the Total Synthesis of the Marine Antimicrobial Cyclic Tetrapeptide Cyclo(GSPE)

Abstract

Head-to-tail cyclization of 12-membered tetrapeptides has been reported to be synthetically challenging due to their highly strained ring systems. Previously, we reported the total synthesis of the marine antimicrobial cyclic tetrapeptide cyclo(GSPE) using the glutamic acid side-chain Wang resin tethering strategy with a 5 % yield under microwave irradiation (Lim et al., Int J Pept Res Ther 16:145–152, 2010). Besides the low yield, this strategy was also constrained to glutamic acid-containing peptides. In this communication, we report the outcomes of two alternate strategies to synthesize cyclo(GSPE): (A) solution-phase cyclization and (B) solid-phase synthesis using the sulfamylbutyryl safety-catch resin. Experimental results using all four possible linear precursors revealed that the former strategy failed to produce the target cyclic peptide while the latter approach afforded an improved overall yield of 8–9 % using the linear precursor H-Ser(tBu)-Pro-Glu(OtBu)-Gly-resin. Interestingly, we discovered that the placement of proline at the N- or C-termini of the linear peptide precursors failed to produce the target cyclic peptide. We also concluded that strategy B could provide the versatility needed to make a cyclic tetrapeptide library for bioactivity screening.