Total Solid Phase Synthesis of a Marine Cyclodepsipeptide IB-01212

Abstract

Introduction A new cytotoxic cyclodepsipeptide IB-01212 was isolated from the mycelium extract of Chlonostachys pitirodes (Fig. 1) [1]. The novo cyclodepsipeptide is a symmetric cyclic peptide formed by the condensation of two chains of the tetrapeptide L-N,NMe2Leu-L-Ser-L-NMeLeu-L-NMePhe. The absolute configuration was determined by our group and it was confirmed that all amino acids were in the L-configuration. Herein we describe several strategies of synthesis on solid phase such as i) dimerization of heterodetic fragment, ii) linear synthesis, and iii) convergent synthesis. All syntheses were performed using Fmoc/tBu chemistry and ester bond resin. A comparison of the yield and quality of the synthetic processes showed that the convergent synthesis that combines fragments synthesized on two different resins gave the best results. Thus, this strategy is particularly suitable for the large-scale synthesis of IB-01212 and other peptides containing the same motifs.