Cyclodepsipeptides from Marine Sponges: Natural Agents for Drug Research

A number of natural products from marine sponges, such as cyclodepsipeptides, have been identified. The structural characteristics of this family of cyclic peptides include various unusual amino acid residues and unique N-terminal polyketide-derived moieties. Papuamides are representatives of a class of marine sponge derived cyclic depsipeptides, including callipeltin A, celebesides A and B, homophymine A, mirabamides, microspinosamide, neamphamide A and theopapuamides. They are thought to have cytoprotective activity against HIV-1 in vitro by inhibiting viral entry. Jasplakinolide, a representative member of marine sponge-derived cyclodepsipeptides that include arenastatin A, geodiamolides, homophymines, spongidepsin and theopapuamides, is a potent inducer of actin polymerization in vitro. Although actin dynamics is essential for tumor metasasis, no actin targeting drugs have been used in clinical trials due to their severe cytotoxicity. Nonetheless, the actin cytoskeleton remains a potential target for anti-cancer drug development. These features imply the use of cyclodepsipeptides as molecular models in drug research

Total synthesis of callipeltin E and towards papuamide B

Papuamide B, a novel cyclic depsipeptide, was shown to possess potent anti-HIV activity. Papuamide B contains several non-proteinogenic amino acids and a previously undescribed 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid (DHTDA) moiety. In pursuit of the total synthesis of papuamide B, the synthesis of Nα-Fmoc-(2S,3 S,4R)-3,4-dimethylglutamine and an efficient method for the on-resin synthesis and macrocylization of a simplified model system were completed. Nα-Fmoc-(2S,3 S,4R)-3,4-dimethylglutamine was synthesized in 79% overall yield in five steps starting from the previously synthesized intermediate tert-butyl N-Boc-(2S,3S,4 R)-3,4-dimethylpyroglutamate. This synthesis involved selective deprotection of the Boc group from a lactam nitrogen in the presence of a tert -butyl ester, Fmoc protection of the lactam, and a lanthanide catalyzed transamidation reaction of the Fmoc-protected lactam. It was also shown that lanthanide triflates catalyze the ammonolysis of Fmoc-protected lactams in conjunction with AlMe3 or Me2AlCl. The reactivity of various metal triflates was found to vary in the order: Yb ∼ Sc \u3e Er ∼ Eu ∼ Sm \u3e Ce ∼ AgI \u3e CuII ∼ Zn. Optimized conditions offer a way to ammonolyze even sterically-hindered, Fmoc-protected lactams. A reliable, solid-phase synthesis for both isomers of callipeltin E was developed. Callipeltin E was synthesized in 7 steps in 26% overall yield. The 1H NMR of synthetic callipeltin E correlated closely with that of the natural product, confirming the reassignment of the configuration of the N-terminal residue in callipeltin E as D-allothreonine. A strategy for the solid phase synthesis of papuamide B has been studied by synthesizing a simplified model system of papuamide B. Key steps in this Fmoc-based solid phase synthesis strategy include anchoring the resin to the phenol of (2R,3R)-Fmoc-β-MeOTyr OAllyl, on resin esterification and macrocyclization