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