Total syntheses of callipeltin B and analogues
Abstract
Callipeltin B is a novel cyclic depsipeptide that exhibits potent antitumor properties. Callipeltin B contains several non-proteinogenic amino acids such as N-methylglutamine, D-allothreonine, dimethylpyroglutamic acid and β-methoxytyrosine (β-MeOTyr). To expedite the total synthesis of callipeltin B and analogues, a solid phase approach has been described. In pursuit of the total synthesis of callipeltin B, β-MeOTyr was synthesized in an enantioselective and diastereoselective fashion. All four diastereomers of β-MeOTyr was synthesized in 7 steps by adapting Schollkopf procedure as reported by Boger which allowed us to determine the configuration of the β-MeOTyr in structurally similar depsipeptides papuamide B and neamphamide A by chemical correlation. Also, a method has been developed to synthesize any single isomer of β-MeOTyr via chiral oxazolines. Callipeltin B was synthesized using an Fmoc-based solid phase strategy in 10 steps with 15% overall yield. The Sieber amide resin, anchored to the sidechain of the N-methylglutamine residue, was chosen for the relatively low amounts of TFA needed for cleavage of the peptide. The crucial on-resin esterification reaction and the challenging macrocyclization were achieved on solid support in high purity and yield. All sidechain protecting groups were chosen for their ability to be removed under mild acidic or hydrogenation conditions. The ambiguity in the configuration of threonine residues of callipeltin B was resolved by the syntheses of two analogues of callipeltin B with different threonine configurations. A desmethoxy analogue of callipeltin B was synthesized to determine the role of β-MeOTyr in the cytotoxicity of callipeltin B. Biological studies revealed that replacing β-MeOTyr with D-Tyr or changing the configuration of threonine residues has no profound effect on the IC50 values.
Degree
Ph.D.
Advisors
Lipton, Purdue University.
Subject Area
Organic chemistry
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