Studies toward the total synthesis of papuamide A
Abstract
Papuamide A is a novel cyclic depsipeptide that exhibits potent antiviral and anticancer properties. Papuamide A contains seven non-proteinogenic amino acids and a previously undescribed 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid (Dhtda) moiety. In pursuit of its total synthesis, effort was directed towards the synthesis of (3S,4R)-3,4-dimethylglutamine, Dhtda and the development of an efficient method for the on-resin synthesis and macrocyclization of the natural product. (3S,4R)-3,4-Dimethylglutamine was synthesized from an intermediate that also leads to (3S,4R)-3,4-dimethylpyroglutamic acid, found in the related cyclic depsipeptide callipeltin B. The diastereoselective introduction of the methyl groups was accomplished by cuprate addition and enolate alkylation followed by a kinetic epimerization of the C-4 methyl substituent. (3S,4R)-3,4-Dimethyl glutamine shows a conformational restriction of its sidechain that may be related to its biological function in the natural products where it is found. All diastereomeric possibilities for the Dhtda residue were synthesized stereoselectively using a Z-selective Wittig reaction of both enantiomers of 2,4-dimethylhex-2-enyl-triphenylphosphonium bromide with all four diastereoisomers of ethyl 5-formyl-2,2-dimethyl[1,3]dioxolane-4-carboxylate. To elucidate the configuration of Dhtda, the NMR spectra of four synthetic isomers were compared to those of the natural residue, resulting in a conclusion that the likely configuration of Dhtda is either (2S',3 S,4R) or (2R',3R,4 S). For the solid phase synthesis of papuamide A, a linker related to Barany's BAL linker was developed that permits photochemical cleavage of the cyclized peptide from the resin. Two linkers based on the ortho-nitrobenzyl functionality were synthesized and tested for their efficiency of photochemical deprotection. It was found that an ortho-nitroveralryl linker provided the most efficient deprotection.
Degree
Ph.D.
Advisors
Lipton, Purdue University.
Subject Area
Organic chemistry
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