Methodology with applications for native chemical ligation, diazoalkane generation, and toward the total synthesis of Callipeltin A

Ryan M Johnson, Purdue University

Abstract

Native chemical ligation (NCL) is a method used to link two peptides together through transthioesterification of a peptide thioester and a thiol of an N-terminal cysteine. The limitations that NCL possesses have been addressed in a number of ways, including the use of prosthetic auxiliaries. Our group wanted to exploit the properties of copperassisted azide-alkyne cycloaddition (CuAAC), or "click" chemistry, to bypass obstacles garnered by the use of prosthetic auxiliaries. In this way "click" chemistry could then have applications toward NCL, without the use of prosthetic auxiliaries. Our experiments showed that while "click" conditions are efficient for forming the wanted triazoles, the triazole linker itself is not labile, and no evidence of amide bond formation was seen. Diazo compounds can be invaluable synthetic tools for organic chemists, even though their use is accompanied by a variety of safety hazards. Because of these hazards, our group wanted to develop a method that would generate diazo compounds in situ, where they could then be functionalized, without direct isolation. Through a three-step one-pot procedure, we tested our method by converting benzyl azide into a variety of benzyl esters. Control experiments and NMR studies ultimately showed that the reaction xiii pathway was not going through a diazo intermediate, but through a diazonium ion that had arisen from a diazotization pathway. Callipeltin A is a novel cyclic depsipeptide that possesses several proteinogenic and non-proteinogenic amino acids. These include (2R,3 R)-β-methoxytyrosine (β-MeOTyr), D-allo-Thr, N-methyl-L-alanine, N-methyl-L-glutamine, (2 S,3S,4R)-3,4-dimethyl-L-glutamine (DiMeGln), (2R,3R,4S)-4-amino-7-guanidino-3,4- dihydroxyheptanoic acid (AGDHE) and (2R,3R,4 S)-3-hydroxy-2,4,6-trimethylheptanoic acid (TMHEA). Callipeltin A also displays a broad range of biological activity, including anti-fungal and anti-tumor activity. In pursuit of the total synthesis of callipeltin A, some of the crucial steps in the synthesis of the required residue AGDHE were re-optimized.

Degree

M.S.

Advisors

Lipton, Purdue University.

Subject Area

Chemistry|Organic chemistry

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