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Synthesis of new alpha-branched alpha-amino acids

Michelle Lee Pedersen, University of Nebraska - Lincoln

Abstract

Amino Acid Decarboxylases are of great interest from both a mechanistic and therapeutic point of view. Several enzymes in this class are very important targets for the development of specific and potent inhibitors. The synthesis of new $\alpha$-branched $\alpha$-amino acids as potential mechanism-based inhibitors is described. A new synthetic approach to the formal $\alpha$-vinylation of $\alpha$-amino acids was developed. Commercially available ethylene oxide serves as the vinyl cation equivalent. Alkylation followed by in situ lactonization occurs. A new reagent for the chemoselective cleavage of $\alpha$-substituted homoserine lactones was discovered. Reduction of diphenyl diselenide with sodium trimethoxyborohydride generates a phenylselenolate anion equivalent which efficiently cleaves the $\alpha$-substituted homoserine lactones without competing lactone reduction. The free $\alpha$-vinyl amino acids were obtained after selenide oxidation, selenoxide pyrolysis and acid hydrolysis. A method for the simultaneous amino group protection (Cbz) and carboxyl group esterification for $\alpha$-amino acids is reported. Heating of an amino acid with excess benzyl chloroformate in the presence of triethylamine and dimethylaminopyridine in DMSO, produces the corresponding N-Cbz amino acid benzyl ester in good yield. Analogues of $\alpha$-amino acids in which the $\alpha$-proton has been replaced by an unsubstituted oxirane ring have been synthesized for the first time. Hydrogenolytically cleavable protecting groups are employed. The oxirane is installed via a direct or indirect epoxidation method. Diastereomerically homogeneous erythro and threo $\alpha$-oxiranyl amino acids are accessible using these procedures. A "double" versus "mono" cyclization method is used to assign relative stereochemistry. The synthesis of free $\alpha$-monovinyl (X = Cl, Br) amino acids is presented. Two regioisomers are obtained, the internal and the (E)-external halovinyl amino acid. 3,4-Dihydroxyphenylalanine decarboxylase (DOPA-DC) was isolated and purified from pig kidneys. Several of the $\alpha$-branched amino acids synthesized herein were assayed for turnover and time-dependent inhibition with DOPA-DC and Lysine DC. A complete Kitz-Wilson analysis of the time-dependent inhibition kinetics of $(\pm)$-$\alpha$-vinyllysine is reported.

Subject Area

Organic chemistry|Biochemistry|Pharmacology

Recommended Citation

Pedersen, Michelle Lee, "Synthesis of new alpha-branched alpha-amino acids" (1996). ETD collection for University of Nebraska-Lincoln. AAI9628247.
https://digitalcommons.unl.edu/dissertations/AAI9628247

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