Amino acid-azetidine chimeras: synthesis of enantiopure 3-substituted azetidine-2-carboxylic acids.
Azetidine-2-carboxylic acid (Aze) analogs possessing various heteroatomic side chains at the 3-position have been synthesized by modification of 1-9-(9-phenylfluorenyl) (PhF)-3-allyl-Aze tert-butyl ester (2S,3S)-1. 3-Allyl-Aze 1 was synthesized by regioselective allylation of alpha-tert-butyl beta-methyl N-(PhF)aspartate 13, followed by selective omega-carboxylate reduction, tosylation, and intramolecular N-alkylation. Removal of the PhF group and olefin reduction by hydrogenation followed by Fmoc protection produced nor-leucine-Aze chimera 2. Regioselective olefin hydroboration of (2S,3S)-1 produced primary alcohol 23, which was protected as a silyl ether, hydrogenated and N-protected to give 1-Fmoc-3-hydroxypropyl-Aze 26. Enantiopure (2S,3S)-3-(3-azidopropyl)-1-Fmoc-azetidine-2-carboxylic acid tert-butyl ester 3 was prepared as a Lys-Aze chimera by activation of 3-hydroxypropyl-Aze 26 as a methanesulfonate and displacement with sodium azide. Moreover, orthogonally protected azetidine dicarboxylic acid 4 was synthesized as an alpha-aminoadipate-Aze chimera by oxidation of alcohol 26. These orthogonally protected amino acid-Aze chimeras are designed to serve as tools for studying the influence of conformation on peptide activity.
Sajjadi
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Departement de Chimie, Université de Montréal, C.P.6128 Succursale, Centre Ville, Montréal, Québec, Canada.
Lubell
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WD
D000596:Amino Acids / Q000737:chemistry*; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*; D001385:Azetines / Q000737:chemistry*
D000596:Amino Acids; D001385:Azetines; D001383:Azetidinecarboxylic Acid