Tuning of the Prolyl trans/cis-Amide Rotamer Population by Use of C-Glucosylproline Hybrids

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• 作者：Neil W. Owens ; Craig Braun ; Frank Schweizer
• 刊名：Journal of Organic Chemistry
• 出版年：2007
• 出版时间：June 22, 2007
• 年：2007
• 卷：72
• 期：13
• 页码：4635 - 4643
• 全文大小：174K
• 年卷期：v.72,no.13(June 22, 2007)
• ISSN：1520-6904

文摘

We describe the synthesis of a fused bicyclic C-glucosylproline hybrid (GlcProH) from commerciallyavailable 2,3,4,6-tetra-O-benzyl-D-glucopyranose. The GlcProH was incorporated into the model peptidesAc-GlcProH-NHMe and Ac-Gly-GlcProH-NHMe. Postsynthetic modifications can be introduced viaderivatization of the carbohydrate scaffold. Conformational analysis of the GlcProH-modified modelpeptides shows that while the conformation of GlcProH remains fixed, the prolyl N-terminal amideequilibrium (K_t/c) can be varied with different modifications of the carbohydrate scaffold. Simple N-acylderivatives studied by NMR spectroscopy showed that in CD₃OD there was an increase in the cis-amidecontent as the sugar substituents changed from benzyl (10%) to hydroxyl (22%) to acetate (36%). Similareffects were observed in DMSO-d₆. The exact nature of the influence is unclear, but it most likely arisesthrough intramolecular interactions between sugar groups and the peptidic amide backbone. Overall, ourGlcProH demonstrates variation in K_t/c through tuning of the carbohydrate scaffold: a new concept inproline peptidomimetics.