Tanya Román, Gerardo Acosta, Constanza Cárdenas, Beatriz G. de la Torre, Fanny Guzmán, Fernando Albericio
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引用次数: 0
摘要
提高多肽体内生物利用度和半衰期的一种方法是对多肽序列中的一个或多个氨基酸进行n -甲基化。然而,市售的fmoc - n - me - aa - oh数量有限,而且往往价格昂贵。本研究采用2-氯三酰氯(2-CTC)树脂作为羧酸策略的临时保护基,建立了固相合成Fmoc-N-Me-AA-OH的方法。比较了在Biron - Kessler法中采用硫酸二甲酯或碘化甲酯的两种烷基化步骤。在这项工作中,我们测试了两种氨基酸:Fmoc- thr (tBu)-OH和Fmoc-βAla-OH。第一个是α氨基酸,非常受阻,胺基直接受到羧基电子效应的影响,而在Fmoc-βAla-OH中,亚甲基的存在由于中间的碳原子而减弱了这种影响。两种方法合成的氨基酸Fmoc-N-Me- thr (tBu)-OH和Fmoc-N-Me-β - ala -OH收率高,纯度高。
Protocol for Facile Synthesis of Fmoc-N-Me-AA-OH Using 2-CTC Resin as Temporary and Reusable Protecting Group
One approach to enhance the bioavailability and half-life of peptides in vivo is through N-methylation of one or more of the amino acids within the peptide sequence. However, commercially available Fmoc-N-Me-AA-OHs are limited and often expensive. In this study, a solid-phase synthesis method for Fmoc-N-Me-AA-OH was developed using a 2-chlorotrityl chloride (2-CTC) resin as a temporary protective group for the carboxylic acid strategy. Two strategies for the alkylation step were compared, employing either dimethyl sulfate or methyl iodide in the Biron−Kessler method. In this work we tested the protocol with two amino acids: Fmoc-Thr(tBu)-OH and Fmoc-βAla-OH. The first one is an alpha amino acid, very hindered and with the amine group directly influenced by the electronic effects of the carboxy group, whereas in Fmoc-βAla-OH, the presence of a methylene group weakens this influence due to the intervening carbon atoms. The desired amino acids, Fmoc-N-Me-Thr(tBu)-OH and Fmoc-N-Me-βAla-OH, were synthesized by both strategies with high yield and purity.