Quaternary β2,2-Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc-Based Solid-Phase Peptide Synthesis
Quaternary β2,2-Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc-Based Solid-Phase Peptide Synthesis
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DOI：
10.1002/anie.201711143
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发表时间：
2018-01-15
影响因子：
16.6
通讯作者：
Shibasaki, Masakatsu
中科院分区：
文献类型：
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作者：
Yu, Jin-Sheng;Noda, Hidetoshi;Shibasaki, Masakatsu
β-氨基酸的引入已成为一种有前景的方法，可增强母体肽的稳定性并提高其生物活性。由于在适合肽合成的条件下缺乏可靠获取β(2,2)-氨基酸的途径，大多数当代研究工作集中在使用β(3)-和某些β(2,3)-氨基酸上。在此，我们报道了β(2,2)-氨基酸的催化不对称合成以及通过基于芴甲氧羰基（Fmoc）的固相肽合成（Fmoc - SPPS）将其引入肽中。通过钯催化的4 - 取代异噁唑烷 - 5 - 酮的脱羧烯丙基化构建了一个季碳中心。产物中的N - O键不仅作为β-氨基酸的无痕保护基，还能与衍生自Fmoc保护的α-氨基酸的α-酮酸形成酰胺，从而为Fmoc - SPPS快速提供了α - β(2,2)-二肽。
beta-Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to beta(2,2)-amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of beta(3)- and certain beta(2,3)-amino acids. Herein, we report the catalytic asymmetric synthesis of beta(2,2)-amino acids and their incorporation into peptides by Fmoc-based solid-phase peptide synthesis (Fmoc-SPPS). A quaternary carbon center was constructed by the palladium-catalyzed decarboxylative allylation of 4-substituted isoxazolidin-5-ones. The N-O bond in the products not only acts as a traceless protecting group for bamino acids but also undergoes amide formation with aketoacids derived from Fmoc-protected alpha-amino acids, thus providing expeditious access to alpha-beta(2,2)-dipeptides ready for Fmoc-SPPS.