Quaternary beta(2,2)-Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc-Based Solid-Phase Peptide Synthesis

摘要

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.