Synthesis and Derivatization of 3-Aroyl Pyroglutamic Acids

摘要

A practical synthetic strategy for the preparation of enantio- merically pure 3-substituted pyroglutamic acid derivatives is described. This procedure pivots on fast 5-exo-tet cyclization of the chloroacetylated amino acids, prepared by the crystalliza- tion induced diastereomeric transformations (CIDT). Further- more, oxidation of obtained 3-substituted pyroglutamic acids afforded highly valuable scaffolds with a quaternary stereo- genic center with excellent diastereoselectivity. The absolute stereochemical configuration of both, 3-aroyl pyroglutamic acid and its 3-hydroxylated derivative, was confirmed by single- crystal X-ray analysis. The versatility of the methodology is exemplified using a variety of aromatic and heteroaromatic amino acids. The efficiency of this chromatography-free approach predestines it for the gram-scale synthesis. This was demonstrated with the synthesis of more than 10 mmol of the model substrate with excellent overall yield and diastereose- lectivity.