Synthesis and Derivatization of 3‐Aroyl Pyroglutamic Acids

Abstract

A practical synthetic strategy for the preparation of enantiomerically 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 crystallization induced diastereomeric transformations (CIDT). Furthermore, oxidation of obtained 3‐substituted pyroglutamic acids afforded highly valuable scaffolds with a quaternary stereogenic 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 diastereoselectivity.

Synthesis of (2S,3S)-3-Aroyl Pyroglutamic Acid Amides

“…This enables isolation of products (3ag) by simple filtration. Recently, we published a strategy of N-acylation of amino acids in the presence of chloroacetyl chloride, which yielded the acetylated derivatives [10]. These intermediates represent suitable starting materials for cyclization in the presence of a base.…”

Stereoselective Mannich Reaction Driven by Crystallization

“…Dissimilar to our previous work, we envisaged to replace glyoxylic acid ( 12 ) for formaldehyde ( 15 ) (Scheme C). This idea was successfully executed for the first time in our previously reported synthesis of tapentadol . However, the procedure optimized for m ‐methoxypropiophenone is more suitable for the industrial application.…”