Multicomponent synthesis of pyroglutamic acid derivatives via Knoevenagel–Michael-hydrolysis-lactamization-decarboxylation (KMHL-D) sequence

Abstract

A straightforward multicomponent synthesis of 3-substituted pyroglutamic acid derivatives starting from Meldrum's acid, aldehyde and Schiff's base.

The Molecular Diversity Scope of Meldrum's Acid in Multicomponent Reactions

“…The one-pot multicomponent reaction of Meldrum's acid 1, with a wide variety of aldehydes 13, and Schiff's base (N-(diphenylmethylene)glycine-tert-butyl ester) 14 through the chemoselective Knoevenagel-Michael-hydrolysis-lactamization-decarboxylation (KMHL-D) domino reaction in the presence of Et 3 N has been designed by Khopade and coworkers to synthesize 4-carboxy-3-substituted pyroglutamic acid derivatives 15 (Scheme 5). [18] The reaction mechanism was shown in Scheme followed by lactamization reaction to offer the corresponding pyroglutamic ester 15.…”

Synthesis and Derivatization of 3‐Aroyl Pyroglutamic Acids

“…The synthetic protocols for the preparation of 3‐(het)aryl or 3‐alkyl‐substituted pyroglutamic acids were developed based on the Michael addition of nucleophilic glycine complexes or organometallics to the corresponding Michael acceptors. Synthesis of 3‐substituted pyroglutamates from tetramates as well as multicomponent approach to 3‐aryl pyroglutamic acids has been recently reported. To our surprise, despite the numerous synthetic approaches towards substituted pyroglutamic acid derivatives and widely recognized importance and utility of these compounds, synthesis of 3‐acyl substituted analogs is still relatively unexplored…”

“…This was demonstrated with the synthesis of more than 10 mmol of the model substrate with excellent overall yield and diastereoselectivity.Pyroglutamic acid and its derivatives are a valuable class of compounds, being found ubiquitously in various natural products and pharmaceuticals. [1] As it represents an important starting material for asymmetric synthesis of many natural products we have witnessed a massive growth of publications on the synthesis, [1][2] chemistry and asymmetric/biological uses of pyroglutamic acid. [3] In particular, stereoselective preparation of 3-substituted analogs [2e,4] (Figure 1), has attracted significant attention.…”

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

“…It represents either an important chiral auxiliary or building block for the asymmetric synthesis of many biologically and pharmaceutically valuable compounds. [1] Moreover, pyroglutamic acid derivatives have recently appeared to be efficient antagonists of specific types of purinergic receptors. Their inhibition has a promising impact on treating neurodegenerative diseases such as Alzheimer, Huntington, and Parkinson's disease [2].…”

“…Coupling constants (J) are given in Hertz (Hz). The multiplicity of1 H NMR signals is reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, bs = broad singlet. Optical rotations were recorded using a JASCO P-2000 polarimeter; [α]D values are reported in deg cm 3 g −1 dm −1 ; concentration (c) is given in g/100 mL at 589 nm.…”