Enantioselective Synthesis of a Novel Thiazoline Core as a Potent Peroxisome Proliferator-Activated Receptor δ Agonist

Abstract

The convergent and enantioselective synthesis of a highly potent human peroxisome proliferator-activated receptor delta agonist is presented. More specifically, the thiazoline structure, which constitutes the biosynthetically distinctive core structure of pulicatin (a secondary metabolite of symbiotic bacteria), was synthesized from a commercially available and inexpensive chiral pool of l-threonine.

Targeting Peroxisome Proliferator-Activated Receptor Delta (PPARδ): A Medicinal Chemistry Perspective

“…From the results of molecular docking studies, in vitro ADME/Tox, and in vivo pharmacokinetic studies, compound 38 demonstrated itself as a promising candidate for the treatment of PPARδ-related diseases. In another study, we reported an enantioselective synthesis of a natural product, pulicatin-inspired, unique methyl-thiazoline-core containing novel compound 39 as a highly potent PPARδ agonist (EC 50 = 6.2 nM) . Furthermore, we recently reported a simple and efficient synthetic route of a dimethyl-thiazoline-core containing compound 40 as a new scaffold for PPARδ agonist …”

Mild and Chemoselective Thioacylation of Amines Enabled by the Nucleophilic Activation of Elemental Sulfur

“…Thiazoline scaffolds with an aromatic ring at the C-2 position are common in various biologically active compounds, including natural products such as pulicatins 21 and the highly potent human peroxisome proliferator-activated receptor-δ agonist. 22 The decarboxylative thioacylation between 45 and threonine derivative 46 furnished thioamide 47 in 71% yield, which was directly converted into thiazoline 49 after treatment with N,N-diethylaminosulfur trifluoride (DAST), followed by reduction with DIBAL-H (Scheme 2A). Furthermore, the synthesis of thioacylated lysine compounds, which exhibit anticancer properties, was also accomplished using this thioacylation (Scheme 2B).…”

“…To demonstrate its synthetic utility, we applied this chemoselective thioacylation reaction to the synthesis of several biologically active compounds (Scheme A,B). Thiazoline scaffolds with an aromatic ring at C-2 are common in various biologically active compounds, including natural products such as pulicatins and the highly potent human peroxisome proliferator-activated receptor-δ agonist . The decarboxylative thioacylation between 45 and threonine derivative 46 furnished thioamide 47 in 71% yield, which was directly converted into thiazoline 49 after treatment with N , N -diethylaminosulfur trifluoride (DAST), followed by reduction with DIBAL-H (Scheme A).…”

Synthesis and spectral characterization of 4-methylthiazole derivatives: DFT approach and biological activities

“…14–21 Moreover, recently, aryl thiazole has been used as a potent pan-HDAC inhibitor and peroxisome proliferator-activated receptor δ agonist. 22,23 Subsequently, these aryl thiazole derivatives are more potent against human β3 agonists and have excellent selectivity against another human β receptor. 24 This aryl thiazole framework is a promising chemical tool for selective CYP1B1 inhibitors.…”