Diastereoselective Synthesis of 3,4-Dihydropyran-3-carboxamides with in Vitro Anti-inflammatory Activity

Abstract

A versatile and economical reaction of diketene (1), aryl amines 2, cyclic 1,3-diketones 3, primary amines 4, and aryl aldehydes 5 was explored to synthesize 3,4-dihydropyran-3-carboxamide derivatives under mild conditions. Three stereogenic centers are generated in the products, and the structure of the major diastereomer of 6{1,1,3,1} was identified by X-ray diffraction and 2D NMR spectroscopy. The scope and limitation investigation provided two series of (2S,3R,4S)-chromene-3-carboxamides in good to excellent yields with high diastereoselectivity. Two products, 6{5,3,1,1} and 6{7,3,1,1}, exhibited in vitro anti-inflammatory activity with significant inhibition of pro-inflammatory cytokine IL-6 and TNF-α expression in lipopolysaccharide (LPS)-treated Raw 264.7 cells.

A novel substrate directed multicomponent reaction for the syntheses of tetrahydro-spiro[pyrazolo[4,3-f]quinoline]-8,5′-pyrimidines and tetrahydro-pyrazolo[4,3-f]pyrimido[4,5-b]quinolines via selective multiple C–C bond formation under metal-free conditions

“…Among the numerous methods available in the literature for the synthesis of nitrogenbearing derivatives, multicomponent reactions (MCRs) are the most advantageous as they offer high atom economy, and provide access to highly complex molecules through multiple bond formation efficiencies. [1][2][3][4][5][6][7][8][9][10] Generally, these techniques avoid the purication and isolation of the intermediates, which minimizes solvent waste and enhances the eco-compatibility of the protocol. Spiro compounds are well-known due to their inherent three-dimensional structure in which the fusion point of the bicyclic system shares a single atom.…”

Diastereomerically pure rarely functionalized alkenoyl dihydropyrans, 1,6-diketones, and cyclopentanes from acetylene gas and ketones

“…The polyfunctional dihydropyran scaffold is a common structural motif in biologically active molecules and natural products, 1 possessing anti-inflammatory, 2 antiprotozoal, 3 antitumor, 4 anticonvulsant and antifungal activities. 5 The synthetic utility of the dihydropyran moiety was demonstrated by its application in the synthesis of various medicinal polyheterocycles 6 and potent anti-hypercholesterolemic 7 and anticancer 8 drugs.…”