Development of a new bicyclic imidazole nucleophilic organocatalyst for direct enantioselective C-acylation

Abstract

A new chiral nucleophilic organocatalyst bearing a 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine skeleton has been developed.

Design, Synthesis, and Application of Chiral Bicyclic Imidazole Catalysts

“…To further expand the structural diversity of chiral bicyclic imidazole catalysts, a new bicyclic imidazole molecule TIP, fused with a 6-membered piperidine ring, was designed and developed by our group based on the “Bond Angle Control” strategy . TIP catalysts possess a proper bond angle ∠θ between the ∠θ of ortho -methyl-substituted NMI and DPI, so that this kind of catalyst can create better stereocontrol compared with DPI catalysts while maintaining a high activity compared with ortho -substituted NMI in direct enantioselective C -acetylation reactions (Figure A). , Furthermore, the TIP catalysts could be synthesized from 3-(benzyloxy)­pyridin-2-amine 7 readily and efficiently. After the cyclization of 7 with chloroacetaldehyde, 8 could be easily converted to the key intermediate rac -HO-TIP by hydrogenation.…”

“…Using the novel chiral nucleophilic organocatalyst TIP bearing a 5,6,7,8-tetrahydroimidazo­[1,2- a ]­pyridine skeleton developed by our group, the asymmetric synthesis of 3,3-disubstituted benzofuranones by the direct C -acylation of 3-substituted benzofuranones has been realized . Very recently, another application of TIP catalysts was reported by our group in the highly efficient direct enantioselective C -acylation of indolones .…”

“…29 TIP catalysts possess a proper bond angle ∠θ between the ∠θ of ortho-methyl-substituted NMI and DPI, so that this kind of catalyst can create better stereocontrol compared with DPI catalysts while maintaining a high activity compared with ortho-substituted NMI in direct enantioselective C-acetylation reactions (Figure 8A). 20,29 Furthermore, the TIP catalysts could be synthesized from 3-(benzyloxy)pyridin-2-amine 7 readily and efficiently. After the cyclization of 7 with chloroacetaldehyde, 8 could be easily converted to the key intermediate rac-HO-TIP by hydrogenation.…”

“…Using the novel chiral nucleophilic organocatalyst TIP bearing a 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine skeleton developed by our group, the asymmetric synthesis of 3,3disubstituted benzofuranones by the direct C-acylation of 3substituted benzofuranones has been realized. 29 Very recently, another application of TIP catalysts was reported by our group in the highly efficient direct enantioselective C-acylation of indolones. 4 As mentioned before in the design of chiral bicyclic imidazole catalysts, a smaller bond angle affords better stereocontrol, therefore we conceived that TIP catalysts bearing a 6-membered piperidine ring can further improve the enantioselectivity in the C-acylation reaction compared with DPI catalysts bearing a 5-membered pyrroridine ring.…”

Chemical Synthesis of the Anti‐COVID‐19 Drug Remdesivir

“…In 2010, a novel chiral bicyclic imidazole organocatalyst was developed by our group (Zhang et al., 2010 ). Over the past decade, this kind of organocatalyst was successfully applied in a number of asymmetric reactions (Liu et al., 2012 ; Wang et al., 2017 ; Wang et al., 2020 ; Wang, Zhang, Liu, Xie, & Zhang, 2014 ; Wang, Zhang, Xie, & Zhang, 2014 ; Wang, Zhou, Zhang, Zhang, & Zhang, 2020 ; Zhang et al., 2019 ; Zhang, Wang, Xie, Sun, & Zhang, 2014 ; Zhou et al., 2019 ; Zhou et al., 2021 ). In 2012, the first catalytic asymmetric synthesis of P ‐stereogenic phosphoric acid derivatives was developed by our group using the chiral bicyclic imidazole catalyst (Liu et al., 2012 ).…”