Enantioselective α-aminomethylation of carbonyl compounds constitutes a powerful protocol for introducing aminomethyl groups to simple organic molecules. However, current strategies rely on ...nucleophile-based enantioselective activation with inherently activated substrates only, and enantioselective protocol based on the activation of in situ-generated unstable formaldimines remains elusive, probably owing to their unstable nature and the lack of steric environment for efficient stereocontrols. Here, based on a rhodium/chiral phosphoric acid cooperative catalysis, we achieved an enantioselective three-component reaction of α-diazo ketones with alcohols and 1,3,5-triazines. A dual hydrogen bonding between the chiral phosphoric acid catalyst and two distinct active intermediates was proposed to be crucial for the efficient electrophile-based enantiocontrol. A series of chiral β-amino-α-hydroxy ketones including those derived from simple aliphatic alcohols, allylic alcohol, propargyl alcohol, complicated natural alcohols and water could all be prepared in high efficiency and enantioselectivity.
Asymmetric functionalization of aromatic CH bonds of N,N‐disubstituted anilines with diazo compounds and imines is reported for the efficient construction of α,α‐diaryl benzylic quaternary ...stereocenters in good yields with high diastereoselectivities and excellent enantioselectivities. This RhII/chiral phosphoric acid cocatalyzed transformation is proposed to proceed through a metal‐carbene‐induced zwitterionic intermediate which undergoes electrophilic trapping. To the best of our knowledge, this is the first asymmetric example of metal carbene‐induced intermolecular functionalization of aryl CH bonds.
Caught in a trap: The title reaction of N,N‐disubstituted anilines with diazo compounds and imines is reported for the efficient construction of α,α‐diaryl benzylic quaternary stereocenters in good yields with high diastereoselectivities and excellent enantioselectivities. Efficient electrophilic trapping of the metal‐carbene‐induced zwitterionic intermediate is crucial for the enantiocontrol under RhII/chiral phosphoric acid (PPA) co‐catalysis.
An unprecedented catalytic asymmetric allylation of isatins and isatin‐derived ketimines is reported enabled by a gold and chiral organocatalyst cooperative catalysis strategy. This method offers ...expeditious access to chiral 2,5‐disubsituted alkylideneoxazolines containing vicinal stereogenic centers, mainly in optically pure form, and which are otherwise impossible to access. Mechanistic evidence reveals the presence of an alkylgold intermediate, and an X‐ray crystal structure of the allylgold species illuminates its unique stability and reactivity. An asymmetric formal hetero‐ene reaction of this gold intermediate, involving a dearomatization process, is enabled with assistance of a quinine‐derived squaramide catalyst. This novel discovery extends the synthetic applications of gold complexes and the versatility of gold catalysis.
An asymmetric allylation reaction of isatins/ketimines with N‐propargylamide is reported that gives access to alkylideneoxazolines mainly in optically pure form. The key alkylgold intermediate, which possesses allylgold reactivity, has been confirmed by X‐ray crystallographic analysis. The asymmetric formal hetero‐ene reaction of this species, involving a dearomatization process is enabled with the assistance of a quinine‐derived squaramide catalyst.
An efficient and novel rhodium-catalyzed formal C–O insertion reaction of alkyne-tethered diazo compounds for the synthesis of 3H-indol-3-ols is described. A type of donor/donor rhodium carbene ...generated in situ via a carbene/alkyne metathesis (CAM) process is the key intermediate and terminates in a unique transformation different from donor/acceptor carbenoids. In addition, 18O-labeling experiments indicate that intramolecular oxygen-atom transfer from the amide group to the carbon–carbon triple bond occurs during this transformation.
Developing an efficient and highly enantioselective protocol to access homopropargyl amines is of high interest to the synthetic community and also remains a formidable challenge for organic ...chemists. Here, we present integrated Rh2(OAc)4- and BINOL-derived chiral phosphoric acid cooperatively catalyzed three-component reactions of alkynyldiazoacetates, imines with various nucleophiles including alcohols, indoles, and N,N-disubstituted anilines, affording the corresponding homopropargyl amines containing two vicinal chiral centers in satisfactory yields with high to excellent diastereo- and enantioselectivities.
The C(sp2)–H function of indole ketone with diazo compound via a rhodium(II)-catalyzed intramolecular electrophilic trapping reaction under mild conditions in air was demonstrated. The established ...methodology provided a highly efficient approach for direct synthesis of mutisubstituted tetrahydrocarbazoles with continuous quaternary carbons. The resulting products facilitate further modification to conveniently construct tetrahydrocarbazoles with additional fused heterocyclic rings. By phenotypic screening, several products exhibit good anticancer bioctivities in osteosarcoma cell lines.
An efficient and novel rhodium-catalyzed formal C-O insertion reaction of alkyne-tethered diazo compounds for the synthesis of 3 H-indol-3-ols is described. A type of donor/donor rhodium carbene ...generated in situ via a carbene/alkyne metathesis (CAM) process is the key intermediate and terminates in a unique transformation different from donor/acceptor carbenoids. In addition,
O-labeling experiments indicate that intramolecular oxygen-atom transfer from the amide group to the carbon-carbon triple bond occurs during this transformation.
Benzoxazines bearing a C4-quaternary stereocenter have been accomplished via the rhodium-catalyzed electrophilic trapping of zwitterionic intermediates by isatins and imines, respectively. The key ...intermediates of the strategy are proposed to generate from the reaction of donor–acceptor rhodium carbenes with secondary amides. Usage of chiral BINOL-phosphoric acid co-catalyst resulted in enrichment of enantioselectivity in the trapping process with imines.
This study introduces a novel approach for synthesizing Benzoxazine‐centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene‐alkyne metathesis‐triggered cascade. Overcoming ...challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis‐mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co‐catalysis, ensuring precise stereo control as validated by X‐ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo‐ and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy‐induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1‐Nav1.7 connection in the context of CIPN.
Search drugs for pain from freshly‐made polychiral heterocycles: Asymmetric Cascade to a C5aR1 inhibitor as a Novel Pain Blocker.
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