Vicinal Tetrasubstituted Stereocenters Research Articles

Asymmetric 1,2-Migration at Vicinal Tetrasubstituted Stereocenters Constructed from α-Keto Imines.

A carbonyl-assisted asymmetric 1,2-migratory allylation through in situ generation of vicinal tetrasubstituted stereocenters is reported to access enantiopure α-amino ketones and amino alcohols with excellent yields and diastereoselectivities. In a remarkable divergence, despite higher steric hindrance, the allylation exclusively occurs on ketones over imines in the first step, followed by a face-selective 1,2-allyl transfer, thus highlighting an exciting interplay between two distinct electrophiles. The methodology distinguishes itself through its adaptability to gram-scale synthesis, showcasing broad functional-group tolerance and stereodivergence. Density functional theory (DFT) analysis led to a deeper understanding of its selectivity and mechanistic framework. Highlighting its transformative potential, the method was applied to the total synthesis of hapalindole alkaloids.

Asymmetric 1,2‐Migration at Vicinal Tetrasubstituted Stereocenters Constructed from α‐Keto Imines

AbstractA carbonyl‐assisted asymmetric 1,2‐migratory allylation through in situ generation of vicinal tetrasubstituted stereocenters is reported to access enantiopure α‐amino ketones and amino alcohols with excellent yields and diastereoselectivities. In a remarkable divergence, despite higher steric hindrance, the allylation exclusively occurs on ketones over imines in the first step, followed by a face‐selective 1,2‐allyl transfer, thus highlighting an exciting interplay between two distinct electrophiles. The methodology distinguishes itself through its adaptability to gram‐scale synthesis, showcasing broad functional‐group tolerance and stereodivergence. Density functional theory (DFT) analysis led to a deeper understanding of its selectivity and mechanistic framework. Highlighting its transformative potential, the method was applied to the total synthesis of hapalindole alkaloids.

Enantio- and Diastereoselective Copper-Catalyzed Synthesis of Chiral Aziridines with Vicinal Tetrasubstituted Stereocenters.

A Cu-catalyzed coupling of cyclic imino esters with 2H-azirines has been developed to synthesize novel optically active aziridines in high yields with excellent levels of diastereo- and enantioselectivities under mild conditions. This novel protocol features a broad substrate scope and good functional group compatibility, and it enriches the existing reaction type of rapid synthesis of optically active aziridines bearing vicinal tetrasubstituted stereogenic carbon centers.

Copper-Catalyzed Diastereo- and Enantioselective Decarboxylative [3 + 2] Cyclization of Alkyne-Substituted Cyclic Carbamates with Azlactones: Access to γ-Butyrolactams Bearing Two Vicinal Tetrasubstituted Carbon Stereocenters

A copper-catalyzed diastereo- and enantioselective decarboxylative [3 + 2] cyclization reaction of alkyne-substituted cyclic carbamates with azlactones has been established. A range of optically pure γ-butyrolactams bearing two vicinal tetrasubstituted carbon stereocenters were obtained in high yields with good to excellent stereoselectivities (up to 99% yield, 99:1 dr, and 99% ee). This is the first example of asymmetric synthesis γ-butyrolactams containing sterically congested vicinal tetrasubstituted stereocenters via a decarboxylative cyclization pathway.

Enantioselective Construction of Vicinal Quaternary-Tetrasubstituted Carbon Stereocenters by Copper-Catalyzed Decarboxylative Propargylic Substitution.

Enantioselective construction of vicinal tetrasubstituted carbon stereocenters is a formidable challenge in organic synthesis. A copper-catalyzed asymmetric decarboxylative propargylic substitution with 3-amino oxindoles as trisubstituted carbon nucleophiles and propargylic cyclic carbonates as tertiary carbon electrophiles was developed. A range of 3-amino-3,3'-disubstituted oxindoles bearing vicinal quaternary-tetrasubstituted carbon stereocenters were obtained in high yields and good to excellent stereoselectivities (up to 98% yield, >20:1 dr, and 98.5:1.5 er).

Palladium‐Catalyzed Asymmetric Allylic Cycloaddition of Vinylethylene Carbonates with Nitroalkenes: A Route to Tetrahydrofurans bearing Vicinal Tetrasubstituted Stereocenters

AbstractAn efficient method for the diastereo‐ and enantioselective construction of tetrahydrofurans bearing three continuous stereocenters including vicinal tetrasubstituted stereocenters via palladium‐catalyzed asymmetric allylic cycloaddition of vinylethylene carbonates with nitroalkenes was developed. By using a palladium complex generated in situ from [Pd2(dba)3] ⋅ CHCl3 and (R)‐BINAP ligand as a catalyst under mild reaction conditions, the process provides multi‐functionalized tetrahydrofurans in good yields with excellent stereoselectivities.

Zn-ProPhenol Catalyzed Enantioselective Mannich Reaction of 2H-Azirines with Alkynyl Ketones.

The enantioselective Mannich reaction of 2H-azirines with alkynyl ketones is achieved under Zn-ProPhenol catalysis, delivering various aziridines with vicinal tetrasubstituted stereocenters in high yields with excellent enantioselectivities. The bimetallic Zn-ProPhenol complexes activate both the nucleophile and the electrophile in the same chiral pocket. A unique intramolecular hydrogen bond is observed in the obtained Mannich adducts, which lowers the basicity of the product's aziridine nitrogen thus favoring enantioselective control and allowing catalyst turnover.

Catalytic Enantioselective [2+2] Cycloaddition of α‐Halo Acroleins: Construction of Cyclobutanes Containing Two Tetrasubstituted Stereocenters

AbstractA catalytic enantioselective formal [2+2] cycloaddition between α‐halo acroleins and electronically diverse arylalkenes is described. In the presence of (S)‐oxazaborolidinium cation as the catalyst, densely functionalized cyclobutanes containing two vicinal tetrasubstituted stereocenters were produced in high yields and high diastereoselectivities with excellent enantioselectivities. Mechanistic studies revealed that the cis isomer could be transformed into the trans isomer via an enantiocontrolled process. A gram‐scale reaction of this catalytic method was used to demonstrate its synthetic potential.

Enantioselective Vinylogous Michael-Aldol Reaction To Synthesize Spirocyclohexene Pyrazolones in Aqueous Media.

An efficient asymmetric vinylogous Michael-aldol domino reaction between α-arylidene pyrazolinones and β,γ-unsaturated-α-ketoesters catalyzed by a chiral N, N'-dioxide-ScIII complex in aqueous media has been established. A variety of spirocyclohexene pyrazolones with three stereocenters including vicinal tetrasubstituted stereocenters were obtained in excellent yields with good diastereoselectivities and enantioselectivities. A retro-aldol process was observed, which led to epimerization at the spirocyclic quaternary carbon center.

Catalytic Asymmetric Mannich Reaction of α-Fluoronitriles with Ketimines: Enantioselective and Diastereodivergent Construction of Vicinal Tetrasubstituted Stereocenters.

Diastereodivergent and enantioselective conversion of isatin ketimines to α-fluoro-β-aminonitriles with vicinal tetrasubstituted stereocenters is achieved by a chiral copper complex/guanidine base catalyzed Mannich reaction with proper choice of the bisphosphine ligand. The reaction is broad in scope, scalable, and provides efficient access to a series of 3-aminoindolinones exhibiting a quaternary carbon-fluorine stereocenter with high yields and stereoselectivities. Selective transformations of the Mannich reaction products into multifunctional 3-aminooxindoles without erosion of enantiomeric and diastereomeric purity highlight the synthetic utility.

Iridium-Catalyzed Enantioselective and Diastereoselective Allylation of Dioxindoles: A One-Step Synthesis of 3-Allyl-3-hydroxyoxindoles.

An iridium-catalyzed asymmetric allylation of dioxindoles, 3-hydroxyoxindoles, regulated by prosthetic groups has been accomplished under mild conditions. The methodology is applicable to a diverse array of 3-hydroxyoxindole and cinnamyl acetate substrates. A range of 3-allyl-3-hydroxyoxindoles containing vicinal tetrasubstituted and trisubstituted stereocenters can be efficiently synthesized in one-step with excellent enantioselectivity (up to >99% enaniomeric excess (ee)) and good diastereoselectivity (up to 11:1 diastereomeric ratio (dr)).

Copper-Catalyzed Asymmetric Addition of Tertiary Carbon Nucleophiles to 2 H-Azirines: Access to Chiral Aziridines with Vicinal Tetrasubstituted Stereocenters.

A catalytic asymmetric nucleophilic addition of tertiary carbon nucleophiles to 2 H-azirines was established in the presence of the chiral N,N'-dioxide/CuII complex. Various chiral aziridines with vicinal tetrasubstituted stereocenters were obtained in high yields with excellent diastereoselectivities and enantioselectivities. Moreover, on the basis of the control experiments, X-ray structures of the products, and catalyst, a possible transition state was proposed to explain the stereoselectivity.

A diastereoselective Mannich reaction of α-fluoroketones with ketimines: Construction of β-fluoroamine motifs with vicinal tetrasubstituted stereocenters

A diastereoselective Mannich reaction has been developed for the synthesis of chiral β-fluoroamine motifs by the reaction of α-fluoroketones with ketimines, including isatin-derived ketimines and phenylglyoxylate-derived ketimines. This method provides a concise route to a variety of biologically important 3-aminooxindoles and α-amino acids featuring fluorine-containing vicinal tetrasubstituted stereocenters.

Construction of Vicinal Tetrasubstituted Stereogenic Centers via a Mannich‐Type Organocatalyzed Addition of Δ2‐Pyrrolin‐4‐ones to Isatin Imines

AbstractRacemic Δ2‐pyrrolin‐4‐ones (i. e. 4‐pyrrolones), easily available in two steps from N‐protected α‐amino acids, undergo organocatalysed asymmetric Mannich‐type addition to isatin‐derived ketimines to furnish the non‐racemic oxindole‐Δ2‐pyrrolin‐4‐one adducts, stereoselectively (up to 96% ee, dr≥15:1). The oxindole–pyrrolone products feature vicinal tetrasubstituted carbon stereocenters. The developed protocol has a broad substrate scope and tolerates diverse substituents at position C‐5 in 4‐pyrrolones and at positions N‐1 and C‐5/7 in isatin imines.magnified image

Enantioselective Mannich reaction between rhodanines and isatin-derived ketimines to construct vicinal tetrasubstituted stereocenters.

An organocatalytic enantioselective Mannich reaction between rhodanines and isatin-derived ketimines was developed. With 2 mol% of a quinine-based tertiary amine-thiourea catalyst C2, 3,3-disubstituted oxindoles with vicinal tetrasubstituted stereocenters were obtained in moderate-to-excellent yields (43-99%) with excellent diastereoselectivities (98 : 2-99 : 1 dr) and good-to-excellent enantioselectivities (up to 97% ee). The readily available substrates, low catalyst loading and high stereoselectivity are the major features.

ChemInform Abstract: Organocatalytic Enantioselective Alkylation of Pyrazol‐3‐ones with Isatin‐Derived Ketimines: Stereocontrolled Construction of Vicinal Tetrasubstituted Stereocenters.

AbstractThe title reaction is efficiently catalyzed by a quinine‐derived thiourea, providing a variety of aminooxindole‐pyrazolone adducts containing congested vicinal tetrasubstituted stereocenters with high diastereoselectivity.

ChemInform Abstract: Enantioselective Construction of Imidazolines Having Vicinal Tetra‐Substituted Stereocenters by Direct Mannich Reaction of α‐Substituted α‐Isocyanoacetates with Ketimines.

The catalytic Mannich reaction of α-substituted α-isocyanoacetates with ketimines has been investigated. A variety of imidazolines containing congested vicinal tetra-substituted stereocenters were obtained in excellent yields with high diastereo- and enantioselectivity using cinchona alkaloid amide/Ni(II) and base catalysts.

Organocatalytic Enantioselective Alkylation of Pyrazol‐3‐ones with Isatin‐Derived Ketimines: Stereocontrolled Construction of Vicinal Tetrasubstituted Stereocenters

AbstractA quinine‐derived thiourea catalysed the enantioselective addition of 4‐substituted pyrazolones to isatin‐derived ketimines, providing a variety of aminooxindole‐pyrazolone adducts containing congested vicinal tetrasubstituted stereocentres with excellent outcomes (up to 98% yield, >20:1 dr and 98% ee).magnified image

ChemInform Abstract: Construction of Vicinal Tetrasubstituted Stereocenters with a C—F Bond Through a Catalytic Enantioselective Detrifluoroacetylative Mannich Reaction.

An efficient asymmetric detrifluoroacetylative Mannich reaction of 2-fluoro-1,3-diketones/hydrates with isatin-derived ketimines catalyzed by a chiral copper(II)-diamine complex has been realized. The reaction afforded a series of 3-substituted 3-amino-2-oxindoles bearing fluorine-containing vicinal tetrasubstituted stereocenters in high yields (up to 99%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 94% ee).

ChemInform Abstract: An Organocatalytic Asymmetric Friedel—Crafts Addition/Fluorination Sequence: Construction of Oxindole—Pyrazolone Conjugates Bearing Vicinal Tetrasubstituted Stereocenters.

AbstractThe scalable highly efficient one‐pot two‐step process delivers novel oxindole‐pyrazolone adducts with two vicinal quaternary stereocenters in high yields and with excellent diastereo‐ and enantiocontrol.