Cu-Catalyzed Asymmetric Arylation of Enone Diesters with Arylboronic Acids.

The Cu-catalyzed asymmetric conjugate addition of arylboronic acids to enone diesters is reported. This operationally simple and scalable reaction proceeded under mild conditions. The practical utility of this approach was demonstrated by the synthesis of structurally important γ-lactones and a cyclopentene that bear an aryl group. Mechanistic studies revealed that two different copper catalytic species work synergistically in the reaction.

One-pot furan synthesis through diethylzinc-mediated coupling reaction between two α-bromocarbonyl compounds.

Polysubstituted furans were synthesized in one-pot through the Et2Zn-mediated coupling reaction between dibromoketones and monobromo carbonyl compounds and the subsequent ß-elimination with bromoacetyl bromide. Polysubstituted pyrroles were also prepared in one-pot by addition of primary amines after the coupling reaction.

Transsulfinamidation of Sulfinamides with Amines.

Metal- and additive-free transsulfinamidation of N-unsubstituted sulfinamides and N-pivaloyl-protected sulfinamides with various amines is reported. With this method, both N-monosubstituted and N,N-disubstituted sulfinamides were obtained in good yields simply by heating. Preliminary experiments also indicate that alcohols can be used as nucleophiles instead of amines and can provide sulfinate esters.

Synthesis of biphenyl-based chiral amine catalysts from dibromopyrenes and their application in enamine catalysis.

Novel axially chiral biphenyl-based amine catalysts have been designed and synthesized from dibromopyrenes. These chiral amines function as effective catalysts for asymmetric reactions through enamine intermediates.

Construction of three contiguous stereocenters through amine-catalyzed asymmetric aldol reactions.

Three contiguous stereocenters were constructed by an amino acid-catalyzed asymmetric aldol reaction of α-siloxyketones with racemizable α-haloaldehydes via dynamic kinetic resolution. One-pot catalytic asymmetric synthesis of the highly functionalized products could also be accomplished by the α-bromination of simple aldehydes and the subsequent asymmetric aldol reaction.

Cu-Catalyzed Asymmetric Alkenylation of Enone Diesters with Trialkenylboroxines.

The Cu-catalyzed asymmetric conjugate addition of trialkenylboroxines to enone diesters is reported. This operationally simple and scalable reaction proceeded at room temperature, and a wide range of enone diesters and boroxines were tolerated under the applied reaction conditions. The practical utility of this approach was demonstrated via the formal synthesis of (+)-methylenolactocin. Mechanistic studies revealed that two different catalytic species work synergistically in the reaction.

Asymmetric Synthesis of Chiral Sulfimides through the O-Alkylation of Enantioenriched Sulfinamides and Addition of Carbon Nucleophiles.

Chiral sulfimides, the aza-analogues of sulfoxides, are valuable compounds in organic synthesis and medicinal chemistry. Herein, we report an efficient method for preparing chiral sulfimides from easily available enantioenriched sulfinamides. The key step of this method is a stereospecific oxygen-selective alkylation of enantioenriched sulfinamides, which is accomplished by using isopropyl iodide, K2 CO3 , and DMPU. The resulting chiral sulfinimidate esters are transformed to chiral sulfimides by the nucleophilic addition of the Grignard reagents under simple conditions. This transformation enables access to the enantioenriched diaryl or dialkyl sulfimides bearing two similar carbon substituents, which are difficult to synthesize by previous methods.

Diethylzinc-Mediated Cross-Coupling Reactions between Dibromoketones and Monobromo Carbonyl Compounds.

A novel route to synthesize 1,4-dicarbonyl compounds is described. α,α-Dibromoketones generate zinc enolates through a diethylzinc-mediated halogen-metal exchange and react with α-bromocarbonyl compounds to furnish 1,4-dicarbonyl compounds via a second generation of zinc enolates. This cross-coupling reaction is enabled by the chemoselective formation of zinc enolates from α,α-dibromoketones in the presence of α-bromocarbonyl compounds. Chiral 1,4-dicarbonyl compounds can be obtained via the enantioselective bromination of aldehydes using a chiral secondary amine catalyst and a subsequent cross-coupling reaction between the resulting chiral α-bromoaldehydes and α,α-dibromoacetophenones.

VCD spectroscopy distinguishes the enamine and iminium ion of a 1,1'-binaphthyl azepine.

We present a VCD spectroscopic characterization of a chiral 1,1'-binaphthyl azepine catalyst and show that the VCD spectra of an in situ generated enamine and an ex situ prepared iminium ion are characteristically different. The study highlights the potential of VCD spectroscopy to distinguish such catalytically relevant stable intermediates and that the spectra can be used to determine the species' dominant conformers in solution.

Practical Asymmetric Synthesis of Chiral Sulfoximines via Sulfur-Selective Alkylation.

Chiral sulfoximines have recently been considered as promising bioisosteres in medicinal chemistry. However, methods for preparing chiral sulfoximines in a stereoselective manner are underdeveloped. Herein, we demonstrate an asymmetric synthesis of chiral sulfoximines through a stereospecific S-alkylation of readily accessible chiral sulfinamides under practical conditions. A key to establishing the practical conditions was the identification of the intermediate structure in our previously reported S-alkylation by X-ray crystallographic analysis.

Ni-Catalyzed C(sp2)-H alkylation of N-quinolylbenzamides using alkylsilyl peroxides as structurally diverse alkyl sources.

A Ni-catalyzed direct C-H alkylation of N-quinolylbenzamides using alkylsilyl peroxides as alkyl-radical precursors is described. The reaction forms a new C(sp3)-C(sp2) bond via the selective cleavage of both C(sp3)-C(sp3) and C(sp2)-H bonds. This transformation shows a high functional-group tolerance and, due to the structural diversity of alkylsilyl peroxides, a wide range of alkyl chains including functional groups and complex structures can be introduced at the ortho-position of readily available N-quinolylbenzamide derivatives. Mechanistic studies suggest that the reaction involves a radical mechanism.

Bifunctional amino sulfonamide-catalyzed asymmetric conjugate addition to alkenyl alkynyl ketimines as enone surrogates.

A bifunctional amino sulfonamide-catalyzed asymmetric conjugate addition of aldehydes to alkenyl alkynyl ketimines as reactive surrogates for enones has been developed. Use of a phenylcyclopropane-based amino sulfonamide catalyst, which can activate and orient the ketimines through hydrogen bonding, affords the desired conjugate adducts with high chemo-, diastereo- and enantioselectivity.

Asymmetric α-Hydroxylation of α-Aryl-δ-lactams with Molecular Oxygen under Phase-Transfer Conditions.

An asymmetric synthesis of α-aryl-α-hydroxy-δ-lactams via phase-transfer-catalyzed hydroxylation with molecular oxygen is described. High yields and high enantioselectivities were achieved using 2,2-diarylvinyl group as an achiral auxiliary. This strategy allows facile access to α-aryl-α-hydroxy-δ-lactam derivatives containing a chiral quaternary center.

Cu-Catalyzed O-alkylation of phenol derivatives with alkylsilyl peroxides.

A Cu-catalyzed O-alkylation of phenol derivatives using alkylsilyl peroxides as alkyl radical precursors is described. The reaction proceeds smoothly under mild reaction conditions and the use of two different ligands with a Cu catalyst provides a wide range of products. A mechanistic study suggested that the reaction proceeds via a radical mechanism.

Cu-Catalyzed Enantioselective Alkylarylation of Vinylarenes Enabled by Chiral Binaphthyl-BOX Hybrid Ligands.

Transition-metal-catalyzed radical relay coupling reactions have recently emerged as one of the most powerful methods to achieve difunctionalization of olefins. However, there has been limited success in applying this method to asymmetric catalysis using an effective chiral ligand. Herein we report the Cu-catalyzed enantioselective alkylarylation of vinylarenes using alkylsilyl peroxides as alkyl radical sources. This reaction proceeds under practical reaction conditions and affords chiral 1,1-diarylalkane structures that are found in a variety of bioactive molecules. Notably, a highly enantioselective reaction was accomplished by combining chiral bis(oxazoline) ligands with chiral binaphthyl scaffolds.

CuCl2 -Mediated Oxidative Intramolecular α-Arylation of Ketones with Phenolic Nucleophiles via Oxy-Allyl Cation Intermediates.

α-Functionalization of ketones in an umpolung fashion can be achieved by nucleophilic addition to the oxy-allyl cation intermediate. However, applicable carbon nucleophiles are limited to ones with high nucleophilicity. Additionally, introduction of a leaving group to the α-position of ketone substrates is required beforehand. Herein, we report the CuCl2 -mediated oxidative intramolecular α-arylation of ketones with less nucleophilic phenolic moieties as carbon nucleophiles via α-chlorination of ketones and the subsequent generation of the oxy-allyl cation intermediates, giving ketones with a quaternary carbon center at the α-position.

Synthesis of Electron-Deficient Chiral Biphenols and Their Applications in Catalytic Asymmetric Reactions.

The axially chiral biphenols are known as a broadly applicable chiral source. However, only a few electron-deficient ones have been reported to date. In the present study, chiral biphenols having several electron-withdrawing groups have been designed, and a facile synthetic route from readily available reagents has been developed. Newly synthesized chiral electron-deficient biphenols and biphenol-derived chiral Brønsted acids functioned as effective catalysts for several catalytic asymmetric reactions.

Organocatalytic Formal (3 + 2) Cycloaddition toward Chiral Pyrrolo[1,2-a]indoles via Dynamic Kinetic Resolution of Allene Intermediates.

We report the chiral phosphoric acid catalyzed formal (3 + 2) cycloaddition of 3-substituted 1H-indoles and propargylic alcohols containing a functional directing group (p-NHAc or p-OH). This work represents a straightforward method to synthesize chiral pyrrolo[1,2-a]indole bearing a tetrasubstituted carbon stereocenter. The reaction proceeds smoothly with a wide array of substrate tolerance to deliver various chiral pyrrolo[1,2-a]indoles in up to 93% yield and 98% ee. The utility of this method is highlighted by the diverse transformations of the products into various indole derivatives.

Construction of chiral α-tert-amine scaffolds via amine-catalyzed asymmetric Mannich reactions of alkyl-substituted ketimines.

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral ß-amino aldehydes that bear an α-tert-amine moiety. However, the structural variation of the ketimines is limited due to the formation of inseparable E/Z isomers, low reactivity, and other synthetic difficulties. In this study, a highly diastereodivergent synthesis of hitherto difficult-to-access ß-amino aldehydes that bear a chiral α-tert-amine moiety was achieved using the amine-catalyzed Mannich reactions of aldehydes with less-activated Z-ketimines that bear both alkyl and alkynyl groups.

Construction of Quaternary Carbon Center by Catalytic Asymmetric Alkylation of 3-Arylpiperidin-2-ones Under Phase-Transfer Conditions.

A highly enantioselective synthesis of δ-lactams having a chiral quaternary carbon center at the α-position has been developed through an asymmetric alkylation of 3-arylpiperidin-2-ones under phase-transfer conditions. In this transformation, a 2,2-diarylvinyl group on the δ-lactam nitrogen atom plays a crucial role as a novel protecting group and an achiral auxiliary for improving both yield and enantioselectivity of the reaction.