Bidirectional Elongation Strategy Using Ambiphilic Radical Linchpin for Modular Access to 1,4-Dicarbonyls via Sequential Photocatalysis.

Organic molecules that can be connected to multiple substrates by sequential C-C bond formations can be utilized as linchpins in multicomponent processes. While they are useful for rapidly increasing molecular complexity, most of the reported linchpin coupling methods rely on the use of organometallic species as strong carbon nucleophiles to form C-C bonds, which narrows the functional group compatibility. Here, we describe a metal-free, radical-mediated coupling approach using a formyl-stabilized phosphonium ylide as a multifunctional linchpin under visible-light photoredox conditions. The present method uses the ambiphilic character of the phosphonium ylide, which serves as both a nucleophilic and an electrophilic carbon-centered radical source. The stepwise and controllable generation of these radical intermediates allows sequential photocatalysis involving two mechanistically distinct radical additions, both of which are initiated by the same photocatalyst in one pot with high functional group tolerance. The methodology enables a bidirectional assembly of the linchpin with two electronically differentiated alkene fragments and thus offers rapid and modular access to 1,4-dicarbonyl compounds as versatile synthetic intermediates.

Impact of Catalyst Deuteration on the Reactivity of Chiral Phase-Transfer Organocatalysts.

Site-specifically deuterated organocatalysts were prepared and found to show improved reactivity over the non-deuterated analogs. Two privileged C2 -symmetric chiral binaphthyl-modified tetraalkylammonium salts were selected for this study. The stability of these phase-transfer catalysts was generally improved by site-specific deuteration, though the degree of improvement was structure dependent. In particular, a large secondary kinetic isotope effect was observed for the tetradeuterated phase-transfer catalyst. The performance of these deuterated catalysts in the asymmetric catalytic alkylation of amino acid derivatives was better than that of non-deuterated analogs at low catalyst loadings. The results suggest that catalyst deuteration is a promising strategy for enhancing the stability and performance of organocatalysts.

Recent Asymmetric Phase-Transfer Catalysis with Chiral Binaphthyl-Modified and Related Phase-Transfer Catalysts over the Last 10 Years.

In this personal account, we describe our recent advances in the three types of phase-transfer catalysis for various transformations including asymmetric induction: Firstly, asymmetric phase-transfer catalysis with Maruoka-type C2 -symmetric chiral biaryl-modified tetraalkylammonium salts and phosphonium salts; Secondly, asymmetric phase-transfer catalysis under base-free and neutral conditions; Thirdly, hydrogen-bonding catalysis using tetraalkylammonium and trialkylsulfonium salts. These three different strategies are illustrated by using various phase-transfer catalyzed transformations.

p-Methoxybenzyl-Radical-Promoted Chemoselective Protection of sec-Alkylamides.

The hitherto difficult site-selective p-methoxybenzylation of secondary amides using p-methoxybenzylated alkylsilyl peroxides as a novel p-methoxybenzylation agent under copper catalysis is reported. The reaction proceeds under mild reaction conditions in a highly chemoselective manner. This approach was successfully applied to the site-selective p-methoxybenzylation of peptides.

Design of Bifunctional Amino Tf-Amide Organocatalysts and Application in Various Asymmetric Transformations.

In this personal account, we describe our recent developments on the four types of amino Tf-amide catalysts in asymmetric transformations. Firstly, axially chiral biaryl-based secondary-amino Tf-amide catalyzed various stereoselective reactions via enamine intermediates. Secondly, pyrrolidine-based secondary-amino aliphatic Tf-amide catalyzed asymmetric direct Mannich reaction. Thirdly, chiral primary-amino aliphatic Tf-amide catalyzed asymmetric direct aldol reaction and conjugate addition. Finally, modified chiral amino aromatic Tf-amide catalyzed asymmetric transformations. These four different strategies are illustrated by using various organocatalyzed asymmetric transformations.

Fe-Catalyzed Three-Component Coupling Reaction of α,ß,γ,δ-Unsaturated Carbonyl Compounds and Conjugate Dienes with Alkylsilyl Peroxides and Nucleophiles.

An Fe(OTf)2-catalyzed three-component coupling reaction of α,ß,γ,δ-unsaturated carbonyl compounds with alkylsilyl peroxides in the presence of certain heteronucleophiles (ROH and indole) is realized under mild reaction conditions. A variety of α,ß,γ,δ-diene carbonyl substrates with different substituents were successfully employable via combination with several different alkylsilyl peroxides. This new approach is also applicable to the double functionalization of diene substrates.

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.

Visible-Light-Induced α-C(sp3)-H Phosphinylation of Unactivated Ethers under Photocatalyst- and Additive-Free Conditions.

A photocatalyst- and additive-free visible-light-induced α-C(sp3)-H phosphinylation of unactivated ethers involving a C-O bond cleavage with molecular oxygen as the sole oxidant at room temperature has been achieved. This method provides a sustainable access to α-hydroxyphosphine oxides in up to 88% yield with good functional group compatibility under mild and neutral conditions (34 examples). Moreover, the subsequent two-step conversion of the resulting dihydroxy diarylphosphine oxides afforded α-phosphinylated cyclic ethers in good overall yields (10 examples).

Radical-Mediated Activation of Esters with a Copper/Selectfluor System: Synthesis of Bulky Amides and Peptides.

Herein, we describe a new approach for the activation of esters via a radical-mediated process enabled by a copper/Selectfluor system. A variety of para-methoxybenzyl esters derived from bulky carboxylic acids and amino acids can be easily converted into the corresponding acyl fluorides, directly used in the one-pot synthesis of amides and peptides. As a proof of concept, this method was applied to the iterative formation of sterically hindered amide bonds.

The copper-catalyzed selective monoalkylation of active methylene compounds with alkylsilyl peroxides.

A novel method for a mild copper-catalyzed selective monoalkylation of active methylene compounds with various alkylsilyl peroxides has been developed. The reaction has a broad substrate scope and our mechanistic studies suggest the participation of radical species in this alkylation reaction.

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.

Development of New Radical-mediated Selective Reactions Promoted by Hypervalent Iodine(III) Reagents.

In this account, we describe our recent developments on the four-types of hypervalent iodine(III)-mediated radical reactions in organic synthesis. Firstly, the activation of aldehydic C-H bonds can be successfully effected with hypervalent iodine(III) reagents, thereby allowing the synthesis of various ketones with high efficiency. Secondly, the site-selective oxidation of unactivated C(sp3 )-H bonds of hydrocarbon substrates was realized with designer hypervalent iodine(III) reagents. Thirdly, various perfluoroalkyl and α-aminoalkyl radicals can be generated from sodium perfluoroalkanesulfinates and sodium α-aminoalkanesulfinates, respectively, under the influence of hypervalent iodine(III) reagents. Finally, the efficient generation of difluoromethyl radical from hypervalent difluoroacetoxyliodine(III) reagent was realized by photolysis. These four different strategies are illustrated by using various selective radical approaches.

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.

Cu-Catalyzed Generation of Alkyl Radicals from Alkylsilyl Peroxides and Subsequent C(sp3)-C(sp2) Cross-Coupling with Arylboronic Acids.

This work describes a novel and practical method for the Cu-catalyzed C(sp3)-C(sp2) cross-coupling of alkylsilyl peroxides with arylboronic acids. The reductive cleavage of the O-O bond of alkylsilyl peroxides and the desired cross-coupling reactions to afford alkyl-substituted aromatic rings proceed smoothly at room temperature promoted by simple Cu-based catalysts and do not require activation by visible light. The results of mechanistic investigations support a radical-mediated C(sp3)-C(sp2) bond formation via ß-scission of the alkoxy radicals generated from the alkylsilyl peroxides.

Design of Bowl-Shaped N-Hydroxyimide Derivatives as New Organoradical Catalysts for Site-Selective C(sp3 )-H Bond Functionalization Reactions.

A series of new bowl-shaped N-hydroxyimide derivatives has been designed and used as selective organoradical catalysts. A number of these bowl-shaped N-hydroxyimide derivatives exhibit excellent site-selectivity in the amination of benzylic C(sp3 )-H bonds in aromatic hydrocarbon substrates.

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.

Asymmetric Synthesis of Chiral Sulfoximines via the S-Arylation of Sulfinamides.

Optically active sulfoximines are a promising substance in medicinal chemistry. However, a methodology for preparing chiral sulfoximines in a stereoselective manner has been underdeveloped. Here, we report an asymmetric synthesis of chiral sulfoximines having an aryl group by the newly developed sulfur-selective arylation of easily accessible chiral sulfinamides. The utility of the present method is demonstrated by the asymmetric synthesis of a key intermediate of a COX-2 inhibitor.

Efficient Synthesis of Cyclic Sulfoximines from N-Propargylsulfinamides through Sulfur-Carbon Bond Formation.

Cyclic sulfoximines were readily synthesized by the cyclization of N-propargylsulfinamides without using expensive and toxic metal catalysts. This cyclization proceeded without loss of optical purity of chiral sulfinamides through the unusual sulfur-carbon bond formation promoted by an inexpensive inorganic base. This stereospecific cyclization offers a general approach to the asymmetric synthesis of chiral cyclic sulfoximines as an emerging heterocycle in medicinal chemistry.

Broad-spectrum antifungal activity of spirooxindolo-pyrrolidine tethered indole/imidazole hybrid heterocycles against fungal pathogens.

Invasive fungal infections are one of the leading causes of nosocomial bloodstream infections with a limited treatment option. A series of derivatized spirooxindolo-pyrrolidine tethered indole and imidazole heterocyclic hybrids have been synthesized, and their antifungal activity against fungal strains were determined. Here we characterize the antifungal activity of a specific spirooxindolo-pyrrolidine hybrid, dubbed compound 9c, a spirooxindolo-pyrrolidine tethered imidazole synthesized with a 2-chloro and trifluoromethoxy substituent. The compound 9c exhibited no cytotoxicity against mammalian cell line at concentrations that inhibited fungal strains. Compound 9c also significantly inhibited the fungal hyphae and biofilm formation. Our results indicate that spirooxindolo-pyrrolidine heterocyclic hybrids potentially represent a broad class of chemical agents with promising antifungal potential.

Benzimidazole tethered pyrrolo[3,4-b]quinoline with broad-spectrum activity against fungal pathogens.

Fungal infections caused by Candida and Cryptococcus are particularly dangerous for immunocompromised individuals. In this study, we identified that benzimidazole fused pyrrolo[3,4-b]quinoline compounds have potent antifungal activity against several clinical isolates of pathogenic fungal strains. Specifically, the compound 6a did not show cytotoxicity against mammalian cells at a concentration that inhibits the growth of fungal strains. In addition, the compound 6a also significantly reduced the metabolic activity of fungal cells in the Candida albicans biofilms. Collectively, our results indicate that benzimidazole fused quinoline compounds have a potential to develop as an antifungal agents.