Grignard Reagent Addition to Pyridinium Salts: A Catalytic Approach to Chiral 1,4-Dihydropyridines.

Catalytic dearomatization of pyridinium salts is a powerful technique for constructing chiral N-heterocycles, which are crucial in alkaloid natural products and drugs. Despite its potential, progress in metal-catalyzed asymmetric dearomatization of pyridinium derivatives has been limited. Here, we present the enantioselective 1,4-dearomatization of pyridinium salts using Grignard reagents and chiral copper catalysis. This approach yields enantioenriched functionalized 1,4-dihydropyridines. Experimental kinetic isotope effects and density functional theory calculations provide insights into the reaction mechanism, regio- and enantioselectivity, and the rate-limiting step.

A highly efficient and sustainable catalyst system for terminal epoxy-carboxylic acid ring opening reactions.

The nucleophilic ring opening of epoxides by carboxylic acids is an indispensable transformation for materials science and coating technologies. Due to this industrial significance, improvements in operational energy consumption and catalyst sustainability are highly desirable for this transformation. Herein, an efficient, environmentally benign and non-toxic halide free cooperative catalyst system based on an iron(iii) benzoate complex and guanidinium carbonate is reported. The novel catalyst system shows improved activity over onium halide catalysts under neat conditions and in several solvents, including anisole and nBuOAc. Detailed mechanistic studies using FeCl3/DMAP as a catalyst revealed the importance of a carboxylate bridged cationic trinuclear µ3-oxo iron cluster and guanidinium carbonate or DMAP as a carboxylate reservoir due to its superior activity.

Unlocking the potential of metal ligand cooperation for enantioselective transformations.

Metal-ligand cooperation, in which both the metal and the ligand of a transition metal complex actively participate in chemical transformations leading to enhanced reactivity or selectivity in chemical reactions, has emerged as a powerful and versatile concept in catalysis. This Viewpoint discusses the development trajectory of transition metal-based complexes as catalysts in (de)hydrogenative processes, in particular those cases where metal-ligand cooperation has been invoked to rationalise the observed high reactivities and excellent selectivities. The historical context, mechanistic aspects and current applications are discussed with the suggestion to explore the potential of the MLC mode of action of such catalysts in enantioselective transformations beyond (de)hydrogenative processes.

Enantioselective Hydrophosphination of Terminal Alkenyl Aza-Heteroarenes.

This paper presents a Mn(I)-catalysed methodology for the enantioselective hydrophosphination of terminal alkenyl aza-heteroarenes. The catalyst operates through H-P bond activation, enabling successful hydrophosphination of a diverse range of alkenyl-heteroarenes with high enantioselectivity. The presented protocol addresses the inherently low reactivity and the commonly encountered suboptimal enantioselectivities of these challenging substrates. As an important application we show that this method facilitates the synthesis of a non-symmetric tridentate P,N,P-containing ligand like structure in just two synthetic steps using a single catalytic system.

A catalytically active oscillator made from small organic molecules.

Oscillatory systems regulate many biological processes, including key cellular functions such as metabolism and cell division, as well as larger-scale processes such as circadian rhythm and heartbeat1-4. Abiotic chemical oscillations, discovered originally in inorganic systems5,6, inspired the development of various synthetic oscillators for application as autonomous time-keeping systems in analytical chemistry, materials chemistry and the biomedical field7-17. Expanding their role beyond that of a pacemaker by having synthetic chemical oscillators periodically drive a secondary function would turn them into significantly more powerful tools. However, this is not trivial because the participation of components of the oscillator in the secondary function might jeopardize its time-keeping ability. We now report a small molecule oscillator that can catalyse an independent chemical reaction in situ without impairing its oscillating properties. In a flow system, the concentration of the catalytically active product of the oscillator shows sustained oscillations and the catalysed reaction is accelerated only during concentration peaks. Augmentation of synthetic oscillators with periodic catalytic action allows the construction of complex systems that, in the future, may benefit applications in automated synthesis, systems and polymerization chemistry and periodic drug delivery.

Manganese(I)-Catalyzed Asymmetric Hydrophosphination of α,ß-Unsaturated Carbonyl Derivatives.

Here we report catalytic asymmetric hydrophosphination of α,ß-unsaturated carbonyl derivatives using a chiral Mn(I) complex as a catalyst. Through H-P bond activation, various phosphine-containing chiral products can be accessed via hydrophosphination of various ketone-, ester-, and carboxamide-based Michael acceptors.

Enantio- and Z-selective synthesis of functionalized alkenes bearing tertiary allylic stereogenic center.

Olefins are ubiquitous in biologically active molecules and frequently used as building blocks in chemical transformations. However, although many strategies exist for the synthesis of stereodefined E-olefines, their thermodynamically less stable Z counterparts are substantially more demanding, while access to those bearing an allylic stereocenter with an adjacent reactive functionality remains unsolved altogether. Even the classic Wittig reaction, arguably the most versatile and widely used approach to construct Z-alkenes, falls short for the synthesis of these particularly challenging yet highly useful structural motives. Here, we report a general methodology for Z-selective synthesis of functionalized chiral alkenes that establishes readily available alkene-derived phosphines as an alternative to alkylating reagents in Wittig olefination, thus offering previously unidentified retrosynthetic disconnections for the formation of functionalized disubstituted alkenes. We demonstrate the potential of this method by structural diversification of several bioactive molecules.

Catalytic Access to Chiral δ-Lactams via Nucleophilic Dearomatization of Pyridine Derivatives.

Nitrogen-bearing rings are common features in the molecular structures of modern drugs, with chiral δ-lactams being an important subclass due to their known pharmacological properties. Catalytic dearomatization of preactivated pyridinium ion derivatives emerged as a powerful method for the rapid construction of chiral N-heterocycles. However, direct catalytic dearomatization of simple pyridine derivatives are scarce and methodologies yielding chiral δ-lactams are yet to be developed. Herein, we describe an enantioselective C4-dearomatization of methoxypyridine derivatives for the preparation of functionalised enantioenriched δ-lactams using chiral copper catalysis. Experimental 13 C kinetic isotope effects and density functional theory calculations shed light on the reaction mechanism and the origin of enantioselectivity.

Organocatalyst based cross-catalytic system.

We present our design of a cross-catalytic system based on organocatalysis. The system features two organic reactions, namely a deprotection reaction of Fmoc protected proline and a Mannich reaction between acetone and dihydroisoquinoline. The products of these two reactions, proline and a tetrahydroisoquinoline, respectively, are capable of reciprocal reaction rate enhancement. Detailed kinetic studies of the system and seeding experiments support the cross-catalytic relationship in the reaction network.

Catalytic Access to 4-(sec-Alkyl)Anilines via 1,6-Conjugate Addition of Grignard Reagents to in Situ Generated aza-p-Quinone Methides.

The synthesis of aniline derivatives, common building blocks in many pharmaceuticals, agrochemicals, dyes or polymers, has been limited to reactions based on benzene-toluene-xylene derivatives (BTX) due to their ample availability. Despite the large number of existing methodologies, the synthesis of chiral 4-(sec-alkyl)anilines has not been accomplished so far. In this work, a tandem strategy based on the generation of a reactive aza-p-quinone methide (aza-p-QM) intermediate followed by Cu(I)-catalyzed addition of Grignard reagents has been developed.

Electrophilic Trapping of Semibenzenes.

In this work, we demonstrate how allylative dearomatization of benzyl chlorides can provide direct access to a variety of semibenzenes. These scaffolds behave as highly reactive nucleophiles in the presence of carbocations. In addition, semibenzenes are susceptible to intramolecular rearrangements rendering a broad scope of functionalized arenes. An analysis of this new reactivity is reported, as well as the rationale behind the observed intramolecular reorganizations.

Manganese(i)-catalyzed access to 1,2-bisphosphine ligands.

Chiral bisphosphine ligands are of key importance in transition-metal-catalyzed asymmetric synthesis of optically active products. However, the transition metals typically used are scarce and expensive noble metals, while the synthetic routes to access chiral phosphine ligands are cumbersome and lengthy. To make homogeneous catalysis more sustainable, progress must be made on both fronts. Herein, we present the first catalytic asymmetric hydrophosphination of α,ß-unsaturated phosphine oxides in the presence of a chiral complex of earth-abundant manganese(i). This catalytic system offers a short two-step, one-pot synthetic sequence to easily accessible and structurally tunable chiral 1,2-bisphosphines in high yields and enantiomeric excess. The resulting bidentate phosphine ligands were successfully used in asymmetric catalysis as part of earth-abundant metal based organometallic catalysts.

Cu(I)-Catalyzed Alkynylation of Quinolones.

Herein we report the first alkynylation of quinolones with terminal alkynes under mild reaction conditions. The reaction is catalyzed by Cu(I) salts in the presence of a Lewis acid, which is essential for the reactivity of the system. The enantioselective version of this transformation has also been explored, and the methodology has been applied in the synthesis of the enantioenriched tetrahydroquinoline alkaloid cuspareine.

Manganese(I)-Catalyzed H-P Bond Activation via Metal-Ligand Cooperation.

Here we report that chiral Mn(I) complexes are capable of H-P bond activation. This activation mode enables a general method for the hydrophosphination of internal and terminal α,ß-unsaturated nitriles. Metal-ligand cooperation, a strategy previously not considered for catalytic H-P bond activation, is at the base of the mechanistic action of the Mn(I)-based catalyst. Our computational studies support a stepwise mechanism for the hydrophosphination and provide insight into the origin of the enantioselectivity.

Pd-catalyzed allylative dearomatisation using Grignard reagents.

Pd-catalyzed allylative dearomatisation of naphthyl halides is shown to be feasible by employing Grignard reagents. The high reactivity of the nucleophile allows for fast reactions and low catalyst loading, while a plethora of successfully substituted compounds illustrate the broad scope. Five membered heteroaromatic compounds are also demonstrated to be reactive under similar conditions.

Enantioselective Catalytic Dearomative Addition of Grignard Reagents to 4-Methoxypyridinium Ions.

We describe a general catalytic methodology for the enantioselective dearomative alkylation of pyridine derivatives with Grignard reagents, allowing direct access to nearly enantiopure chiral dihydro-4-pyridones with yields up to 98%. The methodology involves dearomatization of in situ-formed N-acylpyridinium salts, employing alkyl organomagnesium reagents as nucleophiles and a chiral copper (I) complex as the catalyst. Computational and mechanistic studies provide insights into the origin of the reactivity and enantioselectivity of the catalytic process.

Nucleophilic Dearomatization of N-Heteroaromatics Enabled by Lewis Acids and Copper Catalysis.

Dearomative functionalization of heteroaromatics, a readily available chemical feedstock, is one of the most straightforward approaches for the synthesis of three-dimensional, chiral heterocyclic systems, important synthetic building blocks for both synthetic chemistry and drug discovery. Despite significant efforts, direct nucleophilic additions to heteroaromatics have remained challenging because of the low reactivity of aromatic substrates associated with the loss of aromaticity, as well the regio- and stereoselectivities of the reaction. Here we present a catalytic system that leads to unprecedented, high-yielding dearomative C-4 functionalization of quinolines with organometallics with nearly absolute regio- and stereoselectivities and with a catalyst turnover number (TON) as high as 1000. The synergistic action of the chiral copper catalyst, Lewis acid, and Grignard reagents allows us to overcome the energetic barrier of the dearomatization process and leads to chiral products with selectivities reaching 99% in most cases. Molecular modeling provides important insights into the speciation and the origin of the regio- and enantioselectivity of the catalytic process. The results reveal that the role of the Lewis acid is not only to activate the substrate toward a potential nucleophilic addition but also to subtly control the regiochemistry by preventing the C-2 addition from happening.

Copper-Catalyzed Addition of Grignard Reagents to in situ Generated Indole-Derived Vinylogous Imines.

Chiral indole derivatives are ubiquitous motifs in pharmaceuticals and alkaloids. Herein, the first protocol for catalytic asymmetric conjugate addition of Grignard reagents to various sulfonyl indoles, offering a straightforward approach for the synthesis of chiral 3-sec-alkyl-substituted indoles in high yields and enantiomeric ratios is presented. This methodology makes use of a chiral catalyst based on copper phosphoramidite complexes and in situ formation of vinylogous imine intermediates.

Lewis Acid Promoted Dearomatization of Naphthols.

Two-step dearomative functionalization of naphthols promoted by Lewis acids and copper(I) catalysis was developed. Initially, Lewis acid complexation inverted the electronic properties of the ring and established an equilibrium with the dearomatized counterpart. Subsequent trapping of the dearomatized intermediate with organometallics as well as organophosphines was demonstrated and provided the corresponding dearomatized products.

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents.

Copper-catalysed asymmetric C-C bond-forming reactions using organometallic reagents have developed into a powerful tool for the synthesis of complex molecules with single or multiple stereogenic centres over the past decades. Among the various acceptors employed in such reactions, those with a heterocyclic core are of particular importance because of the frequent occurrence of heterocyclic scaffolds in the structures of chiral natural products and bioactive molecules. Hence, this review focuses on the progress made over the past 20 years for heterocyclic acceptors.