Fischer Carbene Complexes: A Glance at Two Decades of Research on Higher-Order Cycloaddition Reactions

The structure of Fischer carbene complexes (FCCs) is electron deficient. If bearing an α,β-unsaturated system, it can generate a wide variety of compounds by undergoing many different transformations, including higher-order cycloadditions. The latter are described as pericyclic reactions in which more than six electrons participate. These reactions have been employed in various areas of organic synthesis, resulting in highly selective compounds with a broad range of scaffolds. The first studies on higher-order cycloadditions involving FCCs frequently yielded competing byproducts. Many groups have attempted to increase selectivity by exploring distinct reaction conditions, reagents and co-catalysts (e. g., metal-mediated cycloadditions). The present review is the first to focus exclusively on using higher-order cycloadditions involving FCCs to synthesize carbocycles and heterocycles. Based on two decades of reports, an analysis is made of the main aspects of the mechanisms proposed for higher-order cycloadditions and the structural diversity obtained by the substituent effect.     

Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening

Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3 + 2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M^–1 s^–1. Most significantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously.     

Palladium-Catalyzed Asymmetric [8+2] Dipolar Cycloadditions of Vinyl Carbamates and Photogenerated Ketenes

Higher-order cycloadditions, particularly [8+2] cycloadditions, are a straightforward and efficient strategy for constructing significant medium-sized architectures. Typically, configuration-restrained conjugated systems are utilized as 8π-components for higher-order concerted cycloadditions. However, for this reason, 10-membered monocyclic skeletons have never been constructed via catalytic asymmetric [8+2] cycloaddition with high peri- and stereoselectivity. Here, we accomplished an enantioselective [8+2] dipolar cycloaddition via the merger of visible-light activation and asymmetric palladium catalysis. This protocol provides a new route to 10-membered monocyclic architectures bearing chiral quaternary stereocenters with high chemo-, peri-, and enantioselectivity. The success of this strategy relied on the facile in situ generation of Pd-containing 1,8-dipoles and their enantioselective trapping by ketene dipolarophiles, which were formed in situ via a photo-Wolff rearrangement.     

Scaffold-inspired enantioselective synthesis of biologically important spiro[pyrrolidin-3,2'-oxindoles] with structural diversity through catalytic isatin-derived 1,3-dipolar cycloadditions

Catalytic asymmetric construction of the biologically important spiro[pyrrolidin-3,2'-oxindole] scaffold with contiguous quaternary stereogenic centers in excellent stereoselectivities (up to >99:1 d.r., 98% ee) has been established by using an organocatalytic 1,3-dipolar cycloaddition of isatin-based azomethine ylides. This protocol represents the first example of catalytic asymmetric 1,3-dipolar cycloadditions involving azomethine ylides generated in situ from unsymmetrical cyclic ketones. In addition, theoretical calculations were performed on the transition state of the reaction to understand the stereochemistry. Preliminary bioassays with these spiro[pyrrolidin-3,2'-oxindole] revealed that several compounds showed moderate cytotoxicity to SW116 cells.     

[2+1] Cycloaddition Affording Methylene‐ and Vinylidenecyclopropane Derivatives: A Journey around the Reactivity of Metal‐Phosphinito–Phosphinous Acid Complexes

Metal–phosphinito–phosphinous acid complexes are interesting catalysts exhibiting unique reactivities. In this account, we intend to provide a clear overview of palladium– and platinum–phosphinito–phosphinous acid complexes, their preparation from secondary phosphine oxides, and their applications in catalysis. They have been mainly used to develop [2+1] cycloadditions to afford methylenecyclopropane derivatives using norbornenes and various alkynes as partners. As a function of the catalyst, the reaction conditions, or the nature of the reagents, different synthetic transformations have been observed: [2+1] cycloadditions, giving rise to either alkylidenecyclopropanes or vinylidenecyclopropanes; tandem [2+1]/[3+2] cycloadditions, and so forth. The mechanisms of these reactions have been studied to rationalize the different reactivities observed.     

The first general enantioselective catalytic Diels-Alder reaction with simple alpha,beta-unsaturated ketones

The first general approach to enantioselective catalysis of the Diels-Alder reaction with simple ketone dienophiles has been accomplished. The use of iminium catalysis has enabled enantioselective access to a fundamental Diels-Alder reaction variant that has previously been unavailable using chiral Lewis acid catalysis. A new chiral amine catalyst has been developed that allows a variety of monodentate cyclic and acyclic ketones to successfully participate in enantioselective [4 + 2] cycloadditions. A wide spectrum of cyclic and acyclic diene substrates can also be accommodated in this new organocatalytic transformation. A computational model is provided that is in accord with the sense of enantioinduction observed for all reactions conducted during the course of this study.     

Recent advances in asymmetric fluorination and fluoroalkylation reactions via organocatalysis

The past decade has witnessed the significant advances of asymmetric organocatalytic fluorination, monofluoroalkylation, gem-difluoroalkylation, and trifluoromethylation. This digest summarizes the latest progress of these reactions. In the research area of asymmetric organocatalytic fluorination, a new catalysis concept, chiral anion phase-transfer catalysis strategy, has emerged and has proved to be highly efficient. Asymmetric organocatalytic monofluoroalkylation and gem-difluoroalkylation have been much less explored and the Lewis base/acid catalysis has been the most used strategy. Compared with electrophilic trifluoromethylation, nucleophilic trifluoromethylation has been intensively studied in the research field of asymmetric organocatalytic trifluoromethylation.     

Azlactone Reaction Developments

Azlactones (also known as oxazolones) are heterocycles usually employed in the stereoselective synthesis of α,α‐amino acids, heterocycles and natural products. The versatility of the azlactone scaffold arises from the numerous reactive sites, allowing its application in a diversity of transformations. This review aims to cover classical and recent applications of oxazolones, especially those involving stereoselective processes. After a short introduction on their structures and intrinsic reactivities, dynamic kinetic resolution (DKR) processes as well as reactions involving stereoselective formation of a new σ C?C bond, such as alkylation/allylation/arylation, aldol, ene, Michael and Mannich reactions will be exposed. Additionally, cycloadditions, Steglich rearrangement and sulfenylation reactions will also be discussed. Recent developments of the well‐known Erlenmeyer azlactones will be described. For the most examples, the proposed mechanism, activation modes and/or key reaction intermediates will be exposed to rationalize both the final product and the observed stereochemistry. Finally, this review gives an overview of the synthetic utility of oxazolones.     

Organocatalyzed cycloaddition reactions of azomethine imines—A lookback

The versatile and convergent nature of 1,3-dipolar cycloaddition reactions has made them an indispensable tool in organic chemistry for synthesizing five-membered heterocycles. Among the various dipoles, azomethine imines (AMI) constitute a versatile class, increasingly used to synthesize biologically relevant heterocycles. The organocatalytic cycloaddition reactions of azomethine imines are relatively unexplored compared to the corresponding transition metal-catalyzed reactions. This review highlights the unique organocatalytic cycloaddition reactions of AMI with different dipolarophiles. The cycloaddition of azomethine imines catalyzed by organic bases such as prolinol, proline, alkaloids, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), primary amines, tertiary amines, N-heterocyclic carbene, and phosphine are discussed here. The mechanistic and electronic aspects, including broad functional group tolerance, catalyst loading, and reaction conditions, are evaluated. This review also demonstrates the scope and potential reactivity of azomethine imines in organocatalytic cycloadditions. We are positive that the reactions of azomethine imines discussed here will aid in discovering new and efficient reaction pathways in synthesizing biologically active and industrially relevant molecules.     

Ligand effects on rates and regioselectivities of Rh(I)-catalyzed (5 + 2) cycloadditions: a computational study of cyclooctadiene and dinaphthocyclooctatetraene as ligands

The first theoretical study on the effects of ligands on the mechanism, reactivities, and regioselectivities of Rh(I)-catalyzed (5 + 2) cycloadditions of vinylcyclopropanes (VCPs) and alkynes has been performed using density functional theory (DFT) calculations. Highly efficient and selective intermolecular (5 + 2) cycloadditions of VCPs and alkynes have been achieved recently using two novel rhodium catalysts, [Rh(dnCOT)](+)SbF(6)(-) and [Rh(COD)](+)SbF(6)(-), which provide superior reactivities and regioselectivities relative to that of the previously reported [Rh(CO)(2)Cl](2) catalyst. Computationally, the high reactivities of the dnCOT and COD ligands are attributed to the steric repulsions that destabilize the Rh-product complex, the catalyst resting state in the catalytic cycle. The regioselectivities of reactions with various alkynes and different Rh catalysts are investigated, and a predictive model is provided that describes substrate-substrate and ligand-substrate steric repulsions, electronic effects, and noncovalent π/π and C-H/π interactions. In the reactions with dnCOT or COD ligands, the first new C-C bond is formed proximal to the bulky substituent on the alkyne to avoid ligand-substrate steric repulsions. This regioselectivity is reversed either by employing the smaller [Rh(CO)(2)Cl](2) catalyst to diminish the ligand-substrate repulsions or by using aryl alkynes, for which the ligand-substrate interactions become stabilizing due to π/π and C-H/π dispersion interactions. Electron-withdrawing groups on the alkyne prefer to be proximal to the first new C-C bond to maximize metal-substrate back-bonding interactions. These steric, electronic, and dispersion effects can all be utilized in designing new ligands to provide regiochemical control over product formation with high selectivities. The computational studies reveal the potential of employing the dnCOT family of ligands to achieve unique regiochemical control due to the steric influences and dispersion interactions associated with the rigid aryl substituents on the ligand.     

Organocatalytic enantioselective transformations involving quinone derivatives as reaction partners

This digest summarizes the recent progress made in the organocatalytic asymmetric reactions involving 1,4-quinone derivatives. The roles of quinones as Michael donors, Michael acceptors, dienophiles, 1,3-dipolarophiles and cascade reaction partners have been extensively investigated to access complex structural frameworks in the presence of chiral amine catalysts, phosphoric acid catalysts, bifunctional catalysts (Cinchona alkaloids- and thiourea-based), carboxylic acid catalysts, boronic acid catalysts and cationic oxazaborolidinium ions.     

Selectivity in cycloadditions—-XII : The directive effect of enol ethers and thioenol ethers in cycloadditions of nitrile oxides

Cycloadditions of nitrile oxides to 2,3-dihydrofuran are highly regioselective whereas the regioselectivity of the cycloadditions to 2,3-dihydrothiophen is only moderate. The directing effect of oxygen and sulfur in these cycloadditions could be evaluated at 2.8 and 1.1 Kcal mol^-1 respectively. The related acyclic sulfur dipolarophiles, (E)-propenyl methyl and phenyl sulfides, similarly undergo cycloadditions with moderate regiochemistry.The different regioselectivities and reactivities of the dipolarophiles can be related to differences in energies and shapes of their highest occupied orbitals, which are also responsible for the diverging behaviour observed in the electrophilic reactions and 2 + 2 cycloadditions of enol and thioenol ethers.     

The organocatalytic vinylogous aldol reaction: recent advances

Over the past decade, organocatalysis has emerged as a powerful tool for stereoselective carbon-carbon bond formation under exceptionally mild conditions. The organocatalytic versions of a large number of traditional synthetic transformations are now well established and the quest for new applications of the basic concepts of organocatalysis continues. This review addresses the emergent interest in the organocatalytic vinylogous aldol reaction. While noteworthy progress has been made in this area, significant challenges lie ahead.     

Enantioselective organocatalytic intramolecular Diels-Alder reactions. The asymmetric synthesis of solanapyrone D

The first direct enantioselective organocatalytic intramolecular Diels-Alder reaction has been accomplished. The use of iminium catalysis has provided a new catalytic strategy for the enantioselective [4 + 2] cycloisomerization of a wide variety of tethered diene-enal systems. The use of imidazolidinones 1 and 2 as the asymmetric catalysts has been found to mediate the enantioselective construction of [4.4.0] and [4.3.0] ring systems. Application of this methodology to the highly efficient asymmetric synthesis of the marine metabolite solanpyrone D has also been accomplished. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. Importantly, this technology has been utilized to execute the first enantioselective, catalytic Type II IMDA reaction.     

Tandem double intramolecular [4 + 2]/[3 + 2] cycloadditions of nitroalkenes

[reaction: see text]. A new class of tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes is described in which both pericyclic processes are intramolecular. Two subclasses of intra [4 + 2]/intra [3 + 2] cycloadditions have been explored in which the dipolarophile is tethered at either C(5) or C(6) of the nitronate. For both families of precursors, the cycloadditions occur in good yield and are found to be highly regio- and stereoselective. This method converts linear polyenes to functionalized polycyclic systems bearing up to six stereogenic centers.     

Chiral Carbon Nanodots Can Act as Molecular Catalysts in Chemical and Photochemical Reactions

In this work, a microwave synthesis followed by a simple purification process produces a new type of chiral Carbon Nanodots (CNDs). These CNDs are soluble in organic solvents, exhibit amino groups on their surface and display interesting absorption and emission properties along with mirror image profiles in the electronic circular dichroism spectrum. All these features set the stage for CNDs to act as multifunctional catalytic platforms, able to promote diverse chemical transformations. In particular, the outer shell composition of CNDs was instrumental to carry out organocatalytic reactions in an enantioselective fashion. In addition, the redox and light-absorbing properties of the material are suitable to drive photochemical processes. Finally, the photoredox and organocatalytic activations of CNDs were exploited at the same time to promote a cross-dehydrogenative coupling. This work demonstrates that CNDs can be used as catalysts to promote multiple reactivities, previously considered exclusive domain of molecular catalysts.     

Recent advances in cooperative ion pairing in asymmetric organocatalysis

Over the last decade, with the surge in the development of organocatalysis, many processes involving chiral ion pairs have emerged as powerful tools in the design of new efficient organocatalysts. This tutorial review focuses on the recent evolutions of these organocatalytic systems in which both anionic and cationic parts are working in a cooperative fashion in order to develop unique catalytic processes which outperform the existing approaches. In this respect, chiral ion pairs opened new avenues in the design of bifunctional organocatalysts by means of combinatorial approaches.     

Tandem double intramolecular [4+2]/[3+2] cycloadditions of nitroalkenes. The fused/bridged mode

A new class of tandem [4+2]/[3+2] cycloadditions of nitroalkenes is described in which both pericyclic processes are intramolecular. Two subclasses of intra [4+2]/intra [3+2] cycloadditions have been explored in which the dipolarophile is tethered at either C(5) or C(6) of the nitronate. For both families of precursors, the cycloadditions occur in good yield and are found to be highly regio- and stereoselective. This method converts linear polyenes to functionalized polycyclic systems bearing up to six stereogenic centers.     

The first enantioselective organocatalytic Mukaiyama-Michael reaction: a direct method for the synthesis of enantioenriched gamma-butenolide architecture

The first enantioselective organocatalytic Mukaiyama-Michael reaction using alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective addition of 2-silyloxy furans to unsaturated aldehydes to generate a variety of butenolide systems, an important chiral synthon found among many natural isolates. The (2S,5S)-5-benzyl-2-tert-butyl-imidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted silyloxy furans to unsaturated aldehydes. A diverse range of aldehyde substrates can be accommodated in this new organocatalytic transformation. Application of this new asymmetric technology to the enantioselective total synthesis of spiculisporic acid and the corresponding 5-epi-spiculisporic acid analogue is also discussed.     

Characteristics of the two frontier orbital interactions in the Diels-Alder cycloaddition

Two electron-deficient dienes were reacted with a series of twelve electron-poor and electron-rich dienophiles to give, in some cases, the corresponding Diels-Alder adducts. Clear differences in the roles played by the two frontier orbital interactions emerged. It was demonstrated that in the case of normal Diels-Alder cycloadditions, the FMO theory could predict the relative reactivities between dienophiles, while in the case of inverse-electron demand Diels-Alder reactions, it could not. It was shown that the dissymmetry in electron-rich dienophiles increases their reactivities.