Organocatalytic kinetic resolution cascade reactions: new mechanistic and stereochemical manifold in diphenyl prolinol silyl ether catalysis

A new cascade reaction involving an iminium-catalyzed intramolecular oxa-Michael addition followed by an enamine-catalyzed intermolecular Michael addition is reported herein. This cascade reaction generates enantiopure, highly functionalized tetrahydropyrans and tetrahydrofurans in a one-pot reaction and in up to 89?% combined yield and up to 99?% ee. This cascade reaction is catalyzed by diaryl prolinol silyl ethers, which are a privileged class of catalysts. The stereochemical outcome of these cascade reactions is unprecedented. Computational studies indicate that this stereochemical outcome arises from nonclassical hydrogen-bonding interactions between the electrophile and the substrate, and from entropic considerations of preorganization. The unprecedented configurations of the cascade products, combined with the computational models, reveal for the first time that asymmetric induction by diaryl prolinol silyl ether catalysts is not always exclusively reagent controlled. The stereochemical outcome also arises from a kinetic resolution or dynamic kinetic resolution of the β-stereocenter through an enamine-catalyzed intermolecular reaction. This unprecedented organocascade reaction mechanism may be adaptable to diaryl prolinol silyl ether-catalyzed cascade reactions, in which both the iminium- and enamine-catalyzed steps are intermolecular, an underdeveloped type of cascade reaction.     

Catalytic Aerobic Oxidation and Tandem Enantioselective Cycloaddition in Cascade Multicomponent Synthesis

An efficient multicomponent cascade transformation for the highly diastereo‐ and enantioselective synthesis of complex natural product inspired polycyclic products from simple starting materials is described. The cascade is initiated by copper‐catalyzed aerobic C?H oxidation of cyclopentadiene to cyclopentadienone followed by double catalytic asymmetric 1,3‐dipolar cycloaddition of azomethine ylides. The cascade synthesis efficiently yields structurally complex 5,5,5‐tricyclic products with eight stereocenters with good yields and excellent diastereo‐ and enantiocontrol using one catalyst.     

Electrophilic and nucleophilic enzymatic cascade reactions in biosynthesis

The biosynthesis of cyclic terpenoids and polyethers involves enzyme-initiated cascade reactions for ring formation. While the former are obtained by electrophilic cascades through carbenium ions as intermediates, cyclic polyethers are formed by nucleophilic cascade reactions of (poly)epoxide precursors. These mechanistically complementary pathways follow common principles via (i) triggering of the cascade by forming a reactive intermediate ('initiation'), (ii) sequential 'proliferation' of the cyclization and finally (iii) 'termination' of the cascade. As analyzed in this concept paper, the multiplicity of precursors, combined with various initiation and termination routes and kinetically favored or disfavored cyclization modes accounts for the enormous diversity in cyclic terpenoid and polyether scaffolds. Although the essential role of enzymes in the triggering of these cascades is reasonably well understood, remarkably little is known about their influence in proliferation reactions, especially those implying kinetically disfavored (anti-Markovnikov and anti-Baldwin) routes. Mechanistic analysis of enzymatic cascade reactions provides biomimetic strategies for natural product synthesis.     

Thermodynamic work of separation during the distillation of an ideal binary solution in a multistep cascade

The decrement in Gibbs energy during the distillation of an isotopic mixture in a separation cascade is calculated. A thermodynamic interpretation of the total useful work performed by the cascade during fine separation is proposed.     

PCR-like cascade reactions in the context of an allosteric enzyme mimic

A supramolecular allosteric catalyst that exhibits a PCR-like cascade reaction is reported. The complex is triggered by a reaction with an acetate ion, which turns on a catalytic cascade that exponentially increases acetate ion concentration through an acyl transfer reaction.     

Construction of aromatic [5,5] spiroketals via hypoiodite-catalyzed etherification combined in relay cascades

An approach is developed for the synthesis of bisbenzannelated spiro[5,5]ketals via a catalytic relay reaction cascade involving a new cyclo-etherification, which is prompted by fluoride and catalyzed by the hypoiodite species generated in situ from irradiative aerobic oxidation of an iodide ion formed in the former step of the reaction cascade.     

Five-Step Enantioselective Synthesis of Islatravir via Asymmetric Ketone Alkynylation and an Ozonolysis Cascade

A 5-step enantioselective synthesis of the potent anti-HIV nucleoside islatravir is reported. The highly efficient route was enabled by a novel enantioselective alkynylation of an α,β-unsaturated ketone, a unique ozonolysis-dealkylation cascade in water, and an enzymatic aldol-glycosylation cascade.     

Synthesis of fused polycyclic nitrogen-containing heterocycles via cascade cyclization

A novel strategy for the synthesis of fused polycyclic-nitrogen containing heterocycles via cascade cyclization is described. The methodology involves condensation of 1-(2-aminophenyl)-9H-β-carboline-3-carboxylic acid amide with isothiocyanates followed by in situ treatment of the resulting thioureas with HgCl₂ for 1 h at rt. The one-pot cascade cyclization leads to interesting changes in molecular structure and an increase in molecular complexity. A mechanistic rationale for the cascade cyclization is discussed.     

Novel tangential-flow countercurrent cascade ultrafiltration configuration for continuous purification of humanized monoclonal antibody

This paper discusses the use of a novel tangential-flow, three-stage, countercurrent cascade ultrafiltration configuration for continuous purification of monoclonal antibody Campath-1H from simulated mammalian cell culture supernatant. The main limitation of conventional ultrafiltration based bioseparation, particularly when using a single-stage system is the trade-off between recovery and purity. The aim of this study was to try to improve both purity and recovery of the monoclonal antibody by using the novel cascade ultrafiltration system. Purification experiments were carried out with the three-stage cascade system as well as with single-stage and two-stage versions of the proposed system for comparison. The recovery and purification factor were both significantly higher with the three-stage system. The highest purity obtained using the three-stage cascade system was 85%. The experimental purity and recovery were compared with corresponding values obtained by simulation and found to be in reasonably good agreement.     

Additive effects in palladium-indium mediated Barbier type allylations

The effect of adding 1 equiv. of an amine or 0.2 equiv. of CuI to a Pd/In bimetallic cascade reaction is described. In the class 1 cascade reaction of aldehydes, aryl iodides and allene, generating homoallylic alcohols, the reaction time is reduced from 16 to 2 h and is accompanied by an impressive increase in yield.     

Selective Cascade Reaction of Bisallenes via Palladium‐Catalyzed Aerobic Oxidative Carbocyclization–Borylation and Aldehyde Trapping

A cascade reaction, consisting of a palladium‐catalyzed regioselective aerobic oxidative carbocyclization–borylation of bisallenes and a final aldehyde trapping, afforded triene alcohols with high diastereoselectivity. The cascade reaction occurs under mild reaction conditions and proceeds via an allylboron intermediate that is trapped by the aldehyde in a stereoselective manner.     

Penetration of plasma surface modification into porous media. III. Multiple samples exposed to CF4 and C2F4 low temperature cascade arc torch

The depth and possible mechanisms of the penetration of surface modification into porous media by a low temperature cascade are torch are investigated. Two different modes of such penetration (“flow controlled” and “diffusion controlled”) are evaluated. Three porous samples [stacks of 10 sheets of nonwoven fabrics of poly(ethylene terephthalate)each], placed at an axial distance of 24, 28, and 32 cm from the cascade are anode, are exposed to a low temperature cascade arc torch containing argon and CF₄ or C₂F₄, and surface properties of each of the sheets within treated porous samples are examined by ESCA. It is shown that interaction of chemically reactive species, created in the low temperature cascade arc torch, with the surface is not limited to the surface directly contacted by the torch. The flow controlled penetration is more pronounced for the outer layers, while diffusion controlled penetration is within the inner layers of the porous structure. Substantial differences in the fluorination effect of CF₄ (nonpolymer forming gas) and C₂F₄ (polymer forming gas) discharges for the second and third stacks are observed, that can be explained by the fact that the major effect of the CF₄ cascade arc torch treatment is based on the reaction of reactive species with the surface polymer molecules. The effect of C₂F₄ cascade arc torch treatment is based on the reactions of reactive species with polymers as well as reactions of reactive species themselves at the surface (plasma polymerization). Reactivity of the species created in C₂F₄ discharge is much higher compared to that created in CF₄ discharge, which is one of the major factors influencing penetration trends of low temperature cascade arc treatment into porous media. © 1995 John Wiley & Sons, Inc.     

Advancements in Gold-Catalyzed Cascade Reactions to Access Carbocycles and Heterocycles: An Overview

This review summarizes recent developments (from 2006 to 2022) in numerous important and efficient carbo- and heterocycle generations using gold-catalyzed cascade protocols. Herein, methodologies involve selectivity, cost-effectiveness, and ease of product formation being controlled by the ligand as well as the counter anion, catalyst, substrate, and reaction conditions. Gold-catalyzed cascade reactions covered different strategies through the compilation of various approaches such as cyclization, hydroarylation, intermolecular and intramolecular cascade reactions, etc. This entitled reaction is also useful for the synthesis of spiro, fused, bridged carbo- and heterocycles.     

Highly stereoselective Michael reduction/intramolecular Michael reaction cascade to synthesize trans-stereodiad comprising an all-carbon quaternary stereogenic center

A highly stereoselective Michael reduction/intramolecular Michael reaction cascade is described. The cascade is initiated by the regioselective Michael reduction of an α-methylidene ester with L-Selectride. This is followed by the highly stereoselective intramolecular Michael reaction which efficiently constructs a six-membered carbocyclic ring with formation of the trans-stereodiad, composed of an all-carbon quaternary center and a tertiary stereogenic center. The stereoselectivity is perfectly controlled by the choice of alkene geometry in the Michael acceptor.     

A Counterion‐Directed Approach to the Diels–Alder Paradigm: Cascade Synthesis of Tricyclic Fused Cyclopropanes

An approach to the intramolecular Diels–Alder reaction has led to a cascade synthesis of complex carbocycles composed of three fused rings and up to five stereocenters with complete stereocontrol. Computational analysis reveals that the reaction proceeds by a Michael/Michael/cyclopropanation/epimerization cascade in which size and coordination of the counterion is key.     

Regioselective synthesis of N-aminoisoindolones and mono-N- and di-N,N'-substituted phthalazones utilizing hydrazine nucleophiles in a palladium-catalyzed three-component cascade process

A palladium-catalyzed three-component cascade process for the synthesis of isoindolone and phthalazone derivatives is reported. The cascade process involves carbonylation of an aryl iodide/Michael acceptor to give an acylpalladium species which is intercepted by a hydrazine nucleophile. Intramolecular Michael addition follows to give either N-aminoisoindolones or mono- N- and di-N,N'-phthalazones depending on whether a monosubstituted or 1,2-disubstituted hydrazine nucleophile is used.     

Optical emission diagnostics in cascade arc plasma polymerization and surface modification processes

Optical Emission Spectroscopy (OES) was used to identify reactive species and their excitation states in low-temperature cascade arc plasmas of N₂, CF₄, C₂F₄, CH₄, and CH₃OH. In a cascade arc plasma, the plasma gas (argon or helium) was excited in the cascade arc generator and injected into a reactor in vacuum. A reactive gas was injected into the cascade arc torch (CAT) that was expanding in the reactor. What kind of species of a reactive gas, for example, nitrogen, are created in the reactor is dependent on the electronic energy levels of the plasma gas in the cascade arc plasma jet. OES revealed that no ion of nitrogen was found when argon was used as the plasma gas of which metastable species had energy less than the ionization energy of nitrogen. When helium was used, ions of nitrogen were found. While OES is a powerful tool to identify the products of the cascade arc generation (activation process), it is less useful to identify the reactive species that are responsible for surface modification of polymers and also for plasma polymerization. The plasma surface modification and plasma polymerization are deactivation processes that cannot be identified by photoemission, which is also a deactivation process. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 1583–1592, 1998     

Clustering of catalytic nanocompartments for enhancing an extracellular non-native cascade reaction

Compartmentalization is fundamental in nature, where the spatial segregation of biochemical reactions within and between cells ensures optimal conditions for the regulation of cascade reactions. While the distance between compartments or their interaction are essential parameters supporting the efficiency of bio-reactions, so far they have not been exploited to regulate cascade reactions between bioinspired catalytic nanocompartments. Here, we generate individual catalytic nanocompartments (CNCs) by encapsulating within polymersomes or attaching to their surface enzymes involved in a cascade reaction and then, tether the polymersomes together into clusters. By conjugating complementary DNA strands to the polymersomes'' surface, DNA hybridization drove the clusterization process of enzyme-loaded polymersomes and controlled the distance between the respective catalytic nanocompartments. Owing to the close proximity of CNCs within clusters and the overall stability of the cluster architecture, the cascade reaction between spatially segregated enzymes was significantly more efficient than when the catalytic nanocompartments were not linked together by DNA duplexes. Additionally, residual DNA single strands that were not engaged in clustering, allowed for an interaction of the clusters with the cell surface as evidenced by A549 cells, where clusters decorating the surface endowed the cells with a non-native enzymatic cascade. The self-organization into clusters of catalytic nanocompartments confining different enzymes of a cascade reaction allows for a distance control of the reaction spaces which opens new avenues for highly efficient applications in domains such as catalysis or nanomedicine.

Compartmentalization is fundamental in nature, where the spatial segregation of biochemical reactions within and between cells ensures optimal conditions for the regulation of cascade reactions.     

Fabrication of a novel cascade high-pressure electro-osmotic pump

A novel cascade electro-osmotic pump (EOP) has been fabricated by alternately connecting a cation monolithic column and anion monolithic column in series. In this manner, the change of electric polarity between each stage of the cascade EOP is easily achieved and the pressure output of the EOP could be greatly enhanced without increase of the applied voltage.     

Palladium‐Catalyzed Cascade Cyclization/Alkynylation Reactions

Palladium‐catalyzed cascade cyclization reactions have witnessed significant improvements in recent years. Among them, palladium‐catalyzed cascade cyclization/alkynylation are especially attractive, which can assemble structurally diverse monocyclic, bicyclic, fused polycyclic, and spirocyclic skeletons with excellent chemoselectivities. In this Minireview, palladium‐catalyzed cascade cyclization/alkynylation have been summarized and discussed in detail with focus on oxypalladation and aminopalladation‐initiated cascade cyclization, intramolecular Heck‐type cascade cyclization, carbocyclizations, cascade cyclizations, and other types of cascade cyclization reactions. Some significant and representative synthetic methodologies and their synthetic applications and reaction mechanisms have also been described.