Stepwise Pathway Research Articles

Ethambutol and visual assessment in England: current practice and recommendations.

Standard treatment for tuberculosis (TB) in children and adults includes an initial two-month course of ethambutol, a drug that in rare cases can cause optic neuropathy and irreversible vision loss. There is a lack of clear guidance on what vision assessments are needed before and during treatment with ethambutol, with the Royal College of Ophthalmologists, National Institute for Health and Care Excellence, British National Formulary and British Thoracic Society offering different guidance. We aimed to assess how vision is routinely tested in patients treated with ethambutol in TB services across England. An online survey developed by Public Health England was sent to all TB services in England in 2018 to assess current practice and inform the development of best practice recommendations for visual assessment of patients treated with ethambutol for TB. Sixty-six TB professionals from across England responded, a response rate of 54%. The results showed variations in practice, including when to omit ethambutol from treatment, the timing and frequency of visual assessment, the type of visual assessment, referral processes and management of visual changes. This national survey highlights the need for clear guidelines on the testing of vision for patients taking ethambutol at recommended doses, before and during treatment. We suggest a pragmatic approach to visual assessment to reduce variation in practice, proposing a stepwise pathway for patients on standard TB treatment for local adaptation.

Superacid-Assisted Degradation of Polystyrene

We report the degradation pathway of polystyrene in a low-temperature environment by superacid. Polystyrene is a thermoplastic resin widely used in packaging, disposable products, and structural materials. However, economically viable upcycling of polystyrene has yet to be established because of the high cost of chemical recycling and the low value of products. To understand the degradation pathway of polystyrene and establish competitive upcycling practices, we investigated the transformation of normal and deuterated polystyrene chains into small compounds by triflic acid at 20 °C. The degradation study of deuterated polystyrene showed the high stability of the hydrogens at the α carbons of polymerized styrene against triflic acid, which suggests the known β-scission degradation pathway of polystyrene by α-proton abstraction is unlikely. Rather, the polystyrene degradation proceeds through three distinct stages: (i) intrachain cross-linking that forms polymer nanoparticles and simultaneous transformation of polymerized styrene to indan units, (ii) degradation of the polymer nanoparticles into small molecular weight compounds, and (iii) formation of polycyclic aromatic hydrocarbons. The stepwise degradation pathway of polystyrene we report may enable the design of efficient and profitable upcycling processes for end-of-life polystyrene products in low-temperature environments.

Optimization of Milbemycin Component Ratio by Coordinating Acyl-Coenzyme A Supply Pathways in Streptomyces bingchenggensis

Milbemycins are a group of macrolide pesticides with great potential in the agricultural field owing to their high insecticidal activity and environmental compatibility. Milbemycin A3 and A4 with high bioactivities are the main components of milbemycin-derived products, which require a component ratio A4:A3 of 2.3- to 4.0-fold. Streptomyces bingchenggensis BC04 is a promising milbemycin producer, whereas the component ratio of its products (A4:A3 of 9.0-fold) could not meet the requirement for industrial production. To address this issue, we reconstructed the precursor biosynthetic pathways to fine tune the supply of different acyl-coenzyme A precursors required for milbemycin biosynthesis. Based on an analysis of the intracellular acyl-coenzyme A precursors, we reconstructed stepwise heterogeneous biosynthetic pathways of extender units for milbemycin biosynthesis. Then, we coordinated the supply of milbemycin biosynthetic starter units with temporal promoters. Thanks to these manipulations, we obtained an engineered strain with 39.5% milbemycin titer improvement to 3417.88 mg/L and a qualified component ratio A4:A3 of 3.3-fold. This work demonstrated that coordinating the precursor supply is a simple and effective approach to optimize the component ratio of A4:A3 in milbemycin fermentation products. Moreover, this strategy might also be useful to construct high-yield strains with optimized component ratios of fermentation products in other Streptomyces.

Unimolecular Reactivity of [Cu(R)(CF3 )3 ]- Complexes (R=Organyl): Stepwise versus Concerted Mechanism in Copper-Mediated Trifluoromethylation.

The cuprate complexes [Cu(R)(CF3 )3 ]- (R=organyl) offer an efficient synthetic access to valuable trifluoromethylation products RCF3 . Here, electrospray-ionization mass spectrometry is used to analyze the formation of these intermediates in solution and probe their fragmentation pathways in the gas phase. Furthermore, the potential energy surfaces of these systems are explored by quantum chemical calculations. Upon collisional activation, the [Cu(R)(CF3 )3 ]- complexes (R=Me, Et, Bu, s Bu, allyl) afford the product ions [Cu(CF3 )3 ]⋅- and [Cu(CF3 )2 ]- . The former obviously results from an R⋅ loss, whereas the latter originates either from the stepwise release of R⋅ and CF3 ⋅ radicals or a concerted reductive elimination of RCF3 . The gas-phase fragmentation experiments as well as the quantum chemical calculations indicate that the preference for the stepwise reaction toward [Cu(CF3 )2 ]- increases with the stability of the formed organyl radical R⋅. This finding suggests that the recombination of R⋅ and CF3 ⋅ radicals may possibly contribute to the formation of RCF3 from [Cu(R)(CF3 )3 ]- in synthetic applications. In contrast, the [Cu(R)(CF3 )3 ]- complexes (R=aryl) only yield [Cu(CF3 )2 ]- when subjected to collision-induced dissociation. These species exclusively undergo a concerted reductive elimination because the competing stepwise pathway is disfavored by the low stability of aryl radicals.

C.5 Highlighting a novel, stepwise pathway for the in-hospital management of children with acutely worsening dystonia

Background: Dystonia is common in children with acquired and inherited neurological disorders. Status dystonicus (SD) is the most severe form of dystonia that can lead to life-threatening complications if not treated promptly. We identified a local provider knowledge gap in the acute management of dystonia, leading to uncertainty and delays in care. To our knowledge, no in-hospital clinical pathway exists for the ward-based management of acute dystonia. We hypothesized that a stepwise clinical pathway would standardize and improve comfort in managing hyperacute dystonia. Methods: We formed a multidisciplinary working group and developed a pathway based on literature review and expert consensus. Aims of the pathway included: reducing delays in recognition and treatment of acute dystonia, limiting variation in management, and decreasing progression to SD. A survey was administered to providers assessing knowledge and comfort post-implementation. Results: There has been high usability with 58% (18/31) of providers surveyed having used the pathway at least once. Provider comfort has improved, with 89% (25/28) of respondents reporting increased comfort managing SD due to the clarity of the pathway and stepwise directions. Conclusions: The pathway fills a gap in the in-hospital management of dystonia and has led to increased provider comfort.

The Diels–Alder Reaction between Euparin and Dimethyl Acetylenedicarboxylate; a Joint Experimental and Density Functional Theory Study

In this project, we have investigated the Diels–Alder (DA) reaction between euparin (as a natural furan derivative) and dimethyl acetylenedicarboxylate (DMAD) as an electrophilic acetylene. The experimental observations during the reaction in different conditions showed that the yield and the rate of the process would increase with increasing the polarity of the solvent. Such observation suspected us that like several recent reports, the mechanism of this DA reaction takes place through a stepwise route containing a zwitterionic intermediate or at least through a relatively polar transition state (TS). Next, during the density functional theory (DFT) studies and the potential energy surface (PES) investigations, we have detected a stepwise reaction pathway in parallel with the one-step route. The results of this work are in agreement with the recent reports about the competition between the one-step and multisteps routes in the DA reactions.

Multisite Porphyrinic Metal–Organic Frameworks for Biomass Valorization: Computational Design and Mechanistic Investigation

Renewable chemicals and fuels have received significant attention for sustainable economic development. Our aim in this work is to investigate a porphyrinic metal–organic framework (MOF), namely, MOF-525 for the transfer hydrogenation of methyl levulinate (ML) to γ-valerolactone (GVL) through density functional theory calculations. We computationally design five multisite defect-engineered MOF-525(M) (M = CrIII, FeIII, RuIII, RhIII, and IrIII) and examine their catalytic performance for the transformation of ML to methyl valerate (MV) via catalytic transfer hydrogenation (CTH), subsequently for the cyclization of MV to GVL by anchoring a SO3H group as a Brønsted acid site on the metallated linker M-TPP-Cl. The CTH involves three pathways (two concerted and one stepwise) on the defective Zr node and two pathways (one stepwise and one concerted) on the metallated linker, respectively. It is revealed that a stepwise Meerwein–Ponndorf–Verley pathway is energetically preferred on the defective Zr node. A similar stepwise pathway on Ru-TPP-Cl is also found to be favorable, while a concerted pathway is more favorable on Rh-TPP-Cl and Ir-TPP-Cl. The rate-determining activation barriers on M-TPP-Cl are rationalized by geometry analysis, second-order perturbation theory analysis, and the noncovalent interactions. Among the five metallated MOF-525(M), Ru, Rh, and Ir are predicted to be active for the transformation of ML to MV. However, the defective Zr-SBU is found to have a lower activation energy barrier compared to M-TPP-Cl, suggesting its dominant role in CTH. In addition, the Brønsted acid-catalyzed cyclization appears to be rate-determining on the defective Zr node, Rh-TPP-Cl, and Ir-TPP-Cl. This study suggests that MOF-525 might be potentially used as a multisite catalyst platform for the conversion of ML to GVL and would assist in the future rational design of new MOFs for biomass valorization.

Experiences of medical device innovators as they navigate the regulatory system in Uganda.

A medical device must undergo rigorous regulatory processes to verify its safety and effectiveness while in use. In low-and middle-income countries like Uganda however, medical device innovators and designers face challenges around bringing a device from ideation to being market-ready. This is mainly attributed to a lack of clear regulatory procedures among other factors. In this paper, we illustrate the current landscape of investigational medical devices regulation in Uganda. Information about the different bodies involved in regulation of medical devices in Uganda was obtained online. Nine medical device teams whose devices have gone through the Ugandan regulatory system were interviewed to gain insights into their experiences with the regulatory system. Interviews focused on the challenges they faced, how they navigated them, and factors that supported their progress towards putting their devices on the market. We identified different bodies that are part of the stepwise regulatory pathway of investigational medical devices in Uganda and roles played by each in the regulatory process. Experiences of the medical device teams collected showed that navigation through the regulatory system was different for each team and progress towards market readiness was fuelled by funding, simplicity of device, and mentorship. Medical devices regulation exists in Uganda but is characterised by a landscape that is still in development which thereby affects the progress of investigational medical devices.

Growth dynamics and amorphous-to-crystalline phase transformation in natural nacre

Biominerals, such as nacreous bivalve shells, are important archives of environmental information. Most marine calcifiers form their shells from amorphous calcium carbonate, hypothesised to occur via particle attachment and stepwise crystallisation of metastable precursor phases. However, the mechanism of this transformation, including the incorporation of trace elements used for environmental reconstructions, are poorly constrained. Here, using shells of the Mediterranean mussel, we explore the formation of nacre from the meso- to the atomic scale. We use a combination of strontium pulse-chase labelling experiments in aquaculture and correlated micro- to sub-nanoscale analysis to show that nacre grows in a dynamic two-step process with extensional and space-filling growth components. Furthermore, we show that nacre crystallizes via localised dissolution and reprecipitation within nanogranules. Our findings elucidate how stepwise crystallization pathways affect trace element incorporation in natural biominerals, while preserving their intricate hierarchical ultrastructure.

AFM-based force spectroscopy unravels stepwise formation of the DNA transposition complex in the widespread Tn3 family mobile genetic elements.

Transposon Tn4430 belongs to a widespread family of bacterial transposons, the Tn3 family, which plays a prevalent role in the dissemination of antibiotic resistance among pathogens. Despite recent data on the structural architecture of the transposition complex, the molecular mechanisms underlying the replicative transposition of these elements are still poorly understood. Here, we use force-distance curve-based atomic force microscopy to probe the binding of the TnpA transposase of Tn4430 to DNA molecules containing one or two transposon ends and to extract the thermodynamic and kinetic parameters of transposition complex assembly. Comparing wild-type TnpA with previously isolated deregulated TnpA mutants supports a stepwise pathway for transposition complex formation and activation during which TnpA first binds as a dimer to a single transposon end and then undergoes a structural transition that enables it to bind the second end cooperatively and to become activated for transposition catalysis, the latter step occurring at a much faster rate for the TnpA mutants. Our study thus provides an unprecedented approach to probe the dynamic of a complex DNA processing machinery at the single-particle level.

Examination of Electronically Mismatched Diels-Alder Reaction by Online Mass Spectrometry.

Electronically mismatched Diels-Alder reactions have gained much interests as an alternative pathway for C-C bond formation. To faciliate the development of facile organic transformations, mechanistic investigations are required. Spectroscopic methods (NMR, EPR and UV-Vis) are normally adopted for mechainism examinations, but further improvements on direct obtaining of structural information of short-lived intermediates are encouraged. Herein, an electronically mismatched Diels-Alder reaction between indole and 1,3-cyclohexadiene (1,3-CHD) was studied by an in situ electrospray ionization mass spectrometry (in-situ MS). Based on the direct sampling and detection of the in-situ MS without sample pre-treatment, the structures and dynamics of important intermediates were on-line examined. A syringe-based photocatalytic reactor and in-situ AMS evaluation system was constructed for mechanism studies. The role of oxygen was confirmed via control reaction employed in the N2 -bubbled system. The stepwise cation radical-based pathway and the [2+2] cycloaddition process were determined through a series of experiments, including solvent evaluation, MS/MS experiments and dynamic monitoring. The dependence of the reaction on solvent polarity demonstrated that the reaction occurs via the formation of cation radicals, which were captured, identified and dynamically monitored via in situ ESI MS. Without pre-separation, the intermediate of [2+2] cycloaddition was identifiedand the cycloaddition process is thereby determined to be the combination of [4+2] cycloaddition and [2+2] cycloaddition. In addition, oxygen was proved to act as an electron mediator for both catalyst Ru (bpz)3 (PF6 )2 and radical cations. The mechanism of electronically mismatched Diels-Alder reaction was successfully deduced by in-situ MS associated with a syringe-based photocatalytic reactor. The structures and dynamics of cation radicals, the effect of O2 for the reaction and the detailed process of [2+2] cycloaddition have been well demonstrated. This work could not only promote the understanding and development of facile photocatalytic transformations, but also enlarge the application of AMS in on-line monitoring.

Enantioselective Photochemical Carbene Insertion into C–C and C–H Bonds of 1,3-Diketones by a Guanidine-Amide Organocatalyst

A visible-light-induced enantioselective free carbene transfer reaction of α-diazoesters with 1,3-diketones is established by utilizing a chiral bifunctional guanidine-amide organocatalyst. Selective insertion of free carbene into the C–C or C–H bonds of 1,3-diketone could be achieved with α-diazoesters bearing different steric hindrances. The transformations enable the preparation of a series of 1,4-diketones with a quaternary carbon chiral center or chiral 2-substituted-1,3-diketones in good enantioselectivities. On the basis of the control experiments and DFT calculation, a stepwise triplet free carbene coupling pathway is suggested. A possible reaction mechanism is proposed to explain the origin of high enantioselectivities via hydrogen-bonds and electrostatic interactions of the catalyst.

Direct and Indirect Pathways of CdTeSe Magic-Size Cluster Isomerization Induced by Surface Ligands at Room Temperature.

The field of isomerization reactions for colloidal semiconductor magic-size clusters (MSCs) remains largely unexplored. Here, we show that MSCs isomerize via two fundamental pathways that are regulated by the acidity and amount of an incoming ligand, with CdTeSe as the model system. When MSC-399 isomerizes to MSC-422 at room temperature, the peak red-shift from 399 to 422 nm is continuous (pathway 1) and/or stepwise (pathway 2) as monitored in situ and in real time by optical absorption spectroscopy. We propose that pathway 1 is direct, with intracluster configuration changes and a relatively large energy barrier. Pathway 2 is indirect, assisted by the MSC precursor compounds (PCs), from MSC-399 to PC-399 to PC-422 to MSC-422. Pathway 1 is activated when PC-422 to MSC-422 is suppressed. Our findings unambiguously suggest that when a change occurs directly on a nanospecies, its absorption peak continuously shifts. The present study provides an in-depth understanding of the transformative behavior of MSCs via ligand-induced isomerization upon external chemical stimuli.

The stepwise dissociation of the Zn(II)-bound Atox1 homodimer and its energetic asymmetry

The copper chaperone Atox1, which is featured by a peculiar CxxC metal-binding motif, is a protein involved in copper trafficking to the Golgi organelle, allowing the delivery of copper ions to specific target proteins in the secretory pathway. Various experimental studies suggest that this cysteine-containing protein may also be implicated in Zn(II) ion binding, functioning as a regulatory factor. However, despite the relevance of this interaction, the mechanism of zinc ion dissociation from the Atox1 homodimer has not yet been elucidated.We herein devised a simulation workflow based on the combination of parallel bias metadynamics and free energy perturbation theory, to predict the dissociation of the zinc ion from the Atox1 homodimer. The freeenergy simulations successfully predicted the dissociation free energy differences of the process, disclosing a mechanism based on a stepwise dissociation pathway of the zinc ion from the Atox1 homodimer.

PH dependent electro-oxidation of arsenite on gold surface: Relative kinetics and sensitivity

A detailed kinetic investigation of As(III) oxidation was performed on gold surface within pH between ∼3.0 and ∼9.0. It was found that the As(III) oxidation on the gold surface follows a purely adsorption-controlled process irrespective of pH. The evaluated adsorption equilibrium constant decreased from 3.21 × 105 to 1.61 × 105 mol L−1 for acidic to basic medium, which implies the strong affinity of the arsenic species in the acidic medium. Besides, the estimation of Gibbs free energy revealed that an acidic medium promotes arsenic oxidation on gold surface. In mechanistic aspect, the oxidation reaction adopts a stepwise pathway for acidic medium and a concerted pathway for neutral and basic medium. From the substantial kinetic evaluation, it is established that a conducive and compatible environment for the oxidation of arsenic was found in an acidic medium rather than a basic or neutral medium on gold surface. Besides, in sensitivity concern, neutral and highly acidic medium is quite favourable for the arsenite oxidation on gold surface.

Computational Exploration of Dirhodium Complex-Catalyzed Selective Intermolecular Amination of Tertiary vs. Benzylic C-H Bonds.

The mechanism and origins of site-selectivity of Rh2(S-tfpttl)4-catalyzed C(sp3)-H bond aminations were studied using density functional theory (DFT) calculations. The synergistic combination of the dirhodium complex Rh2(S-tfpttl)4 with tert-butylphenol sulfamate TBPhsNH2 composes a pocket that can access both tertiary and benzylic C-H bonds. The nonactivated tertiary C-H bond was selectively aminated in the presence of an electronically activated benzylic C-H bond. Both singlet and triplet energy surfaces were investigated in this study. The computational results suggest that the triplet stepwise pathway is more favorable than the singlet concerted pathway. In the hydrogen atom abstraction by Rh-nitrene species, which is the rate- and site-selectivity-determining step, there is an attractive π-π stacking interaction between the phenyl group of the substrate and the phthalimido group of the ligand in the tertiary C-H activation transition structure. By contrast, such attractive interaction is absent in the benzylic C-H amination transition structure. Therefore, the DFT computational results clearly demonstrate how the synergistic combination of the dirhodium complex with sulfamate overrides the intrinsic preference for benzylic C-H amination to achieve the amination of the nonactivated tertiary C-H bond.

O and S co-doping induced N-vacancy in graphitic carbon nitride towards photocatalytic peroxymonosulfate activation for sulfamethoxazole degradation

Doping-induced vacancy engineering of graphitic carbon nitride (GCN) is beneficial for bandgap modulation, efficient electronic excitation, and facilitated charge carrier migration. In this study, synthesis of oxygen and sulphur co-doped induced N vacancies (OSGCN) by the hydrothermal method was performed to activate peroxymonosulfate (PMS) for sulfamethoxazole (SMX) antibiotic degradation and H2 production. The results from experimental and DFT simulation studies validate the synergistic effects of co-dopants and N-vacancies, i.e., bandgap lowering, electron-hole pairs separation, and high solar energy utilization. The substitution of sp2 N atom by O and S co-dopants causes strong delocalization of HOMO-LUMO distribution, enhancing carrier mobility, increasing reactive sites, and facilitating charge-carrier separation. Remarkably, OSGCN/PMS photocatalytic system achieved 99.4% SMX degradation efficiency and a high H2 generation rate of 548.23 μ mol g−1 h−1 within 60 min and 36 h, respectively under visible light irradiations. The SMX degradation kinetics was pseudo-first-order with retained recycling efficiency up to 4 catalytic cycles. The results of EPR and chemical scavenging experiments revealed the redox action of reactive oxidative species, wherein 1O2 was the dominant reactive species in SMX degradation. The identification of formed intermediates and the SMX stepwise degradation pathway was investigated via LC-MS analysis and DFT studies, respectively. The results from this work anticipated deepening the understanding of PMS activation by substitutional co-doping favoring N-vacancy formation in GCN lattice for improved photocatalytic activity.

Computational study of the alcoholysis for organophosphorus pesticides: The reaction of phoxim with methanol

The alcoholysis process for one of organophosphorus pesticides, phoxim, was systematically examined by using the M06-2X/6–311++G(d,p) and MP2/6–311++G(d,p)//M06-2X/6–311++G(d,p) levels. Two possible alcoholysis mechanisms, P–OR1, P–OEt rupture channels together with the concerted and stepwise steps, were theoretically evaluated. The catalytic role of an extra methanol was also simulated. Furthermore, the influence of solvent on water was also taken into consideration for the M06-2X/6–311++G(d,p) level of theory. Our predicted results show convincingly that the P–OEt disintegration pathway is slightly more favorable than the P–OR removal channel. The stepwise pathway is calculated to be more prominent than the concerted one for all reactions. It can be observed that the methanol-assisted alcoholysis is more easier to take place than the direct alcoholysis. Solvent effect does not have remarkable effect on the reaction mechanism.

Multiple Stepwise Synthetic Pathways toward Complex Plasmonic 2D and 3D Nanoframes for Generation of Electromagnetic Hot Zones in a Single Entity

ConspectusRational design of nanocrystals with high controllability via wet chemistry is of critical importance in all areas of nanoscience and nanotechnology research. Specifically, morphologically complex plasmonic nanoparticles have received considerable attention because light-matter interactions are strongly associated with the size and shape of nanoparticles. Among many types of nanostructures, plasmonic nanoframes (NFs) with controllable structural intricacy could be excellent candidates as strong light-entrappers with inner voids as well as high surface area, leading to highly effective interaction with light and analytes compared to their solid counterparts. However, so far studies on single-rim-based NFs have suffered from insufficient near-field focusing capability due to their structural simplicity (e.g., a single rim or NF molded from simple platonic solids), which necessitates a conceptually new NF architecture. If one considers a stereoscopic nanostructure with dual, triple, and multiple resonant intra-nanogaps on each crystallographic facet of nanocrystals, unprecedented physicochemical properties could be expected. Realizing such complex multiple NFs with intraparticle surface plasmon coupling via localized surface plasmon resonance is very challenging due to the lack of synthetic strategic principles with systematic structural control, all of which require a deep understanding of surface chemistry. Moreover, realizing those complex architectures with high homogeneity in size and shape via a bottom-up method where diverse particle interactions are involved is more challenging. Although there have been several reports on NFs used for catalysis, techniques for production of structurally complex NFs with high uniformity and an understanding of the correlation between such complexity in a single plasmonic entity and electromagnetic near-field focusing have remained highly elusive.In this Account, we will summarize and highlight the rational synthetic pathways for the design of complex two-dimensional (2D) and three-dimensional (3D) NFs with unique inner rim structures and characterize their optical properties. This systematic strategy is based on publications from our group during the last 10 years. First, we will introduce a chemical step of shape transformation of triangular Au nanoplates to circular and hexagonal plates, which are used as sacrificial layers for the formation of NFs. Then, we will describe the methods on how to synthesize monorim-based plasmonic NFs using Pt scaffolds with different shapes and correlate with their electromagnetic near-field. Then, we will describe a multiple stepwise synthetic method for the formation of 2D complex NFs wherein different starting Au nanocrystals evolved from systematic shape transformation are used to produce circular, triangular, hexagonal, crescent, and Y-shaped inner hot zones. Then, we will discuss how one can synthesize NFs with multiple rims wherein rims with different diameters are concentrically connected, by exploiting chemical toolkits such as eccentric and concentric growth of Au, borrowing the concept of total synthesis that is frequently adopted in organic chemistry. We then introduce dual-rim-faceted NFs and frame-in-frame 3D matryoshka NF geometries via well-faceted growth of Au with high control of intra-nanogaps. Finally, and importantly, we will provide examples of more advanced hierarchical NF architectures produced by controlling geometrical shapes of nanoparticles, number of rims, and different components, leading to the expansion of the NF library.

A Enamide‐Based Diastereoselective Synthesis of Isoindolo[2,1‐a]quinolin‐11(5H)‐ones with Three Contiguous Stereogenic Centers

AbstractA stereoselective synthesis of isoindolo[2,1‐a]quinolin‐11(5H)‐ones containing three contiguous stereogenic centers is described. This Lewis‐acid mediated reaction of enamides with N‐aryl‐acylimines affords the desired fused heterocyclic isoindolinones in high yields and diastereoselectivities. Scope and limitations of this method are discussed. The stereochemical outcome of this transformation indicates a stepwise reaction pathway.