Recent Advances in the Synthesis of Peptidomimetics via Ugi Reactions.

Peptidomimetics have been extensively explored in many area due to their ability to improve pharmacological qualities and interesting biological activities. Cycles could be incorporated in peptides to reduce their flexibility, often enhancing the affinity for a certain receptor. Many efforts have been made to synthesize various peptidomimetics. Among them, the Ugi reaction is a popular way for the synthesis of peptidomimetics because it provides peptide-like products. The Ugi reaction consists of the condensation of an aldehyde or ketone, a carboxylic acid, an amine, and an isocyanide usually giving a linear peptidomimetic. In order to obtain other linear, cyclic or polycyclic peptidomimetics, the acyclic products have to undergo additional transformations or cyclizations. This review covers the years from 2018-2023, regarding the synthesis of linear, cyclic and polycyclic peptidomimetics, employing Ugi reactions eventually followed by post-Ugi transformations. Organo-catalyzed reactions, base-promoted reactions, and metal-free reactions toward peptidomimetics are highlighted.

Divergent and Nucleophile-Assisted Rearrangement in the Construction of Pyrrolo[2,1-b][3]benzazepine and Pyrido[2,1-a]isoquinoline Scaffolds.

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines.

Photoinduced copper-catalyzed enantioselective coupling reactions.

Copper-catalyzed enantioselective coupling has been widely investigated, which allows rapid construction of various chiral molecules. Despite important advances via polar and radical mechanisms, exploring general and practical strategies for the regio-, enantio- and diastereoselective assembly of stereogenic centers is of significant value but remains highly problematic. The integration of photocatalysis with asymmetric copper catalysis could provide appealing access to the development of new reaction pathways and structurally diverse chiral compounds, and extend the boundaries of radical chemistry. This review summarizes recent advances in photoinduced copper-catalyzed enantioselective coupling reactions, and discusses the mechanistic aspects.

Visible light-mediated halogenation of organic compounds.

The use of visible light and photoredox catalysis emerged as a powerful and sustainable tool for organic synthesis, showing high value for distinctly different ways of bond creation. Halogenated compounds are the cornerstone of contemporary organic synthesis: it is almost impossible to develop a route towards a pharmaceutical reagent, agrochemical, natural product, etc. without the involvement of halogen-containing intermediates. Moreover, the halogenated derivatives as final products became indispensable for drug discovery and materials science. The idea of this review is to understand and summarise the impact of visible light-promoted chemistry on halogenation and halofunctionalisation reactions.

Recent Advances in the Synthesis of Rosettacin.

Camptothecin and its analogues show important antitumor activity and have been used in clinical studies. However, hydrolysis of lactone in the E ring seriously attenuates the antitumor activity. To change this situation, aromathecin alkaloids are investigated in order to replace camptothecins. Potential antitumor activity has obtained more and more attention from organic and pharmaceutical chemists. As a member of the aromathecin alkaloids, rosettacin has been synthesized via different methods. This review summarizes recent advances in the synthesis of rosettacin.

Transition Metal-Free N-S Bond Cleavage and C-N Bond Activation of Ugi-Adducts for Rapid Preparation of Primary Amides and α-Ketoamides.

A novel method of transition metal-free N-S bond cleavage and subsequent C-N bond activation of Ugi-adducts was developed. Diverse primary amides and α-ketoamides were prepared in a rapid, step-economical and highly efficient manner in two steps. This strategy features excellent chemoselectivity, high yield and functional-group tolerance. Primary amides derived from the pharmaceuticals probenecid and febuxostat were prepared. This method opens a new pathway for the simultaneous synthesis of primary amides and α-ketoamides in an environmentally friendly manner.

Transition Metal-Catalyzed C-H Activation/Annulation Approaches to Isoindolo[2,1-b]isoquinolin-5(7H)-ones.

The isoindolo[2,1-b]isoquinolin-5(7H)-one scaffold is widely present in lots of bioactive natural products. Diverse types of strategies have been developed to construct this scaffold. Recently, transition metal-catalyzed C-H activation/annulation is emerging as a powerful and straightforward method to construct diverse polyheterocycles with high atom- and step-economy. It also has been employed for the synthesis of the isoindolo[2,1-b]isoquinolin-5(7H)-one scaffold. This review provides an introduction to recent advances for the preparation of isoindolo[2,1-b]isoquinolin-5(7H)-ones by using transition metal-catalyzed C-H activation/annulation. It will help researchers to find hidden opportunities and accelerate the discovery of novel transformations based on C-H activation/annulation.

Application of Metal-Free Dearomatization Reaction as a Sustainable Strategy to Direct Access Complex Cyclic Compounds.

The highly efficient construction of complicated heterocyclic frameworks in an atom- and step-economic manner is still one of the cores of synthetic chemistry. Dearomatization reactions show the unique advantage for the construction of functionalized heterocycles and have attracted widespread attention over the past two decades. The metal-free approach has proved to be a green and sustainable paradigm for the synthesis of spirocyclic, polycyclic and heterocyclic scaffolds, which are widely present in natural products and bioactive molecules. In this review, the advances in the recent six years (2017-2023) in metal-free dearomatization reactions are highlighted. Emphasis is placed on developments in the field of organo-catalyzed dearomatization reactions, oxidative dearomatization reactions, Brønsted acid- or base-promoted dearomatization reactions, photoredox-catalyzed dearomatization reactions, and electrochemical oxidation dearomatization reactions.

Post-Ugi Cyclizations Towards Polycyclic N-Heterocycles.

The Ugi reaction has become one of the highly explored reactions for the formation of multifunctional adducts, due to the mild reaction conditions, wide scope and high variability. By carefully selecting the starting four components, Ugi-adducts could undergo different kinds of post-transformations for the synthesis of bioactive heterocycles, natural products and macrocycles. Considering the significance of polycycles, diverse post-Ugi transformations have been developed over the years for constructing structurally novel polycycles. In this account, we summarize important efforts for the synthesis of polycyclic N-heterocycles via post-Ugi cyclizations from the Van der Eycken laboratory onwards 2016. With the aid of transition metal catalysis from gold, rhodium, silver and palladium, as well as metal-free strategies, versatile polyheterocycles are prepared with high efficiency and step-economy.

Effectiveness of Self-guided Tailored Implementation Strategies in Integrating and Embedding Internet-Based Cognitive Behavioral Therapy in Routine Mental Health Care: Results of a Multicenter Stepped-Wedge Cluster Randomized Trial.

BACKGROUND: Internet-based cognitive behavioral therapy (iCBT) services for common mental health disorders have been found to be effective. There is a need for strategies that improve implementation in routine practice. One-size-fits-all strategies are likely to be ineffective. Tailored implementation is considered as a promising approach. The self-guided integrated theory-based Framework for intervention tailoring strategies toolkit (ItFits-toolkit) supports local implementers in developing tailored implementation strategies. Tailoring involves identifying local barriers; matching selected barriers to implementation strategies; developing an actionable work plan; and applying, monitoring, and adapting where necessary. OBJECTIVE: This study aimed to compare the effectiveness of the ItFits-toolkit with implementation-as-usual (IAU) in implementing iCBT services in 12 routine mental health care organizations in 9 countries in Europe and Australia. METHODS: A stepped-wedge cluster randomized trial design with repeated measures was applied. The trial period lasted 30 months. The primary outcome was the normalization of iCBT delivery by service providers (therapists, referrers, IT developers, and administrators), which was measured with the Normalization Measure Development as a proxy for implementation success. A 3-level linear mixed-effects modeling was applied to estimate the effects. iCBT service uptake (referral and treatment completion rates) and implementation effort (hours) were used as secondary outcomes. The perceived satisfaction (Client Satisfaction Questionnaire), usability (System Usability Scale), and impact of the ItFits-toolkit by implementers were used to assess the acceptability of the ItFits-toolkit. RESULTS: In total, 456 mental health service providers were included in this study. Compared with IAU, the ItFits-toolkit had a small positive statistically significant effect on normalization levels in service providers (mean 0.09, SD 0.04; P=.02; Cohen d=0.12). The uptake of iCBT by patients was similar to that of IAU. Implementers did not spend more time on implementation work when using the ItFits-toolkit and generally regarded the ItFits-toolkit as usable and were satisfied with it. CONCLUSIONS: The ItFits-toolkit performed better than the usual implementation activities in implementing iCBT services in routine practice. There is practical utility in the ItFits-toolkit for supporting implementers in developing and applying effective tailored implementation strategies. However, the effect on normalization levels among mental health service providers was small. These findings warrant modesty regarding the effectiveness of self-guided tailored implementation of iCBT services in routine practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03652883; https://clinicaltrials.gov/ct2/show/NCT03652883. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-020-04686-4.

Multicomponent reactions and photo/electrochemistry join forces: atom economy meets energy efficiency.

Visible-light photoredox catalysis has been regarded as an extremely powerful tool in organic chemistry, bringing the spotlight back to radical processes. The versatility of photocatalyzed reactions has already been demonstrated to be effective in providing alternative routes for cross-coupling as well as multicomponent reactions. The photocatalyst allows the generation of high-energy intermediates through light irradiation rather than using highly reactive reagents or harsh reaction conditions. In a similar vein, organic electrochemistry has experienced a fruitful renaissance as a tool for generating reactive intermediates without the need for any catalyst. Such milder approaches pose the basis toward higher selectivity and broader applicability. In photocatalyzed and electrochemical multicomponent reactions, the generation of the radical species acts as a starter of the cascade of events. This allows for diverse reactivity and the use of reagents is usually not covered by classical methods. Owing to the availability of cheaper and more standardized photo- and electrochemical reactors, as well as easily scalable flow-setups, it is not surprising that these two fields have become areas of increased research interest. Keeping these in view, this review is aimed at providing an overview of the synthetic approaches in the design of MCRs involving photoredox catalysis and/or electrochemical activation as a crucial step with particular focus on the choice of the difunctionalized reagent.

Going with the µFlow: Reinterpreting Energy Input in Organic Synthesis.

The popularity of microflow chemistry has skyrocketed in the last 20 years, more and more chemists are switching from macro-batch reactors to miniaturized flow devices. As a result, microfluidics is paving its way into the future by consolidating its position in organic chemistry not only as a trend but as a new, effective, and sustainable way of conducting chemistry, that clearly will continue to grow and evolve. This perspective highlights the most relevant examples of innovative enhancing technologies applied to microflow reactors aimed to improve and intensify chemical processes. The extensive applicability of microflow chemistry is further illustrated by briefly discussing examples of complex integrated microsystems and scale-up technologies, demonstrating ultimately that microflow chemistry has the potential to become the ideal technology for the future.

Microwave-Assisted Post-Ugi Reactions for the Synthesis of Polycycles.

Microwave irradiation and post-Ugi reactions own their respective advantages in comparison with other strategies. The combination of microwave irradiation and post-Ugi reactions shows paramount importance in the construction of polycycles. This minireview outlines the recent developments of microwave-assisted post-Ugi reactions for the synthesis of polycycles. Through transition metal-catalyzed or transition metal-free transformations, diverse polycycles are prepared in an efficient, rapid, and step-economical manner.

Transition Metal-Catalyzed Intermolecular Cascade C-H Activation/Annulation Processes for the Synthesis of Polycycles.

Polycycles are abundantly present in numerous advanced chemicals, functional materials, bioactive molecules and natural products. However, the strategies for the synthesis of polycycles are limited to classical reactions and transition metal-catalyzed cross-coupling reactions, requiring pre-functionalized starting materials and lengthy synthetic operations. The emergence of novel approaches shows great promise for the fields of organic/medicinal/materials chemistry. Among them, transition metal-catalyzed C-H activation followed by intermolecular annulation reactions prevail, due to their straightforward manner with high atom- and step-economy, providing rapid, concise and efficient methods for the construction of diverse polycycles. Several strategies have been developed for the synthesis of polycycles, relying on sequential multiple C-H activation/annulation, or combination of C-H activation/annulation and further interaction with a proximal group, or merger of C-H activation with a cycloaddition reaction, or in situ formation of the directing group. These are attractive, efficient, step- and atom-economic methods starting from commercially available materials. This Minireview will provide an introduction to transition metal-catalyzed C-H activation for the synthesis of polycycles, helping researchers to discover indirect connections and reveal hidden opportunities. It will also promote the discovery of novel synthetic strategies relying on C-H activation.

Microwave-Assisted Cu(I)-Catalyzed Synthesis of Unsymmetrical 1,4-Diamino-2-butynes via Cross-A3-Coupling/Decarboxylative A3-Coupling.

1,4-Diamino-2-butynes display both chemical and physiological properties. Here a highly efficient synthesis avenue to generate unsymmetric 1,4-diamino-2-butynes has been developed by microwave-assisted Cu(I)-catalyzed cross-A3-coupling/decarboxylative coupling of two different amines, formaldehyde, and propiolic acid through a domino process. This multicomponent reaction provides a series of target products in moderate to good yields with high chemoselectivity.

Palladium-catalyzed post-Ugi arylative dearomatization/Michael addition cascade towards plicamine analogues.

A palladium-catalyzed intramolecular cyclization of Ugi-adducts via a cascade dearomatization/aza-Michael addition process has been developed. Diverse plicamine analogues are constructed in a rapid, highly efficient and step-economical manner, through the combination of an Ugi-4CR and a palladium-catalyzed dearomatization. The synthetic utility of this approach is illustrated by further functional group transformations.

2-Aminoimidazoles as potent inhibitors of contaminating brewery biofilms.

Cleaning and disinfection protocols are not always able to remove biofilm microbes present in breweries, indicating that novel anti-biofilm strategies are needed. The preventive activities of three in-house synthesized members of the 2-aminoimidazole class of anti-biofilm molecules were studied against 17 natural brewery biofilms and benchmarked against 18 known inhibitors. Two 2-aminoimidazoles belonged to the top six inhibitors, which were retested against 12 defined brewery biofilm models. For the three best inhibitors, tannic acid (n° 1), 2-aminoimidazole imi-AAC-5 (n° 2), and baicalein (n° 3), the effect on the microbial metabolic activity was evaluated. Here, the top three inhibitors showed similar effectiveness, with baicalein possessing a slightly higher efficacy. Even though the 2-aminoimidazole was the second-best inhibitor, it showed a lower biocidal activity than tannic acid, making it less prone to resistance evolution. Overall, this study supports the potential of 2-aminoimidazoles as a preventive anti-biofilm strategy.

Sequential and direct multicomponent reaction (MCR)-based dearomatization strategies.

Dearomatization strategies in a multicomponent fashion often result in complex heterocyclic frameworks, which have attracted the attention of chemists due to their natural product-like structures. The combination of these two processes can easily achieve extended molecular complexity and diversity from simple starting materials with high atom economy. Thus, this field has attracted extensive interest owing to its potential significance in both asymmetric catalysis and convenient build-up of libraries of molecules with novel three-dimensional scaffolds, which may find application in medicinal chemistry. Accordingly, a systematic review on this topic will provide the synthetic organic community with a conceptual overview and comprehensive understanding of the different multicomponent reaction (MCR) cascades involving dearomatization as the characteristic step. In addition, this review will help researchers to look at this promising area from a different perspective with respect to drug discovery, new MCR-based disconnections and often hidden opportunities.

Peptide macrocyclization by transition metal catalysis.

Peptide macrocyclization has traditionally relied on lactam, lactone and disulfide bond-forming reactions that aim at introducing conformational constraints into small peptide sequences. With the advent of ruthenium-catalyzed ring-closing metathesis and copper-catalyzed alkyne-azide cycloaddition, peptide chemists embraced transition metal catalysis as a powerful macrocyclization tool with relevant applications in chemical biological and peptide drug discovery. This article provides a comprehensive overview of the reactivity and methodological diversification of metal-catalyzed peptide macrocyclization as a special class of late-stage peptide derivatization method. We report the evolution from classic palladium-catalyzed cross-coupling approaches to more modern oxidative versions based on C-H activation, heteroatom alkylation/arylation and annulation processes, in which aspects such as chemoselectivity and diversity generation at the ring-closing moiety became dominant over the last years. The transit from early cycloadditions and alkyne couplings as ring-closing steps to very recent 3d metal-catalyzed macrocyclization methods is highlighted. Similarly, the new trends in decarboxylative radical macrocyclizations and the interplay between photoredox and transition metal catalysis are included. This review charts future perspectives in the field hoping to encourage further progress and applications, while bringing attention to the countless possibilities available by diversifying not only the metal, but also the reactivity modes and tactics to bring peptide functional groups together and produce structurally diverse macrocycles.

Synthetic Strategies in the Preparation of Phenanthridinones.

Phenanthridinones are important heterocyclic frameworks present in a variety of complex natural products, pharmaceuticals and displaying wide range of pharmacological actions. Its structural importance has evoked a great deal of interest in the domains of organic synthesis and medicinal chemistry to develop new synthetic methodologies, as well as novel compounds of pharmaceutical interest. This review focuses on the synthesis of phenanthridinone scaffolds by employing aryl-aryl, N-aryl, and biaryl coupling reactions, decarboxylative amidations, and photocatalyzed reactions.