Development of a Continuous Flow Baldwin Rearrangement Process and Its Comparison to Traditional Batch Mode.

A new and highly efficient continuous flow process is presented for the synthesis of aziridines via the thermal Baldwin rearrangement. The process was initially explored using traditional batch synthesis techniques but suffered from moderate yields, long reaction times, and moderate diastereoselectivities. Here we demonstrate that the process can be greatly improved upon its transfer to continuous flow, which afforded the aziridine targets in high yields, short reaction times, and consistently high diastereoselectivities, with the high-throughput process rendering multigram quantities of product in short periods of time. In addition, flow processing extended the substrate scope including several examples that had failed in batch mode, thus demonstrating the value of this overlooked entry into valuable aziridine species.

Continuous Flow Oxidation of Alcohols Using TEMPO/NaOCl for the Selective and Scalable Synthesis of Aldehydes.

A simple and benign continuous flow oxidation protocol for the selective conversion of primary and secondary alcohols into their respective aldehyde and ketone products is reported. This approach makes use of catalytic amounts of TEMPO in combination with sodium bromide and sodium hypochlorite in a biphasic solvent system. A variety of substrates are tolerated including those containing heterocycles based on potentially sensitive nitrogen and sulfur moieties. The flow approach can be coupled with inline reactive extraction by formation of the carbonyl-bisulfite adduct which aids in separation of remaining substrate or other impurities. Process robustness is evaluated for the preparation of phenylpropanal at decagram scale, a trifluoromethylated oxazole building block as well as a late-stage intermediate for the anti-HIV drug maraviroc which demonstrates the potential value of this continuous oxidation method.

Telescoped Flow Synthesis of Azacyclic Scaffolds Exploiting the Chromoselective Photolysis of Vinyl Azides and Azirines.

An efficient chromoselective photochemical process is presented for the synthesis of 2H-azirines and 1,3-diazabicylo[3.1.0]hex-3-enes from readily available vinyl azides. The method exploits continuous flow photochemistry to enable the safe consumption of the hazardous azide group and provides uniform irradiation using high-power LEDs at 365-450 nm. Additionally, a scaled telescoped process has been developed providing access to drug-like 1,6-dihydropyrimidines and pyrimidines via integrated ring-expansion and oxidation reactions. Given the prevalence of various azacyclic targets in pharmaceutical, agrochemical and materials applications it is anticipated that this methodology will enable further exploitations of these important scaffolds.

Advances in the Continuous Flow Synthesis of 3- and 4-Membered Ring Systems.

Small carbo- and heterocyclic ring systems have experienced a significant increase in importance in recent years due to their relevance in modern pharmaceuticals, as building blocks for designer materials or as synthetic intermediates. This necessitated the development of new synthetic methods for the preparation of these strained ring systems focusing on effectiveness and scalability. The high ring strain of these entities as well as the use of high-energy reagents and intermediates has often challenged their synthesis. Continuous flow approaches have thus emerged as highly effective means to safely and reliably access these strained scaffolds. In this short review, key developments in this field are summarised showcasing the power of continuous flow approaches for accessing 3- and 4-membered ring systems via thermal, photo- and electrochemical processes.

Continuous flow synthesis enabling reaction discovery.

This article defines the role that continuous flow chemistry can have in new reaction discovery, thereby creating molecular assembly opportunities beyond our current capabilities. Most notably the focus is based upon photochemical, electrochemical and temperature sensitive processes where continuous flow methods and machine assisted processing can have significant impact on chemical reactivity patterns. These flow chemical platforms are ideally placed to exploit future innovation in data acquisition, feed-back and control through artificial intelligence (AI) and machine learning (ML) techniques.

Continuous Flow Synthesis of Benzotriazin-4(3H)-ones via Visible Light Mediated Nitrogen-Centered Norrish Reaction.

We report a new protocol for the synthesis of substituted benzotriazin-4(3H)-ones which are underrepresented heterocyclic scaffolds with important pharmacological properties. Our method exploits acyclic aryl triazine precursors that undergo a photocyclization reaction upon exposure to violet light (420 nm). Continuous flow reactor technology is exploited to afford excellent yields in only 10 min residence time with no additives or photocatalysts needed. The underlying reaction mechanism appears to be based on an unprecedented variation of the classical Norrish type II reaction with concomitant fragmentation and formation of N-N bonds. Scalability, process robustness, and green credentials of this intriguing transformation are highlighted.

Modular Synthesis of Benzoylpyridines Exploiting a Reductive Arylation Strategy.

Herein we disclose a telescoped flow strategy to access electronically differentiated bisaryl ketones as potentially new and tunable photosensitizers containing both electron-rich benzene systems and electron-deficient pyridyl moieties. Our approach merges a light-driven (365 nm) and catalyst-free reductive arylation between aromatic aldehydes and cyanopyridines with a subsequent oxidation process. The addition of electron-donating and withdrawing substituents on the scaffold allowed effective modification of the absorbance of these compounds in the UV-vis region, while the continuous flow process affords high yields, short residence time, and high throughput.

Continuous Flow Synthesis of Nitrosoarenes via Photochemical Rearrangement of Aryl Imines.

Nitrosoarenes are versatile organic building blocks; however, their intrinsic instability and limited synthetic accessibility have so far restricted their widespread use. Herein, we present a new continuous flow route toward these entities that is based on a direct photochemical rearrangement process using o-nitrophenylimines as starting materials. Due to the underlying redox mechanism, a new amide group accompanies the formation of the nitroso group. Crucial to the success of this approach is the use of trifluoroethanol as a solvent and high-power light-emitting diodes (365 nm) as light sources that provide uniform irradiation and high efficiency of the resulting continuous flow method. The process is fast and robust, with high functional group tolerance and high throughput. The formation of the nitroso moiety is supported by full spectroscopic analysis, including X-ray crystallography. The scalability of this flow approach allows access to gram quantities of nitroso species for which we highlight a small set of derivatization reactions underlining their synthetic utility.

Synthesis of Highly Reactive Ketenimines via Photochemical Rearrangement of Isoxazoles.

Ketenimines are highly electrophilic species with multiple applications as building blocks in organic synthesis; however, the effective preparation of these versatile entities remains a synthetic challenge. Here we report a continuous photochemical process that generates ketenimines via skeletal rearrangement of trisubstituted isoxazoles. The resulting flow process is noteworthy, as it provides for the first time a straightforward entry into these ketenimines that were previously only observed spectroscopically. The value of this methodology toward heterocyclic transposition reactions is demonstrated by converting isoxazoles via isolable ketenimines into pharmaceutically relevant pyrazoles.

[3+2]-Cycloaddition Reactions of gem-Difluorocyclopropenes with Azomethine Ylides - Access to Novel Fluorinated Scaffolds.

The introduction of fluorinated moieties into drugs as well as the increase of their overall three-dimensionality have become key strategies amongst medicinal chemists to generate sets of compounds with favorable drug-like properties. However, the introduction of fluorinated cyclopropane ring systems which combines both strategies is not widely exploited to date. This paper reports synthetic strategies exploiting the reactivity of gem-difluorocyclopropenes in dipolar cycloaddition reactions with azomethine ylides to afford sets of new fluorine-containing 3-azabicyclo[3.1.0]hexanes. In addition, the unexpected formation of complex trifluorinated scaffolds arising from proline esters and gem-difluorocyclopropenes is highlighted along with computational studies to elucidate the underlying mechanism. This study presents new avenues towards pharmaceutically relevant fluorinated 3-azabicyclo[3.1.0]hexanes that are accessible via robust and short synthetic sequences.

Flow photolysis of aryldiazoacetates leading to dihydrobenzofurans via intramolecular C-H insertion.

Flow photolysis of aryldiazoacetates 3-5 leads to C-H insertion to form dihydrobenzofurans 6-8 in a metal-free process, using either a medium pressure mercury lamp (250-390 nm) or LEDs (365 nm or 450 nm) with comparable synthetic outcomes. Significantly, addition of 4,4'-dimethoxybenzophenone 9 results in an increased yield and also alters the stereochemical outcome leading to preferential isolation of the trans dihydrobenzofurans 6a-8a (up to 50% yield), while the cis and trans diastereomers of 6-8 are recovered in essentially equimolar amounts in the absence of a photosensitiser (up to 26% yield).

Antimicrobial Evaluation of New Pyrazoles, Indazoles and Pyrazolines Prepared in Continuous Flow Mode.

Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically inactive today. As the de-novo development of effective antibiotics is a very costly and time-consuming process, alternative strategies such as the screening of natural and synthetic compound libraries is a simple approach towards finding new lead compounds. We thus report on the antimicrobial evaluation of a small collection of fourteen drug-like compounds featuring indazoles, pyrazoles and pyrazolines as key heterocyclic moieties whose synthesis was achieved in continuous flow mode. It was found that several compounds possessed significant antibacterial potency against clinical and MDR strains of the Staphylococcus and Enterococcus genera, with the lead compound (9) reaching MIC values of 4 µg/mL on those species. In addition, time killing experiments performed on compound 9 on Staphylococcus aureus MDR strains highlight its activity as bacteriostatic. Additional evaluations regarding the physiochemical and pharmacokinetic properties of the most active compounds are reported and showcased, promising drug-likeness, which warrants further explorations of the newly identified antimicrobial lead compound.

Carbene-controlled regioselectivity in photochemical cascades.

A highly regioselective route to complex carbocyclic scaffolds through a continuous photochemical process is reported. Crucially, we uncovered that ortho substitutents on the right-hand aryl ring are placed away from a transient carbene species which induces the exclusive regioselectivity observed. By varying the non-symmetrically substituted aryl moiety, we demonstrate how the product outcome favors cyclobutenes for electron-poor and neutral substituents and cycloheptatrienes for more electron-rich systems. Additionally, a photochemically induced rearrangement was uncovered for highly electron-rich substrates that ultimately generates complex hydroperoxides. Overall, this facile one-step process is fast and high yielding and demonstrates the power of photochemistry towards the exploration of new chemical space.

Synthesis of Modified Poly(vinyl Alcohol)s and Their Degradation Using an Enzymatic Cascade.

Poly(vinyl alcohol) (PVA) is a water-soluble synthetic vinyl polymer with remarkable physical properties including thermostability and viscosity. Its biodegradability, however, is low even though a large amount of PVA is released into the environment. Established physical-chemical degradation methods for PVA have several disadvantages such as high price, low efficiency, and secondary pollution. Biodegradation of PVA by microorganisms is slow and frequently involves pyrroloquinoline quinone (PQQ)-dependent enzymes, making it expensive due to the costly cofactor and hence unattractive for industrial applications. In this study, we present a modified PVA film with improved properties as well as a PQQ-independent novel enzymatic cascade for the degradation of modified and unmodified PVA. The cascade consists of four steps catalyzed by three enzymes with in situ cofactor recycling technology making this cascade suitable for industrial applications.

Consecutive photochemical reactions enabled by a dual flow reactor coil strategy.

The application of a dual reactor coil for consecutive photochemical reactions is presented in continuous flow mode. This strategy enables for the first time the use of a single LED-based light source to perform two distinct photochemical reactions in an uninterrupted fashion. This approach is demonstrated for the telescoped synthesis and functionalisation of drug-like quinolines and compared to alternatives exploiting two photochemical reactor set-ups operated in sequence. The presented strategy enables the intensified exploitation of photochemical reactions in modern synthesis.

Continuous Flow Technology as an Enabler for Innovative Transformations Exploiting Carbenes, Nitrenes, and Benzynes.

Miniaturization offered by microreactors provides for superb reaction control as well as excellent heat and mass transfer. By performing chemical reactions in microreactors or tubular systems under continuous flow conditions, increased safety can be harnessed which allows exploitation of these technologies for the generation and immediate consumption of high-energy intermediates. This Synopsis demonstrates the use of flow technology to effectively exploit benzynes, carbenes, and nitrenes in synthetic chemistry programs.

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography.

An efficient continuous flow process is reported for the synthesis of various 1,3,4-oxadiazoles via an iodine-mediated oxidative cyclisation approach. This entails the use of a heated packed-bed reactor filled with solid K2CO3 as a base. Using DMSO as solvent, this flow method generates the target heterocycles within short residence times of 10 minutes and in yields up to 93%. Scale-up of this flow process was achieved (34 mmol/h) and featured an integrated quenching and extraction step. Lastly, the use of an automated in-line chromatography system was exploited to realise a powerful flow platform for the generation of the heterocyclic targets.

The synergistic activity of SBC3 in combination with Ebselen against Escherichia coli infection.

Escherichia coli ranks as the number one clinical isolate in the past years in China according to The China Antimicrobial Surveillance Network (CHINET), and its multidrug-resistant (MDR) pathogenic strains account for over 160 million cases of dysentery and one million deaths per year. Here, our work demonstrates that E. coli is highly sensitive to the synergistic combination of SBC3 [1,3-Dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver (I) acetate] and Ebselen, which shows no synergistic toxicity on mammalian cells. The proposed mechanism for the synergistic antibacterial effect of SBC3 in combination with Ebselen is based on directly inhibiting E. coli thioredoxin reductase and rapidly depleting glutathione, resulting in the increase of reactive oxygen species that cause bacterial cell death. Furthermore, the bactericidal efficacy of SBC3 in combination with Ebselen has been confirmed in mild and acute peritonitis mice. In addition, the five most difficult to treat Gram-negative bacteria (including E. coli, Acinetobacter baumannii, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa) are also highly sensitive to a synergistic combination of SBC3 and Ebselen. Thus, SBC3 in combination with Ebselen has potential as a treatment for clinically important Gram-negative bacterial infections.

Continuous Flow Synthesis of Anticancer Drugs.

Continuous flow chemistry is by now an established and valued synthesis technology regularly exploited in academic and industrial laboratories to bring about the improved preparation of a variety of molecular structures. Benefits such as better heat and mass transfer, improved process control and safety, a small equipment footprint, as well as the ability to integrate in-line analysis and purification tools into telescoped sequences are often cited when comparing flow to analogous batch processes. In this short review, the latest developments regarding the exploitation of continuous flow protocols towards the synthesis of anticancer drugs are evaluated. Our efforts focus predominately on the period of 2016-2021 and highlight key case studies where either the final active pharmaceutical ingredient (API) or its building blocks were produced continuously. It is hoped that this manuscript will serve as a useful synopsis showcasing the impact of continuous flow chemistry towards the generation of important anticancer drugs.

Protein domain-based prediction of drug/compound-target interactions and experimental validation on LIM kinases.

Predictive approaches such as virtual screening have been used in drug discovery with the objective of reducing developmental time and costs. Current machine learning and network-based approaches have issues related to generalization, usability, or model interpretability, especially due to the complexity of target proteins' structure/function, and bias in system training datasets. Here, we propose a new method "DRUIDom" (DRUg Interacting Domain prediction) to identify bio-interactions between drug candidate compounds and targets by utilizing the domain modularity of proteins, to overcome problems associated with current approaches. DRUIDom is composed of two methodological steps. First, ligands/compounds are statistically mapped to structural domains of their target proteins, with the aim of identifying their interactions. As such, other proteins containing the same mapped domain or domain pair become new candidate targets for the corresponding compounds. Next, a million-scale dataset of small molecule compounds, including those mapped to domains in the previous step, are clustered based on their molecular similarities, and their domain associations are propagated to other compounds within the same clusters. Experimentally verified bioactivity data points, obtained from public databases, are meticulously filtered to construct datasets of active/interacting and inactive/non-interacting drug/compound-target pairs (~2.9M data points), and used as training data for calculating parameters of compound-domain mappings, which led to 27,032 high-confidence associations between 250 domains and 8,165 compounds, and a finalized output of ~5 million new compound-protein interactions. DRUIDom is experimentally validated by syntheses and bioactivity analyses of compounds predicted to target LIM-kinase proteins, which play critical roles in the regulation of cell motility, cell cycle progression, and differentiation through actin filament dynamics. We showed that LIMK-inhibitor-2 and its derivatives significantly block the cancer cell migration through inhibition of LIMK phosphorylation and the downstream protein cofilin. One of the derivative compounds (LIMKi-2d) was identified as a promising candidate due to its action on resistant Mahlavu liver cancer cells. The results demonstrated that DRUIDom can be exploited to identify drug candidate compounds for intended targets and to predict new target proteins based on the defined compound-domain relationships. Datasets, results, and the source code of DRUIDom are fully-available at: https://github.com/cansyl/DRUIDom.