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.

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.

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.

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.

A scalable continuous photochemical process for the generation of aminopropylsulfones.

An efficient continuous photochemical process is presented that delivers a series of novel γ-aminopropylsulfones via a tetrabutylammonium decatungstate (TBADT) catalysed HAT-process. Crucial to this success is the exploitation of a new high-power LED emitting at 365 nm that was found to be superior to an alternative medium-pressure Hg lamp. The resulting flow process enabled the scale-up of this transformation reaching throughputs of 20 mmol h-1 at substrate concentrations up to 500 mM. Additionally, the substrate scope of this transformation was evaluated demonstrating the straightforward incorporation of different amine substituents as well as alkyl appendages next to the sulfone moiety. It is anticipated that this methodology will allow for further exploitations of these underrepresented γ-aminopropylsulfone scaffolds in the future.

Continuous Flow Photochemistry for the Preparation of Bioactive Molecules.

The last decade has witnessed a remarkable development towards improved and new photochemical transformations in response to greener and more sustainable chemical synthesis needs. Additionally, the availability of modern continuous flow reactors has enabled widespread applications in view of more streamlined and custom designed flow processes. In this focused review article, we wish to evaluate the standing of the field of continuous flow photochemistry with a specific emphasis on the generation of bioactive entities, including natural products, drugs and their precursors. To this end we highlight key developments in this field that have contributed to the progress achieved to date. Dedicated sections present the variety of suitable reactor designs and set-ups available; a short discussion on the relevance of greener and more sustainable approaches; and selected key applications in the area of bioactive structures. A final section outlines remaining challenges and areas that will benefit from further developments in this fast-moving area. It is hoped that this report provides a valuable update on this important field of synthetic chemistry which may fuel developments in the future.

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.

Discovery of a photochemical cascade process by flow-based interception of isomerising alkenes.

Herein we report the discovery of a new photochemical cascade process through a flow-based strategy for intercepting diradicals generated from simple alkenes. This continuous process delivers a series of unprecedented polycyclic reaction products. Exploring the scope of this novel process revealed that this approach is general and affords a variety of structurally complex reaction products in high yields (up to 81%), short reaction times (7 min) and high throughputs (up to 5.5 mmol h-1). A mechanistic rationale is presented that is supported by computations as well as isolation of key intermediates whose identity is confirmed by X-ray crystallography. The presented photochemical cascade process demonstrates the discovery of new chemical reactivity and complex chemical scaffolds by continuously generating and intercepting high-energy intermediates in a highly practical manner.

Strontium substituted hydroxyapatite with ß-lactam integrin agonists to enhance mesenchymal cells adhesion and to promote bone regeneration.

Multi-functionalization of calcium phosphates to get delivery systems of therapeutic agents is gaining increasing relevance for the development of functional biomaterials aimed to solve problems related to disorders of the muscolo-skeletal system. In this regard, we functionalized Strontium substituted hydroxyapatite (SrHA) with some ß-lactam integrin agonists to develop materials with enhanced properties in promoting cell adhesion and activation of intracellular signaling as well as in counteracting abnormal bone resorption. For this purpose, we selected two monocyclic ß-lactams on the basis of their activities towards specific integrins on promoting cell adhesion and signalling. The amount of ß-lactams loaded on SrHA could be modulated on changing the polarity of the loading solution, from 3.5-24 wt% for compound 1 and from 3.2-8.4 wt% for compound 2. Studies on the release of the ß-lactams from the functionalized SrHA in aqueous medium showed an initial burst followed by a steady-release that ensures a small but constant amount of the compounds over time. The new composites were fully characterized. Co-culture of human primary mesenchymal stem cells (hMSC) and human primary osteoclast (OC) demonstrated that the presence of ß-lactams on SrHA favors hMSC adhesion and viability, as well as differentiation towards osteoblastic lineage. Moreover, the ß-lactams were found to enhance the inhibitory role of Strontium on osteoclast viability and differentiation.