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14 pages, 2632 KiB

Open AccessArticle

A One-Pot Divergent Sequence to Pyrazole and Quinoline Derivatives

by Guido Gambacorta, David C. Apperley and Ian R. Baxendale

Molecules 2020, 25(9), 2160; https://doi.org/10.3390/molecules25092160 - 5 May 2020

Cited by 4 | Viewed by 2662

Abstract

The hydroxy-pyrazole and 3-hydroxy-oxindole motifs have been utilised in several pharma and agrochemical leads but are distinctly underrepresented in the scientific literature due to the limited routes of preparation. We have developed a one-pot procedure for their synthesis starting from simple isatins. The [...] Read more.

The hydroxy-pyrazole and 3-hydroxy-oxindole motifs have been utilised in several pharma and agrochemical leads but are distinctly underrepresented in the scientific literature due to the limited routes of preparation. We have developed a one-pot procedure for their synthesis starting from simple isatins. The method employs cheap and easy-to-handle building blocks and allows easy isolation. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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16 pages, 2016 KiB

Open AccessArticle

Parallel Interconnected Kinetic Asymmetric Transformation (PIKAT) with an Immobilized ω-Transaminase in Neat Organic Solvent

by Wesley Böhmer, Lucien Koenekoop, Timothée Simon and Francesco G. Mutti

Molecules 2020, 25(9), 2140; https://doi.org/10.3390/molecules25092140 - 3 May 2020

Cited by 7 | Viewed by 3270

Abstract

Comprising approximately 40% of the commercially available optically active drugs, α-chiral amines are pivotal for pharmaceutical manufacture. In this context, the enzymatic asymmetric amination of ketones represents a more sustainable alternative than traditional chemical procedures for chiral amine synthesis. Notable advantages are higher [...] Read more.

Comprising approximately 40% of the commercially available optically active drugs, α-chiral amines are pivotal for pharmaceutical manufacture. In this context, the enzymatic asymmetric amination of ketones represents a more sustainable alternative than traditional chemical procedures for chiral amine synthesis. Notable advantages are higher atom-economy and selectivity, shorter synthesis routes, milder reaction conditions and the elimination of toxic catalysts. A parallel interconnected kinetic asymmetric transformation (PIKAT) is a cascade in which one or two enzymes use the same cofactor to convert two reagents into more useful products. Herein, we describe a PIKAT catalyzed by an immobilized ω-transaminase (ωTA) in neat toluene, which concurrently combines an asymmetric transamination of a ketone with an anti-parallel kinetic resolution of an amine racemate. The applicability of the PIKAT was tested on a set of prochiral ketones and racemic α-chiral amines in a 1:2 molar ratio, which yielded elevated conversions (up to >99%) and enantiomeric excess (ee, up to >99%) for the desired products. The progress of the conversion and ee was also monitored in a selected case. This is the first report of a PIKAT using an immobilized ωTA in a non-aqueous environment. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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11 pages, 857 KiB

Open AccessArticle

An Enzymatic Flow-Based Preparative Route to Vidarabine

by Lucia Tamborini, Clelia Previtali, Francesca Annunziata, Teodora Bavaro, Marco Terreni, Enrica Calleri, Francesca Rinaldi, Andrea Pinto, Giovanna Speranza, Daniela Ubiali and Paola Conti

Molecules 2020, 25(5), 1223; https://doi.org/10.3390/molecules25051223 - 9 Mar 2020

Cited by 15 | Viewed by 4139

Abstract

The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP), was re-designed under continuous-flow conditions. Glyoxyl–agarose and EziG^TM1 (Opal) were [...] Read more.

The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP), was re-designed under continuous-flow conditions. Glyoxyl–agarose and EziG^TM1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of CpUP and AhPNP, the results obtained pave the way to the use of the CpUP/AhPNP-based bioreactor for the preparation of other purine nucleosides. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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11 pages, 1880 KiB

Open AccessFeature PaperArticle

Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines

by Bruno Cerra, Antonio Macchiarulo, Andrea Carotti, Emidio Camaioni, Ina Varfaj, Roccaldo Sardella and Antimo Gioiello

Molecules 2020, 25(3), 640; https://doi.org/10.3390/molecules25030640 - 2 Feb 2020

Cited by 8 | Viewed by 2539

Abstract

In the present work, we illustrate the ability of high-performance liquid chromatography (HPLC) analysis to assist the synthesis of chiral imidazolines within our medicinal chemistry programs. In particular, a Chiralpak^® IB^® column containing cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto a 5 μm silica [...] Read more.

In the present work, we illustrate the ability of high-performance liquid chromatography (HPLC) analysis to assist the synthesis of chiral imidazolines within our medicinal chemistry programs. In particular, a Chiralpak^® IB^® column containing cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto a 5 μm silica gel was used for the enantioselective HPLC analysis of chiral imidazolines synthesized in the frame of hit-to-lead explorations and designed for exploring the effect of diverse amide substitutions. Very profitably, reversed-phase (RP) conditions succeeded in resolving the enantiomers in nine out of the 10 investigated enantiomeric pairs, with α values always higher than 1.10 and R_S values up to 2.31. All compounds were analysed with 50% (v) water while varying the content of the two organic modifiers acetonitrile and methanol. All the employed eluent systems were buffered with 40 mM ammonium acetate while the apparent pH was fixed at 7.5. Based on the experimental results, the prominent role of π-π stacking interactions between the substituted electron-rich phenyl groups outside of the polymeric selector and the complementary aromatic region in defining analyte retention and stereodiscrimination was identified. The importance of compound polarity in explaining the retention behaviour with the employed RP system was readily evident when a quantitative structure-property relationship study was performed on the retention factor values (k) of the 10 compounds, as computed with a 30% (v) methanol containing mobile phase. Indeed, good Pearson correlation coefficients of retention factors (r - log k_1st = −0.93; r - log k_2nd = −0.94) were obtained with a water solubility descriptor (Ali-logS). Interestingly, a n-hexane/chloroform/ethanol (88:10:2, v/v/v)-based non-standard mobile phase allowed the almost base-line enantioseparation (α = 1.06; R_S = 1.26) of the unique compound undiscriminated under RP conditions. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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10 pages, 2701 KiB

Open AccessArticle

Optimisation by Design of Experiment of Benzimidazol-2-One Synthesis under Flow Conditions

by Serena Mostarda, Tugçe Gür Maz, Alessandro Piccinno, Bruno Cerra and Erden Banoglu

Molecules 2019, 24(13), 2447; https://doi.org/10.3390/molecules24132447 - 3 Jul 2019

Cited by 7 | Viewed by 3709

Abstract

A novel flow-based approach for the preparation of benzimidazol-2-one (1) scaffold by the 1,1′-carbonyldiimidazole (CDI)-promoted cyclocarbonylation of o-phenylenediamine (2) is reported. Starting from a preliminary batch screening, the model reaction was successfully translated under flow conditions and optimised [...] Read more.

A novel flow-based approach for the preparation of benzimidazol-2-one (1) scaffold by the 1,1′-carbonyldiimidazole (CDI)-promoted cyclocarbonylation of o-phenylenediamine (2) is reported. Starting from a preliminary batch screening, the model reaction was successfully translated under flow conditions and optimised by means of design of experiment (DoE). The method allowed the efficient preparation of this privileged scaffold and to set up a general protocol for the multigram-scale preparation in high yield, purity, and productivity, and was successfully applied for the multigram flow synthesis of N-(2-chlorobenzyl)-5-cyano-benzimidazol-2-one, which is a key synthon for hit-to-lead explorations in our anti-inflammatory drug discovery program. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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17 pages, 3138 KiB

Open AccessArticle

Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines

by Ubaldina Galli, Rejdia Hysenlika, Fiorella Meneghetti, Erika Del Grosso, Sveva Pelliccia, Ettore Novellino, Mariateresa Giustiniano and Gian Cesare Tron

Molecules 2019, 24(10), 1959; https://doi.org/10.3390/molecules24101959 - 21 May 2019

Cited by 3 | Viewed by 3322

Abstract

A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to [...] Read more.

A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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Review

Jump to: Research

47 pages, 10111 KiB

Open AccessReview

Allosteric GABA_A Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

by Blanca Angelica Vega Alanis, Maria Teresa Iorio, Luca L. Silva, Konstantina Bampali, Margot Ernst, Michael Schnürch and Marko D. Mihovilovic

Molecules 2020, 25(4), 999; https://doi.org/10.3390/molecules25040999 - 24 Feb 2020

Cited by 19 | Viewed by 9295

Abstract

GABA_A receptor modulators are structurally almost as diverse as their target protein. A plethora of heterocyclic scaffolds has been described as modulating this extremely important receptor family. Some made it into clinical trials and, even on the market, some were dismissed. This [...] Read more.

GABA_A receptor modulators are structurally almost as diverse as their target protein. A plethora of heterocyclic scaffolds has been described as modulating this extremely important receptor family. Some made it into clinical trials and, even on the market, some were dismissed. This review focuses on the synthetic accessibility and potential for library synthesis of GABA_A receptor modulators containing at least one heterocyclic scaffold, which were disclosed within the last 10 years. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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12 pages, 2180 KiB

Open AccessReview

Flow Synthesis of Biologically-Relevant Compound Libraries

by Pilar María Luque Navarro and Daniela Lanari

Molecules 2020, 25(4), 909; https://doi.org/10.3390/molecules25040909 - 18 Feb 2020

Cited by 4 | Viewed by 2587

Abstract

Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists’ approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be [...] Read more.

Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists’ approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be tested for biological properties. The aim of the present review is to comment on some representative examples from the last five years of literature that highlight how flow procedures are becoming of increasing importance for the synthesis of biologically-relevant molecules. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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13 pages, 2624 KiB

Open AccessReview

Continuous Flow Photochemistry for the Preparation of Bioactive Molecules

by Mara Di Filippo, Cormac Bracken and Marcus Baumann

Molecules 2020, 25(2), 356; https://doi.org/10.3390/molecules25020356 - 15 Jan 2020

Cited by 77 | Viewed by 6868

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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