High-Pressure Promoted Nazarov-like Electrocyclization Enables Access to trans-4,5-Diamino-cyclopent-2-enones Bearing Electron-Poor Anilines.

Unlike secondary alkyl amines and electron-rich anilines, secondary electron-poor anilines are challenging amine sources to explore the chemical space of Lewis acid-catalyzed condensation-based transformations with furfural. In this work, we report the efficient synthesis of trans-4,5-diamino cyclopentenones (DCP) using a high-pressure promoted Nazarov-like electrocyclization of Stenhouse salts arising from the Sc(III)-catalyzed condensation of furfural with secondary electron-poor anilines. The reaction enables access to otherwise difficult-to-access DCP and compatibility with a large scope of alkyl and aryl secondary amines. A 2- to 18-fold increase in yields for electron-poor anilines was highlighted using this approach in the synthesis of a pharmacologically active compound.

Ecotoxicological assessment of biomass-derived furan platform chemicals using aquatic and terrestrial bioassays.

An environmental toxicological assessment of fourteen furanic compounds serving as valuable building blocks produced from biomass was performed. The molecules selected included well studied compounds serving as control examples to compare the toxicity exerted against a variety of highly novel furans which have been additionally targeted as potential or current alternatives to biofuels, building blocks and polymer monomers. The impact of the furan platform chemicals targeted on widely applied ecotoxicity model organisms was determined employing the marine bioluminescent bacterium Aliivibrio fischeri and the freshwater green microalgae Raphidocelis subcapitata, while their ecotoxicity effects on plants were assessed using dicotyledonous plants Sinapis alba and Lepidium sativum. Regarding the specific endpoints evaluated, the furans tested were slightly toxic or practically nontoxic for A. fischeri following 5 and 15 min of exposure. Moreover, most of the building blocks did not affect the growth of L. sativum and S. alba at 150 mg L-1 for 72 h of exposure. Specifically, 9 and 11 out of the 14 furan platform chemicals tested were non-effective or stimulant for L. sativum and S. alba respectively. Given that furans comprise common inhibitors in biorefinery fermentations, the growth inhibition of the specific building blocks was studied using the industrial workhorse yeast Saccharomyces cerevisiae, demonstrating insignificant inhibition on eukaryotic cell growth following 6, 12 and 16 h of exposure at a concentration of 500 mg L-1. The study provides baseline information to unravel the ecotoxic effects and to confirm the green aspects of a range of versatile biobased platform molecules.

Preparation of Aminals under Continuous Flow Conditions.

A laboratory experiment was developed for the continuous flow preparation of an aminal derived from the condensation of furfural with morpholine. The experiment introduces the students to concepts of green chemistry, heterogeneous catalysis, and continuous flow. A cheap and easy setup allows the heterogeneous catalyst reactor to be built in class. The use of furfural reinforces the importance of green chemistry by using one of the key synthons obtained from biomass.

Unlocking the Potential of Bio-Based Nitrogen-Rich Furanic Platforms as Biomass Synthons.

The demand for new biomass-derived fine and commodity chemicals propels the discovery of new methodologies and synthons. Whereas furfural and 5-hydroxymethylfurfural are cornerstones of sustainable chemistry, 3-acetamido-5-acetyl furan (3A5AF), an N-rich furan obtained from chitin biomass, remains unexplored, due to the poor reactivity of the acetyl group relative to previous furanic aldehydes. Here we developed a reactive 3-acetamido-5-furfuryl aldehyde (3A5F) and demonstrated the utility of this synthon as a source of bio-derived nitrogen-rich heteroaromatics, carbocycles, and as a bioconjugation reagent.

Orthogonally Protected Diaminocyclopentenones as Synthons: Total Synthesis of (±)-Agelastatin A.

Natural products containing aminocyclopentanes are common secondary metabolites, often biologically active. This work aims at the preparation of a useful synthon for total synthesis containing orthogonally protected amines. To this end, furfural and two amines were employed to form mixed trans-4,5-diaminocyclopentenones promoted by Cu(OTf)2. The selected amines can be orthogonally deprotected, allowing selective modification of the amines on the cyclopentane core. Their utility was showcased for the total synthesis of highly complex (±)-Agelastatin A.

Functionalized Cyclopentenones with Low Electrophilic Character as Anticancer Agents.

In this study were synthesized non-Michael acceptor cyclopentenones (CP) from biomass derivative furfural as anticancer agents. Cyclic enones, both from natural sources and synthetic analogues, have been described as cytotoxic agents. Most of these agents were unsuccessful in becoming valuable therapeutic agents due to toxicity problems derived from unselective critical biomacromolecule alkylation. This may be caused by Michael addition to the enone system. Ab initio studies revealed that 2,4-substituted CPs are less prone to Michael additions, and as such were tested three families of those derivatives. We prepare the new CPs from furfural through a tandem furan ring opening/Nazarov electrocyclization and further functionalization. Experimentally the 2,4-substituted CPs exhibited no reactivity towards sulphur nucleophiles, while maintaining cytotoxicity against HT-29, MCF-7, NCI-H460, HCT-116 and MDA-MB 231 cells lines. Moreover, the selected CP are non-toxic against healthy HEK 293T cell lines and present proper calculated drug-like properties.

Functionalized Cyclopentenes via the Formal [4+1] Cycloaddition of Photogenerated Siloxycarbenes from Acyl Silanes.

This work describes the first formal cycloaddition reaction of photogenerated nucleophilic carbenes derived from acylsilanes with electrophilic dienes. The resulting transient donor-acceptor cyclopropane rearranges to its stable and highly functionalized cyclopentene isomer in an unprecedented metal-free process. The cyclopropanation-vinyl cyclopropane rearrangement sequence was corroborated by computational calculations. The cyclopropane formation corresponds to a higher energetic barrier, and the vinylcyclopropane-cyclopentene rearrangement proceeds through different mechanisms, although of comparable energies, depending on the stereochemistry of the cyclopropane.

Preparation of Thioaminals in Water.

The presence of sulfur-carbon bonds is transversal to several areas of chemistry, e.g., drug discovery, materials, and chemical biology. However, a lack of efficient and sustainable procedures for the preparation of thioaminals, the N,S-analogues of O,O-acetals, contributes to this functional group often being overlooked by the scientific community. In this work is described the formation of thioaminals in water promoted by copper(II) triflate.

Tandem Thio-Michael Addition/Remote Lactone Activation of 5-Hydroxymethylfurfural-Derived δ-Lactone-Fused Cyclopentenones.

The creation of structurally diverse chemical entities from fairly simple biorefinery products remains a challenge. In this work 5-hydroxymethylfurfural (HMF) was identified as a key synthon for preparing highly complex cyclopentenones (CP) via tandem 1,4-addition/elimination/remote lactone activation to external O- and N-nucleophiles in δ-lactone-fused-CPs hotspots. This scaffold was also reactive enough to be incorporated into model cysteine-peptides in low concentrations, paving the way to a potential translation generating complexity in the synthesis of small peptides. The new enones also exhibited activity against intraerythrocytic Plasmodium falciparum (IC50 =1.32 µm).

Functionalized Cyclopentenones and an Oxime Ether as Antimicrobial Agents.

Several naturally occurring cyclopentenones, such as palmenones and nigrosporiones, exhibit antimicrobial activity. Herein we describe the antimicrobial activity of cyclopentenones and derivatives that can be easily accessed from biomass derivatives furfural and 5-hydroxymethylfurfural. Upon screening a range of functionalized trans-diamino-cyclopentenones (DCPs) and δ-lactone-fused cyclopentenones (LCPs), an oxime ether derivative of DCP was identified that exhibited remarkable antimicrobial activity against Gram-positive bacteria, including resistant strains such as methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE) strains.

Recent Advances on Diels-Alder-Driven Preparation of Bio-Based Aromatics.

The preparation of high value-added chemicals from renewable resources is a crucial approach towards a sustainable economy. One prominent alternative to the production of petroleum-based chemicals from fossil resources is through the sequential Diels-Alder/aromatization reactions of biomass-derived furan platforms. This Concept is focused on the recent boom in bio-based furan DA strategies for aromatization of bio-based platform chemicals, particularly that of furfurals, ranging from indirect use and activation strategies to recent examples of direct DA reaction of these electron-withdrawing biomass-derived furans.

MedChemTrain e-School 2020: Event Highlights and Insights into Virtual Symposium Organization.

Virtual events are flourishing with the world lockdown due to the COVID-19 pandemic. As a result of the cancelation or postponement of scheduled physical meetings, a revolution in medicinal chemistry scientific meetings occurred, leading to an increase in new strategies to share science. One example are online events, namely e-schools or webinars. Taking this into consideration, we decided to promote the MedChemTrain e-School 2020, a virtual event aiming to bring together the scientific community and share some updates in the medicinal chemistry field. After organizing this free event, with more than 1.4 thousand participants worldwide, we decided to share some insights about the logistics behind organizing a virtual symposium to help scientists with this new challenge in science communication.

Direct Conversion of Activated 5-Hydroxymethylfurfural into δ-Lactone-Fused Cyclopentenones.

Valorization of biomass derived feedstock (e.g., 5-hydroxymethylfurfural platform) is a very active field of chemical research. In this study, 5-hydroxymethylfurfural is converted into cyclopenten-2-ones by virtue of furfural's activation and Meldrum's acid's tendency to undergo decomposition/esterification. Experimental and computational studies suggest a domino rearrangement-lactonization reaction involving BINOL-catalyzed lactonization as the rate-determining step. The novel lactone-fused cyclopenten-2-ones, which bear a quaternary carbon and resemble a didemnenone natural product structure, are converted into several derivatives with potential interest for the fields of synthetic and medicinal chemistry.

Valorization of Oleuropein via Tunable Acid-Promoted Methanolysis.

The acid-promoted methanolysis of oleuropein was studied using a variety of homogeneous and heterogeneous acid catalysts. Exclusive cleavage of the acetal bond between the glucoside and the monoterpene subunits or further hydrolysis of the hydroxytyrosol ester and subsequent intramolecular rearrangement were observed upon identification of the most efficient catalyst and experimental conditions. Furthermore, selected conditions were tested using oleuropein under continuous flow and using a crude mixture extracted from olive leaves under batch. Formation of (-)-methyl elenolate was also observed in this study, which is a reported precursor for the synthesis of the antihypertensive drug (-)-ajmalicine.

Going Beyond the Limits of the Biorenewable Platform: Sodium Dithionite-Promoted Stabilization of 5-Hydroxymethylfurfural.

The lack of thermal and storage stability and occurrence of side reactions during the processing of 5-hydroxymethylfurfural (5-HMF) limits its potential as biorenewable platform molecule. The addition of small amounts of the readily available sodium dithionite has a remarkable effect on promoting the stability of 5-HMF and inhibiting side reactions, thus helping to circumvent such limitations. The addition of sodium dithionite led to improvements in thermal stability (120 °C, 4 h, neat; 100 % vs. 37 %), under distillation (yield: 85 % vs. 52 %), and in a wide range of reactions, including 5-HMF synthesis under biphasic conditions (yield: 98 % vs. 67 %; purity: 92 % vs. 83 %) and 5-HMF transformations, such as Knoevenagel condensation with Meldrum's acid (yield: 96 % vs. 74 %), Cannizaro reaction (yield: quantitative vs. 83 %), and condensation with primary diamines to give pyridinium salts (yield: 88 % vs. 60 %).

Synthesis and Applications of Stenhouse Salts and Derivatives.

In recent years, Stenhouse salts have attracted much attention as intermediates for the synthesis of cyclopenten-2-enones. This Minireview aims to present an overview of the methods for preparation, further transformation and applications of Stenhouse and Stenhouse-like salts. In this context, the Piancatelli rearrangement and its variants, and the recently reported donor-acceptor Stenhouse salts (DASA) will be addressed. The photophysical properties of DASA and its applications in colorimetric detection of amines, functionalization of polymers for detection of heat and nerve agents, photolithography and orthogonal photoswitching systems are discussed.

Copper(II) Triflate As a Reusable Catalyst for the Synthesis of trans-4,5-Diamino-cyclopent-2-enones in Water.

trans-4,5-Diamino-cyclopent-2-enones (CP) are usually prepared by Lewis acid-catalyzed condensation of furfural and a secondary amine in an organic solvent. The reaction proceeds through the formation of a Stenhouse salt (SS) intermediate followed by an electrocyclization reaction to afford the desired CP. Herein, we described the use of Cu(OTf)2 as a very efficient catalyst for the synthesis of CP in water at room temperature. Furthermore, the mild reaction conditions, catalyst reusability, and outstanding functional group tolerance suggest that this CP platform can be further used in chemical biology.

Synthesis of Symmetric Bis(N-alkylaniline)triarylmethanes via Friedel-Crafts-Catalyzed Reaction between Secondary Anilines and Aldehydes.

The first general protocol for the preparation of symmetric triarylmethanes bearing secondary anilines by ytterbium-catalyzed Friedel-Crafts reaction of hetero(aryl) aldehydes and secondary anilines is reported. Mechanistic studies indicated that the iminium ion intermediate is the electrophilic partner. The reaction is greatly accelerated by high pressure (9 kbar) and showed a broad substrate scope on the hetero(aryl) aldehyde. The new triarylmethanes exhibited activity against HT-29 cancer cell lines, with the best result scoring an IC50 of 1.74 µM.