Biocatalysis in Non-Conventional Media: Unlocking the Potential for Sustainable Chiral Amine Synthesis.

The application of biocatalysis has become essential in both academic and industrial domains for the asymmetric synthesis of chiral amines, and it serves as an alternative tool to transition-metal catalysis and complements traditional chemical methods. It relies on the swift expansion of available processes, primarily as a result of advanced tools for enzyme discovery, combined with high-throughput laboratory evolution techniques for optimising biocatalysts. This manuscript highlights recent chemical and technological developments contributing to the sustainable applications of biocatalysis with industrial interest. Specifically, the use of non-conventional reaction media and the combination with photocatalysis can enhance production of chiral amines by allowing higher working concentrations and cascade transformations, leading to high yields and enantiomeric excesses. Furthermore, a selection of both known and modern strategies for enzyme immobilisation, along with the use of fed-batch and flow synthesis, demonstrates the potential to translate laboratory synthesis to effective scaled-up applications and improve the processing of large reaction volumes.

Wittig Reaction in Deep Eutectic Solvents: Expanding the DES Toolbox in Synthesis.

Wittig reaction between substituted phosphonium salts and (hetero)aromatic and alkyl carbonyl compounds in Deep Eutectic Solvents has been developed under a scalable and friendly protocol. Highly efficient reactions were successfully run with a wide range of bases including organic (DBU, LiTMP, t-BuOK) and inorganic (NaOH, Na2CO3, K2CO3) ones in ChCl/Gly 1:2 (mol/mol) as solvent under mild conditions, at room temperature and under air. The proposed protocol was applied to a wide range of substrates, including (hetero)aromatic aldehydes with substituents as halogens (I, Br, Cl), EDG (alkoxy, methyl), EWG (NO2, CF3) or reactive groups as CN, esters, and ketones. Vinylic, alkynyl and cycloalkyl, alicyclic and α,ß-unsaturated aldehydes can also be used. Highly electrophilic ketones gave good yields. The diastereoselectivity of the reaction is in complete agreement with the E/Z ratio observed under traditional conditions. We demonstrated that the reaction is scalable to 2 g (5 mmol) of phosphonium salt, furthermore the proposed workup protocol allows to remove TPPO without need of additional chromatographic purification.

Antiherpetic Activity of a Root Exudate from Solanum lycopersicum.

The rise of drug resistance to antivirals poses a significant global concern for public health; therefore, there is a pressing need to identify novel compounds that can effectively counteract strains resistant to current antiviral treatments. In light of this, researchers have been exploring new approaches, including the investigation of natural compounds as alternative sources for developing potent antiviral therapies. Thus, this work aimed to evaluate the antiviral properties of the organic-soluble fraction of a root exudate derived from the tomato plant Solanum lycopersicum in the context of herpesvirus infections. Our findings demonstrated that a root exudate from Solanum lycopersicum exhibits remarkable efficacy against prominent members of the family Herpesviridae, specifically herpes simplex virus type 1 (HSV-1) (EC50 25.57 µg/mL, SI > 15.64) and human cytomegalovirus (HCMV) (EC50 9.17 µg/mL, SI 32.28) by inhibiting a molecular event during the herpesvirus replication phase. Moreover, the phytochemical fingerprint of the Solanum lycopersicum root exudate was characterized through mass spectrometry. Overall, these data have unveiled a novel natural product with antiherpetic activity, presenting a promising and valuable alternative to existing drugs.

Asymmetric Reduction of Cyclic Imines by Imine Reductase Enzymes in Non-Conventional Solvents.

The first enantioselective reduction of 2-substituted cyclic imines to the corresponding amines (pyrrolidines, piperidines, and azepines) by imine reductases (IREDs) in non-conventional solvents is reported. The best results were obtained in a glycerol/phosphate buffer 1 : 1 mixture, in which heterocyclic amines were produced with full conversions (>99 %), moderate to good yields (22-84 %) and excellent S-enantioselectivities (up to >99 % ee). Remarkably, the process can be performed at a 100 mM substrate loading, which, for the model compound, means a concentration of 14.5 g L-1 . A fed-batch protocol was also developed for a convenient scale-up transformation, and one millimole of substrate 1 a was readily converted into 120 mg of enantiopure amine (S)-2 a with a remarkable 80 % overall yield. This aspect strongly contributes to making the process potentially attractive for large-scale applications in terms of economic and environmental sustainability for a good number of substrates used to produce enantiopure cyclic amines of high pharmaceutical interest.

Strigolactones as Broad-Spectrum Antivirals against ß-Coronaviruses through Targeting the Main Protease Mpro.

The current SARS-CoV-2 pandemic and the likelihood that new coronavirus strains will emerge in the immediate future point out the urgent need to identify new pan-coronavirus inhibitors. Strigolactones (SLs) are a class of plant hormones with multifaceted activities whose roles in plant-related fields have been extensively explored. Recently, we proved that SLs also exert antiviral activity toward herpesviruses, such as human cytomegalovirus (HCMV). Here we show that the synthetic SLs TH-EGO and EDOT-EGO impair ß-coronavirus replication including SARS-CoV-2 and the common cold human coronavirus HCoV-OC43. Interestingly, in silico simulations suggest the binding of SLs in the SARS-CoV-2 main protease (Mpro) active site, and this was further confirmed by an in vitro activity assay. Overall, our results highlight the potential efficacy of SLs as broad-spectrum antivirals against ß-coronaviruses, which may provide the rationale for repurposing this class of hormones for the treatment of COVID-19 patients.

One-Pot, Telescoped Alkenylation of Amides via Stable Tetrahedral Intermediates as Lithium Enolate Precursors.

A mild and efficient telescoped procedure for the stereoselective alkenylation of simple, non-activated amides using LiCH2SiMe3 and carbonyl compounds as surrogates of alkenyllithium reagents is reported. Our methodology relies on the formation of stable tetrahedral intermediates, which, upon collapse into highly reactive lithium enolates in a solvent-dependent fashion, allows for the assembly of α,ß-unsaturated ketones in a single synthetic operation with high stereoselectivity.

Efficient and Low-Impact Acetalization Reactions in Deep Eutectic Solvents.

The synthesis of acetals in acidic natural deep eutectic solvents (NADES), in which the solvent itself participates in the catalytic promotion of the reaction, is reported herein. The reaction is performed under feasible conditions, open air, without the need of external additives, catalysts or water-removing techniques, and it is wide in scope. The products are easily recovered, and the reaction medium is fully recycled and reused without weakening of its catalytic activity after 10 times. Remarkably, the entire process has been realized on gram scale.

A Mild, Efficient and Sustainable Tetrahydropyranylation of Alcohols Promoted by Acidic Natural Deep Eutectic Solvents.

A straightforward protocol to promote the tetrahydropyranylation of alcohols, using for the first time bioinspired acidic natural deep eutectic solvents (NADESs) as non-innocent reaction media under mild reaction conditions, was reported. This approach enables the preparation of several tetrahydropyranyl (THP) ethers starting from primary, secondary and tertiary alcohols in short reaction times and with high levels of chemoselectivity, working under air and without the need of additional catalyst. The sustainability of the methodology was further highlighted by its scalability and the easy recyclability of the NADES, allowing multigram preparations of THP ethers without any loss of the catalytic activity of the reaction media up to ten recycling steps. Telescoped, one-pot tetrahydropyranylation/nucleophilic acyl substitution transformations using the same eutectic mixture were also demonstrated.

Design of a New Chiral Deep Eutectic Solvent Based on 3-Amino-1,2-propanediol and Its Application in Organolithium Chemistry.

A chiral glycerol derivative, namely 3-amino-1,2-propanediol, was employed for as the hydrogen bond donor (HBD) in the design of a new deep eutectic solvent (DES) with choline chloride acting as the hydrogen bond acceptor (HBA). The novel mixture was characterized and unambiguously classified as a DES. Furthermore, its synthetic usefulness was demonstrated in the room-temperature n-butyllithium-addition under air to carbonyl compounds and benzyl chloride. In some cases, pure products (100% conversion) were obtained by a simple extractive work-up in up to 72% isolated yield, thus suggesting the potential practical usefulness of this procedure as a green alternative to the classical Schenk procedure in volatile organic solvents for the synthesis of tertiary alcohols. The chirality of the HBD, bearing an interesting basic primary amino group, is an intriguing feature currently under investigation for further exploitation.

Enhanced and specific epoxidation activity of P450 BM3 mutants for the production of high value terpene derivatives.

Terpenes are natural molecules of valuable interest for different industrial applications. Cytochromes P450 enzymes can functionalize terpenoids to form high value oxidized derivatives in a green and sustainable manner, representing a valid alternative to chemical catalysis. In this work, an enhanced and specific epoxidation activity of cytochrome P450 BM3 mutants was found for the terpenes geraniol and linalool. This is the first report showing the epoxidation of linalool by P450 BM3 and its mutant A2 (Asp251Gly/Gln307His) with the formation of valuable oxide derivatives, highlighting the relevance of this enzymes for industrial applications.

Chemo- and Regioselective Anionic Fries Rearrangement Promoted by Lithium Amides under Aerobic Conditions in Sustainable Reaction Media.

A straightforward and efficient protocol to promote the metalation/anionic Fries rearrangements of O-aryl carbamates, using for the first time a lithium amide as metalating agent under aerobic/ambient-friendly reaction conditions, is reported. This approach enables the sustainable preparation of salicylamide derivatives with high levels of chemoselectivity within ultrafast reaction times, working at room temperature in the presence of air/moisture, and using environmentally responsible cyclopentyl methyl ether as a solvent. Furthermore, the regioselective manipulation of O-2-tolyl carbamates has been accomplished using interchangeably alkyllithiums or lithium amides, with an unexpected beneficial contribution from the employment of biorenewable protic eutectic mixtures as non-innocent reaction media.

Promising Technological and Industrial Applications of Deep Eutectic Systems.

Deep Eutectic Systems (DESs) are obtained by combining Hydrogen Bond Acceptors (HBAs) and Hydrogen Bond Donors (HBDs) in specific molar ratios. Since their first appearance in the literature in 2003, they have shown a wide range of applications, ranging from the selective extraction of biomass or metals to medicine, as well as from pollution control systems to catalytic active solvents and co-solvents. The very peculiar physical properties of DESs, such as the elevated density and viscosity, reduced conductivity, improved solvent ability and a peculiar optical behavior, can be exploited for engineering modular systems which cannot be obtained with other non-eutectic mixtures. In the present review, selected DESs research fields, as their use in materials synthesis, as solvents for volatile organic compounds, as ingredients in pharmaceutical formulations and as active solvents and cosolvents in organic synthesis, are reported and discussed in terms of application and future perspectives.

Extraction of short chain chitooligosaccharides from fungal biomass and their use as promoters of arbuscular mycorrhizal symbiosis.

Short chain chitooligosaccharides (COs) are chitin derivative molecules involved in plant-fungus signaling during arbuscular mycorrhizal (AM) interactions. In host plants, COs activate a symbiotic signalling pathway that regulates AM-related gene expression. Furthermore, exogenous CO application was shown to promote AM establishment, with a major interest for agricultural applications of AM fungi as biofertilizers. Currently, the main source of commercial COs is from the shrimp processing industry, but purification costs and environmental concerns limit the convenience of this approach. In an attempt to find a low cost and low impact alternative, this work aimed to isolate, characterize and test the bioactivity of COs from selected strains of phylogenetically distant filamentous fungi: Pleurotus ostreatus, Cunninghamella bertholletiae and Trichoderma viride. Our optimized protocol successfully isolated short chain COs from lyophilized fungal biomass. Fungal COs were more acetylated and displayed a higher biological activity compared to shrimp-derived COs, a feature that-alongside low production costs-opens promising perspectives for the large scale use of COs in agriculture.

A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects.

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over-addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale-up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre-activated amides, as recommended.

Optimization of Nazarov Cyclization of 2,4-Dimethyl-1,5-diphenylpenta-1,4-dien-3-one in Deep Eutectic Solvents by a Design of Experiments Approach.

The unprecedented Nazarov cyclization of a model divinyl ketone using phosphonium-based Deep Eutectic Solvents as sustainable non-innocent reaction media is described. A two-level full factorial Design of Experiments was conducted for elucidating the effect of the components of the eutectic mixture and optimizing the reaction conditions in terms of temperature, time, and substrate concentration. In the presence of the Deep Eutectic Solvent (DES) triphenylmethylphosphonium bromide/ethylene glycol, it was possible to convert more than 80% of the 2,4-dimethyl-1,5-diphenylpenta-1,4-dien-3-one, with a specific conversion, into the cyclopentenone Nazarov derivative of 62% (16 h, 60 °C). For the reactions conducted in the DES triphenylmethylphosphonium bromide/acetic acid, quantitative conversions were obtained with percentages of the Nazarov product above 95% even at 25 °C. Surface Responding Analysis of the optimized data furnished a useful tool to determine the best operating conditions leading to quantitative conversion of the starting material, with complete suppression of undesired side-reactions, high yields and selectivity. After optimization, it was possible to convert more than 90% of the model substrate into the desired cyclopentenone with cis percentages up to 77%. Experimental validation of the implemented model confirmed the robustness and the suitability of the procedure, leading to possible further extension to this specific combination of experimental designs to other substrates or even to other synthetic processes of industrial interest.

Strigolactone Analogs Are Promising Antiviral Agents for the Treatment of Human Cytomegalovirus Infection.

The human cytomegalovirus (HCMV) is a widespread pathogen and is associated with severe diseases in immunocompromised individuals. Moreover, HCMV infection is the most frequent cause of congenital malformation in developed countries. Although nucleoside analogs have been successfully employed against HCMV, their use is hampered by the occurrence of serious side effects. There is thus an urgent clinical need for less toxic, but highly effective, antiviral drugs. Strigolactones (SLs) are a novel class of plant hormones with a multifaceted activity. While their role in plant-related fields has been extensively explored, their effects on human cells and their potential applications in medicine are far from being fully exploited. In particular, their antiviral activity has never been investigated. In the present study, a panel of SL analogs has been assessed for antiviral activity against HCMV. We demonstrate that TH-EGO and EDOT-EGO significantly inhibit HCMV replication in vitro, impairing late protein expression. Moreover, we show that the SL-dependent induction of apoptosis in HCMV-infected cells is a contributing mechanism to SL antiviral properties. Overall, our results indicate that SLs may be a promising alternative to nucleoside analogs for the treatment of HCMV infections.

Lateral lithiation in deep eutectic solvents: regioselective functionalization of substituted toluene derivatives.

The heteroatom-directed lateral lithiation of functionalized toluenes in a choline chloride-based eutectic mixture is reported. The metalations proceed within ultrafast reaction times, with a broad substrate and electrophile scope. The directing groups provide a rapid and high regioselective access to functionalized aromatic derivatives of remarkable synthetic value.

Combination of PDT and NOPDT with a Tailored BODIPY Derivative.

The engineering of photosensitizers (PS) for photodynamic therapy (PDT) with nitric oxide (NO) photodonors (NOPD) is broadening the horizons for new and yet to be fully explored unconventional anticancer treatment modalities that are entirely controlled by light stimuli. In this work, we report a tailored boron-dipyrromethene (BODIPY) derivative that acts as a PS and a NOPD simultaneously upon single photon excitation with highly biocompatible green light. The photogeneration of the two key species for PDT and NOPDT, singlet oxygen (1O2) and NO, has been demonstrated by their direct detection, while the formation of NO is shown not to be dependent on the presence of oxygen. Biological studies carried out using A375 and SKMEL28 cancer cell lines, with the aid of suitable model compounds that are based on the same BODIPY light harvesting core, unambiguously reveal the combined action of 1O2 and NO in inducing amplified cancer cell mortality exclusively under irradiation with visible green light.

Directed ortho-metalation-nucleophilic acyl substitution strategies in deep eutectic solvents: the organolithium base dictates the chemoselectivity.

Directed ortho metalation (DoM) or nucleophilic acyl substitution (SNAc) can be efficiently programmed on the same aromatic carboxylic acid amide, in a choline chloride-based eutectic mixture, by simply switching the nature of the organolithium reagent. Telescoped, one-pot ortho-lithiation/Suzuki-Miyaura cross-couplings have also been demonstrated for the first time in Deep Eutectic Solvents.

Correction to "Light-Regulated NO Release as a Novel Strategy To Overcome Doxorubicin Multidrug Resistance".

[This corrects the article DOI: 10.1021/acsmedchemlett.7b00016.].