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The design of a hybrid one-pot tandem protocol through the combination of biodeoximations (promoted by laccase from Trametes versicolor) and s-block polar organometallics (RLi/RMgX) in aqueous media, at room temperature and under air is reported.

Addition of lithium amides (LiNR2) to carbodiimides/nitriles was achieved in sustainable solvents, under air, allowing the synthesis of guanidines/amidines.

University of Bari "Aldo Moro" [2017A5HXFC 002, 2020SBNHLH]; Interuniversity Consortium C.I.N.M.P.I.S. [2017A5HXFC 002, 2020SBNHLH]; Ministero dell'Universita e della Ricerca (MUR-PRIN) [2017A5HXFC 002, 2020SBNHLH]; MCIN/AEI [PID2020-113473GB I00]; Programa Severo Ochoa para la formación en investigación y docencia del Principado de Asturias [PA-21-PF-BP20-093, PA-22-PF-BP21-088]

Fast addition of highly polar organometallic reagents (RMgX/RLi) to cyclic carbonates (derived from CO2 as a sustainable C1 synthon) has been studied in 2-methyltetrahydrofuran as a green reaction medium or in the absence of external volatile organic solvents, at room temperature, and in the presence of air/moisture. These reaction conditions are generally forbidden with these highly reactive main-group organometallic compounds. The correct stoichiometry and nature of the polar organometallic alkylating or arylating reagent allows straightforward synthesis of: highly substituted tertiary alcohols, β-hydroxy esters, or symmetric ketones, working always under air and at room temperature. Finally, an unprecedented one-pot/two-step hybrid protocol is developed through combination of an Al-catalyzed cycloaddition of CO2 and propylene oxide with the concomitant fast addition of RLi reagents to the in situ and transiently formed cyclic carbonate, thus allowing indirect conversion of CO2 into the desired highly substituted tertiary alcohols without need for isolation or purification of any reaction intermediates.

Highly-efficient and selective one-pot/two-step modular double addition of different highly polar organometallic reagents (RLi/RMgX) to nitriles en route to asymmetric tertiary alcohols (without the need for isolation/purification of any halfway reaction intermediate) has been studied, for the first time, in the absence of external/additional organic solvents (neat conditions), at room temperature and under air/moisture (no protecting atmosphere is required), which are generally forbidden reaction conditions in the field of highly-reactive organolithium/organomagnesium reagents. The one-pot modular tandem protocol demonstrated high chemoselectivity with a broad range of nitriles, as no side reactions (Li/halogen exchange, ortho-lithiations or benzylic metalations) were detected. Finally, this protocol could be scaled up, thus proving that this environmentally friendly methodology is amenable for a possible applied synthesis of asymmetric tertiary alcohols under bench type reaction conditions and in the absence of external organic solvents.

Ministerio de Economía y Competitividad [RED2018-102387-T]; Agencia Estatal de Investigación [PID2019-104652GB-I00, PID2020-113473GB-I00]; Programa Severo Ochoa para la formación en investigación y docencia del Principado de Asturias [PA-21-PF-BP20-093]

The one-pot/two-step combination of enzymes and polar organometallic chemistry in aqueous media is for the first time presented as a proof-of-concept study. The unprecedented combination of the catalytic oxidation of secondary alcohols by the system laccase/TEMPO with the ultrafast addition (3 s reaction time) of polar organometallic reagents (RLi/RMgX) to the in situ formed ketones, run under air at room temperature, allows the straightforward and chemoselective synthesis of tertiary alcohols with broad substrate scope and excellent conversions (up to 96%).

Highly polarized organometallic compounds of s-block elements are added smoothly to chiral N-tert-butanesulfinyl imines in the biodegradable d-sorbitol/choline chloride eutectic mixture, thereby granting access to enantioenriched primary amines after quantitatively removing the sulfinyl group. The practicality of the method is further highlighted by proceeding at ambient temperature and under air, with very short reaction times (2 min), enabling the preparation of diastereoisomeric sulfinamides in very good yields (74-98 %) and with a broad substrate scope, and the possibility of scaling up the process. The method is demonstrated in the asymmetric syntheses of both the chiral amine side-chain of (R,R)-Formoterol (96 % ee) and the pharmaceutically relevant (R)-Cinacalcet (98 % ee).

An efficient and novel protocol was developed for a Cu-catalyzed Ullmann-type aryl alkyl ether synthesis by reacting various (hetero)aryl halides (Cl, Br, I) with alcohols as active components of environmentally benign choline chloride-based eutectic mixtures. Under optimized conditions, the reaction proceeds under mild conditions (80 °C) in air, in the absence of additional ligands, with a catalyst [Cu(I) or Cu(II) species] loading up to 5 mol% and K 2 CO 3 as the base, providing the desired aryloxy derivatives in up to 98% yield. The potential application of the methodology is demonstrated in the valorization of cheap, easily available, and naturally occurring polyols (e.g., glycerol) for the synthesis of some pharmacologically active aryloxypropanediols (Guaiphenesin, Mephenesin and Chlorphenesin) on a 2-gram scale in 70-96% yield. The catalyst, the base, and the DES could easily and successfully be recycled up to seven times with an E-factor as low as 5.76.

A tandem protocol to access tertiary alcohols has been developed which combines the organocatalytic oxidation of secondary alcohols to ketones followed by their chemoselective addition by several RLi reagents. Reactions take place at room temperature, under air and in aqueous solutions, a trio of conditions that are typically forbidden in polar organometallic chemistry.

S.E.G.-G. and J.G.A thank the Spanish MINECO and MIC (Project PID2020-113473GB-I00). J.G.-A. thanks: i) the Fundación BBVA for the award of a “Beca Leonardo a Investigadores y Creadores Culturales 2017”; and ii) PhosAgro/UNESCO/IUPAC for the award of a “Green Chemistry for Life Grant”. A.P.S is indebted to Spanish MINECO (Project CTQ2014-56345-P, CTQ2017-88357-P, and RYC-2012-09800), and Gobierno del Principado de Asturias (FICYT, Project FC-15-GRUPIN14-106) for financial support. E.H. acknowledges the SNF (188573) and the EPSRC (EP/S020837/2) for their generous financial support

An efficient and selective N-functionalization of amides is first reported via a CuI-catalyzed Goldberg-type C–N coupling reaction between aryl iodides and primary/secondary amides run either in Deep Eutectic Solvents (DESs) or water as sustainable reaction media, under mild and bench-type reaction conditions (absence of protecting atmosphere). Higher activities were observed in an aqueous medium, though the employment of DESs expanded and improved the scope of the reaction to include also aliphatic amides. Additional valuable features of the reported protocol include: (i) the possibility to scale up the reaction without any erosion of the yield/reaction time; (ii) the recyclability of both the catalyst and the eutectic solvent up to 4 consecutive runs; and (iii) the feasibility of the proposed catalytic system for the synthesis of biologically active molecules.

The Meyer-Schuster rearrangement of propargylic alcohols into α,β-unsaturated carbonyl compounds has been revisited by setting up an atom-economic process catalyzed by a deep eutectic solvent FeCl3·6H2O/glycerol. Isomerizations take place smoothly, at room temperature, under air and with short reaction times. The unique solubilizing properties of the eutectic mixture enabled the use of a substrate concentration up to 1.0 M with the medium being recycled up to ten runs without any loss of catalytic activity.

A straightforward alkali-metal-mediated hydroamination of styrenes using biorenewable 2-methyltetrahydrofuran as a solvent is reported. Refuting the conventional wisdom of the incompatibility of organolithium reagents with air and moisture, shown here is that the presence of moisture is key in favoring formation of the target phenethylamines over competing olefin polymerization products. The method is also compatible with sodium amides, with the latter showing excellent promise as highly efficient catalysts under inert atmosphere conditions.

Atom Transfer Radical Polymerisation (ATRP) is one of the most important techniques to synthesize well-defined polymers with predetermined molecular weight, designed microstructure and tailor-made functionalities. Although ATRP has been extensively studied in a variety of common Volatile Organic Solvents (VOCs) and water, there is significantly less work done using fashionable and environmentally friendly Deep Eutectic Solvents (DESs). Aiming to develop greener ATRP routes by allowing the recycling of the employed transition metal catalyst, we herein present the homogeneous and heterogeneous Cu-catalysed ARGET variation of the ATRP processes using methyl methacrylate (MMA) as the model monomer and a DES as a green solvent. The homogeneous ARGET ATRP was performed employing CuCl2 as a catalyst and FDA-approved tin(II) 2-ethylhexanoate [Sn(EH)2] as a reducing ARGET agent, under an air atmosphere. The polymerisations proceeded in a controlled/“living” fashion according to reversible deactivation radical polymerisation (RDRP) standards. Heterogeneous ARGET ATRP was carried out by using a DES-insoluble Cu(II) Metal–Organic Framework (MOF) as a recyclable catalyst in the absence of organic ligands, employing Sn(EH)2 as a reducing agent, under an air atmosphere. Under these experimental conditions, well-defined poly(methyl methacrylate) (PMMA) was obtained (Đ ≈ 1.2) under controlled RDRP conditions. Importantly, both the MOF catalyst and DES were successfully recycled up to 6 consecutive catalytic cycles to synthesize PMMAs with comparable macromolecular features and yields.

Mixed s-block metal organometallic reagents have been successfully utilised in the catalytic intramolecular hydroalkoxylation of alkynols. This success has been attributed to the unique manner in which these reagents can overcome the challenges of the reaction: namely OH activation and coordination to and then addition across a C≡C bond. In order to optimise the reaction conditions and to garner vital catalytic system requirements, a series of alkali metal magnesiates were enlisted for the catalytic intramolecular hydroalkoxylation of 4-pentynol. In a prelude to the main investigation, the homometallic magnesium dialkyl reagent MgR2 (where R = CH2SiMe3) was utilised. This reagent was unsuccessful in cyclising the alcohol into 2-methylenetetrahydrofuran 2a or 5-methyl-2,3-dihydrofuran 2b, even in the presence of multidentate Lewis donor molecules such as N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDETA). Alkali metal magnesiates MIMgR3 (when MI = Li, Na or K) performed the cyclisation unsatisfactorily both in the absence/presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) or PMDETA. When higher-order magnesiates (i.e., MI2MgR4) were employed, in general a marked increase in yield was observed for MI = Na or K; however, the reactions were still sluggish with long reaction times (22–36 h). A major improvement in the catalytic activity of the magnesiates was observed when the crown ether molecule 15-crown-5 was combined with sodium magnesiate Na2MgR4(TMEDA)2 furnishing yields of 87% with 2a : 2b ratios of 95 : 5 after 5 h. Similar high yields of 88% with 2a : 2b ratios of 90 : 10 after 3 h were obtained combining 18-crown-6 with potassium magnesiate K2MgR4(PMDETA)2. Having optimised these systems, substrate scope was examined to probe the range and robustness of 18-crown-6/K2MgR4(PMDETA)2 as a catalyst. A wide series of alkynols, including terminal and internal alkynes which contain a variety of potentially reactive functional groups, were cyclised. In comparison to previously reported monometallic systems, bimetallic 18-crown-6/K2MgR4(PMDETA)2 displays enhanced reactivity towards internal alkynol-cyclisation. Kinetic studies revealed an inhibition effect of substrate on the catalysts via adduct formation and requiring dissociation prior to the rate limiting cyclisation step.

The combination of the metal-catalyzed cycloisomerization of alkynes containing a tethered nucleophile as substituent in aqueous media (followed by the spontaneous hydrolysis, hydroalkoxylation, or aminolysis of the transiently formed five-membered heterocycles) with the subsequent enantioselective ketone bioreduction (mediated by KREDs) has been achieved. The overall transformations, which formally involve a three-step one-pot reaction, provide a variety of enantiopure valuable molecules (e.g., 1,4-diols, lactones, and γ-hydroxy-carbonyl compounds (carboxylic acids, esters, and amides)) with high conversions and enantioselectivities and under mild reaction conditions, disclosing the concept of integrated metal-catalyzed cycloisomerizations of alkynes and enzymatic catalysis in water.

The synthesis and characterisation of five novel copper (II) complexes incorporating an amido pincer ligand derived from the deprotonation of N-(2-{4,4-dimethyl-4,5-Dihydrooxazol-2-yl}phenyl)picolinamide (i.e., L1H) or a chiral indanol-based congener (L2H) are described. These Cu materials are obtained from the treatment of EtOH solutions of L1H or L2H with CuX2(OH2)n species (X = Cl, Br, NO3, BF4). All of these compounds have been characterised by single crystal X-ray diffraction methods, which confirms a k3-N,N′,N″-binding mode of the formally anionic L1 or L2 displaying an amido N-Cu bond following H+ loss. Complexes of stoichiometry Cu(L1)X (X = Cl [1], Br [2]) are shown to be slightly distorted square planar compounds with an N3X ligand binding set. For X = BF4, the Cu compound retains a coordinated H2O molecule and a non-coordinated BF4 counteranion to form [Cu(L1)(OH2)]BF4·H2O (3). This species demonstrates extended solid-state structure which is likewise detailed. In the case of X = NO3, the isolated species (4) is six-coordinate in nature with a κ2-O,O′-NO3 ligand and a non-coordinated solvent of crystallisation (H2O). This latter species displays a bridged dimeric structure in the solid-state and can alternatively be produced, albeit in reduced yields, from 1 and AgNO3 in wet THF mixtures. A chiral derivative, Cu(L2)Cl (i.e., 5), has also be produced by similar synthetic protocols and structurally elucidated; it displays a solid-state structure somewhat different to that of 1. The catalytic activity of both 1 and 3 was investigated towards C-C bond forming chemistry, notably the Henry (i.e., nitroaldol) reaction and methyl methacrylate polymerisation. Electrochemical investigations of these complexes display irreversible one-electron reduction potentials; a facet which helps to explain their negligible catalytic activity in (presumed) ATRP. However, both 1 and 3 are marginally active in promoting the nitroaldol reaction but the product profile is hampered by both low conversions and the formation of by-product alkenes. In contrast, 1–4 are very effective catalytic promoters of the heteroannulation reaction of 2-iodophenol and phenylacetylene to yield the corresponding 2-phenylbenzofuran in the presence of base.

The self-assembly of styrene-type olefins into the corresponding stilbenes was conveniently performed in the Deep Eutectic Solvent (DES) mixture 1ChCl/2Gly under air and in the absence of hazardous organic co-solvents using a one-pot chemo-biocatalytic route. Here, an enzymatic decarboxylation of p-hydroxycinnamic acids sequentially followed by a ruthenium-catalyzed metathesis of olefins has been investigated in DES. Moreover, and to extend the design of chemoenzymatic processes in DESs, we also coupled the aforementioned enzymatic decarboxylation reaction to now concomitant Pd-catalyzed Heck-type C-C coupling to produce biaryl derivatives under environmentally friendly reaction conditions.

L.C. and J.G.A thank the Spanish MINECO (Project CTQ2016-75986-P and CTQ2016-81797-REDC). A.F. A.S.-C., G.A.C and A.P.Sare indebted to Spanish MINECO (Project CTQ2014-56345-P,CTQ2017-88357-P, and RYC-2012-09800), and Gobierno delPrincipado de Asturias (FICYT, Project FC-15-GRUPIN14-106) forfinancial support. A.P.S. is also grateful to the COST action SmartInorganic Polymers (SIPs-CM1302 – http://www.sips-cost.org/home/index.html), and Spanish MEC for the Juan de la Cierva and Ramón y Cajal programs. J. G.-A. thanks: i) the Fundación BBVAfor the award of a “Beca Leonardo a Investigadores y Creadores Culturales 2017”;[33]and ii) PhosAgro/UNESCO/IUPAC for the awardof a “Green Chemistry for Life Grant”. This work was carried out under the framework of the project “Development of Sustainable Synthetic Processes in Unconventional Solvents for the Preparationof Molecules of Pharmaceutical Interest” realized with the contribution of Fondazione Puglia, which is gratefully acknowledged by L.C. and V.C.

This mini-review presents a general overview of the progress achieved during the last decade on the amalgamation of CuAAC processes (copper-catalyzed azide-alkyne cycloaddition) with the employment of sustainable solvents as reaction media. In most of the presented examples, the use of water, glycerol (Gly), or deep eutectic solvents (DESs) as non-conventional reaction media allowed not only to recycle the catalytic system (thus reducing the amount of the copper catalyst needed per mole of substrate), but also to achieve higher conversions and selectivities when compared with the reaction promoted in hazardous and volatile organic solvents (VOCs). Moreover, the use of the aforementioned green solvents also permits the improvement of the overall sustainability of the Cu-catalyzed 1,3-dipolar cycloaddition process, thus fulfilling several important principles of green chemistry.

New iminophosphorane-phosphine AuI complexes [AuCl(κ1 -P-Ph2 PCH2 P{=NP(=S)(OR)2 }Ph2 )] (3 a,b) and [Au2 Cl2 (μ2 -P,S-Ph2 PCH2 P{=NP(=S)(OR)2 }Ph2 )] (4 a,b) proved to be general, very efficient, and recyclable (up to four consecutive runs) catalysts for the cycloisomerization of alkynyl amides in water or choline chloride-based eutectic mixtures as green solvents. Remarkably, this cycloisomerization reaction took place under mild conditions (low catalyst loading, at room temperature, and in the absence of cocatalysts or protecting atmosphere) to give the corresponding alkylidene lactams by employing an efficient and sustainable methodology.

Efficient catalytic processes employing the bis(allyl)-ruthenium(IV) complexes [{RuCl( μ -Cl)( η 3 : η 3 -C 10 H 16 )} 2 ] (C 10 H 16 = 2,7-dimethylocta-2,6-diene-1,8-diyl), [RuCl 2 ( η 3 : η 2 : η 3 -C 12 H 18 )] (C 12 H 18 = dodeca-2,6,10-triene-1,12-diyl) and [RuCl 2 ( η 3 : η 3 -C 10 H 16 )(L)] (L = neutral 2e − donor ligand) have been developed in our group during the last years, most of them operating in environmentally friendly aqueous media. In this short review a survey of this chemistry is presented.

Ru(IV)-Catalysed redox isomerisation of allylic alcohols has, for the first time, been successfully assembled with the chemoselective addition of organolithium or organomagnesium reagents to the in situ formed ketones, en route to tertiary alcohols, employing deep eutectic solvents as environmentally friendly reaction media. The overall transformation, which formally involves three consecutive and different steps such as (i) the reduction of a C–C double bond, (ii) the oxidation of a secondary carbinol moiety, and (iii) a chemoselective C–C bond formation, takes place in protic and biorenewable eutectic mixtures in a sequential one-pot fashion using a commercially and easily available catalytic system, with excellent conversions (up to 99% yield), at room temperature and under air in the last step, with no concomitant reduction or enolisation processes, and with high atom economy, in agreement with the principles of the so-called green chemistry.

An efficient protocol was developed for the synthesis of tertiary alcohols via nucleophilic addition of organometallic compounds of s-block elements (Grignard and organolithium reagents) to esters performed in the biodegradable choline chloride/urea eutectic mixture or in water. This approach displays a broad substrate scope, with the addition reaction proceeding quickly (20 s reaction time) and cleanly, at ambient temperature and under air, straightforwardly furnishing the expected tertiary alcohols in yields of up to 98%. The practicability of the method is exemplified by the sustainable synthesis of some representative S-trityl- l -cysteine derivatives, which are a potent class of Eg5 inhibitors, also via telescoped one-pot processes.

Despite their ubiquitous presence in synthesis, the use of polar organolithium reagents under environmentally benign conditions constitutes one of the greatest challenges in sustainable chemistry. Their high reactivity imposes the use of severely restrictive protocols (e.g., moisture- and oxygen-free, toxic organic solvents, inert atmospheres, low temperatures, etc.). Making inroads towards meeting this challenge, a new air- and moisture-compatible organolithium-mediated methodology for the anionic polymerization of different olefins (e.g., styrenes and vinylpyridines) was established by pioneering the use of deep eutectic solvents (DESs) as an eco-friendly reaction medium in this type of transformation. Fine-tuning of the conditions (sonication of the reaction mixture at 40 °C in the absence of protecting atmosphere) along with careful choice of components of the DES [choline chloride (ChCl) and glycerol (Gly) in a 1:2 ratio] furnished the desired organic polymers (homopolymers and random copolymers) in excellent yields (up to 90 %) and low polydispersities (IPD 1.1-1.3). Remarkably, the in situ-formed polystyril lithium intermediates exhibited a great resistance to hydrolysis in the eutectic mixture 1ChCl/2Gly (up to 1.5 h), hinting at an unexpected high stability of these otherwise highly reactive organolithium species in these unconventional reaction media. This unique stability can be exploited to create well defined block-copolymers.

Two individual catalytic platforms (metal- and organo-catalyzed) based on the use of an ionic liquid phase were successfully integrated for the synthesis of α-cyano-amine and cyanohydrin trimethylsilyl ethers from allylic alcohol. The right combination of continuous flow processes enabled access to the divergent preparation of two alternative and interesting intermediate compounds from the same starting material.

This microreview is intended to cover the progress made in metal-mediated and metal-catalysed organic reactions performed in a new family of inexpensive, greener and biorenewable eutectic mixtures, the so-called Deep Eutectic Solvents (DESs), as environmentally friendly reaction media. This ambitious research is focused on studies of particular interest in organometallic chemistry, in search of synthetic strategies able to optimise the overall process in an eco-friendly manner. This microreview aims to provide an overview of the application of DESs in the fields of: (i) Ru- and Au-catalysed isomerisation and cycloisomerisation of organic substrates, (ii) Cu-catalysed click chemistry and C–C bond-formation reactions, (iii) Pd-catalysed cross-coupling processes and Tsuji–Trost reactions, (iv) Rh-catalysed hydrogenation and hydroformylation of alkenes, (v) addition of RMgX and RLi compounds to ketones, and (vi) regioselective ortho- and lateral lithiation of aryltetrahydrofurans.

Developing new green solvents in designing chemical products and processes or successfully employing the already existing ones is one of the key subjects in green chemistry and is especially important in organometallic chemistry, which is an interdisciplinary field. Can we advantageously also use unconventional reaction media in place of current harsh organic solvents for polar organometallic compounds? This microreview critically analyses the state of the art with regard to this topic and showcases recent developments and breakthroughs that are becoming new research directions in this field. Because metals cover a vast swath of the Periodic Table the content is organised into three sections discussing the reactivity of organometallic compounds of s-, p- and d-block elements in unconventional solvents.

This work describes the catalytic activity of palladium(II) species in the cycloisomerization of alkynoic acids and their derivatives in aqueous media as well as in Deep Eutectic Solvents (DESs), with one of the lowest metal catalyst loadings reported so far in the literature. Different substrates such as terminal and internal alkynes or alkynyl sulfonylimides were studied, obtaining selectivity either to the cyclic compound or the hydrolysed keto derivative. This new system avoids the use of harmful solvents and employs very efficient and recoverable heterogeneous catalysts. This work was supported by the University of Alicante (UAUSTI16-10, VIGROB-173), and the Spanish Ministerio de Economía, Industria y Competitividad (CTQ2015-66624-P). B. S. thanks the Generalitat Valenciana (ACIF/2017/211) for a fellowship. M. J. R.-A and J. G.-A. are indebted to the MINECO of Spain (CTQ2016-81797-REDC and CTQ2016-75986-P) and the Gobierno del Principado de Asturias (project GRUPIN14-006) for financial support. J. G.-A. thanks the Fundación BBVA for the award of a “Beca Leonardo a Investigadores y Creadores Culturales 2017”.

A dual ruthenium/ketoreductase catalytic system has been developed for the conversion of β‐ketonitriles into optically active β‐hydroxyamides through an unprecedented hydration/bioreduction cascade process in aqueous medium working in concurrent mode. The ketoreductase‐mediated ketone reduction took place with exquisite stereoselectivity and it was simultaneous to the nitrile hydration promoted by the ruthenium catalyst. The overall transformation occurred: (i) employing commercially and readily available catalytic systems (ii) under mild reaction conditions, (iii) with high degree of conversion and excellent stereoselectivity, and (iv) without the need to isolate intermediates and with high final product yields. This genuine process demonstrates the benefits of combining metal and enzymatic catalysis to tackle the limitations arising from each field., We are indebted to the MINECO of Spain (CTQ2013‐40591‐P and CTQ2016‐75986‐P) and the Gobierno del Principado de Asturias (Project GRUPIN14‐006) for financial support. E. Liardo acknowledges funding from the European Union's Horizon 2020 MSCA ITN‐EID program (grant agreement No 634200). The authors also thank Dr. Martin Schürmann (InnoSyn) and Prof. Harald Gröger (Bielefeld University) for the generous gift of the KRED of Rhodococcus ruber and Lactobacillus kefir, respectively.

The first application of Deep Eutectic Solvents (DESs) in the asymmetric bioreduction of ketones has been accomplished for purified ketoreductases (KREDs). The performance of the biocatalysts was enhanced by increasing the percentage of neoteric solvent in DES-buffer mixtures. At a buffer content of 50% (w/w) and even 20% (w/w), the combination of either choline chloride (ChCl)/glycerol (Gly) (1 : 2) or ChCl/sorbitol (1 : 1) proved to be most effective for achieving up to >99% conversion and up to >99% enantiomeric excess of the corresponding secondary alcohols. Moreover, this reaction medium was used to perform the first example of a chemoenzymatic cascade process in DES-buffer mixtures, namely the ruthenium-catalysed isomerisation of racemic allylic alcohols coupled with a further enantioselective bioreduction, in both sequential and concurrent modes.

Cycloisomerisation reactions of (Z)-enynols into furans can be conveniently performed, for the first time, in the eutectic mixture 1ChCl/2Gly as a solvent and under standard bench conditions (at room temperature and under air) by using the new bis(iminophosphorane)–Au(I) complex [Au2Cl2(μ2-S,S-CH2{P(NP(S)(OPh)2)Ph2}2)] as a catalyst. Furthermore, a one-pot tandem reaction involving the fast cycloisomerisation of (Z)-enynols followed by an intermolecular atom economical process, i.e. the Diels–Alder reaction with activated alkynes or alkenes, is reported. This tandem cycloisomerisation/Diels–Alder reaction proceeds also in the eutectic mixture 1ChCl/2Gly, in the absence of co-catalysts and under aerobic conditions, giving rise to the corresponding 7-oxanorbornadienes and 7-oxanorbornenes under the principles of the so-called Green Chemistry.

Edging closer towards developing air and moisture compatible polar organometallic chemistry, the chemoselective and ultrafast addition of a range of aryllithium reagents to nitriles has been accomplished by using glycerol as a solvent, at ambient temperature in the presence of air, establishing a novel sustainable access to aromatic ketones. Addition reactions occur heterogeneously ("on glycerol conditions"), where the lack of solubility of the nitriles in glycerol and the ability of the latter to form strong intermolecular hydrogen bonds seem key to favouring nucleophilic addition over competitive hydrolysis. Remarkably, PhLi exhibits a greater resistance to hydrolysis working "on glycerol" conditions than "on water". Introducing glycerol as a new solvent in organolithium chemistry unlocks a myriad of opportunities for developing more sustainable, air and moisture tolerant main-group-metal-mediated organic synthesis.