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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.

Kaplan-Meier plots

Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myelogenous leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here, we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as PIM kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell-cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared with midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate inhibition of FLT3-STAT5, Akt-mTOR-S6, and PIM-BAD pathways. Oral administration of EC-70124 in FLT3-ITD xenograft models demonstrates high efficacy, reaching complete tumor regression. Ex vivo, EC-70124 impaired cell viability in leukemic blasts, especially from FLT3-ITD patients. Our results demonstrate the ability of EC-70124 to reduce proliferation and induce cell death in AML cell lines, patient-derived leukemic blast and xenograft animal models, reaching best results in FLT3 mutants that carry other molecular pathways' alterations. Thus, its unique inhibition profile warrants EC-70124 as a promising agent for AML treatment based on its ability to interfere the complex oncogenic events activated in AML at several levels. Mol Cancer Ther; 17(3); 614–24. ©2018 AACR.

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).

A series of optically active β-hydroxy sulfones has been obtained through an oxosulfonylation-stereoselective reduction sequence in aqueous medium. Firstly, β-keto sulfones were synthesized from arylacetylenes and sodium sulfinates to subsequently develop the carbonyl reduction in a highly selective fashion using alcohol dehydrogenases as biocatalysts. Optimization of the chemical oxosulfonylation reaction was investigated, finding inexpensive iron(III) chloride hexahydrate (FeCl3 ⋅ 6H2 O) as the catalyst of choice. The selection of isopropanol in the alcohol-water media resulted in high compatibility with the enzymatic process for enzyme cofactor recycling purposes, providing a straightforward access to both (R)- and (S)-β-hydroxy sulfones. The practical usefulness of this transformation was illustrated by describing the synthesis of a chiral intermediate of Apremilast. Interestingly, the development of a chemoenzymatic cascade approach avoided the isolation of β-keto sulfone intermediates, which allowed the preparation of chiral β-hydroxy sulfones in high conversion values (83-94 %) and excellent optical purities (94 to >99 % ee).

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.

The efficient multifunctionalization by one-pot or cascade catalytic systems has developed as an important research field, but is often challenging due to incompatibilities or cross-reactivities of the catalysts leading to side product formation. Herein we report the stereoselective preparation of cis- and trans-4-aminocyclohexanol from the potentially bio-based precursor 1,4-cyclohexanedione. We identified regio- and stereoselective enzymes catalyzing reduction and transamination of the diketone, which can be performed in a one-pot sequential or cascade mode. For this, we identified regioselective keto reductases for the selective mono reduction of the diketone to give 4-hydroxycyclohexanone. The system is modular and by choosing stereocomplementary amine transaminases, both cis- and trans-4-aminocyclohexanol were synthesized with good to excellent diastereomeric ratios. Furthermore, we identified an amine transaminase that produces cis-1,4-cyclohexanediamine with diastereomeric ratios >98 : 2. These examples highlight that the high selectivity of enzymes enable short and stereoselective cascade multifunctionalizations to generate high-value building blocks from renewable starting materials. Introduction

Phenolic acid decarboxylase from Bacillus subtilis (BsPAD) converts several p-hydroxycinnamic acid derivatives into the corresponding p-hydroxystyrenes, which are considered to be promising bio-bas...

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.

Several chemoenzymatic routes have been explored for the preparation of cinacalcet, a calcimimetic agent. Transaminases (TAs) and ketoreductases (KREDs) turned out to be useful biocatalysts for the preparation of key optically active precursors. Thus, the asymmetric amination of 1-acetonaphthone yielded an enantiopure (R)-amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (S)-alcohol, which was easily converted into the previous (R)-amine. In addition, the reduction was efficiently performed with the KRED and its cofactor co-immobilized on the same porous surface. This self-sufficient heterogeneous biocatalyst presented an accumulated total turnover number (TTN) for the cofactor of 675 after 5 consecutive operational cycles. Finally, in a preparative scale synthesis the TA-based approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield.

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 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.

Amine transaminases (ATAs) are used to synthesize enantiomerically pure amines, which are building blocks for pharmaceuticals and agrochemicals. R‐selective ATAs belong to the fold type IV PLP‐dependent enzymes, and different sequence‐, structure‐ and substrate scope‐based features have been identified in the past decade. However, our knowledge is still restricted due to the limited number of characterized (R)‐ATAs, with additional bias towards fungal origin. We aimed to expand the toolbox of (R)‐ATAs and contribute to the understanding of this enzyme subfamily. We identified and characterized four new (R)‐ATAs. The ATA from Exophiala sideris contains a motif characteristic for d‐ATAs, which was previously believed to be a disqualifying factor for (R)‐ATA activity. The crystal structure of the ATA from Shinella is the first from a Gram‐negative bacterium. The ATAs from Pseudonocardia acaciae and Tetrasphaera japonica are the first characterized (R)‐ATAs with a shortened/missing N‐terminal helix. The active‐site charges vary significantly between the new and known ATAs, correlating with their diverging substrate scope., Diversifying: The toolbox of R‐selective amine transaminases (ATAs) has been expanded by an ATA containing a motif characteristic for d‐ATAs, two ATAs with a shortened/missing N‐terminal helix and the first ATA with known structure from a Gram‐negative bacterium. Their active site charges vary significantly compared to known ATAs correlating with their diverging substrate scope.

A novel series of enantiopure naphthalimide-cycloalkanediamine conjugates were designed, synthetized and evaluated for in vitro cytotoxicity against human colon adenocarcinoma (LoVo), human lung adenocarcinoma (A549), human cervical carcinoma (Hela) and human promyelocytic leukemia cell lines (HL-60). The cytotoxicity of the compounds was highly dependent on size and relative stereochemistry of the cycloalkyl ring as well as length of the spacer. By contrast, any kind of enantioselection was observed for each pair of enantiomers. Flow cytometric analysis indicated that compounds 22 and 23 could effectively induce G2/M arrest in the four previous cell lines despite a mild apoptotic effect.

The first application of Deep Eutectic Solvents (DESs) in asymmetric bioamination of ketones has been accomplished. The amine transaminases (ATAs) turned out to be particularly stable in DES-buffer mixtures at a percentage of up to 75% (w/w) neoteric solvent. Moreover, this reaction medium was used to perform a chemoenzymatic cascade toward biaryl amines by coupling a Suzuki reaction sequentially with an enantioselective bioamination catalyzed by the recently discovered ATA from Exophiala xenobiotica (EX-wTA). The solubilizing properties of DESs enabled the metal catalyzed step at 200 mM loading of substrate and the subsequent biotransformation at 25 mM.

Analogues of the natural product collismycin bearing a carboxylic acid moiety has been efficiently synthesised from several collismycin precursors through a laccase-catalysed oxidation under mild conditions with TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) as a mediator and aerial O2 as an oxidant in aqueous medium. The biotransformations proceeded with excellent yields (85–95%) and involved, depending on the precursor, the oxidation of a benzylic hydroxyl group or the bioconversion of an aldoxime group into carboxylic acid. Since the latter is herein reported for the first time, we explored the potential of this novel oxime cleavage with several synthetic aldo- and ketoximes. Thus, the laccase/TEMPO system proved to be an efficient and green alternative for the deprotection of both aromatic and aliphatic ketoximes into the corresponding ketones. On the other hand, the reaction with aldoximes leads to dimeric species generated by coupling reactions.

One of the pioneering examples of chemoenzymatic cascades in water such as the palladium-catalysed Suzuki-cross coupling followed by an enzymatic reduction has been revisited by the employment of a medium containing Deep Eutectic Solvents (DESs) for the catalytic performance. Thus, the unique properties of these neoteric solvents enabled to reach high substrate concentration for the overall process. Moreover, both isolated enzymes and whole cells exhibited excellent activities which allowed to obtain a set of chiral biaryl alcohols in good yields and very high enantiomeric excess (> 99%).

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.

E. Liardo acknowledges funding from the European Union's Horizon 2020 MSCA ITN‐EID program under grant agreement no. 634200 (Project BIOCASCADES). Authors from the University of Oviedo thank the Ministerio de Ciencia e Innovación of Spain (Project CTQ 2014‐55015) and Principado de Asturias (FC‐15‐GRUPIN‐14‐002) for financial support.

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.

A mild one-pot methodology has been developed to deracemise rac-2-phenyl-1-propanol by combining the use of non-selective laccase/TEMPO-mediated oxidation with enantioselective bioreduction of the racemic aldehyde intermediate under dynamic conditions. The process was easily scalable and stereocontrollable by selecting the suitable biocatalyst.

The development of cell-free and self-sufficient biocatalytic systems represents an emerging approach to address more complex synthetic schemes under nonphysiological conditions. Herein, we report the development of a self-sufficient heterogeneous biocatalyst for the synthesis of chiral alcohols without the need to add an exogenous cofactor. In this work, an NADPH-dependent ketoreductase was primarily stabilized and further co-immobilized with NADPH to catalyze asymmetric reductions without the addition of an exogenous cofactor. As a result, the immobilized cofactor is accessible, and thus, it is recycled inside the porous structure without diffusing out into the bulk, as demonstrated by single-particle in operando studies. This self-sufficient heterogeneous biocatalyst was used and recycled for the asymmetric reduction of eleven carbonyl compounds in a batch reactor without the addition of exogenous NADPH to achieve the corresponding alcohols in 100 % yield and >99 % ee; this high performance was maintained over five consecutive reaction cycles. Likewise, the self-sufficient heterogeneous biocatalyst was integrated into a plug flow reactor for the continuous synthesis of one model secondary alcohol, which gave rise to a space-time yield of 97-112 g L-1 day-1 ; additionally, the immobilized cofactor accumulated a total turnover number of 1076 for 120 h. This is one of the few examples of the successful implementation of continuous reactions in aqueous media catalyzed by cell-free and immobilized systems that integrate both enzymes and cofactors into the solid phase.

Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myelogenous leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here, we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as PIM kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell-cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared with midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate inhibition of FLT3-STAT5, Akt-mTOR-S6, and PIM-BAD pathways. Oral administration of EC-70124 in FLT3-ITD xenograft models demonstrates high efficacy, reaching complete tumor regression. Ex vivo, EC-70124 impaired cell viability in leukemic blasts, especially from FLT3-ITD patients. Our results demonstrate the ability of EC-70124 to reduce proliferation and induce cell death in AML cell lines, patient-derived leukemic blast and xenograft animal models, reaching best results in FLT3 mutants that carry other molecular pathways' alterations. Thus, its unique inhibition profile warrants EC-70124 as a promising agent for AML treatment based on its ability to interfere the complex oncogenic events activated in AML at several levels. Mol Cancer Ther; 17(3); 614–24. ©2018 AACR.

Chemoenzymatic syntheses of both enantiomers of cis- and trans-2-aminocyclopentanol as well as cis- and trans-2-aminocyclohexanol, which are valuable building blocks for a plethora of ligands and pharmaceuticals have been efficiently carried out. The strategy involves the stereospecific syntheses of racemic aminocycloalkanol precursors via tagging of a phthalimide as a masking group and subsequent lipase-catalyzed kinetic resolution. Most of the lipases exhibited excellent enantioselectivity (E ≫ 200) in the transesterification reactions of trans-derivatives, with both N-protected (R,R)-amino acetates and (S,S)-amino alcohols being isolated in enantiopure form. With regard to cis-derivatives, lipases were also very selective, even though the biotransformations were significantly slower.

Two polymeric ionic liquids, 3-(but-3″-en-1″-yl)-1-[2'-hydroxycyclohexyl]-1H-imidazol-3-ium bis(trifluoromethanesulfonyl)imide (IL-1) and 1-(2'-hydroxycyclohexyl)-3-(4″-vinylbenzyl)-1H-imidazol-3-ium bis(trifluoromethylsulfonyl)imide (IL-2), have been synthesized by a free radical polymerization reaction and used as coatings for solid-phase microextraction (SPME). These new fibers exhibit good film stability, high thermal stability (270-290°C) and long lifetimes, and are used for the extraction of volatile compounds in lemon beer using gas chromatography separation and flame ionization detection. The scanning electron micrographs of the fiber surface revealed a polymeric ionic liquid (PIL) film, which is distributed homogeneously on the fiber. The developed PIL fiber showed good linearity between 50 and 2000μg/L with regression coefficients in the range of 0.996-0.999. The relative standard deviations (RSD) obtained in the peak area were found to vary between 1% and 12%, which assured that adequate repeatability was achieved. The spiked recoveries for three beer samples ranged from 78.4% to 123.6%. Experimental design has been employed in the optimization of extraction factors and robustness assessment. The polymeric IL-1 butenyl fiber showed a greater efficiency compared to the PDMS-DVB (65μm) and CAR-PDMS (75μm) for the extraction of all of the analytes studied.

A hybrid organo- and biocatalytic system for the asymmetric conversion of racemic alcohols into amines was developed. Combining an organocatalyst, AZADO, an oxidant, NaOCl, and an enzyme, ω-transaminase, we implemented a one-pot oxidation–transamination sequential process in aqueous medium. The method showed broad substrate scope and was successfully applied to conventional secondary alcohols and sterically hindered β-substituted cycloalkanols, where a highly stereoselective dynamic asymmetric bioamination enabled us to set up both contiguous stereocenters with very high enantio- and diastereomeric ratio (>90% yield, >99% ee, and up to 49:1 dr).

The ruthenium-catalyzed redox isomerization of allylic alcohols was successfully coupled with the enantioselective enzymatic ketone reduction (mediated by KREDs) in a concurrent process in aqueous medium. The overall transformation, formally the asymmetric reduction of allylic alcohols, took place with excellent conversions and enantioselectivities, under mild reaction conditions, employing commercially and readily available catalytic systems, and without external coenzymes or cofactors. Optimization resulted in a multistep approach and a genuine cascade reaction where the metal catalyst and biocatalyst coexist from the beginning.

Seven new functionalized polymerizable ionic liquids were chemically prepared, and later applied for the preparation of polymeric stationary phases in gas chromatography. These coated GC columns, which exhibited good thermal stabilities (240–300 °C) and very high efficiencies (3120–4200 plates/m), have been characterized using the Abraham solvation parameter model. The chromatographic behavior of these polymeric IL columns has been deeply studied observing excellent selectivities in the separation of many organic substances such as alkanes, ketones, alcohols, amines or esters in mixtures of polar and non polar solvents or fragrances. Remarkably, the challenging separation of xylene isomers has been possible using a bis(trifluoromethylsulfonyl)amide based imidazolium IL coated column as a gas chromatography stationary phase.

Polycationic ionic liquids (ILs) are an attractive class of ILs with great potential applicability as gas chromatography stationary phases. A family of hexacationic imidazolium ILs derived from the cycloalkanol family was chemically first prepared in a straightforward manner and then applied for analytical separation purposes. Four tuneable engineering vectors, namely cation ring size structure, anion nature, spatial disposition of cycloalkanol substituents and O-substitution, were considered as experimental parameters for the design of the desired ionic liquids. A total number of five new phases based on a common benzene core respectively exhibited column efficiencies around to 2500 plates/m, broad operating temperature ranges and also, even more importantly, good thermal stabilities (bleeding temperature between 260 and 365°C), finding variations in the selectivity and analytes elution orders depending on the IL structures. Their solvation characteristics were evaluated using the Abraham solvation parameter model, establishing clear correlations between their cation structure and retention capability with respect to certain analytes. The study of relationships between the ILs structure and solvation parameters gives us an idea of the IL stationary phase to be used for specific separations.

A general approach for the highly efficient chemical preparation of novel optically active 2-substituted propane-1,3-diamines is described. Diamines have been obtained from the corresponding commercially available aldehydes in a straightforward two-step synthesis via the corresponding 1,3-dinitro compounds, which were hydrogenated under mild reaction conditions by using platinum dioxide as the catalyst. Subsequent enzymatic enantioselective desymmetrization mediated by Pseudomonas cepacia lipase allowed the recovery of a family of monocarbamates in good to high enantiomeric excesses (70―90 % ee).

The ruthenium‐catalyzed redox isomerization of allylic alcohols was successfully coupled with the enantioselective enzymatic ketone reduction (mediated by KREDs) in a concurrent process in aqueous medium. The overall transformation, formally the asymmetric reduction of allylic alcohols, took place with excellent conversions and enantioselectivities, under mild reaction conditions, employing commercially and readily available catalytic systems, and without external coenzymes or cofactors. Optimization resulted in a multistep approach and a genuine cascade reaction where the metal catalyst and biocatalyst coexist from the beginning., We are indebted to the MINECO of Spain (RYC‐2011‐08451 and CTQ2013‐40591‐P), the Gobierno del Principado de Asturias (Project GRUPIN14‐006), and the COST Action SIPs‐CM1302 for financial support. J.G.‐A. thanks the MINECO and the European Social Fund for a "Ramón y Cajal" contract. E.L. acknowledges funding from the European Union's Horizon 2020 MSCA ITN‐EID program (grant agreement No 634200). N.R.‐L. acknowledges MINECO for funding under Torres‐Quevedo program (PTQ‐12‐05 407).

A stereoselective bioreduction of 2-oxocycloalkanecarbonitriles was concurrently coupled to a whole cell-catalyzed nitrile hydrolysis in one-pot. The first step, mediated by ketoreductases, involved a dynamic reductive kinetic resolution, which led to 2-hydroxycycloalkanenitriles in very high enantio- and diastereomeric ratios. Then, the simultaneous exposure to nitrile hydratase and amidase from whole cells of Rhodococcus rhodochrous provided the corresponding 2-hydroxycycloalkanecarboxylic acids with excellent overall yield and optical purity for the all-enzymatic cascade.

The ruthenium-catalysed isomerisation of allylic alcohols was coupled, for the first time, with asymmetric bioamination in a one-pot process in an aqueous medium. In the cases involving prochiral ketones, the ω-TA exhibited excellent enantioselectivity, identical to that observed in the single step. As a result, amines were obtained from allylic alcohols with high overall yields and excellent enantiomeric excesses.

During the last decade, the combination of different metal- and bio-catalyzed organic reactions in aqueous media has permitted the flourishing of a variety of one-pot asymmetric multi-catalytic reactions devoted to the construction of enantiopure and high added-value chemicals under mild reaction conditions (usually room temperature) and in the presence of air. Herein, a comprehensive account of the state-of-the-art in the development of catalytic networks by combining metallic and biological catalysts in aqueous media (the natural environment of enzymes) is presented. Among others, the combination of metal-catalyzed isomerizations, cycloadditions, hydrations, olefin metathesis, oxidations, C-C cross-coupling and hydrogenation reactions, with several biocatalyzed transformations of organic groups (enzymatic reduction, epoxidation, halogenation or ester hydrolysis), are discussed.

A series of racemic trans -1,2,3,4-tetrahydronaphthalen-2-ols bearing an azole nucleus at the C-1 or C-3 position has been synthesized by ring opening reactions of the corresponding epoxides using imidazole or 1,2,4-triazole. The kinetic resolutions of these racemates were undertaken through transesterification processes, finding good levels of activities and high to excellent enantiodiscrimination values for the Pseudomonas cepacia lipase immobilized on a ceramic carrier. Investigations into the optimum reaction conditions were carried out by consideration of different organic solvents, temperatures, enzyme loadings, and reaction times. With the best conditions in hand, the experiments were later carried out toward the resolution of the related racemic cis -alcohols, which were previously obtained through a Mitsunobu and deprotection chemical sequence from the trans -stereoisomers.

A chemoenzymatic and selective method for the epoxidation of a series of linear and cyclic alkenes is described.

The synthesis and enzyme-catalyzed desymmetrization of meso-1,2-diaryl-1,2-diaminoethanes have been investigated. A family of aromatic meso-1,2-diamines, containing different substitution patterns in the aromatic ring, was first prepared and then desymmetrized enantioselectively using lipases as biocatalysts. Selective alkoxycarbonylation of one of the amino groups was achieved using allyl carbonates, isolating the corresponding allyl monocarbamates with moderate to high enantiomeric excess at 45 °C. Candida antarctica lipase types A (CAL-A) and B (CAL-B) displayed the best activities and stereopreferences, with a dramatic influence being observed depending on the diamine structure. Non substituted and para-substituted aryldiamines led to the formation of allyl carbamates with good enantiomeric excess, using CAL-A for the less hindered substrates and CAL-B for the more hindered ones. On the other hand meta- and ortho-derivatives afforded low or negligible conversions and selectivities, respectively.

A chemoenzymatic and selective method for the epoxidation of a series of cyclic and linear alkenes is described. Epoxides have been obtained in moderate to excellent conversions under mild reaction conditions through a two-step sequence, carried out in one-pot. This chemoenzymatic approach is based on a Rhizomucor miehei lipase-catalyzed perhydrolysis reaction to form the corresponding peracid, and subsequent epoxidation of the corresponding alkenes. Reaction parameters with influence in the biotransformation have been optimized specially focusing in the efficient enzymatic peracid formation by means of the correct choice of solvent, oxidant, and peracid precursor. This chemoenzymatic approach has been efficiently applied for the first time, in the regioselective chemical oxidation of (S)-carvone and limonene, both showing an opposite behavior for the oxidation of the internal and external C–C double bond, respectively.

The development of continuous flow processes for the synthesis of chiral enantiopure 1-(2-hydroxycycloalkyl)imidazoles is reported. For the ring-opening reaction microwave batch processes and continuous flow reactions have led to similar results in terms of conversion, although the productivity is clearly improved under flow. The use of continuous flow systems for the lipase-catalyzed kinetic resolution of the racemic 2-(1H-imidazol-yl)cycloalkanols with either immobilized CAL-B or PSL-C has been demonstrated to be significantly more efficient than the corresponding batch processes. The continuous flow biotransformations have allowed us to easily increase the production of these chiral imidazoles, adequate building blocks in the synthesis of chiral ionic liquids.

Polycationic ionic liquids (ILs) are an attractive class of ILs with great potential applicability as gas chromatography stationary phases. A family of hexacationic imidazolium ILs derived from the cycloalkanol family was chemically first prepared in a straightforward manner and then applied for analytical separation purposes. Four tuneable engineering vectors, namely cation ring size structure, anion nature, spatial disposition of cycloalkanol substituents and O-substitution, were considered as experimental parameters for the design of the desired ionic liquids. A total number of five new phases based on a common benzene core respectively exhibited column efficiencies around to 2500 plates/m, broad operating temperature ranges and also, even more importantly, good thermal stabilities (bleeding temperature between 260 and 365°C), finding variations in the selectivity and analytes elution orders depending on the IL structures. Their solvation characteristics were evaluated using the Abraham solvation parameter model, establishing clear correlations between their cation structure and retention capability with respect to certain analytes. The study of relationships between the ILs structure and solvation parameters gives us an idea of the IL stationary phase to be used for specific separations.

A novel family of prochiral pentane-1,5-diamines has been efficiently synthesized, possessing stabilities significantly higher than those of corresponding propane-1,3-diamine analogues. Diamines have been later desymmetrized using Pseudomonas cepacia lipase as an efficient biocatalyst for the mono- but also stereoselective protection of one of their amino groups. Reaction parameters such as type and loading of enzyme, temperature, solvent, and acyl donor have been exhaustively analyzed, searching for optimal conditions for the production of interesting optically active nitrogenated compounds. Thus, acylation and alkoxycarbonylation processes have been compared in terms of conversion and enantiomeric excess values. The best results were found in the reaction of prochiral diamines with ethyl methoxyacetate as acyl donor and 1,4-dioxane as solvent, yielding (S)-monoamides in 33–59% isolated yield and 54–99% ee, depending on the aromatic pattern substitution.

Two ionic liquids (ILs), namely (S,S)-1-butyl-3-(2'-hydroxy-cyclohexyl)-3H-imidazol-1-ium tetrafluoroborate and (S,S)-1-butyl-3-(2'-acetyl-cyclohexyl)-3H-imidazol-1-ium tetrafluoroborate have been employed as stationary phases in capillary gas chromatography. These new phases exhibit a column efficiency of 1,600 and 2,100 plates m(-1) for IL 1 and IL 2, respectively, a wide operating temperature range and good thermal stability (bleeding temperature of 250 °C for IL 1 and 160 °C for IL 2). Inverse gas chromatography (GC) analyses were used to study the solvation properties of these ILs through a linear solvation energy model. The application of these ILs as new GC stationary phases was studied. These stationary phases exhibited unique selectivity for many organic substances, such as alkanes, ketones, esters, and aromatic compounds. The efficient separation of several mixtures containing compounds of different polarities and the good separation of fatty acid methyl esters (FAMEs) and cis/trans isomers indicate that these ILs may be applicable as a new type of GC stationary phases.