catalysts

Review One-Pot Combination of Metal- and Bio-Catalysis in Water for the Synthesis of Chiral Molecules

Nicolás Ríos-Lombardía 1,*, Joaquín García-Álvarez 2,* ID and Javier González-Sabín 1,* ID

1 EntreChem SL, Vivero Ciencias de la Salud, Santo Domingo de Guzmán, 33011 Oviedo, Spain 2 Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, E-33006 Oviedo, Spain * Correspondence: [email protected] (N.R.-L.); [email protected] (J.G.-A.); [email protected] (J.G.-S.); Tel.: +34-985-103-464 (J.G.-A.); +34-985-259-021(J.G.-S.)

Received: 22 January 2018; Accepted: 8 February 2018; Published: 10 February 2018

Abstract: 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.

Keywords: one-pot processes; cascade reactions; tandem catalysis; metal-catalysis; biocatalysis; enantioselective; water

1. Introduction Challenges faced by today’s synthetic organic chemists when trying to access highly-functionalized small molecules are evolving rapidly due to the new safety and economic needs imposed by our society [1]. In this sense, finding new ways of perfecting (i) chemo-, regio- and stereo-selectivities, (ii) functional group tolerance and (iii) reaction yields, have been always present, but, with the end of last century, a new awareness arose to produce chemicals and materials also under mild reaction conditions [2]. Thus, and for a successful proposal of new chemical processes, synthetic chemists try to design reactions that should: (i) be safe (even when scaled-up); (ii) take place under mild reactions conditions (room temperature and the absence of a protecting atmosphere are desirable); (iii) be catalytic [3]; and (iv) be performed using inexpensive and non-dangerous solvents [4,5] (i.e., water). Bearing in mind these challenges, the use of enzymes or whole microorganisms (nature’s catalysts, which are usually non-toxic, biodegradable and biocompatible) has experienced a spectacular growth for the synthesis of small organic molecules containing chiral units [6] (which are widespread within the fine chemical industry) under physiological conditions, thus achieving numerous safety and economic benefits. Recent years have also seen an impressive advance in multi-enzymatic systems of remarkable complexity [7–10], which try to emulate Nature, as living organisms use a great number of enzymatic cascades (in different metabolic pathways) employing the same reaction media (i.e., the cytosol). Thus, the in vitro development of these one-pot asymmetric multi-catalytic enzymatic reactions permits the synthesis of valuable target molecules under practical and economic advantages

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(for example, minimization of waste production, time- and energy-consuming and tedious purification steps) [11]. While greater attention has been placed on the development of the aforementioned multi-catalytic enzymatic reactions [7–10], the combination of two different catalytic disciplines (for example chemo- and bio-catalysis) is still in its infancy. Among the two possible combinations (organo-/bio-catalysis [12] and metal-/biocatalysis), the potential of assembling transition-metal-catalyzed reactions with enzymatic transformations remains particularly appealing as both catalytic methodologies: (i) present important differences in terms of productivity, reactivity and selectivity; and (ii) constitute two of the most important pillars in the toolbox of synthetic organic chemistry [13]. However, the vast majority of examples reported in this field (e.g., dynamic kinetic resolution (DKRs) by combining racemizing metal catalysts with an enzymatic transformation) rely on the use of volatile organic solvents (VOCs; e.g., toluene, THF, diethyl ether, etc.) [14–19] in order to avoid the degradation usually exhibited by the transition-metal catalysts in aqueous solutions (the natural environment of enzymes). Nevertheless, and during the last decade, a plethora of studies has demonstrated the possibility to perform metal-catalyzed organic reactions in water, finding, in some cases, an enhancement of the rate or a change in the selectivity of a given reaction [20]. Thus, this gradual emergence of metal-catalyzed transformations in water along with the advances in protein engineering to produce more stable enzymes has boosted the search for new catalytic systems, merging the advantages of both catalytic worlds (metal- and bio-catalysis) in water. At this point, we should point out that these catalytic networks imply important challenges [21,22], like: (i) metal- and bio-catalyst compatibility and stability; (ii) undesired cross-reactivity; (iii) the employment of different catalytic reaction conditions (basically related to temperature and concentration); and (iv) the use of different co-solvents, co-catalysts or co-factors. Thus, this review intends to provide a general overview, including our own investigations and contributions by other research groups, of the field of metal- and bio-catalyzed organic reactions in water, with particular focus on work reported during the last three years [23]. The contents of this review are organized into six main sections according to the nature of the metal-catalyzed organic reaction.

2. Metal-Catalyzed Isomerization of Unsaturated Organic Substrates Coupled with Enzymatic Aminations, Reductions or Hydrolyses Metal-catalyzed isomerizations or cycloisomerizations of unsaturated organic substrates are good examples of atom economic processes [24–26] as they usually proceed with a total mass transfer from starting reagents to products. Thus, in this section, we describe the modular combination of: (i) the Ru(IV)-catalyzed redox isomerization of allylic alcohols with the enantioselective bioamination or bioreduction of the transiently-formed prochiral ketones [27,28]; (ii) the Pd(II)- or Au(III)-catalyzed cycloisomerization/hydrolysis of alkynes containing a tethered nucleophile as the substituent with a concomitant bioreduction (ketoreductase (KRED)) of the in situ generated carbonyl compounds [29]; and (iii) the tandem esterase- or lipase-mediated hydrolysis of allenyl acetates followed by the Au(I)-catalyzed cyclization of the corresponding allenols to produce chiral tetrahydrofurans [30].

2.1. Combination of Ru(IV)-Catalyzed Redox Isomerization of Allylic Alcohols and Bioamination or Bioreduction in Aqueous Media The metal-catalyzed redox isomerization of allylic alcohols, which involves the migration of a C=C bond followed by the spontaneous tautomerization of the transiently-formed enol [31–35], is an elegant and powerful synthetic route for the production of saturated carbonyl compounds in quantitative yields. In particular, a family of bis(allyl)-ruthenium(IV) complexes (1–3; Figure1) were described as active and selective catalysts for the isomerization of a wide variety allylic alcohols in water, under mild reaction conditions (temperature from rt to 40 ◦C), and in the absence of co-catalyst [36–39], which are ideal conditions for further biotransformations. Catalysts 2018, 8, 75 3 of 28 Catalysts 2018, 8, 74 3 of 28

Catalysts 2018, 8, 74 3 of 28

FigureFigure 1. Highly 1. Highly-efficient‐efficient and selective and selective bis(allyl)‐ruthenium(IV) bis(allyl)-ruthenium(IV) catalysts (1–3 catalysts) for the redox (1–3 )isomerization for the redox of

allylicisomerization alcohols in of water allylic and alcohols under mild in water reaction and conditions. under mild reaction conditions. Figure 1. Highly‐efficient and selective bis(allyl)‐ruthenium(IV) catalysts (1–3) for the redox isomerization of allylicThus, alcohols the in starting water and point under of mild our reactioninvestigations, conditions. devoted to the combination of metal‐ and bio‐ catalystsThus, in the aqueous starting media, point was of the our design investigations, of a one‐pot devoted tandem process to the through combination the assembly of metal- of the and bio-catalystsRu(IV)Thus,‐catalyzed inthe aqueous starting redox media, point isomerization of was our the investigations, of design allylic of alcohols a one-pot devoted with tandem to athe ω‐ combinationtransaminase process through of (ω‐ metalTA) the‐‐ mediated assemblyand bio‐ of thebioaminationcatalysts Ru(IV)-catalyzed in aqueous reaction redox media, [27]. isomerization Initially, was the designthe catalytic of of allylic a one activity alcohols‐pot tandem of Complexes with process a ω-transaminase 1 through–3 (Figure the 1) assembly ( ωwas-TA)-mediated evaluated of the bioaminationinRu(IV) the redox‐catalyzed reaction isomerization redox [27 ].isomerization Initially, of racemic the allylic catalyticof allylic alcohols activityalcohols into of with prochiral Complexes a ω‐ transaminaseketones1–3 (Figure (Scheme (ω‐1)TA) 1), was ‐butmediated evaluated in the in theconditionsbioamination redox isomerizationimposed reaction by [27]. the of secondInitially, racemic step the allylic of catalytic the process, alcohols activity namely into of Complexes prochiral the employment ketones 1–3 (Figure of (Scheme a phosphate1) was1 ),evaluated but buffer in the conditionssolutionin the redox imposedcontaining isomerization by iPrNH the second2 of(as racemic a source step ofallylic for the the process,alcohols amino group). namelyinto prochiral Pleasantly, the employment ketones we found(Scheme of athat phosphate 1), under but in these bufferthe conditions imposedi by the second step of the process, namely the employment of a phosphate buffer solution“bio‐conditions”, containing ComplexPrNH2 (as 3 was a source an efficient for the and amino selective group). catalyst Pleasantly, for the isomerization we found that reaction under (50 these i “bio-conditions”,°Csolution and 1 containingmol% in Complex [Ru]) PrNH yielding23 (aswas a sourcethe an desired efficient for the ketones andamino selective in group). almost catalystPleasantly, quantitative for we the yields found isomerization (Scheme that under 1). reactionNext,these “bio‐conditions”, Complex 3 was an efficient and selective catalyst for the isomerization reaction (50 (50we◦C studied and 1 mol% separately in [Ru]) the yieldingsecond step, the namely desired the ketones bioamination in almost of quantitativethe aforementioned yields (Schemecarbonyl 1). °C and 1 mol% in [Ru]) yielding the desired ketones in almost quantitative yields (Scheme 1). Next, Next,compounds we studied mediated separately by ω‐ theTAs, second but step,in the namely presence the of bioamination catalytic amounts of the of aforementioned the bis(allyl)‐Ru(IV) carbonyl Complexwe studied 3. Thisseparately enzymatic the secondscreening step, of namelycommercially the bioamination available ω‐ TAsof the enabled aforementioned identifying carbonyl highly‐ compounds mediated by ω-TAs, but in the presence of catalytic amounts of the bis(allyl)-Ru(IV) efficientcompounds biocatalysts, mediated whichby ω‐ TAs,produced but in boththe presence enantiomers of catalytic of each amounts amine inof thealmost bis(allyl) quantitative‐Ru(IV) Complex 3. This enzymatic screening of commercially available ω-TAs enabled identifying conversionComplex 3 .and This excellent enzymatic enantiomeric screening ofexcess, commercially even in the available company ω‐ TAsof the enabled ruthenium identifying Catalyst highly 3. ‐ highly-efficientefficient biocatalysts, biocatalysts, which which produced produced both both enantiomers enantiomers of each of each amine amine in inalmost almost quantitative quantitative conversionconversion and and excellent excellent enantiomeric enantiomeric excess, excess, eveneven in the company of of the the ruthenium ruthenium Catalyst Catalyst 3. 3.

Scheme 1. Ru(IV)‐catalyzed isomerization of a variety of allylic alcohols and sequential bioamination promoted by ω‐transaminases (ω‐TAs). SchemeScheme 1. Ru(IV)-catalyzed1. Ru(IV)‐catalyzed isomerization isomerization of of aa variety of allylic allylic alcohols alcohols and and sequential sequential bioamination bioamination With both individual steps optimized, the compatibility studies revealed a strong inhibition promotedpromoted by byω ω‐-transaminasestransaminases ( ω(ω‐-TAs).TAs). exerted by the enzymatic system on the metal Catalyst 3. However, this drawback could be easily circumventedWith both just individual by adopting steps a optimized,one‐pot/two the‐step compatibility methodology studies (Scheme revealed 1). Thus, a strong once inhibitionthe initial Ru(IV)exertedWith‐ catalyzed bothby the individual enzymatic isomerization stepssystem optimized,of on the the desired metal the allylicCatalyst compatibility alcohol 3. However, was studies completed this revealed drawback in the a buffercould strong besolution, inhibition easily exertedthecircumvented corresponding by the enzymatic just ω‐byTA adopting systemand its aco on one‐factor the‐pot/two metal (PLP,‐step Catalyst pyridoxal methodology3 .5’ However,‐phosphate) (Scheme this were 1). drawback addedThus, onceto could the the reaction beinitial easily circumventedmedia.Ru(IV)‐ catalyzedThis justmethodology by isomerization adopting enabled a of one-pot/two-step the transforming desired allylic racemic methodology alcohol allylic was completedalcohols (Scheme into1 ).in Thus, thethe buffercorresponding once solution, the initial Ru(IV)-catalyzedenantiopurethe corresponding saturated isomerization ω‐TA amines, and its without of co the‐factor desired the (PLP, need allylic pyridoxalfor any alcohol halfway 5’‐phosphate) was isolation completed were or purification added in the to buffer the steps. reaction solution, themedia. correspondingTrying This tomethodology moveω-TA one and step enabled its forward co-factor transforming in (PLP, the design pyridoxal racemic of real 5’-phosphate)allylic concurrent alcohols werechemoenzymatic into addedthe corresponding to the one reaction‐pot media.processes,enantiopure This in methodology saturated which the amines, metal enabled ‐withoutcatalyst transforming theand need the forenzyme racemic any halfway work allylic together isolation alcohols from or purification into the beginning the corresponding steps. of the enantiopurecatalyticTrying reaction, saturated to move we amines, one decided step without forward to explore the in need the commercially design for any of halfway real available concurrent isolation ketoreductases chemoenzymatic or purification (KREDs) steps. one‐ potas processes, in which the metal‐catalyst and the enzyme work together from the beginning of the catalytic reaction, we decided to explore commercially available ketoreductases (KREDs) as

Catalysts 2018, 8, 75 4 of 28

Trying to move one step forward in the design of real concurrent chemoenzymatic one-pot processes, in which the metal-catalyst and the enzyme work together from the beginning of theCatalysts catalytic 2018, reaction, 8, 74 we decided to explore commercially available ketoreductases (KREDs)4 of 28 as alternative biocatalysts [40]. Again, we firstly tested the catalytic activity of the aforementioned bis(allyl)-ruthenium(IV)alternative biocatalysts Complexes [40]. Again,1– 3we(Figure firstly1 )tested in the the isomerization catalytic activity of a set of of the allylic aforementioned alcohols in the mediumbis(allyl) required‐ruthenium(IV) by KREDs Complexes (phosphate 1–3 buffer (Figure containing 1) in the isomerizationiPrOH as the of hydrogen a set of allylic source) alcohols [28]. In in this case,the only medium the acetate-Ru(IV) required by KREDs Complex (phosphate2 retained buffer its containing high catalytic iPrOH activity as the (99% hydrogen conversions source) [28]. in 1–10 In h) andthis selectivity, case, only as the undesired acetate‐Ru(IV) simultaneous Complex reduction 2 retained of its the high obtained catalytic ketones activity (through (99% conversions Ru-catalyzed in 1–10 h) and selectivity, as undesired simultaneous reduction of the obtained ketones (through Ru‐ transfer hydrogenation [41]) was not observed. In this case, the compatibility studies unveiled the catalyzed transfer hydrogenation [41]) was not observed. In this case, the compatibility studies same catalytic activity for Complex 2 (99% conversion in the desired ketones) in the presence of KREDs unveiled the same catalytic activity for Complex 2 (99% conversion in the desired ketones) in the and their co-factor NADPH. Similarly and as previously detected with ω-TAs [27], no inhibition presence of KREDs and their co‐factor NADPH. Similarly and as previously detected with ω‐TAs was observed in the biocatalytic system when the ruthenium catalyst was present in the reaction [27], no inhibition was observed in the biocatalytic system when the ruthenium catalyst was present media.in the After reaction both media. steps After (metal- both and steps bio-catalysis) (metal‐ and were bio‐catalysis) independently were independently optimized and optimized several and issues i (suchseveral as reaction issues medium(such as optimization reaction medium (i.e., percentage optimization of PrOH, (i.e., 15%percentagev/v), concentration of iPrOH, 15% of co-factor, v/v), ◦ metal-catalystconcentration loading of co‐factor, (5 mol%) metal and‐catalyst reaction loading temperature (5 mol%) (30 andC)) reaction were addressed temperature (Scheme (30 °C))2), we were were ableaddressed to develop, (Scheme for the 2), first we time, were a genuineable to develop, one-pot concurrentfor the first process time, a wheregenuine the one metal‐pot Catalyst concurrent2 and theprocess biocatalyst where coexist the metal from theCatalyst beginning 2 and in the aqueous biocatalyst medium, coexist giving from risethe tobeginning enantiopure in aqueous saturated alcoholsmedium, starting giving from rise racemicto enantiopure allylic saturated alcohols. alcohols starting from racemic allylic alcohols.

SchemeScheme 2. 2.Concurrent Concurrent (one-pot (one‐pot cascade) cascade) metal-catalyzedmetal‐catalyzed isomerization/enzymatic reduction reduction of of racemicracemic allylic allylic alcohols alcohols by by combining combining ruthenium ruthenium ComplexComplex 2 andand ketoreductases ketoreductases (KREDs). (KREDs).

Prior to our work, Bergman, Raymond, Toste and co‐workers reported a non‐chiral methodologyPrior to our that work, combines Bergman, the Ru(II) Raymond,‐catalyzed Toste isomerization and co-workers of the reported allylic alcohol a non-chiral (2‐propenol) methodology into thatpropanal combines with the a Ru(II)-catalyzed subsequent bioreduction isomerization process of thepromoted allylic alcoholby horse (2-propenol)‐liver alcohol into dehydrogenase propanal with a subsequent(HL‐ADH) bioreduction[30]. In this processcontext, promoted the authors by horse-liverincorporated alcohol the dehydrogenasecationic ruthenium (HL -ADH)complex [30 ]. + In[RuCp(MeCN) this context,3] the+ into authors a supramolecular incorporated [Ga the4L cationic6]12− tetrahedral ruthenium assembly complex (L [RuCp(MeCN)= N,N’‐bis(2,3‐3] 12− 0 intodihydroxybenzoyl) a supramolecular‐1,5‐ [Gadiaminonaphthalene)4L6] tetrahedral and assembly tested the (L resulting = N,N -bis(2,3-dihydroxybenzoyl)-water‐soluble host‐guest 1,5-diaminonaphthalene)System 4 in the isomerization and of tested the aforementioned the resulting allylic water-soluble alcohol in water host-guest [42]. Thus, System treatment4 in of the isomerization2‐propenol with of the a combo aforementioned mixture containing allylic alcohol (i) the metallic in water host [42‐guest]. Thus, System treatment 4, (ii) the of horse 2-propenol‐liver withalcohol a combo dehydrogenase mixture containing (HL‐ADH) (i) and the metallic(iii) NADPH, host-guest yeast formate System 4dehydrogenase, (ii) the horse-liver (FDH) alcoholand dehydrogenasesodium formate (HL led-ADH) to the and formation (iii) NADPH, of propanol yeast formate in 61% dehydrogenaseyield after six hours (FDH) of and reaction sodium at 37 formate °C led(Scheme to the formation 3). Finally, of it propanol was also demonstrated in 61% yield afterthat neither six hours the of enzymatic reaction system, at 37 ◦C nor (Scheme the ruthenium3). Finally, it wascatalystalso could demonstrated promote thatthe tandem neither isomerization/reduction the enzymatic system, norreaction the ruthenium on its own. catalyst could promote the tandem isomerization/reduction reaction on its own.

Catalysts 2018, 8, 75 5 of 28 Catalysts 2018, 8, 74 5 of 28

SchemeScheme 3. Synthesis3. Synthesis of Ru(II)-host-guest of Ru(II)‐host‐guest Complex Complex4 and the4 and design the of design a tandem of isomerization/a tandem bioreductionisomerization/bioreduction of the allylic alcohol of the (2-propenol). allylic alcohol (2‐propenol).

2.2. Assembly of Metal‐Catalyzed Cycloisomerization of Allenyl Acetates or Terminal Alkynes with 2.2. Assembly of Metal-Catalyzed Cycloisomerization of Allenyl Acetates or Terminal Alkynes with Esterases, Esterases, Lipases or Ketoreductases in Aqueous Media Lipases or Ketoreductases in Aqueous Media + + In addition to the aforementioned [RuCp(MeCN)3]+, the cationic metallic fragment [Au(PMe3)] + In addition to the aforementioned [RuCp(MeCN)3] , the cationic metallic fragment [Au(PMe3)] was also successfully encapsulated in the previously‐mentioned host assembly [Ga4L6]12−, giving rise 12− wasto also the successfullygold(I) host‐guest encapsulated Complex in 5, the which previously-mentioned is stable at neutral pH host in assembly water (Scheme [Ga4L 64)] [30]., giving In this rise to thecase, gold(I) it was found host-guest that the Complex supramolecular5, which Complex is stable 5 atexhibited neutral an pH eight in‐ waterfold rate (Scheme enhancement4)[ 30]. when In this case,compared it was found with thatthe thefree supramolecular gold complex [AuCl(PMe Complex 53exhibited)] in the hydroalkoxylation an eight-fold rate enhancementof linear allenyl when comparedalcohols with (Scheme the free 4A). gold Bearing complex this [AuCl(PMe result in mind,3)] in theit was hydroalkoxylation hypothesized that of lineara prior allenyl enzymatic alcohols (Schemehydrolysis4A). Bearingof allenyl this acetates result (promoted in mind, itby was lipases hypothesized or esterases) that could a prior produce enzymatic in situ hydrolysisthe desired of allenylallenols. acetates Following (promoted this byidea, lipases the tandem or esterases) acetate could hydrolysis/hydroalkoxylation produce in situ the desired reaction allenols. of Followingallenyl thisacetates idea, the was tandem examined acetate with hydrolysis/hydroalkoxylation a variety of esterases (rabbit liver reaction esterase, of allenylhog liver acetates esterase was and examined horse withliver a variety esterase) of esterasesor lipases (rabbit (Mucor liver miehei esterase, lipase, hogAmano liver lipase) esterase and and the horse supramolecular liver esterase) Complex or lipases 5 (Mucor(Scheme miehei 4B),lipase, being Amanoable to achieve lipase) quantitative and the supramolecular yields of the final Complex substituted5 (Scheme tetrahydrofuran4B), being when able to achieverabbit quantitative liver esterase yields was employed of the final [31]. substituted To further explore tetrahydrofuran their hypothesis, when rabbitthe authors liver designed esterase wasa employedtandem [31enzymatic]. To further kinetic explore resolution/hydroalkoxylation their hypothesis, the authors reaction designed finding a tandem enantiomeric enzymatic excesses kinetic resolution/hydroalkoxylationranging from 46% (hog liver esterase) reaction to finding 96% (Amano enantiomeric lipase). Additionally, excesses ranging some kinetic from 46%experiments (hog liver revealed that supramolecular Complex 5 had little effect on the studied enzymes, while free esterase) to 96% (Amano lipase). Additionally, some kinetic experiments revealed that supramolecular [AuCl(PMe3)] eroded the catalytic activity of the esterases or lipases. Complex 5 had little effect on the studied enzymes, while free [AuCl(PMe3)] eroded the catalytic activity of the esterases or lipases.

Catalysts 2018, 8, 75 6 of 28 Catalysts 2018, 8, 74 6 of 28

Catalysts 2018, 8, 74 6 of 28 O O O O N H O [Au] O N H guest encapsulation[Au] [Au] H N O guest encapsulation O [Au] H [Au] = Au PMe N O 3 5 OO [Au] = Au PMe3 5 O =Ga3+ =Ga3+ [Au] O [Au] (A) O OH (A) OH eight-fold rate enhancement when compared with [AuCl(PMe3)]

eight-fold rate enhancement when compared with [AuCl(PMe3)]

RO HO Enzyme 5 O RO HO (B) Tris bufferEnzyme pH 8.0 5 O 20 h/37 ºC (B) Tris buffer pH 8.0 20 h/37 ºC SchemeScheme 4. 4.Synthesis Synthesis of of Au(I)-host-guest Au(I)‐host‐guest ComplexComplex 5 and design of of tandem tandem esterase/lipase esterase/lipase acetate acetate hydrolysisSchemehydrolysis (4.A ()SynthesisA and) and Au(I)-catalyzed Au(I) of ‐Au(I)catalyzed‐host hydroalkoxylation ‐hydroalkoxylationguest Complex 5 and of allenyl design acetates acetates of tandem (B (B).). esterase/lipase acetate hydrolysis (A) and Au(I)‐catalyzed hydroalkoxylation of allenyl acetates (B). Inspired by these results and with the aim of expanding the synthetic scope of one‐pot cascade Inspired by these results and with the aim of expanding the synthetic scope of one-pot cascade processesInspired involving by these metal results‐ and and bio with‐catalytic the aim events of expanding in aqueous the media, synthetic we turned scope ourof one attention‐pot cascade to the processes involving metal- and bio-catalytic events in aqueous media, we turned our attention to processespossible combination involving metal of the‐ and metal bio‐‐catalyticcatalyzed events cycloisomerization in aqueous media, of alkynes we turned containing our attention a tethered to the the possible combination of the metal-catalyzed cycloisomerization of alkynes containing a tethered possiblenucleophile combination (NuH; followed of the by metal the spontaneous‐catalyzed cycloisomerization hydrolysis of the transiently of alkynes‐formed containing five‐ membereda tethered nucleophilenucleophileheterocycles) (NuH; (NuH; with followed followeda concomitant by by the the bioreduction spontaneous spontaneous of hydrolysis the transiently of of the the ‐transientlyformed transiently-formed prochiral‐formed ketones five five-membered‐membered without heterocycles)heterocycles)the need for with any with ahalfway concomitant a concomitant isolation bioreduction bioreduction or purification of of the stepsthe transiently-formed transiently (Scheme 5)‐formed [29]. prochiral prochiral ketones ketones without without the needthe for need any for halfway any halfway isolation isolation or purification or purification steps steps (Scheme (Scheme5)[ 295)]. [29].

Scheme 5. One‐pot conversion of alkynyl amides, alkynols or γ‐alkynoic acids into chiral γ‐hydroxy‐carbonyl compounds. SchemeScheme 5. 5. One-potOne‐pot conversionconversion of alkynyl amides, amides, alkynols alkynols or or γ‐γalkynoic-alkynoic acids acids into into chiral chiral γ‐hydroxy‐carbonyl compounds. γ-hydroxy-carbonylThus, we started compounds. our investigations by exploring the Pd(II)‐catalyzed cycloisomerization of 4‐ pentynThus,‐1‐ol we into started 5‐methyl our ‐investigations2,3‐dihydrofuran by exploringin water theas thePd(II) solvent‐catalyzed at 30 cycloisomerization °C and under aerobic of 4‐ pentynconditions.Thus,‐1‐ weol However,into started 5‐methyl ourand‐ 2,3 investigationsinstead‐dihydrofuran of the byexpected in exploringwater dihydrofuran, as the the solvent Pd(II)-catalyzed we at observed30 °C and cycloisomerizationthe under quantitative aerobic ◦ ofconditions.formation 4-pentyn-1-ol ofHowever, 5 into‐hydroxy 5-methyl-2,3-dihydrofuran and‐2 ‐insteadpentanone of the(via expected formal in dihydrofuran,hydration water as theof wethe solvent observed C≡C atbond) 30the quantitativeCwhen and underthe aerobicformationiminophosphorane conditions. of 5‐hydroxy‐Pd(II) However, ‐2Complex‐pentanone and 6 instead was(via usedformal of theas hydrationthe expected catalyst of dihydrofuran, (Schemethe C≡ C6). bond) The we observedsubsequentwhen the the iminophosphorane‐Pd(II) Complex 6 was used as the catalyst (Scheme 6). The≡ subsequent quantitative formation of 5-hydroxy-2-pentanone (via formal hydration of the C C bond) when

Catalysts 2018, 8, 75 7 of 28 theCatalysts iminophosphorane-Pd(II) 2018, 8, 74 Complex 6 was used as the catalyst (Scheme6). The subsequent7 of 28 combination of this subrogated hydration process with a concomitant bioreduction step promoted Catalystscombination 2018, 8 , of74 this subrogated hydration process with a concomitant bioreduction step promoted7 of 28 by KREDs allowed us to obtain the corresponding 1,4-pentanediol in good yields (up to 90%) and by KREDs allowed us to obtain the corresponding 1,4‐pentanediol in good yields (up to 90%) and excellent enantiomeric excesses for both possible enantiomers after 24 h of reaction (Scheme6)[ 29]. combinationexcellent enantiomeric of this subrogated excesses forhydration both possible process enantiomers with a concomitant after 24 h bioreduction of reaction (Scheme step promoted 6) [29]. At thisbyAt thisKREDs point, point, itallowed isit is important important us to obtain to to note note the that that corresponding the the reaction media1,4 media‐pentanediol coming coming from fromin good the the metal yields metal-catalyzed‐catalyzed (up to 90%) reaction reaction and (containingexcellent(containing enantiomeric the the Pd(II)-Complex Pd(II)‐ Complexexcesses 6 for6)) was wasboth employed employedpossible enantiomers directly to to afterfeed feed 24the the h biocatalyst. of biocatalyst. reaction (SchemeFinally, Finally, a6) triple a[29]. triple metal-/bio-/bio-catalyzedAtmetal this‐/bio point,‐/bio it‐ iscatalyzed important reaction reaction to note wasthat was theestablished established reaction mediaby by combining combining coming fromthe theaforementioned the aforementioned metal‐catalyzed synthesis reaction synthesis of of chiral(containingchiral 1,4-pentandiol1,4‐pentandiol the Pd(II) ‐Complex withwith aa laccase/(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl) laccase/(2,2,6,66) was employed‐Tetramethylpiperidin directly to feed the‐1 ‐biocatalyst.yl)oxyl) TEMPO TEMPO-catalyzed Finally,‐catalyzed a triple oxidationmetaloxidation‐/bio reaction reaction‐/bio‐catalyzed giving giving rise risereaction to to both both was antipodes antipodes established of γ‐γ -valerolactonebyvalerolactone combining inthe in quantitative quantitative aforementioned yield yield and synthesis and excellent excellent of enantiomericchiralenantiomeric 1,4‐pentandiol excess excess [43 [43].]. with a laccase/(2,2,6,6‐Tetramethylpiperidin‐1‐yl)oxyl) TEMPO‐catalyzed oxidation reaction giving rise to both antipodes of γ‐valerolactone in quantitative yield and excellent enantiomeric excess [43].

Scheme 6. One‐pot synthesis of 1,4‐pentanediol and concomitant oxidation triggered by the catalytic Scheme 6. One-pot synthesis of 1,4-pentanediol and concomitant oxidation triggered by the catalytic system laccase/TEMPO towards enantiopure γ‐γ valerolactone. systemScheme laccase/TEMPO 6. One‐pot synthesis towards of enantiopure1,4‐pentanediol-valerolactone. and concomitant oxidation triggered by the catalytic systemMetal‐ catalyzedlaccase/TEMPO cycloisomerization towards enantiopure of γ‐ γ‐alkynoicvalerolactone. acids provides an efficient entry to cyclic enol‐ lactonesMetal-catalyzed [44–47], which cycloisomerization could easily undergo of γa-alkynoic hydrolysis acidsreaction provides yielding anacyclic efficient keto‐acids entry as to cyclicproducts enol-lactonesMetal ‐catalyzed[48]. Following [44 cycloisomerization–47], which the couldmethodology of γ‐ easilyalkynoic undergo acidsdescribed provides a hydrolysis above, an efficient reactionthe entryAu(III) yielding to cyclic‐catalyzed enol acyclic‐ keto-acidslactonescycloisomerization/hydrolysis as[44–47], products which [48 could]. Following ofeasily 4‐pentynoic undergo the methodology acid a hydrolysis into levulinic describedreaction acid wasyielding above, explored acyclic the (Scheme Au(III)-catalyzed keto‐acids 7) [49– as products [48]. Following the methodology described above, the Au(III)‐catalyzed cycloisomerization/hydrolysis51]. In this case, the best results of were 4-pentynoic obtained acid when into KAuCl levulinic4 was acid used was as exploredthe catalyst (Scheme (5 mol%)7)[ at49 50–51 ]. cycloisomerization/hydrolysis of 4‐pentynoic acid into levulinic acid was explored (Scheme 7) [49– ◦ In this°C in case, water the (the best use results of other were gold obtained (i.e., [AuCl(SMe2)]) when KAuCl or palladium4 was used (complex as the catalyst6) catalysts (5 mol%)and/or lower at 50 C in water51].reaction In (the this temperatures usecase, of the other best (30 goldresults °C) (i.e., yielded were [AuCl(SMe2)]) obtained mixtures when of products or KAuCl palladium 4containing was (complexused asboth the6 cyclic)catalyst catalysts enol (5‐ mol%)lactone and/or at and lower 50 °C in water (the use of other gold (i.e., [AuCl(SMe2)]) or palladium (complex 6) catalysts and/or lower reactionlevulinic temperatures acid). Next, (30 we◦ C)focused yielded on mixturesthe design of of products a new one containing‐pot process both in cyclic which enol-lactone the obtained and reaction temperatures (30 °C) yielded mixtures of products containing both cyclic enol‐lactone and levuliniclevulinic acid). acid could Next, be we enantioselectively focused on the reduced design ofby aKREDs, new one-pot employing process directly in the which reaction the obtainedmedia levulinic acid). Next, we focused on the design of a new one‐pot process in which the obtained levuliniccoming acid from could the beAu(III) enantioselectively‐catalyzed reaction reduced (Scheme by KREDs, 7) [29]. employing Unfortunately, directly KAuCl the4 reaction eroded mediathe levulinic acid could be enantioselectively reduced by KREDs, employing directly the reaction media comingcatalytic from activity the Au(III)-catalyzed of the biocatalyst, reaction giving (Scheme rise to7 )[an 29incomplete]. Unfortunately, reduction KAuCl of levuliniceroded acid the catalytic(50% coming from the Au(III)‐catalyzed reaction (Scheme 7) [29]. Unfortunately, KAuCl4 4 eroded the activitymaximum). of the This biocatalyst, shortcoming giving was rise easily to an by‐ incompletepassed just by reduction the addition of levulinic of a coordinating acid (50% solvent maximum). (i.e., catalyticDMSO in activity a 5% vof/v )the to biocatalyst,the reaction giving media, rise rendering to an incomplete the enantiopure reduction γ‐hydroxyvaleric of levulinic acid acid (50% in This shortcoming was easily by-passed just by the addition of a coordinating solvent (i.e., DMSO in a maximum).quantitative This yield, shortcoming employing wasa one easily‐pot metal/biocatalyzedby‐passed just by the procedure. addition of a coordinating solvent (i.e., 5%DMSOv/v) to in the a reaction5% v/v) media,to the reaction rendering media, the enantiopure rendering theγ-hydroxyvaleric enantiopure γ‐ acidhydroxyvaleric in quantitative acid yield,in employingquantitative a one-pot yield, employing metal/biocatalyzed a one‐pot metal/biocatalyzed procedure. procedure.

Scheme 7. Enantioselective one‐pot conversion of 4‐pentynoic acid into γ‐hydroxyvaleric acid in

aqueous media through a chemoenzymatic cycloisomerization/hydrolysis/bioreduction process. SchemeScheme 7. 7.Enantioselective Enantioselective one-pot one‐pot conversionconversion of 4 4-pentynoic‐pentynoic acid acid into into γ‐γhydroxyvaleric-hydroxyvaleric acid acid in in aqueousaqueousFinally, media mediathis through onethrough‐pot a chemoenzymaticaprotocol chemoenzymatic (cycloisomerization/hydrolysis/bioreduction cycloisomerization/hydrolysis/bioreduction cycloisomerization/hydrolysis/bioreduction of process. alkynes) process. was extended to other tethered nucleophiles, namely the conversion of alkynyl amides into the Finally, this one‐pot protocol (cycloisomerization/hydrolysis/bioreduction of alkynes) was correspondingFinally, this γ‐ one-potketo amides protocol [52], through (cycloisomerization/hydrolysis/bioreduction the hydrolysis of the transiently‐formed cyclic of alkynes) alkylidene was extendedlactam (Scheme to other 8A) tethered[53]. In thisnucleophiles, case, the cycloisomerization/hydrolysis namely the conversion of ofalkynyl N‐tosylpent amides‐4 ‐ynamideinto the extendedcorresponding to other γ‐keto tethered amides nucleophiles, [52], through the namely hydrolysis the of conversion the transiently of‐ alkynylformed cyclic amides alkylidene into the could be effectively accomplished by KAuCl4 (5 mol%) in water at 50 °C, yielding the corresponding corresponding γ-keto amides [52], through the hydrolysis of the transiently-formed cyclic alkylidene lactam4‐oxo‐N (Scheme‐tosylpentanamide 8A) [53]. In in this quantitative case, the yieldcycloisomerization/hydrolysis after 5 h of reaction [29]. However, of N‐tosylpent in this‐4 particular‐ynamide lactam (Scheme8A) [ 53]. In this case, the cycloisomerization/hydrolysis of N-tosylpent-4-ynamide couldcase, only be effectively one KRED accomplished was able to giveby KAuCl rise to4 (5the mol%) desired in γ‐ waterhydroxy at 50 amide°C, yielding in good the yield corresponding (96%) and could be effectively accomplished by KAuCl (5 mol%) in water at 50 ◦C, yielding the corresponding 4excellent‐oxo‐N‐tosylpentanamide enantiomeric excess in quantitative(99%). This unexpected yield4 after 5 setback h of reaction could [29].be straightforwardly However, in this eludedparticular by case, only one KRED was able to give rise to the desired γ‐hydroxy amide in good yield (96%) and

excellent enantiomeric excess (99%). This unexpected setback could be straightforwardly eluded by

Catalysts 2018, 8, 75 8 of 28

4-oxo-N-tosylpentanamide in quantitative yield after 5 h of reaction [29]. However, in this particular case, only one KRED was able to give rise to the desired γ-hydroxy amide in good yield (96%) andCatalysts excellent 2018, 8 enantiomeric, 74 excess (99%). This unexpected setback could be straightforwardly8 of 28 eluded by designing an intermolecular cascade cyclization process between 4-pentynoic acid and a designing an intermolecular cascade cyclization process between 4‐pentynoic acid and a variety of variety of functionalized anilines, through initial Au(III)-catalyzed cycloisomerization of the alkynoic functionalized anilines, through initial Au(III)‐catalyzed cycloisomerization of the alkynoic acid and acid and simultaneous nucleophilic aperture of the transiently-obtained cyclic enol-lactone by the simultaneous nucleophilic aperture of the transiently‐obtained cyclic enol‐lactone by the aromatic γ aromaticamine amineunder underneat conditions neat conditions (Scheme (Scheme 8B). 8Lastly,B). Lastly, the theobtained obtained γ‐keto-keto amides amides (via (via the the cycloisomerization/aminolysiscycloisomerization/aminolysis procedure)procedure) were were successfully successfully transformed transformed into into the the corresponding corresponding enantiopureenantiopureγ-hydroxy γ‐hydroxy amides amides by by adding adding KREDs KREDs toto the reaction media media [29]. [29].

SchemeScheme 8. (8.A ()A Enantioselective) Enantioselective one-pot one‐pot conversion conversion of N‐-tosylpent-4-ynamidetosylpent‐4‐ynamide into into γ‐γhydroxy-hydroxy amide amide in aqueous media through a chemoenzymatic cycloisomerization/hydrolysis/bioreduction process. (B) in aqueous media through a chemoenzymatic cycloisomerization/hydrolysis/bioreduction process. Chemoenzymatic one‐pot conversion of 4‐pentynoic acid into enantiopure γ‐hydroxy amides (B) Chemoenzymatic one-pot conversion of 4-pentynoic acid into enantiopure γ-hydroxy amides through the combination of metal‐catalyzed cycloisomerization/aminolysis and biocatalyzed through the combination of metal-catalyzed cycloisomerization/aminolysis and biocatalyzed reactions. reactions.

3. Metal-Catalyzed3. Metal‐Catalyzed Hydrogenations Hydrogenations Combined Combined with Bioreductions, Hydrogen Hydrogen-Generating‐Generating Living Living MicroorganismsMicroorganisms and and Biooxidations Biooxidations Metal-catalyzedMetal‐catalyzed hydrogenations hydrogenations (both (both in in homogeneoushomogeneous or or heterogeneous heterogeneous conditions) conditions) are are among among thethe most most frequently frequently encountered encountered transformationstransformations in chemical synthesis synthesis [54,55]. [54,55 ].In Inthis this sense, sense, heterogeneousheterogeneous hydrogenation hydrogenation is is mainlymainly usedused in the production of of large large-scale‐scale chemical chemical products products (NH(NH3, MeOH3, MeOH or or cyclohexane, cyclohexane, amongamong others),others), whereas homogeneous homogeneous hydrogenation hydrogenation is isusually usually employedemployed in in the the synthesis synthesis of of finefine chemical products products (drugs, (drugs, hormones, hormones, fragrances, fragrances, etc.). etc.). Bearing Bearing in in mind the the fact fact that that hydrogenation hydrogenation (as a metal (as a‐catalyzed metal-catalyzed reduction reductionwith H2) is one with of Hthe2) most is one studied of the mostreactions studied in reactionsaqueous media in aqueous (since 1960–1970) media (since [56], 1960–1970) is not surprising [56], to is find not surprisingin the literature to find several in the literaturereports severalon the reports combination on the of combination metal‐catalyzed of metal-catalyzed hydrogenations hydrogenations in water with in waterdifferent with differentbiotransformations. biotransformations. Thus, this Thus, section this sectioncovers the covers progress the progress made in made the incombination the combination of the of theaforementioned aforementioned reactions reactions in inwater. water.

3.1.3.1. Combination Combination of of Pd-Nanoparticles-Catalyzed Pd‐Nanoparticles‐Catalyzed HydrogenationHydrogenation of of Azides Azides and and Alcohol‐Dehydrogenase‐ Alcohol-Dehydrogenase-CatalyzedCatalyzed Reduction of Azido‐Ketones Reduction in Water of Azido-Ketones in Water MetallicMetallic nanoparticles nanoparticles (NPs) (NPs) have have emerged emerged as a sustainable alternative alternative to to conventional conventional metallic metallic catalysts,catalysts, as as they they usually usually combine combine the the advantages advantages of heterogeneous heterogeneous (insolubility (insolubility in in the the reaction reaction media media permitspermits an an easy easy separation) separation) and and homogeneous homogeneous (high surface surface area area increases increases the the contact contact with with the the reactants) traditional catalysts [57]. In this sense, Schritttwieser, Kroutil, Hollmann and co‐workers reactants) traditional catalysts [57]. In this sense, Schritttwieser, Kroutil, Hollmann and co-workers explored the activity of lignin‐stabilized palladium nanoparticles (Pd‐NPs) in the hydrogenation of explored the activity of lignin-stabilized palladium nanoparticles (Pd-NPs) in the hydrogenation 2‐azido‐1‐alcohols as a straightforward route to racemic 1,2‐amino alcohols by employing H2 (10 bar) of 2-azido-1-alcohols as a straightforward route to racemic 1,2-amino alcohols by employing H2 as the reducing agent, in a phosphate buffer and at 30 °C, which◦ are the reaction conditions required (10for bar the) as subsequent the reducing biocatalytic agent, in step a phosphate (asymmetric buffer bioreduction and at 30 ofC, 2 which‐azido areketones the reactionwith ADH) conditions [58]. requiredHaving for identified the subsequent the conditions biocatalytic to obtain step the desired (asymmetric 1,2‐amino bioreduction alcohols in ofpure 2-azido form, the ketones authors with ADH)next [ 58extended]. Having their identified studies to the the conditions bioreduction to obtain of 2‐azido the desired ketones 1,2-amino mediated alcoholsby 79 different in pure and form, thecommercially authors next‐ extendedavailable ADHs their studies and four to bacterial the bioreduction ADH (ADH of 2-azido‐A from ketones Rhodococcus mediated ruber DSM by 79 44541, different Tb‐ADH from Thermoanaerobium brockii, Lk‐ADH from Lactobacillus kefir and Lb‐ADH from Lactobacillus brevis) employing iPrOH as the hydrogen source and NADH or NADPH as co‐factors.

Catalysts 2018, 8, 75 9 of 28 and commercially-available ADHs and four bacterial ADH (ADH-A from Rhodococcus ruber DSM 44541, Tb-ADH from Thermoanaerobium brockii, Lk-ADH from Lactobacillus kefir and Lb-ADH from i LactobacillusCatalysts 2018 brevis), 8, 74 employing PrOH as the hydrogen source and NADH or NADPH as co-factors.9 of 28 From this parametrization study, ADH-A emerged as the best biocatalyst in terms of reaction yield, enantiomericFrom this parametrization excess, enzyme study, loading ADH and‐A emerged substrate as concentration. the best biocatalyst With in both terms synthetic of reaction procedures yield, independentlyenantiomeric optimized,excess, enzyme the authorsloading and explored substrate a concurrent concentration. one-pot With process both synthetic with both procedures ADH and theindependently Pd-NPs working optimized, simultaneously. the authors However, explored a and concurrent despite one the‐pot compatibility process with of both the ADH catalysts and the in the samePd‐ reactionNPs working media, simultaneously. an important issueHowever, was and the formationdespite the of compatibility a side product of the (2,2-dimethyloxazolidine catalysts in the same in 4–10%).reaction media, This drawback an important could issue be was easily the avoided formation by of designing a side product a one-pot/two-step (2,2‐dimethyloxazolidine methodology in 4–10%). This drawback could be easily avoided by designing a one‐pot/two‐step methodology (Scheme9A) in which the bioreduction is performed under reduced pressure to eliminate acetone (Scheme 9A) in which the bioreduction is performed under reduced pressure to eliminate acetone of of the reaction mixture (byproduct of the ADH-catalyzed reaction). Moreover, a chemoenzymatic the reaction mixture (byproduct of the ADH‐catalyzed reaction). Moreover, a chemoenzymatic three‐ three-step transformation was also described in which the organic azide was in situ generated by a step transformation was also described in which the organic azide was in situ generated by a halogen‐ halogen-azide exchange reaction in different 1,2-halo-ketones promoted by the system NaN /KIcat azide exchange reaction in different 1,2‐halo‐ketones promoted by the system NaN3/KIcat (Scheme3 (Scheme9B). Finally,9B). Finally, this three this‐step three-step methodology methodology was applied was for applied the asymmetric for the asymmetric synthesis of synthesis the antiviral of the antiviral(HIV) ( (HIV)S)‐tembamide. (S)-tembamide.

Scheme 9. (A) Chemoenzymatic one‐pot/two‐step conversion of 2‐azido ketones into enantiopure 1,2‐ Scheme 9. (A) Chemoenzymatic one-pot/two-step conversion of 2-azido ketones into enantiopure amino alcohols through the combination of Pd‐NP‐catalyzed hydrogenation and asymmetric 1,2-amino alcohols through the combination of Pd-NP-catalyzed hydrogenation and asymmetric bioreduction (ADH). (B) Chemoenzymatic one‐pot/three‐steps conversion of 2‐halo ketones into bioreduction (ADH). (B) Chemoenzymatic one-pot/three-steps conversion of 2-halo ketones into enantiopure 1,2‐amino alcohols. enantiopure 1,2-amino alcohols.

3.2. Assembly of Pd‐Catalyzed Hydrogenation of Olefins and Living‐Microorganism‐H2‐Generation 3.2.(Escherichia Assembly of coli) Pd-Catalyzed in Aqueous HydrogenationMedia of Olefins and Living-Microorganism-H2-Generation (Escherichia coli) in Aqueous Media Going one step further in the combination of both metal‐catalyzed hydrogenation reactions and biocatalysis,Going one Balskus step further and co in‐workers the combination have demonstrated of both metal-catalyzed the possibility to hydrogenation implement a Pd reactions‐catalyzed and biocatalysis,hydrogenation Balskus of andalkenes co-workers in which have the demonstratedhydrogen gas the(H2 possibility) was generated to implement in situ aby Pd-catalyzed a living hydrogenationmicroorganism of [59]. alkenes Firstly, in the which authors the assayed, hydrogen as a model gas (H reaction,2) was the generated hydrogenation in situ of the by water a living‐ microorganismsoluble alkene [ caffeic59]. Firstly, acid catalyzed the authors by the assayed, Royer palladium as a model catalyst reaction, [60,61] the in a hydrogenation reaction media able of the water-solubleto allow the alkenegrowth caffeicof Escherichia acid catalyzedcoli DD‐2 (optical by the density Royer (OD) palladium = 0.4), catalystwhich is responsible [60,61] in a for reaction the mediaproduction able to of allow hydrogen the growth from glucose of Escherichia employing coli anDD-2 inducible (optical pathway density involving (OD) = ferredoxin, 0.4), which a is responsiblepyruvate forferredoxin the production oxidoreductase of hydrogen and a from[Fe‐Fe] glucose hydrogenase employing [62] an(Scheme inducible 10A). pathway To boost involving the in ferredoxin,situ hydrogen a pyruvate generation ferredoxin (by increasing oxidoreductase the amount and of functional a [Fe-Fe] [Fe hydrogenase‐Fe] hydrogenase [62] generated (Scheme 10in A). To boostcells [63]), the in both situ iron hydrogen and casamino generation acids (by were increasing added to the the amount reaction of media. functional Under [Fe-Fe] these hydrogenaseoptimized generatedconditions, in cells the [63caffeic]), both acid iron was and casaminoquantitatively acids hydrogenated were added tointo the reactionthe desired media. alkane Under (3,4 these‐ optimizeddihydroxyhydrocinnamic conditions, the acid) caffeic after acid 18 wash of incubation quantitatively at 37 °C. hydrogenated Notably, the reaction into the was desired scaled alkane up to 1.6 g (9 mmol) of caffeic acid in just one batch of reaction. Moreover, the process was extended to (3,4-dihydroxyhydrocinnamic acid) after 18 h of incubation at 37 ◦C. Notably, the reaction was scaled other functionalized alkenes finding that the metal‐/bio‐catalytic hydrogenation system tolerates the up to 1.6 g (9 mmol) of caffeic acid in just one batch of reaction. Moreover, the process was extended presence of esters, nitriles, amides or alcohols as substituents in the starting olefins (Scheme 10B). to other functionalized alkenes finding that the metal-/bio-catalytic hydrogenation system tolerates Finally, not only alkenes, but also alkynes (i.e., phenylpropiolic acid) could be successfully reduced theinto presence the corresponding of esters, nitriles, alkane amides (phenylpropanoic or alcohols acid). as substituents in the starting olefins (Scheme 10B). Finally, not only alkenes, but also alkynes (i.e., phenylpropiolic acid) could be successfully reduced into the corresponding alkane (phenylpropanoic acid).

Catalysts 2018, 8, 75 10 of 28 Catalysts 2018, 8, 74 10 of 28

SchemeScheme 10. 10.Hydrogenation Hydrogenation of of caffeic caffeic acid acid (A ()A and) and functionalized functionalized olefins olefins ( B(B)) in in cell cell grow grow media media ( E.(E. coli coli DD‐2) catalyzed by Royer catalyst (Pd‐NPs) employing H2 generated in situ by microbial DD-2) catalyzed by Royer catalyst (Pd-NPs) employing H2 generated in situ by microbial metabolism. metabolism.

3.3.3.3. Combination Combination of of Rh-Catalyzed Rh‐Catalyzed Hydrogenation Hydrogenation ofof Phenol, Double Double Biooxidations Biooxidations (Alcohol (Alcohol Dehydrogenase/Monooxygenase) and Lipase-Catalyzed Polymerization for the Chemoenzymatic Synthesis Dehydrogenase/Monooxygenase) and Lipase‐Catalyzed Polymerization for the Chemoenzymatic Synthesis of of Poly-ε-caprolactone Poly‐ε‐caprolactone Aromatic rings are usually difficult to saturate due to the concomitant loss of the aromaticity; Aromatic rings are usually difficult to saturate due to the concomitant loss of the aromaticity; thus,thus, this this hydrogenation hydrogenation reaction reaction is is commonly commonly effected with with heterogeneous heterogeneous catalysts. catalysts. In Inthis this sense, sense, commercially-availablecommercially‐available Rh/C Rh/C catalyst catalyst is is able able to to hydrogenate hydrogenate a variety a variety of aromaticof aromatic rings rings in water in water under mildunder reaction mild conditions reaction conditions [64]. Taking [64]. this Taking idea this into idea account, into Gröger,account, Liese Gröger, and Liese co-workers and co‐ designedworkers a chemoenzymaticdesigned a chemoenzymatic route for the route synthesis for the of synthesis poly-ε-caprolactone of poly‐ε‐caprolactone by utilizing by the utilizing following the following sequence of reactions:sequence (i) of aqueous reactions: Rh-catalyzed (i) aqueous Rh hydrogenation‐catalyzed hydrogenation of phenol (PhOH) of phenol into (PhOH) cyclohexanol; into cyclohexanol; (ii) alcohol dehydrogenase/monooxygenase(ii) alcohol dehydrogenase/monooxygenase biocatalyzed double biocatalyzed oxidation double of PhOH oxidation into ε -caprolactoneof PhOH into in ε‐ water; andcaprolactone (iii) lipase-catalyzed in water; and polymerization (iii) lipase‐catalyzed of ε-caprolactone polymerization in an of organic ε‐caprolactone solvent [65in ]an (Scheme organic 11 ). Metal-catalyzedsolvent [65] (Scheme hydrogenation 11). Metal of phenols‐catalyzed in waterhydrogenation and under of heterogeneousphenols in water conditions and under usually givesheterogeneous rise to both conditions cyclohexanone usually and gives cyclohexanol rise to both cyclohexanone as a mixture and of products. cyclohexanol However, as a mixture by using of theproducts. heterogeneous However, catalyst by Rh(0)-SBA-15using the heterogeneous (consisting ofcatalyst Rh-NPs Rh(0) entrapped‐SBA‐15 in(consisting mesoporous of silicaRh‐NPs [66 ]), PhOHentrapped could in be mesoporous converted into silica the [66]), desired PhOH cyclohexanol could be converted in almost into quantitative the desired conversioncyclohexanol (99%), in almost quantitative conversion (99%), in aqueous media ◦and under mild reaction conditions (75 °C in aqueous media and under mild reaction conditions (75 C and 1 bar of H2). This on-water-obtained cyclohexanoland 1 bar wasof H directly2). This double on‐water oxidized‐obtained into εcyclohexanol-caprolactone was (without directly further double isolation oxidized step) into by means ε‐ caprolactone (without further isolation step) by means of an alcohol dehydrogenase from Lactobacillus of an alcohol dehydrogenase from Lactobacillus kefir (Lk-ADH) and a cyclohexanone monooxygenase kefir (Lk‐ADH) and a cyclohexanone monooxygenase from Acinetobacter sp. NCIMB (CHMO), from Acinetobacter sp. NCIMB (CHMO), following a previously-described methodology reported by following a previously‐described methodology reported by the authors [67,68]. At this point, it is the authors [67,68]. At this point, it is worth noting that: (i) both enzymes just required O2 as oxidizing worth noting that: (i) both enzymes just required O2 as oxidizing reagent (avoiding co‐catalysts); and reagent (avoiding co-catalysts); and (ii) the desired ε-caprolactone was obtained in 90% yield after 24 h (ii) the desired ε‐caprolactone was obtained in 90% yield after 24 h of reaction. In order to avoid the ε of reaction.possible inhibition In order to effect avoid of ε‐ thecaprolactone possible inhibition on the biocatalyst effect of CHMO,-caprolactone an in situ on protocol the biocatalyst for the direct CHMO, anextraction in situ protocol of ε‐caprolactone for the direct from extraction the aqueous of ε -caprolactonereaction media from to an the organic aqueous solvent reaction was assayed media by to an organicemploying solvent a permeable was assayed polydimethylsiloxane by employing a permeable membrane. polydimethylsiloxane Finally, the ε‐caprolactone membrane. contained Finally, in thetheε-caprolactone organic phase contained (methylcyclohexane) in the organic could phase be utilized (methylcyclohexane) as starting material could for be a utilizedlipase‐catalyzed as starting materialpolymerization for a lipase-catalyzed towards poly‐ε‐ polymerizationcaprolactone. towards poly-ε-caprolactone.

Catalysts 2018, 8, 75 11 of 28 Catalysts 2018, 8, 74 11 of 28

Catalysts 2018, 8, 74 11 of 28

SchemeScheme 11. 11.Chemoenzymatic Chemoenzymatic conversion of of phenol phenol into into poly poly-‐ε‐caprolactoneε-caprolactone by combination by combination of: (i) of: (i) Rh-catalyzedSchemeRh‐catalyzed 11. Chemoenzymatic hydrogenation; hydrogenation; (ii) (ii)conversion LkLk‐ADH-ADH and of and phenol cyclohexanone cyclohexanone into poly monooxygenase‐ε‐ monooxygenasecaprolactone doubleby combination double biooxidation biooxidation of: (i)of cyclohexanol; and (iii) lipase‐catalyzed polymerization of ε‐caprolactone. of cyclohexanol;Rh‐catalyzed hydrogenation; and (iii) lipase-catalyzed (ii) Lk‐ADH polymerizationand cyclohexanone of εmonooxygenase-caprolactone. double biooxidation of cyclohexanol; and (iii) lipase‐catalyzed polymerization of ε‐caprolactone. 3.4. Combination of Rh‐Catalyzed Hydrogenation of Quinolines and Whole Cell‐Mediated Asymmetric 3.4. Combination of Rh-Catalyzed Hydrogenation of Quinolines and Whole Cell-Mediated Asymmetric Hydroxylation for the Chemoenzymatic Synthesis of 2‐Substituted Tetrahydroquinoline‐4‐ols Hydroxylation3.4. Combination for the of ChemoenzymaticRh‐Catalyzed Hydrogenation Synthesis of of 2-SubstitutedQuinolines and Tetrahydroquinoline-4-ols Whole Cell‐Mediated Asymmetric HydroxylationVery recently for the (2017), Chemoenzymatic Chen and Synthesis co‐workers of 2 ‐combinedSubstituted the Tetrahydroquinoline asymmetric transfer‐4‐ols hydrogenation Very recently (2017), Chen and co-workers combined the asymmetric transfer hydrogenation (ATH), a process efficiently carried out by transition metal complexes, with a further (ATH), aVery process recently efficiently (2017), carried Chen and out co by‐workers transition combined metal complexes, the asymmetric with a transfer further biohydroxylationhydrogenation (ATH),biohydroxylation a process performed efficiently by wholecarried cells out in aby sequential transition procedure metal (Schemecomplexes, 12) [69].with Thus, a severalfurther performed by whole cells in a sequential procedure (Scheme 12)[69]. Thus, several 2-substituted- biohydroxylation2‐substituted‐quinolines performed were by subjected whole cells in ain first a sequential instance procedureto ATH by (Scheme the action 12) of [69]. a metal Thus, complex several quinolines were subjected in a first instance to ATH by the action of a metal complex 2(10‐substituted mol%) prepared‐quinolines in situ were from subjected [Cp*RhCl in a2] 2first and instance Noyori’s to ligand ATH by((R the,R) ‐actionN‐(p‐toluenesulfonyl) of a metal complex‐1,2‐ (10 mol%) prepared in situ from [Cp*RhCl2]2 and Noyori’s ligand ((R,R)-N-(p-toluenesulfonyl)-1,2- (10diphenylethylenediamine) mol%) prepared in situ using from sodium[Cp*RhCl formate2]2 and asNoyori’s the hydrogen ligand source((R,R)‐ Nin‐ (acetatep‐toluenesulfonyl) buffer (pH ‐5)1,2 at‐ diphenylethylenediamine)diphenylethylenediamine)40 °C. After 12 h, the mixture using using was sodiumsodiumdiluted andformate formate incubated as as the the at hydrogen 30 hydrogen °C for sourcean sourceextra in 24 acetate in h prior acetate buffer to the buffer (pH addition 5) (pH at 5) ◦ ◦ at 4040of °C.cellsC. After After of 12Rhodococcus 12 h, h, the the mixture mixture equi was ZMU was diluted‐LK19. diluted and As incubated and a incubatedresult, at 30the °C at forcorresponding 30 anC extra for 24 an h extra chiralprior 24to 2 the‐ hsubstituted prior addition to the additionoftetrahydroquinoline cells of of cells Rhodococcus of Rhodococcus‐4‐ols equiwere equiZMU obtainedZMU-LK19.‐LK19. in Asmoderate a As result, a result,yields the the(14–47%) corresponding corresponding and enabled chiral chiral setting 2‐substituted 2-substituted up two tetrahydroquinoline-4-olstetrahydroquinolinestereocenters with excellent‐4‐ols were were diastereo obtained obtained‐ and inin enantion moderatemoderate‐selectivity yields yields (14–47%) (14–47%) in some andcases and enabled ( enableddr 99:1 settingand setting ee >99%).up up two two stereocentersstereocenters with with excellent excellent diastereo- diastereo‐ andand enantion-selectivity enantion‐selectivity in in some some cases cases (dr (dr 99:199:1 and and ee ee>99%).>99%).

Scheme 12. One‐pot/two‐step combination of Rh‐catalyzed asymmetric transfer hydrogenation and whole cell‐mediated asymmetric hydroxylation in aqueous media. SchemeScheme 12. 12.One-pot/two-step One‐pot/two‐step combination combination of Rh Rh-catalyzed‐catalyzed asymmetric asymmetric transfer transfer hydrogenation hydrogenation and and whole cell‐mediated asymmetric hydroxylation in aqueous media. 4. wholeCombination cell-mediated of Metal asymmetric‐Catalyzed hydroxylation Alkene Metathesis in aqueous in media. Water with Enzymatic Hydrolyses, 4.Epoxidations, Combination Decarboxylations of Metal‐Catalyzed and Alkene Oxidations/Aromatizations Metathesis in Water with Enzymatic Hydrolyses, 4. Combination of Metal-Catalyzed Alkene Metathesis in Water with Enzymatic Hydrolyses, Epoxidations, Decarboxylations and Oxidations/Aromatizations Epoxidations,Metal‐catalyzed Decarboxylations alkene metathesis and Oxidations/Aromatizations is one of the most efficient tools for accomplishing the formationMetal ‐ofcatalyzed new C‐ Calkene bonds metathesis [70–72]. In is this one sense, of the the most development efficient toolsof a plethorafor accomplishing of new metal the Metal-catalyzed alkene metathesis is one of the most efficient tools for accomplishing the formationcatalyst (usually of new based C‐C inbonds ruthenium) [70–72]. and In thisthe optimizationsense, the development of the reaction of aconditions plethora ofhas new led tometal the formation of new C-C bonds [70–72]. In this sense, the development of a plethora of new metal catalystestablishment (usually of basedalkene in metathesisruthenium) as and a generalthe optimization and reliable of the methodology reaction conditions in organic has synthesis.led to the catalystestablishmentSeveral (usually types of basedof alkenemetathesis in ruthenium)metathesis transformations as and a thegeneral optimization (RCM and reliable(ring of‐closing themethodology reaction metathesis) conditions in organicand CM has synthesis. led(cross to‐ the establishmentSeveralmetathesis), types of among alkeneof metathesis others) metathesis have transformations asbeen a general carried and out(RCM reliablein water (ring methodology by:‐closing (i) introducing metathesis) in organic modifications and synthesis. CM (cross in Several the‐ typesmetathesis),catalyst of metathesis structure; among transformations (ii) others) using haveco‐solvents; been (RCM carried or (ring-closing (iii) out employing in water metathesis) surfactants by: (i) introducing and [73–75]. CM (cross-metathesis), Thus,modifications in this section, in among the others)catalystwe cover have structure; the been fruitful carried (ii) combination using out co in‐solvents; water of two by: ordifferent (iii) (i) employing introducing Ru‐catalyzed surfactants modifications metathesis [73–75]. protocols in Thus, the catalyst (RCM in this and section, structure; CM) (ii)wein using aqueouscover co-solvents; the mediafruitful or withcombination (iii) several employing ofbiocatalyzed two surfactants different organic Ru [73‐catalyzed–75 reactions]. Thus, metathesis in [76–80]. this section, protocols Although we (RCM cover none and the of CM) fruitful the combinationindiscussed aqueous protocols of media two different withpermits several Ru-catalyzedthe synthesis biocatalyzed of metathesis enantiopure organic protocols reactions products, (RCM[76–80]. they andconstitute Although CM) in very aqueousnone important of mediathe withdiscussed several biocatalyzedprotocols permits organic the reactionssynthesis [of76 –enantiopure80]. Although products, none of they the discussedconstitute very protocols important permits

Catalysts 2018, 8, 75 12 of 28

Catalysts 2018, 8, 74 12 of 28 the synthesis of enantiopure products, they constitute very important contributions in the field of chemoenzymaticcontributions in cascade the field processes of chemoenzymatic performed cascade in aqueous processes media performed and are worth in aqueous mention media in this and review. are worth mention in this review. 4.1. Combination of Ru-Catalyzed Ring-Closing Metathesis of Diallyl Malonates or Anilines with Ester Hydrolysis4.1. Combination or Whole of Cell-Promoted Ru‐Catalyzed Oxidation/AromatizationRing‐Closing Metathesis of Diallyl Malonates or Anilines with Ester HydrolysisAt the endor Whole of 2011, Cell‐Promoted Gröger, Oxidation/Aromatization Schatz and co-workers illuminated the way to follow in the combinationAt the of end Ru-catalyzed of 2011, Gröger, metathesis Schatz of alkenesand co‐workers and biocatalysis illuminated in aqueous the way media, to followby reportingin the thecombination preparation of Ru of‐catalyzed cyclic malonic metathesis acid of monoestersalkenes and biocatalysis in water in through aqueous the media, amalgamation by reporting of ruthenium-catalyzedthe preparation of cyclic RCM malonic of diallyl acid malonates monoesters with in water the through subsequent the amalgamation hydrolysis promoted of ruthenium by‐ pig livercatalyzed esterase RCM (Scheme of diallyl 13)[76 malonates]. Firstly, thewith metal-catalyzed the subsequent ringhydrolysis closing promoted metathesis by of pig the liver desired esterase diallyl malonate(Scheme was 13) promoted [76]. Firstly, by the Grubbs metal II‐catalyzed catalyst inring water closing [81 ],metathesis either at theof the analytical desired (NMRdiallyl malonate tube) or the preparativewas promoted scale (5.0–7.0by Grubbs mL II of catalyst a 0.5 M in solution water of[81], diallyl either malonate), at the analytical finding (NMR excellent tube) conversions or the independentpreparative of scale the magnitude (5.0–7.0 mL of of the a 0.5 process M solution (Scheme of diallyl 13A). malonate), Secondly, the finding enzymatic excellent mono-hydrolysis conversions of theindependent corresponding of the cyclopentene magnitude dicarboxylateof the process was (Scheme parametrized 13A). Secondly, by employing the enzymatic a pig liver mono esterase‐ in water.hydrolysis An of important the corresponding finding was cyclopentene that the usedicarboxylate of tBuOH was as theparametrized co-solvent by unlocks employing the a desired pig t mono-hydrolysisliver esterase in (hampering water. An important both decarboxylation finding was that and the transesterification use of BuOH as side the co reactions)‐solvent unlocks and yields the the desired mono‐hydrolysis (hampering both decarboxylation and transesterification side reactions) desired cyclic malonic acid monoesters in high yield (92%) and excellent selectivity (100%, Scheme 13B). and yields the desired cyclic malonic acid monoesters in high yield (92%) and excellent selectivity The authors also investigated the compatibility of the Grubbs II catalyst and the enzyme (pig liver (100%, Scheme 13B). The authors also investigated the compatibility of the Grubbs II catalyst and the esterase) by studying the enzymatic hydrolysis in the presence of the ruthenium complex. Interestingly, enzyme (pig liver esterase) by studying the enzymatic hydrolysis in the presence of the ruthenium almostcomplex. the same Interestingly, enzymatic almost activity the was same observed enzymatic in the activity presence was or observed in the absence in the presence of Grubbs or II in catalyst. the Accordingly,absence of a Grubbs one-pot/two-step II catalyst. methodologyAccordingly, alloweda one‐pot/two the direct‐step conversion methodology of diallylallowed malonates the direct into cyclicconversion monoacid of diallyl esters inmalonates aqueous into media cyclic (Scheme monoacid 13C). esters in aqueous media (Scheme 13C).

SchemeScheme 13. 13.Ru-catalyzed Ru‐catalyzed ring-closing ring‐closing metathesis metathesis (RCM) ( (AA),), enzymatic enzymatic ester ester hydrolysis hydrolysis catalyzed catalyzed by by PLE (B) and one‐pot/two‐step combination of both in aqueous media (C). PLE (B) and one-pot/two-step combination of both in aqueous media (C). Recently, and following this idea (Ru‐catalyzed RCM + enzymatic organic transformations), Turner,Recently, Castagnolo and following and co‐workers this idea have (Ru-catalyzed reported the combination RCM + enzymatic of the Ru organic‐catalyzed transformations), ring‐closing Turner,metathesis Castagnolo of diallyl and co-workersanilines (to haveproduce reported the corresponding the combination 3‐pyrrolines) of the Ru-catalyzed and the subsequent ring-closing metathesisbiocatalytic of diallylaromatization anilines of (to the produce resulting the heterocycles corresponding (mediated 3-pyrrolines) by whole and cells the containing subsequent biocatalyticmonoamine aromatization oxidases MAO of the‐N resultingvariants D5, heterocycles D9 and D11 (mediated [82–84] or by the whole nicotine cells oxidase containing biocatalyst monoamine 6‐ oxidasesHDNO MAO-N (HDNO = variants 6‐hydroxy D5,‐D‐ D9nicotine and oxidase) D11 [82 –[85])84] for or the synthesis nicotine of oxidase pyrroles biocatalyst in aqueous 6-HDNO media (HDNO(Scheme = 6-hydroxy- 14) [77]. InD this-nicotine case, and oxidase) in contrast [85 ])to forthe aforementioned the synthesis ofresults pyrroles reported in by aqueous Gröger, mediathe (Schemeauthors 14 firstly)[77]. parametrized In this case, the and biocatalytic in contrast transformation, to the aforementioned thus studying results the reported aromatization by Gröger, of thedifferent authors 3 firstly‐pyrrolines parametrized promoted the by biocatalyticmonoamine oxidases transformation, MAO‐N thusor 6‐HDNO studying (Scheme the aromatization 14A). All the of differentenzymatic 3-pyrrolines studies were promoted carried by out monoamine at 37 °C, in oxidasesa buffer solution MAO-N (pH or 6-HDNO7.8) and using (Scheme DMF 14 asA). the All co‐ the solvent when necessary. The desired pyrroles were obtained in moderate to excellent yields enzymatic studies were carried out at 37 ◦C, in a buffer solution (pH 7.8) and using DMF as the depending on: (i) the substituents on the starting 3‐pyrrolines; and (ii) the nature of the monoamine

Catalysts 2018, 8, 75 13 of 28 co-solvent when necessary. The desired pyrroles were obtained in moderate to excellent yields dependingCatalysts 2018 on:, 8, (i) 74 the substituents on the starting 3-pyrrolines; and (ii) the nature of the monoamine13 of 28 oxidase (the best conversion was obtained when MAO-D5 was used). Once the parametrization study of theoxidase biocatalyzed (the best conversion aromatization was obtained was accomplished, when MAO‐D5 the was authors used). examined Once the parametrization the combination study of the Grubbsof the II-catalyzed biocatalyzed RCM aromatization of diallyl anilineswas accomplished, (Scheme 14 theB) withauthors the examined enzymatic the aromatization combination of the in situ-obtainedGrubbs II‐catalyzed 3-pyrrolines, RCM findingof diallyl a anilines dramatic (Scheme effect 14B) of the with co-solvent the enzymatic employed. aromatization Thus, when of the DMF in situ‐obtained 3‐pyrrolines, finding a dramatic effect of the co‐solvent employed. Thus, when DMF was utilized, only 10% of the pyrroline was obtained. This result was attributed to an erosion of the was utilized, only 10% of the pyrroline was obtained. This result was attributed to an erosion of the catalytic activity of monoxide aminase (MAO-D5) due to the presence of the ruthenium catalyst in catalytic activity of monoxide aminase (MAO‐D5) due to the presence of the ruthenium catalyst in the reaction medium. This unexpected shortcoming was circumvented by the use of a non-water the reaction medium. This unexpected shortcoming was circumvented by the use of a non‐water miscible co-solvent (isooctane), which prevents the deactivation of the enzyme (suspended in water) miscible co‐solvent (isooctane), which prevents the deactivation of the enzyme (suspended in water) as theas the ruthenium ruthenium catalyst catalyst remained remained in in the the immiscible immiscible organic phase. phase. Under Under these these biphasic biphasic reaction reaction conditionsconditions (Scheme (Scheme 14 14C),C), this this chemoenzymatic chemoenzymatic cascade was was extended extended to to a avariety variety of of diallyl diallyl amines amines givinggiving rise rise to theto the corresponding corresponding pyrroles pyrroles in in moderate moderate toto good yields.

SchemeScheme 14. 14. EnzymaticEnzymatic aromatization (A (A), ),Ru Ru-catalyzed‐catalyzed ring ring-closing‐closing metathesis metathesis (RCM) (RCM) (B), and ( B), andchemoenzymatic chemoenzymatic cascade cascade reaction reaction for the for synthesis the synthesis of pyrroles of pyrroles through their through combination their combination in aqueous in aqueousmedia media (C). (C).

4.2. Assembly of Ru‐Catalyzed Cross‐Metathesis (RCM) of Functionalized Olefins with Enzymatic 4.2. Assembly of Ru-Catalyzed Cross-Metathesis (RCM) of Functionalized Olefins with Enzymatic Decarboxylation or P450 Promoted Epoxidation Reactions Decarboxylation or P450 Promoted Epoxidation Reactions Not only the Ru‐catalyzed ring‐closing metathesis (RCM) of different diallyl compounds, but Not only the Ru-catalyzed ring-closing metathesis (RCM) of different diallyl compounds, but also also the Ru‐catalyzed cross‐metathesis (CM) of functionalized olefins has been productively theassembled Ru-catalyzed with cross-metathesis different biotransformations (CM) of functionalized [78–80]. Thus, olefins the hasfirst been work productively in this field was assembled reported with differentby Zhao, biotransformations Hartwig and co‐workers [78–80]. in Thus, 2014 by the describing first work the in combination this field was of reported the ruthenium by Zhao,‐catalyzed Hartwig andCM co-workers between 10 in‐undecenoic 2014 by describing acid and trans the‐3 combination‐hexene with ofthe the subsequent ruthenium-catalyzed epoxidation of CMthe in between situ‐ 10-undecenoicgenerated 10‐ acidtridecenoic and trans acid-3-hexene using P450 with BM3 the from subsequent Bacillus megaterium epoxidation in a ofbiphasic the in medium situ-generated [78]. 10-tridecenoicPrior to this acidstudy, using the authors P450 BM3 assessed from thatBacillus P450 megaterium BM3 (combinedin a biphasic with a phosphite medium dehydrogenase [78]. Prior to this study,regeneration the authors system) assessed reacted that P450with BM3more (combined than five‐ withfold apreference phosphite for dehydrogenase the epoxidation regeneration of 10‐ system)tridecenoic reacted acid with over more10‐undecenoic than five-fold acid. Based preference on these for results, the epoxidationdifferent variants of 10-tridecenoic of the Hoveyda– acid overGrubbs 10-undecenoic II catalysts acid. (several Based Hoveyda on these‐Grubbs results, II catalysts different have variants been of described the Hoveyda–Grubbs as air stable II catalystscompounds (several able Hoveyda-Grubbs to operate in protic IImedia catalysts [86,87]) have were been tested described in a biphasic as air isooctane/aqueous stable compounds buffer able to operatemedium incontaining protic media P450 BM3. [86,87 Thus,]) were the testedbest results in a were biphasic observed isooctane/aqueous for the ruthenium buffer Complex medium 7 containing(Scheme P450 15), which BM3. Thus,gives therise bestto an results equilibrium were observed mixture containing for the ruthenium the expected Complex cross7‐metathesis(Scheme 15 ), whichproducts gives rise(cis‐ toand an equilibriumtrans‐10‐tridecenoic mixture acids) containing and the the corresponding expected cross-metathesis self‐assembly products product. (cis The- and utilization of this biphasic catalytic system permitted the metathesis reactions to take place in the trans-10-tridecenoic acids) and the corresponding self-assembly product. The utilization of this biphasic organic phase, while the biocatalyzed epoxidation occurred in the buffer solution. Further catalytic system permitted the metathesis reactions to take place in the organic phase, while the parametrization studies, related to the concentration of the fatty acid and the ratio of trans‐3‐hexene biocatalyzed epoxidation occurred in the buffer solution. Further parametrization studies, related to and 10‐undecenoic acid, were needed to achieve yields up to 90% of the final epoxide product after the concentration of the fatty acid and the ratio of trans-3-hexene and 10-undecenoic acid, were needed 12 h of reaction. Finally, the tandem olefin cross‐metathesis/epoxidation process was extended to the mixture 4‐butenyloxybenzoic acid/trans‐3‐hexene.

Catalysts 2018, 8, 75 14 of 28 to achieve yields up to 90% of the final epoxide product after 12 h of reaction. Finally, the tandem olefin cross-metathesis/epoxidation process was extended to the mixture 4-butenyloxybenzoic acid/Catalyststrans 2018-3-hexene.,, 8,, 74 14 of 28

SchemeScheme 15. 15.Chemoenzymatic Chemoenzymatic tandem tandem olefin olefin cross-metathesis/epoxidation cross‐metathesis/epoxidation of of 10 10-undecenoic‐undecenoic acid acid with with trans‐3‐hexene in a biphasic reaction media catalyzed by Hoveyda–Grubbs II Catalyst 6 and transtrans-3-hexene‐3‐hexene in ain biphasic a biphasic reaction reaction media media catalyzed catalyzed by Hoveyda–Grubbs by Hoveyda–Grubbs II Catalyst II Catalyst6 and P450 6 and BM3. P450 BM3.

MoreMore recently, recently, Kourist Kourist and and co-workers co‐workers werewere ableable to couple couple the the enzymatic enzymatic decarboxylation decarboxylation of of differentdifferent hydroxycinnamic hydroxycinnamic acidsacids with with a a ruthenium ruthenium catalyzed catalyzed self‐ self-assemblyassembly metathesis metathesis of the in of situ the‐ in situ-generatedgenerated functionalized functionalized styrenes styrenes [79] [79 (Scheme] (Scheme 16). 16 Firstly,). Firstly, the the biocatalyzed biocatalyzed decarboxylation decarboxylation of of severalseveral hydroxycinnamic hydroxycinnamic acids acids promoted promoted byby thethe co co-factor-free‐factor‐free phenolic phenolic acid acid decarboxylase decarboxylase (bsPAD) (bsPAD) waswas studied studied in in a potassium a potassium phosphate phosphate buffer buffer (KPi (KPi pHpH 6) at at 30 30 °C◦C (Scheme (Scheme 16A). 16A). Under Under these these reaction reaction conditions,conditions, the the corresponding corresponding styrenes styrenes were were obtained obtained in in excellent excellent yields yields (80–95%). (80–95%). Posteriorly, and as previouslyas previously observed observed by Gröger by Gröger [76 [76]] and and Castagnolo Castagnolo [ 77[77],], it it waswas found that that the the best best results results for for the the Ru-catalyzedRu‐catalyzed self-assembly self‐assembly metathesismetathesis of of the the resulting resulting styrenes styrenes were were obtained obtained when when water waterand air and‐ air-toleranttolerant Grubbs Grubbs II II (Scheme (Scheme 13) 13 )or or Hoveyda–Grubbs Hoveyda–Grubbs II II7 7(Scheme(Scheme 15) 15 catalysts) catalysts were were employed employed (Scheme 16B). Once the enzymatic decarboxylation and the ruthenium‐catalyzed reactions were (Scheme(Scheme 16 B).16B). Once Once the the enzymatic enzymatic decarboxylation decarboxylation and the the ruthenium ruthenium-catalyzed‐catalyzed reactions reactions were were independently studied, the efforts were focused on the design of a one‐pot/one‐step reaction. independentlyindependently studied, studied, the the efforts efforts were were focused focused on the on design the design of a one-pot/one-step of a one‐pot/one reaction.‐step reaction. However, However, the authors observed that: (i) the ruthenium catalysts did not show satisfactory activity the authors observed that: (i) the ruthenium catalysts did not show satisfactory activity under under aqueous conditions; and (ii) the catalytic activity of the enzyme was significantly reduced in aqueous conditions; and (ii) the catalytic activity of the enzyme was significantly reduced in the the presence of an organic solvent. Thus, these drawbacks could be addressed with the following presence of an organic solvent. Thus, these drawbacks could be addressed with the following settings: settings: (i) chemoenzymatic reaction was performed in a sequential fashion (one‐pot/two‐step (i) chemoenzymatic reaction was performed in a sequential fashion (one-pot/two-step methodology) methodology) in an organic solvent (MTBE, methyl tert‐butyl ether); (ii) encapsulation of the in andecarboxylase organic solvent in a PVA/PEG (MTBE, methylcryogel (tertbsPAD@PVA/PEG)-butyl ether); (ii) [88]; encapsulation and (iii) an extra of the intermediate decarboxylase drying in a PVA/PEGstep (employing cryogel (anhydrousbsPAD@PVA/PEG) MgSO4) before [88]; and the (iii) metathesis an extra reaction intermediate (Scheme drying 16C). step Finally, (employing this anhydrouscombination MgSO of 4 reactions) before the has metathesis been very reactionrecently (Schemeextended 16 byC). the Finally, same authors this combination to ω‐ ω‐hydroxy of reactions fatty hasacids been [80]. very recently extended by the same authors to ω-hydroxy fatty acids [80].

Scheme 16. Decarboxylation of acids by phenolic acid decarboxylase (bsPAD) (A), Ru‐catalyzed self‐ Scheme 16. Decarboxylation of acids by phenolic acid decarboxylase (bsPAD) (A), Ru-catalyzed assembly metathesis (B), and chemoenzymatic one‐pot/two‐step combination of encapsulated self-assembly metathesis (B), and chemoenzymatic one-pot/two-step combination of encapsulated phenolic acid decarboxylase (bsPAD) and Ru‐catalyzed self‐assembly metathesis (C). phenolic acid decarboxylase (bsPAD) and Ru-catalyzed self-assembly metathesis (C). 5. Combination of Copper‐Catalyzed Click Chemistry Cycloadditions (CuAAC) with Biocatalytic Ring‐Opening Reactions or Bioreductions The independent findings by Meldal [89] and Sharpless [90] on the regioselective Copper(I)‐ catalyzed Azide‐Alkyne Cycloadditions (CuAAC) permitted the discovery of a highly‐reliable tool

Catalysts 2018, 8, 75 15 of 28

5. Combination of Copper-Catalyzed Click Chemistry Cycloadditions (CuAAC) with Biocatalytic Ring-Opening Reactions or Bioreductions The independent findings by Meldal [89] and Sharpless [90] on the regioselective Copper(I)-catalyzed Azide-Alkyne Cycloadditions (CuAAC) permitted the discovery of a highly-reliable tool for the synthesis of 1,2,3-triazoles under “click chemistry” conditions [91]. ThisCatalysts copper-catalyzed 2018, 8, 74 cycloaddition reaction presents several attractive features (water tolerability,15 of 28 usually conducted at room temperature and orthogonality) that make this transformation an ideal for the synthesis of 1,2,3‐triazoles under “click chemistry” conditions [91]. This copper‐catalyzed candidate for the design of metal- and bio-catalyzed tandem transformation in aqueous media. Thus, cycloaddition reaction presents several attractive features (water tolerability, usually conducted at weroom review temperature in this section and orthogonality) the amalgamation that make of this CuAAC transformation reactions an in ideal aqueous candidate media for withthe design several biocatalyticof metal‐ and transformations, bio‐catalyzed liketandem the epoxidetransformation ring-opening in aqueous [92] media. or the Thus, enantioselective we review in bioreduction this section of prochiralthe amalgamation ketones [93 of,94 CuAAC]. reactions in aqueous media with several biocatalytic transformations, like the epoxide ring‐opening [92] or the enantioselective bioreduction of prochiral ketones [93,94]. 5.1. Combination of Biocatalytic Epoxide Ring-Opening (Halohydrin Dehalogenase) with Cu(I)-Catalyzed Cycloaddition of 1,2-Azido Alcohols and Terminal Alkynes in Aqueous Media 5.1. Combination of Biocatalytic Epoxide Ring‐Opening (Halohydrin Dehalogenase) with Cu(I)‐Catalyzed CycloadditionThe first of reported 1,2‐Azido exampleAlcohols and of Terminal the sequential Alkynes in Aqueous combination Media of CuAAC reactions and biotransformationsThe first reported in aqueous example media of was the described sequential by combination the Nobel Prize of laureateCuAAC Prof.reactions Ben Feringaand andbiotransformations co-workers, through in aqueous studying media the was one-pot described combination by the Nobel of the Prize enantioselective laureate Prof. Ben azidolysis Feringa of functionalizedand co‐workers, styrene through oxides studying (performed the one by‐pot halohydrin combination dehalogenase of the enantioselective (HheC) from azidolysisAgrobacterium of radiobacterfunctionalized) with styrene the subsequent oxides (performed CuAAC by reactionhalohydrin with dehalogenase terminal (HheC) alkynes from to Agrobacterium produce chiral hydroxyl-triazolesradiobacter) with the with subsequent excellent CuAAC enantiomeric reaction excess with terminal [92]. In alkynes this work, to produce the authors chiral startedhydroxyl their‐ investigationstriazoles with by excellent studying enantiomeric the catalytic excess activity [92]. ofIn this a halohydrin work, the authors dehalogenase started their (HheC investigations with cysteine 153by mutated studying into the serinecatalytic [95 activity]) towards of a halohydrin the enantioselective dehalogenase azidolysis (HheC with of different cysteine 153 aromatic mutated epoxides into in theserine presence [95]) towards of a “click” the enantioselective catalytic system azidolysis containing of different CuSO aromatic4·5H2O, theepoxides required in the reducing presence agent of (sodiuma “click” ascorbate, catalytic NaAsc)system containing and Feringa‘s CuSO ligand4∙5H2O, MonoPhos the required in areducing potassium agent phosphate (sodium ascorbate, buffer (KPi) (SchemeNaAsc) 17 andA). Feringa‘s Under these ligand conditions, MonoPhos nearly in a potassium full conversion phosphate was buffer achieved (KPi) for (Schemep-nitro 17A). styrene Under oxide withthese >99% conditions, and 83% nearlyee for full the conversion azido alcohol was achieved and the epoxide,for p‐nitro respectively. styrene oxide Having with >99% proven and 83% that ee the for the azido alcohol and the epoxide, respectively. Having proven that the biocatalyzed azidolysis biocatalyzed azidolysis is able to proceed in the presence of the copper catalyst, the one-pot ring is able to proceed in the presence of the copper catalyst, the one‐pot ring opening and subsequent opening and subsequent click reaction was attempted with the following findings: (i) the first step click reaction was attempted with the following findings: (i) the first step sustains its selectivity; and sustains its selectivity; and (ii) the click reaction (5 mol% of CuSO4·5H2O) is able to convert all the in (ii) the click reaction (5 mol% of CuSO4∙5H2O) is able to convert all the in situ‐generated azido alcohol situ-generatedinto the desired azido triazole. alcohol Finally, into the a desiredCu‐free triazole.click chemistry Finally, reaction a Cu-free was click reported chemistry by employing reaction was reportedhighly‐ bystrained employing alkynes highly-strained like cyclooctyne. alkynes like cyclooctyne.

Scheme 17. Azidolysis of styrene oxides (halohydrin dehalogenase, HheC) (A) and its Scheme 17. Azidolysis of styrene oxides (halohydrin dehalogenase, HheC) (A) and its chemoenzymatic chemoenzymatic one‐pot combination with a subsequent CuAAC (B) in aqueous media. one-pot combination with a subsequent CuAAC (B) in aqueous media. 5.2. Combination of Whole Cell‐Promoted Bioreduction/Azidolysis or ADH Biocatalyzed Reactions with 5.2.Cu(I) Combination‐Catalyzed of Cycloaddition Whole Cell-Promoted in Aqueous Bioreduction/Azidolysis Media or ADH Biocatalyzed Reactions with Cu(I)-Catalyzed Cycloaddition in Aqueous Media After the previously‐mentioned work from Feringa’s group [92], the same authors decided to go oneAfter step the forward previously-mentioned by combining whole work cell from‐catalyzed Feringa’s tandem group conversion [92], the of same β‐halo authors ketones decided into to goenantiopure one step β‐ forwardazido alcohols by combining and subsequent whole CuAAC cell-catalyzed reaction tandem with PhC conversion≡CH [93]. In of theβ -halofirst step ketones of this sequence, prochiral β‐halo ketones were transformed directly into enantiopure β‐azido alcohols by employing engineered cells that overexpress the two enzymes used in this cascade biotransformation: (i) alcohol dehydrogenases (AdhT (an R‐selective alcohol dehydrogenase from Thermoanaerobacter sp.); or AdhL (an S‐selective alcohol dehydrogenase from Lactobacillus brevis)); and (ii) halohydrin dehalogenases (HheC (an R‐selective halohydrin dehalogenase from Agrobacterium radiobacter) or halohydrin dehalogenase from Mycobacterium sp.)). This tandem procedure was carried

Catalysts 2018, 8, 75 16 of 28 into enantiopure β-azido alcohols and subsequent CuAAC reaction with PhC≡CH [93]. In the first step of this sequence, prochiral β-halo ketones were transformed directly into enantiopure β-azido alcohols by employing engineered cells that overexpress the two enzymes used in this cascade biotransformation: (i) alcohol dehydrogenases (AdhT (an R-selective alcohol dehydrogenase from Thermoanaerobacter sp.); or AdhL (an S-selective alcohol dehydrogenase from Lactobacillus brevis)); and (ii) halohydrin dehalogenases (HheC (an R-selective halohydrin dehalogenase from Agrobacterium radiobacterCatalysts 2018) or, 8, halohydrin 74 dehalogenase from Mycobacterium sp.)). This tandem procedure16 of 28 was carried out: (i) in a biphasic reaction media based on a mixture of HEPES buffer (0.1 M pH 7.5, KOH,out: 1(i) mM in a biphasic MgSO4, reaction 1 mM ZnSOmedia4 based) and on octane; a mixture (ii) of at HEPES room buffer temperature; (0.1 M pH and 7.5, (iii) KOH, employing 1 mM isopropanolMgSO4, 1 formM regeneration ZnSO4) and of octane; the NADPH (ii) at room co-factor. temperature; Overnight and incubation (iii) employing of the reactions isopropanol under for the aforementionedregeneration conditionsof the NADPH permitted co‐factor. the synthesis Overnight of the incubation desired β -azidoof the alcohols reactions in full under conversion the (isolatedaforementioned yield 35–70%) conditions and enantioselectivities permitted the synthesis ranging of the from desired 96–99% β‐azidoee (Scheme alcohols 18 inA). full Finally, conversion and in (isolated yield 35–70%) and enantioselectivities ranging from 96–99% ee (Scheme 18A). Finally, and view of the previous positive combination of halohydrin dehalogenase and CuAAC reactions [92], in view of the previous positive combination of halohydrin dehalogenase and CuAAC reactions [92], the authors designed a new chemoenzymatic route for the direct conversion of β-halo ketones into the the authors designed a new chemoenzymatic route for the direct conversion of β‐halo ketones into above-mentioned enantioenriched β-hydroxy triazoles (Scheme 18B). In the parametrization studies the above‐mentioned enantioenriched β‐hydroxy triazoles (Scheme 18B). In the parametrization of thisstudies chemoenzymatic of this chemoenzymatic transformation, transformation, the addition the addition of octane of octane as an as organic an organic solvent solvent resulted resulted in a reductionin a reduction of the click of the reactivity click reactivity (probably (probably due to due extraction to extraction of the of PhC the≡ CHPhC≡ intoCH theinto organic the organic phase). Thisphase). unexpected This unexpected drawback drawback could be could evaded be just evaded by avoiding just by avoiding this co-solvent. this co‐solvent.

SchemeScheme 18. 18.Whole Whole Cell-Promoted Cell‐Promoted Bioreduction/Azidolysis Bioreduction/Azidolysis of of β‐βhalo-halo ketones ketones (A ()A and) and its its one one-pot‐pot combination with CuAAC reaction for the enantioenriched synthesis of β‐hydroxy triazoles in combination with CuAAC reaction for the enantioenriched synthesis of β-hydroxy triazoles in aqueous aqueous media (B). media (B). More recently, Gotor and co‐workers described a fully‐convergent one‐pot/two‐step procedure forMore the recently,synthesis Gotor of enantioenriched and co-workers 1,2,3 described‐triazole‐ aderived fully-convergent diols by combining one-pot/two-step a single procedurealcohol fordehydrogenase the synthesis of(ADH) enantioenriched with a CuAAC 1,2,3-triazole-derived catalytic system [94]. diols Thus, by combining two different a single prochiral alcohol dehydrogenasecompounds, (ADH)namely withan α‐ aazido CuAAC‐ and catalytic an alkynyl system‐ketone, [94]. were Thus, converted two different into prochiral the corresponding compounds, namelychiral an alcoholsα-azido- by andemploying an alkynyl-ketone, different alcohol were dehydrogenases converted into (ADH the corresponding‐A from Rhodococcus chiral alcoholsruber; byADH employing‐T from different Thermoanaerobium alcohol dehydrogenases sp.; and Tes‐ADH (ADH-A from from ThermoanaerobacterRhodococcus ruber ethanolicus; ADH-T fromor Thermoanaerobiumcommercially‐availablesp.; and LbTes‐ADH-ADH from from LactobacillusThermoanaerobacter brevis/Lk‐ ethanolicusADH fromor Lactobacillus commercially-available kefir) in a Lb-ADHreaction from mixtureLactobacillus containingbrevis/ a phosphateLk-ADH buffer from Lactobacillussolution (pH kefir7.5)) and in a iPrOH reaction at mixture30 °C (Scheme containing 19). a phosphateUnder these buffer conditions solution (pHADH 7.5)‐A andand iLbPrOH‐ADH at gave 30 ◦C rise (Scheme to the 19 corresponding). Under these chiral conditions alcohols ADH-A in andquantitativeLb-ADH gave conversion rise to theand correspondingexcellent enantiomeric chiral alcoholsexcess. The in subsequent quantitative click conversion reaction between and excellent the in situ‐obtained chiral propargylic alcohols and the corresponding chiral azido‐alcohols took place at enantiomeric excess. The subsequent click reaction between the in situ-obtained chiral propargylic 60 °C by employing a copper wire with a catalytic amount of CuSO4 allowing obtaining the required alcohols and the corresponding chiral azido-alcohols took place at 60 ◦C by employing a copper wire Cu(I)‐catalyst via a Cu(0)/Cu(II) comproportionation reaction (Scheme 19). This one‐pot/two‐step with a catalytic amount of CuSO allowing obtaining the required Cu(I)-catalyst via a Cu(0)/Cu(II) chemoenzymatic methodology furnished4 the desired enantiopure 1,2,3‐triazole‐derived diols after 24 comproportionationh of reaction. reaction (Scheme 19). This one-pot/two-step chemoenzymatic methodology furnished the desired enantiopure 1,2,3-triazole-derived diols after 24 h of reaction.

Scheme 19. Chemoenzymatic one‐pot/two‐step protocol for the synthesis of chiral 1,2,3‐triazole‐derived diols in aqueous media.

6. Combination of Metal‐Catalyzed C‐C Coupling Reactions with Enzymatic Reductions, Aminations or Halogenations

Catalysts 2018, 8, 74 16 of 28

out: (i) in a biphasic reaction media based on a mixture of HEPES buffer (0.1 M pH 7.5, KOH, 1 mM MgSO4, 1 mM ZnSO4) and octane; (ii) at room temperature; and (iii) employing isopropanol for regeneration of the NADPH co‐factor. Overnight incubation of the reactions under the aforementioned conditions permitted the synthesis of the desired β‐azido alcohols in full conversion (isolated yield 35–70%) and enantioselectivities ranging from 96–99% ee (Scheme 18A). Finally, and in view of the previous positive combination of halohydrin dehalogenase and CuAAC reactions [92], the authors designed a new chemoenzymatic route for the direct conversion of β‐halo ketones into the above‐mentioned enantioenriched β‐hydroxy triazoles (Scheme 18B). In the parametrization studies of this chemoenzymatic transformation, the addition of octane as an organic solvent resulted in a reduction of the click reactivity (probably due to extraction of the PhC≡CH into the organic phase). This unexpected drawback could be evaded just by avoiding this co‐solvent.

Scheme 18. Whole Cell‐Promoted Bioreduction/Azidolysis of β‐halo ketones (A) and its one‐pot combination with CuAAC reaction for the enantioenriched synthesis of β‐hydroxy triazoles in aqueous media (B).

More recently, Gotor and co‐workers described a fully‐convergent one‐pot/two‐step procedure for the synthesis of enantioenriched 1,2,3‐triazole‐derived diols by combining a single alcohol dehydrogenase (ADH) with a CuAAC catalytic system [94]. Thus, two different prochiral compounds, namely an α‐azido‐ and an alkynyl‐ketone, were converted into the corresponding chiral alcohols by employing different alcohol dehydrogenases (ADH‐A from Rhodococcus ruber; ADH‐T from Thermoanaerobium sp.; and Tes‐ADH from Thermoanaerobacter ethanolicus or commercially‐available Lb‐ADH from Lactobacillus brevis/Lk‐ADH from Lactobacillus kefir) in a reaction mixture containing a phosphate buffer solution (pH 7.5) and iPrOH at 30 °C (Scheme 19). Under these conditions ADH‐A and Lb‐ADH gave rise to the corresponding chiral alcohols in quantitative conversion and excellent enantiomeric excess. The subsequent click reaction between the in situ‐obtained chiral propargylic alcohols and the corresponding chiral azido‐alcohols took place at 60 °C by employing a copper wire with a catalytic amount of CuSO4 allowing obtaining the required Cu(I)‐catalyst via a Cu(0)/Cu(II) comproportionation reaction (Scheme 19). This one‐pot/two‐step Catalystschemoenzymatic2018, 8, 75 methodology furnished the desired enantiopure 1,2,3‐triazole‐derived diols after17 24 of 28 h of reaction.

SchemeScheme 19. 19. Chemoenzymatic one one-pot/two-step‐pot/two‐step protocol protocol for forthe the synthesis synthesis of ofchiral chiral 1,2,3-triazole-derived1,2,3‐triazole‐derived diols diols in in aqueous aqueous media. media.

6. Combination of Metal‐Catalyzed C‐C Coupling Reactions with Enzymatic Reductions, 6. Combination of Metal-Catalyzed C-C Coupling Reactions with Enzymatic Reductions, Aminations or Halogenations Aminations or Halogenations

Metal-catalyzed C-C coupling reactions constitute nowadays a staple of modern organic chemistry [96–98], as demonstrated by the Nobel Prize award in chemistry to Heck, Negishi and Suzuki in 2010. These C-C coupling reactions are usually promoted by palladium catalysts and form one of the most robust and versatile synthetic tools to achieve the selective and fruitful coupling or organic electrophiles (usually an organic halide or triflate) with a sp−-, sp2−- or sp3-hybridised carbon. Moreover, water has been extensively used as a reaction medium for these metal-catalyzed C-C coupling reactions [99]. Thus, it is not surprising to find in the literature several examples that reported the combination of metal-catalyzed C-C coupling reactions in aqueous media with different biotransformations. In this sense, this section covers the combination of: (i) Pd-catalyzed Suzuki coupling with bioreductions [100], bioaminations [101] or enzymatic halogenations [102,103]; and (ii) Pd-catalyzed Heck reaction and bioreduction [104]. Furthermore, and in the final part of this section, we review the combination of indium-mediated Barbier-type coupling [105] or Zn-catalyzed aldol reactions [106] with enzymatic oxidations or bioreductions, respectively.

6.1. Combination of Pd-Catalyzed Suzuki Coupling with Bioreductions (ADH), Bioamination (Phenylalanine Ammonia Lyases/D-Amino Acid Dehydrogenase) or Enzymatic Halogenation (Halogenase) in Aqueous Media Pd-catalyzed Suzuki cross-coupling of aryl, vinyl or alkyl halides (or pseudohalides) with organoboron reagents is one of the most efficient and selective methodologies for the construction of C-C bonds [97,107,108]. Importantly for the design of tandem chemoenzymatic procedures, there are several key points that make this metal-catalyzed cross-coupling reaction the ideal partner for biocatalyzed reactions: (i) it usually takes place under mild reaction conditions; (ii) the boron reagents (boronic acids or boronic esters) are generally stable in water, non-toxic and commercially available [109]; and (iii) it tolerates a wide variety of functional groups. The pioneering study in this field was reported in 2008 by Gröger and co-workers through the combination of the Pd-catalyzed Suzuki cross-coupling of p-bromo-acetophenone and phenyl boronic acid [PhB(OH)2] in aqueous medium with the subsequent bioreduction (ADH from Rhodococcus sp.) of the obtained biaryl ketones in a phosphate buffer (pH 7) and using iPrOH as co-factor regenerator [100]. Although both reactions proceeded efficiently (conversions greater than 93% and enantiomeric excess >99%) when carried out separately (Scheme 20A), an unexpected incompatibility of the metal catalytic system [Pd(PPh3)2Cl2]/PPh3/PhB(OH)2 and the enzyme was observed. After several competitive experiments, it was found that while the metal catalyst only had a minor impact on the enzyme, the phosphine (PPh3) and the boronic acid PhB(OH)2 had a stronger negative impact on the enzyme activity. By performing these parametrization experiments, the best reaction conditions for a successful sequential process implied: (i) the use of water as solvent; (ii) avoiding the use of the phosphine ligand; and (iii) the employment of a stoichiometric amount of the boronic acid (which should also be entirely consumed in the coupling process). Accordingly, the first step progresses effectively in aqueous media giving rise to the expected biaryl ketone in good yield (95%). Next, the subsequent bioreduction (promoted by (S)-ADH from Rhodococcus sp.) produced the desired chiral biaryl-substituted alcohol with good conversion (91%) and excellent enantioselectivity (>99%). Catalysts 2018, 8, 74 18 of 28

the glucose/glucose dehydrogenase (GDH) recycling system for its regeneration. Secondly, an additional Boc‐protection step of the primary amino group in either L‐ or D‐4‐bromophenylalanine was mandatory to achieve quantitative yields of the desired biarylalanine derivatives. Finally, and after this Boc‐protection step, it was possible to perform the desired Pd‐catalyzed Suzuki reaction by Catalystsemploying2018, 8, 75the complex [Pd(CH3CN)2Cl2] as the catalyst (10 mol%) with the aid of microwave18 of 28 irradiation at 120 °C for 20 min (Scheme 21).

SchemeScheme 20. 20.Chemoenzymatic Chemoenzymatic one-pot/two-stepone‐pot/two‐step (A (A) )or or sequential sequential (B ()B synthesis) synthesis of ofchiral chiral biaryl biaryl-‐ substitutedsubstituted alcohols alcohols in in aqueous aqueous media. media.

CatalystsLater, 2018 and, 8, following74 the aforementioned pioneer work of Gröger and co-workers, Turner18 of 28 et al. reported the successful assembly of the Pd-catalyzed Suzuki C-C coupling reaction with two different the glucose/glucose dehydrogenase (GDH) recycling system for its regeneration. Secondly, an enzymaticadditional transformations Boc‐protection [ 101step]: of (i) the the primary asymmetric amino hydroamination group in either ofL‐ arylpropenoicor D‐4‐bromophenylalanine acids, catalyzed bywas phenylalanine mandatory to ammonia achieve quantitative lyases (PALs) yields [110 of]; the or desired (ii) the biarylalanine reductive amination derivatives. of Finally,α-keto and acids promotedafter this by Boc an‐protection NADPH-dependent step, it was possibleD-amino to perform acid dehydrogenase the desired Pd (DAADH),‐catalyzed Suzuki engineered reaction from by a meso-diaminopimelate dehydrogenase from Corynebacterium glutamicum [111]. Firstly, the authors employing the complex [Pd(CH3CN)2Cl2] as the catalyst (10 mol%) with the aid of microwave studiedirradiation the biotransformation at 120 °C for 20 min of (Scheme 4-bromocinnamic 21). acid into L-4-bromophenylalanine promoted by Scheme 21. Chemoenzymatic sequential synthesis of L‐ or D‐biarylalanine derivatives◦ in aqueous different PALs in a 5 M aqueous ammonia solution (NH4OH, pH 9.6) at 37 C for 24 h, obtaining the media. best results (80% of conversion, >99% ee) with a wild-type PAL overproduced in Escherichia coli whole cells fromFinally,Anabaena not only variabilis bioreductions(AvPAL-F107A). [100] or Thebioaminations corresponding [101], antipodebut also enzymatic (D-4-bromophenylalanine, halogenations 99%[102,103] conversion, have been >99% efficientlyee) was coupled easily with accessed Pd‐catalyzed by promoting Suzuki reactions. a DAADH-catalyzed In this sense, Sewald reductive and aminationco‐workers of 4-bromophenylpyruvic [102] were the first to report acid employing the combination NADPH of the as co-factorbiocatalyzed and halogenation the glucose/glucose of L‐ dehydrogenasetryptophan with (GDH) the recycling subsequent system Pd for‐catalyzed its regeneration. Suzuki Secondly, cross‐coupling an additional reaction Boc-protection for the stepchemoenzymatic of the primary synthesis amino group of different in either arylL-‐ orsubstitutedD-4-bromophenylalanine tryptophans (Scheme was 22). mandatory Thus, firstly, to achieve the quantitativeregioselective yields bromination of the desired in the 5 biarylalanine‐, 6‐ or 7‐position derivatives. of the indole Finally, molecule and of tryptophan after this Boc-protection was studied step,by it employing was possible Trp to 5 perform‐halogenase the PyrH, desired Trp Pd-catalyzed 6‐halogenase Suzuki Thal reactionor Trp 7 by‐halogenase employing Rebh the complex[112], respectively. For this biotransformation, the so‐called “combiCLEAs methodology” (combiCLEAS◦ = [Pd(CHScheme3CN)2Cl 20.2] asChemoenzymatic the catalyst (10 one mol%)‐pot/two with‐step the (A aid) or of sequential microwave (B) irradiationsynthesis of atchiral 120 biarylC for‐ 20 min (SchemeCrosssubstituted ‐21Linked). Enzyme alcohols Aggregate) in aqueous media. was followed, which selectively brominates L‐tryptophan with full conversion in the aforementioned positions. This combiCLEAs methodology consists of the precipitation and the cross‐linking of the Trp halogenases in the presence of all auxiliary enzymes necessary for concomitant co‐factor regeneration [112]. In a second step, the cross‐coupling reaction was conducted under Ar atmosphere with different aromatic boronic acids, employing in this case a palladium(II) salt (Na2PdCl4) as the catalyst in the presence of: (i) the water‐soluble Buchwald sulfonated phosphine ligand sSPhos; (ii) water as the solvent at 95 °C; and (iii) K3PO4 as the base. Lastly, the extraction of the final zwitterionic products from the aqueous media could be facilitated just by protecting the primary amino group with Boc2O (Scheme 22). In the same year (2016), Latham, Henry and co‐workers designed a closely‐related and integrated catalytic system for the regioselectiveScheme 21. biocatalytic Chemoenzymatic bromination sequential of asynthesis range of of aromatic L‐ or D‐ biarylalaninescaffolds (anthranilamide, derivatives in aqueous tryptophol, Scheme 21. Chemoenzymatic sequential synthesis of L- or D-biarylalanine derivatives in media. 3‐aqueousindole propionate media. or 6‐hydroxy isoquinoline) and subsequent Pd‐catalyzed Suzuki coupling reaction. The observed issues of enzyme and transition metal (Pd) compatibility were overcome throughFinally, membrane not only compartmentalization bioreductions [100] orof bioaminationsthe different catalytic [101], but systems also enzymatic [103]. halogenations [102,103]Finally, have not been only efficiently bioreductions coupled with [100 Pd]‐catalyzed or bioaminations Suzuki reactions. [101 In], this but sense, also Sewald enzymatic and halogenationsco‐workers [102] [102, 103were] have the first been to efficiently report the coupled combination with of Pd-catalyzed the biocatalyzed Suzuki halogenation reactions. of In L this‐ sense,tryptophan Sewald andwith co-workers the subsequent [102] were Pd‐catalyzed the first toSuzuki report thecross combination‐coupling reaction of the biocatalyzedfor the halogenationchemoenzymatic of L-tryptophan synthesis of with different the subsequent aryl‐substituted Pd-catalyzed tryptophans Suzuki (Scheme cross-coupling 22). Thus, firstly, reaction the for theregioselective chemoenzymatic bromination synthesis in the of 5 different‐, 6‐ or 7‐position aryl-substituted of the indole tryptophans molecule of (Scheme tryptophan 22). was Thus, studied firstly, theby regioselective employing Trp bromination 5‐halogenase in the PyrH, 5-, 6-Trp or 6 7-position‐halogenase of Thal the indole or Trp molecule 7‐halogenase of tryptophan Rebh [112], was studiedrespectively. by employing For this Trp biotransformation, 5-halogenase PyrH, the so Trp‐called 6-halogenase “combiCLEAs Thal methodology” or Trp 7-halogenase (combiCLEAS Rebh [ 112= ], respectively.Cross‐Linked For Enzyme this biotransformation, Aggregate) was followed, the so-called which selectively “combiCLEAs brominates methodology” L‐tryptophan (combiCLEAS with full conversion in the aforementioned positions. This combiCLEAs methodology consists of the = Cross-Linked Enzyme Aggregate) was followed, which selectively brominates L-tryptophan with precipitation and the cross‐linking of the Trp halogenases in the presence of all auxiliary enzymes necessary for concomitant co‐factor regeneration [112]. In a second step, the cross‐coupling reaction was conducted under Ar atmosphere with different aromatic boronic acids, employing in this case a palladium(II) salt (Na2PdCl4) as the catalyst in the presence of: (i) the water‐soluble Buchwald sulfonated phosphine ligand sSPhos; (ii) water as the solvent at 95 °C; and (iii) K3PO4 as the base. Lastly, the extraction of the final zwitterionic products from the aqueous media could be facilitated just by protecting the primary amino group with Boc2O (Scheme 22). In the same year (2016), Latham, Henry and co‐workers designed a closely‐related and integrated catalytic system for the regioselective biocatalytic bromination of a range of aromatic scaffolds (anthranilamide, tryptophol, 3‐indole propionate or 6‐hydroxy isoquinoline) and subsequent Pd‐catalyzed Suzuki coupling reaction. The observed issues of enzyme and transition metal (Pd) compatibility were overcome through membrane compartmentalization of the different catalytic systems [103].

Catalysts 2018, 8, 75 19 of 28 full conversion in the aforementioned positions. This combiCLEAs methodology consists of the precipitation and the cross-linking of the Trp halogenases in the presence of all auxiliary enzymes necessary for concomitant co-factor regeneration [112]. In a second step, the cross-coupling reaction was conducted under Ar atmosphere with different aromatic boronic acids, employing in this case a palladium(II) salt (Na2PdCl4) as the catalyst in the presence of: (i) the water-soluble Buchwald ◦ sulfonated phosphine ligand sSPhos; (ii) water as the solvent at 95 C; and (iii) K3PO4 as the base. Lastly, the extraction of the final zwitterionic products from the aqueous media could be facilitated just by protecting the primary amino group with Boc2O (Scheme 22). In the same year (2016), Latham, Henry and co-workers designed a closely-related and integrated catalytic system for the regioselective biocatalytic bromination of a range of aromatic scaffolds (anthranilamide, tryptophol, 3-indole propionate or 6-hydroxy isoquinoline) and subsequent Pd-catalyzed Suzuki coupling reaction. The observed issues of enzyme and transition metal (Pd) compatibility were overcome through membraneCatalysts 2018 compartmentalization, 8, 74 of the different catalytic systems [103]. 19 of 28

Scheme 22. Chemoenzymatic modular combination of enzymatic bromination of tryptophan (Trp) Scheme 22. Chemoenzymatic modular combination of enzymatic bromination of tryptophan (Trp) with the Pd‐catalyzed Suzuki reaction in aqueous media. with the Pd-catalyzed Suzuki reaction in aqueous media. 6.2. Combination of Pd‐Catalyzed Heck Reaction of Aryl Iodides and Allylic Alcohols with a Subsequent 6.2.Bioreduction Combination (Lb of‐ADH Pd-Catalyzed from Lactobacillus Heck Reaction brevis) of in Aryl Aqueous Iodides Media and Allylic Alcohols with a Subsequent Bioreduction (Lb-ADH from Lactobacillus brevis) in Aqueous Media The catalytic Heck coupling reaction (also called Mizoroki–Heck coupling after the pioneering andThe independent catalytic Heck reports coupling of T. Mizoroki reaction [113] (also and called R.F. Mizoroki–Heck Heck [114]) is an coupling essential after catalytic the pioneering tool in andorganic independent synthesis reports as it allows of T. the Mizoroki selective [ 113and] efficient and R.F. formation Heck [114 of ])new is anC‐C essential bonds between catalytic two tool in organicsp2‐hybridized synthesis carbon as itatoms allows (activated the selective alkenes and and efficient aryl/vinyl formation halides). of In new this C-Csense, bonds palladium between‐ 2 twonanoparticles sp -hybridized (Pd‐NPs) carbon have atoms been extensively (activated employed alkenes as and catalyst aryl/vinyl for the halides).Heck reaction, In since this the sense, palladium-nanoparticlespioneering work from (Pd-NPs)Beller [115]. have The been major extensively advantages employed related as to catalyst the employment for the Heck of reaction,metal sincenanoparticles the pioneering in the work Heck from reaction Beller include [115]. The [116]: major (i) high advantages catalytic related activity; to (ii) the excellent employment selectivity; of metal nanoparticlesand (iii) tolerance in the of Heck water reaction [117,118]. include Bearing [ 116in mind]: (i) these high benefits catalytic of activity;Pd‐NP‐catalyzed (ii) excellent Heck selectivity;reaction andin (iii) water,tolerance Cacchi of and water co‐workers [117,118 reported]. Bearing a inone mind‐pot/two these‐step benefits process of connecting Pd-NP-catalyzed the aqueous Heck reactionHeck in water,reaction Cacchi with an and enantioselective co-workers reported ADH‐catalyzed a one-pot/two-step bioreduction process of the transiently connecting‐formed the aqueous prochiral Heck reactionhydroxyl with‐ketone an enantioselective to produce the ADH-catalyzedchiral alcohol (R) bioreduction‐(‐)‐rhododendrol of the (Scheme transiently-formed 23) [104]. In the prochiral first hydroxyl-ketonestep, the Heck toreaction produce of aryl the iodides chiral alcohol and allylic (R)-(-)-rhododendrol alcohols was performed (Scheme under 23)[ standard104]. In bench the first step,experimental the Heck reactionconditions of (aqueous aryl iodides media, and under allylic air alcohols and in the was presence performed of NaHCO under3/NaOH standard as benchthe base) at 100 °C promoted by a phosphine‐free perfluoro‐tagged Pd‐NPs immobilized on fluorous experimental conditions (aqueous media, under air and in the presence of NaHCO3/NaOH as the silica gel (Pd‐NP‐FSG) (two different kinds of Pd‐NPs immobilized on fluorous silica gel (through F‐ base) at 100 ◦C promoted by a phosphine-free perfluoro-tagged Pd-NPs immobilized on fluorous F interactions or covalent bonding) have been employed by the authors). After cooling down the silica gel (Pd-NP-FSG) (two different kinds of Pd-NPs immobilized on fluorous silica gel (through F-F reaction, ADH from Lactobacillus brevis (Lb‐ADH), NADPH and iPrOH were added to the reaction interactionscrude and or the covalent obtained bonding) mixture have stirred been at employed room temperature by the authors). for 24 h, After yielding cooling the down desired the (R reaction,)‐(‐)‐ i ADHrhododendrol from Lactobacillus (Scheme brevis 23) in( Lbgood-ADH), isolated NADPH yield (90%) and andPrOH excellent were addedenantiomeric to the reactionexcess (>99%). crude and the obtained mixture stirred at room temperature for 24 h, yielding the desired (R)-(-)-rhododendrol (Scheme 23) in good isolated yield (90%) and excellent enantiomeric excess (>99%).

Scheme 23. Chemoenzymatic synthesis of (R)‐(‐)‐rhododendrol through the combination of the Pd‐catalyzed Heck reaction and ADH‐catalyzed enantioselective bioreduction of a prochiral ketone in aqueous media. FSG, fluorous silica gel.

6.3. Combination of Indium‐Mediated Barbier‐Type Coupling and Zn‐Catalyzed aldol Reaction with Enzymatic Oxidations (Galactose Oxidase) or Bioreductions (Oxidoreductases), Respectively

The metal‐mediated (Mg, Al, Zn, In, Sn or their salts) Barbier reaction [119], which involves the reaction between a carbonyl compound and an organic halide or pseudohalide [120], is an important methodology for producing new C‐C bonds and has been extensively developed in non‐conventional solvents (like water) [121]. In addition, it is important to note that the allylation of aldehydes under Barbier conditions typically takes place faster and produces the desired alcohols in higher yields when water is used as the solvent [122]. Accordingly, Faber, Kroutil and co‐workers explored the chemoenzymatic one‐pot/two‐step transformation of benzyl or cinnamic alcohols to the corresponding homoallylic alcohols in water through the combination of: (i) the enzymatic alcohol oxidation to produce the corresponding aldehydes (promoted by galactose oxidase); with (ii) the indium(0)‐mediated Barbier type reaction with allyl bromide (Scheme 24) [105]. Firstly, the aqueous oxidation of benzyl alcohol promoted by galactose oxidase from Fusarium NRRL2903 in the presence

Catalysts 2018, 8, 74 19 of 28

Scheme 22. Chemoenzymatic modular combination of enzymatic bromination of tryptophan (Trp) with the Pd‐catalyzed Suzuki reaction in aqueous media.

6.2. Combination of Pd‐Catalyzed Heck Reaction of Aryl Iodides and Allylic Alcohols with a Subsequent Bioreduction (Lb‐ADH from Lactobacillus brevis) in Aqueous Media The catalytic Heck coupling reaction (also called Mizoroki–Heck coupling after the pioneering and independent reports of T. Mizoroki [113] and R.F. Heck [114]) is an essential catalytic tool in organic synthesis as it allows the selective and efficient formation of new C‐C bonds between two sp2‐hybridized carbon atoms (activated alkenes and aryl/vinyl halides). In this sense, palladium‐ nanoparticles (Pd‐NPs) have been extensively employed as catalyst for the Heck reaction, since the pioneering work from Beller [115]. The major advantages related to the employment of metal nanoparticles in the Heck reaction include [116]: (i) high catalytic activity; (ii) excellent selectivity; and (iii) tolerance of water [117,118]. Bearing in mind these benefits of Pd‐NP‐catalyzed Heck reaction in water, Cacchi and co‐workers reported a one‐pot/two‐step process connecting the aqueous Heck reaction with an enantioselective ADH‐catalyzed bioreduction of the transiently‐formed prochiral hydroxyl‐ketone to produce the chiral alcohol (R)‐(‐)‐rhododendrol (Scheme 23) [104]. In the first step, the Heck reaction of aryl iodides and allylic alcohols was performed under standard bench experimental conditions (aqueous media, under air and in the presence of NaHCO3/NaOH as the base) at 100 °C promoted by a phosphine‐free perfluoro‐tagged Pd‐NPs immobilized on fluorous silica gel (Pd‐NP‐FSG) (two different kinds of Pd‐NPs immobilized on fluorous silica gel (through F‐ F interactions or covalent bonding) have been employed by the authors). After cooling down the reaction, ADH from Lactobacillus brevis (Lb‐ADH), NADPH and iPrOH were added to the reaction Catalystscrude2018 and, 8 ,the 75 obtained mixture stirred at room temperature for 24 h, yielding the desired (R)‐20(‐) of‐ 28 rhododendrol (Scheme 23) in good isolated yield (90%) and excellent enantiomeric excess (>99%).

Scheme 23. Chemoenzymatic synthesis of (R)‐(‐)‐rhododendrol through the combination of the Scheme 23. Chemoenzymatic synthesis of (R)-(-)-rhododendrol through the combination of the Pd‐catalyzed Heck reaction and ADH‐catalyzed enantioselective bioreduction of a prochiral ketone Pd-catalyzed Heck reaction and ADH-catalyzed enantioselective bioreduction of a prochiral ketone in in aqueous media. FSG, fluorous silica gel. aqueous media. FSG, fluorous silica gel. 6.3. Combination of Indium‐Mediated Barbier‐Type Coupling and Zn‐Catalyzed aldol Reaction with 6.3.Enzymatic Combination Oxidations of Indium-Mediated (Galactose Oxidase) Barbier-Type or Bioreductions Coupling (Oxidoreductases), and Zn-Catalyzed Respectively aldol Reaction with Enzymatic Oxidations (Galactose Oxidase) or Bioreductions (Oxidoreductases), Respectively TheThe metal-mediated metal‐mediated (Mg, (Mg, Al,Al, Zn, In, In, Sn Sn or or their their salts) salts) Barbier Barbier reaction reaction [119], [ 119which], which involves involves the thereaction reaction between between a carbonyl a carbonyl compound compound and an and organic an organichalide or halide pseudohalide or pseudohalide [120], is an important [120], is an methodology for producing new C‐C bonds and has been extensively developed in non‐conventional important methodology for producing new C-C bonds and has been extensively developed in solvents (like water) [121]. In addition, it is important to note that the allylation of aldehydes under non-conventional solvents (like water) [121]. In addition, it is important to note that the allylation of Barbier conditions typically takes place faster and produces the desired alcohols in higher yields aldehydes under Barbier conditions typically takes place faster and produces the desired alcohols in when water is used as the solvent [122]. Accordingly, Faber, Kroutil and co‐workers explored the higherchemoenzymatic yields when waterone‐pot/two is used‐step as thetransformation solvent [122 ].of Accordingly, benzyl or Faber,cinnamic Kroutil alcohols and co-workersto the exploredcorresponding the chemoenzymatic homoallylic alcohols one-pot/two-step in water through transformation the combination of benzyl of: or(i) cinnamicthe enzymatic alcohols alcohol to the correspondingoxidation to homoallylicproduce the corresponding alcohols in water aldehydes through (promoted the combination by galactose of: (i) oxidase); the enzymatic with (ii) alcohol the oxidationindium(0) to‐mediated produce theBarbier corresponding type reaction aldehydes with allyl bromide (promoted (Scheme by galactose 24) [105]. oxidase); Firstly, the with aqueous (ii) the indium(0)-mediatedoxidation of benzyl Barbier alcohol typepromoted reaction by galactose with allyl oxidase bromide from (Scheme Fusarium 24 NRRL2903)[105]. Firstly, in the the presence aqueous Catalysts 2018, 8, 74 20 of 28 oxidation of benzyl alcohol promoted by galactose oxidase from Fusarium NRRL2903 in the presence of horseradish peroxidase (HRP) and 2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) of horseradish peroxidase (HRP) and 2,2’‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) was parametrized for the removal of hydrogen peroxide under atmospheric air (4 bar) and with was parametrized for the removal of hydrogen peroxide under atmospheric air (4 bar) and with CuSO4 (10 mM) as the co-catalyst. Under these conditions, the desired benzaldehyde was obtained in CuSO4 (10 mM) as the co‐catalyst. Under these conditions, the desired benzaldehyde was obtained quantitativein quantitative yield yield (>99%). (>99%). Unfortunately, Unfortunately, this this enzymatic enzymatic oxidation oxidation was was completely completely inhibited inhibited in the in the presencepresence of of the the reagents reagents required required for for the the second second reaction (the (the In(0) In(0)-promoted‐promoted allylation). allylation). However, However, thisthis undesired undesired circumstance circumstance was was circumvented circumvented by performing performing the the reaction reaction in in a sequential a sequential fashion. fashion. Thus,Thus, the the allylation allylation reaction reaction proceeded proceeded smoothlysmoothly even in in the the presence presence of of the the enzymatic enzymatic catalytic catalytic system,system, giving giving rise rise to to the the desired desired homoallylic homoallylic alcoholsalcohols in good yields yields (51 (51->99%).‐>99%).

SchemeScheme 24. 24. EnzymaticEnzymatic alcoholalcohol oxidation/In-mediatedoxidation/In‐mediated Barbier Barbier coupling coupling cascade cascade reaction reaction in in aqueousaqueous media. media.

To finish this section, we would like to point out that Aoki and co‐workers [106] have reported theTo combination finish this section, of an weenantioselective would like to Zn point‐catalyzed out that aldol Aoki reaction and co-workers (between [106 different] have reportedaromatic the combinationaldehydes ofand an acetone) enantioselective with the Zn-catalyzed subsequent enantioselective aldol reaction (between bioreduction different of the aromatic aldol products aldehydes andpromoted acetone) by with commercially the subsequent‐available enantioselective NADH‐dependent bioreduction oxidoreductases of the aldol (i.e., from products baker‘s promoted yeast, S. by commercially-availablecerevisiae, L. kefir or Daicel NADH-dependent Co. Ltd., Tokyo, oxidoreductases Japan) employing (i.e., a phosphate from baker‘s buffer yeast, (pHS. 7.2) cerevisiae as reaction, L. kefir or Daicelmedia. Co.All four Ltd., possible Tokyo, Japan)stereoisomers employing of the a obtained phosphate optically buffer‐active (pH 7.2) 1,3‐ asdiols reaction could be media. selectively All four possibleproduced stereoisomers by employing of this the chemoenzymatic obtained optically-active methodology. 1,3-diols could be selectively produced by employing this chemoenzymatic methodology. 7. Combination of Metal‐Catalyzed Oxidations with Enzymatic Reductions 7. CombinationMetal‐catalyzed of Metal-Catalyzed selective oxidation Oxidations of alcohols with is Enzymatic widely recognized Reductions as a particularly useful methodologyMetal-catalyzed in the selective production oxidation of aldehydes of alcohols or ketones is widely [123], which recognized are very as important a particularly building useful methodologyblocks in the in theproduction production of offlavors, aldehydes fragrances or ketones or biologically [123], which‐active are verycompounds, important among building others. blocks in theHowever, production the vast of flavors, majority fragrances of these protocols or biologically-active are incompatible compounds, with biotransformations, among others. as However, they theusually vast majority require of the these use protocols of: (i) highly are incompatible reactive chemicals with biotransformations, (chromium salts, as oxalyl they usuallychloride require or hypervalent iodines); (ii) volatile organic solvents (toluene) or solvent‐free conditions; and (iii) strong bases (i.e., NaOH, KOtBu) as co‐catalysts. Nevertheless, Kroutil and co‐workers were able to design an iridium‐catalyzed oxidation of secondary alcohols in an aqueous/toluene reaction mixture via hydrogen transfer by employing a sterically‐hindered ketone as the hydrogen acceptor (Scheme 25A) [124]. The selection of the suitable hydrogen acceptor was crucial to minimize its possible cross‐ bioreduction with ADH‐A. However, and even under the best catalytic conditions (10 equiv. of the acceptor and 5 mol% of iridium catalyst), only 67% conversion could be reached.

Catalysts 2018, 8, 75 21 of 28 the use of: (i) highly reactive chemicals (chromium salts, oxalyl chloride or hypervalent iodines); (ii) volatile organic solvents (toluene) or solvent-free conditions; and (iii) strong bases (i.e., NaOH, KOtBu) as co-catalysts. Nevertheless, Kroutil and co-workers were able to design an iridium-catalyzed oxidation of secondary alcohols in an aqueous/toluene reaction mixture via hydrogen transfer by employing a sterically-hindered ketone as the hydrogen acceptor (Scheme 25A) [124]. The selection of the suitable hydrogen acceptor was crucial to minimize its possible cross-bioreduction with ADH-A. However, and even under the best catalytic conditions (10 equiv. of the acceptor and 5 mol% of iridium catalyst),Catalysts only2018, 8 67%, 74 conversion could be reached. 21 of 28

SchemeScheme 25. 25.Ir-catalyzed Ir‐catalyzed oxidation oxidation ofof halohydrins (A (A),), bioreduction bioreduction of of ‐halo -halo ketones ketones (B () Band) and their their combinationcombination in in aqueous aqueous media media ( C(C).).

Posteriorly, the authors studied the compatibility of the iridium catalyst and the ADH‐A from RhodococcusPosteriorly, ruber the by authors carrying studied out the thebioreduction compatibility of the of desired the iridium chloroketone catalyst in andthe presence the ADH-A of both from Rhodococcuscatalysts (metal ruber byand carrying enzyme) out employing the bioreduction formate ofdehydrogenase/formate the desired chloroketone (FDH/formate) in the presence as a of bothrecycling catalysts system (metal for and the co enzyme)‐factor NADH employing (Scheme formate 25B). dehydrogenase/formateSatisfactorily, after 4 h of reaction, (FDH/formate) the alcohol as a recyclingwas produced system forin 82% the co-factorconversion NADH and 97% (Scheme enantiomeric 25B). Satisfactorily, excess, thus after proving 4 h ofthat reaction, the biocatalytic the alcohol wassystem produced ADH‐ inA/NADH/FDH/formate 82% conversion and was 97% active enantiomeric even in the excess, presence thus of the proving iridium that catalyst. the biocatalytic Finally, systemthe iridium ADH-A/NADH/FDH/formate‐catalyzed oxidation and the was bioreduction active even were in theconnected presence in ofa concurrent the iridium process catalyst. Finally,(Scheme the 25C), iridium-catalyzed allowing the conversion oxidation of and the the starting bioreduction racemate were into the connected enantioenriched in a concurrent alcohol processwith (Schemea 40% 25ee andC), allowing in the absence the conversion of the intermediate of the starting ketone racemate (the obtained into ee the is lower enantioenriched than 97% thus alcohol showing with a 40%thatee andthe metal in the catalyst absence can of the perform intermediate an undesired ketone racemization (the obtained ofee theis lowerfinal ( thanR)‐enantiomer 97% thus of showing the thatalcohol the metal in the catalyst presence can of perform the biocatalytic an undesired sytem racemization [125]). of the final (R)-enantiomer of the alcohol in the presenceMore recently of the (2015), biocatalytic Gröger sytem and co [125‐workers]). reported the combination of the Pd/Cu‐catalyzed WackerMore recentlyoxidation (2015), of olefins Gröger with andthe concomitant co-workers reportedbioreduction the of combination the transiently of the‐formed Pd/Cu-catalyzed ketones in a one‐pot process in aqueous media (Scheme 26) [126]. The initial studies showed that the presence Wacker oxidation of olefins with the concomitant bioreduction of the transiently-formed ketones in of the copper and palladium salts in the reaction media eroded dramatically the activity of the alcohol a one-pot process in aqueous media (Scheme 26)[126]. The initial studies showed that the presence dehydrogenase from Lactobacillus kefir (Lk‐ADH). To overcome this drawback, an ingenious strategy of the copper and palladium salts in the reaction media eroded dramatically the activity of the based on the compartmentalization of the two different catalytic systems (metals and enzyme) was Lactobacillus kefir Lk alcoholdesigned dehydrogenase by employing from a polydimethylsiloxane( (PDMS)-ADH). thimble To overcome [127]. The this hydrophobic drawback, anproperties ingenious strategyof this basedmembrane on theallow compartmentalization the in situ‐formed ketone of theto selective two different flux through catalytic the membrane systems (metals while the and enzyme)metallic was salts designed remained by employing in the interior a polydimethylsiloxane of the thimble. Moreover, (PDMS) thimblethe biocatalytic [127]. The system hydrophobic (Lk‐ propertiesADH/NADP of this+) remains membrane in the allow exterior the in of situ-formed the thimble, ketonethus preventing to selective the flux erosion through of the the biocatalyst membrane by the metal salt. However, under these one‐pot/one‐step conditions, the Wacker oxidation inside the thimble only produced the desired ketone in a 20% yield. This unexpected limitation is related to the flux to the exterior of the membrane of the co‐solvent (MeOH) employed in the Wacker oxidation. To suppress this leaching of methanol, the Wacker oxidation and the enzymatic reduction were conducted in a sequential fashion (the biocatalytic system was added to the exterior of the thimble once the oxidation was finished in the interior). As a result, it was possible to convert several aromatic alkenes into the corresponding 1‐arylethanols with high conversion (>95%) and excellent enantiomeric excess (98–99%).

Catalysts 2018, 8, 75 22 of 28 while the metallic salts remained in the interior of the thimble. Moreover, the biocatalytic system (Lk-ADH/NADP+) remains in the exterior of the thimble, thus preventing the erosion of the biocatalyst by the metal salt. However, under these one-pot/one-step conditions, the Wacker oxidation inside the thimble only produced the desired ketone in a 20% yield. This unexpected limitation is related to the flux to the exterior of the membrane of the co-solvent (MeOH) employed in the Wacker oxidation. To suppress this leaching of methanol, the Wacker oxidation and the enzymatic reduction were conducted in a sequential fashion (the biocatalytic system was added to the exterior of the thimble once the oxidation was finished in the interior). As a result, it was possible to convert several aromatic alkenes into the corresponding 1-arylethanols with high conversion (>95%) and excellent enantiomeric excessCatalysts (98–99%). 2018, 8, 74 22 of 28

Scheme 26. Compartmentalization strategy for Pd/Cu‐catalyzed Wacker oxidation of olefins and Scheme 26. Compartmentalization strategy for Pd/Cu-catalyzed Wacker oxidation of olefins and ADH‐mediated bioreduction of aromatic ketones by employing a polydimethylsiloxane (PDMS) ADH-mediated bioreduction of aromatic ketones by employing a polydimethylsiloxane (PDMS) thimble in aqueous media. thimble in aqueous media. 8. Conclusions 8. Conclusions This review presents a summary of the recent findings in the development of new catalytic networksThis review that combine presents both a summary metallic and of thebiological recent catalysts findings in in aqueous the development media for the of synthesis new catalytic of networksenantiopure that combineorganic molecules. both metallic Although and biological the assembly catalysts of these in aqueousdifferent mediacatalytic for worlds the synthesis implies of enantiopureimportant challenges organic molecules. like (i) metal Although‐ and bio the‐catalyst assembly compatibility of these and different stability, catalytic (ii) undesired worlds cross implies‐ importantreactivity challenges and (iii) the like employment (i) metal- of anddifferent bio-catalyst catalytic reaction compatibility conditions, and we stability, have shown (ii) undesireda series cross-reactivityof ingenious and and straightforward (iii) the employment chemoenzymatic of different processes catalytic able to reaction produce conditions,highly‐added we‐value have shownenantioenriched a series of organic ingenious products and under straightforward mild reaction chemoenzymaticconditions. Among processesothers, the combination able to produce of highly-added-valuemetal‐catalyzed isomerizations, enantioenriched cycloadditions, organic products hydrations, under olefin mild metathesis, reaction conditions. oxidations, Among C‐C cross others,‐ thecoupling combination and hydrogenation of metal-catalyzed reactions, isomerizations, with several cycloadditions, biotransformations hydrations, (enzymatic olefin reduction, metathesis, oxidations,amination, C-C epoxidation, cross-coupling halogenation and or hydrogenation ester hydrolysis) reactions, have been with covered. several biotransformations (enzymaticNow reduction, that the first amination, seeds have epoxidation, been planted halogenation and bearing or in ester mind hydrolysis) the almost have infinite been possible covered. combinations of metal‐ and bio‐catalyzed organic reactions, we strongly believe that this Now that the first seeds have been planted and bearing in mind the almost infinite chemoenzymatic methodology will play a more prominent role within the toolbox of synthetic possible combinations of metal- and bio-catalyzed organic reactions, we strongly believe that this organic chemists in the near future, with new and astonishing breakthroughs to be discovered. chemoenzymatic methodology will play a more prominent role within the toolbox of synthetic organic chemistsAcknowledgments: in the near future,We are indebted with new to the and MINECO astonishing of Spain breakthroughs (CTQ2016‐81797 to‐REDC be discovered. and CTQ2016‐75986‐P) and the Gobierno del Principado de Asturias (Project GRUPIN14‐006) for financial support. Joaquín García‐ Acknowledgments:Álvarez thanks theWe Fundación are indebted BBVA to for the the MINECO award of of a “Beca Spain Leonardo (CTQ2016-81797-REDC a Investigadores and y Creadores CTQ2016-75986-P) Culturales and the2017”. Gobierno del Principado de Asturias (Project GRUPIN14-006) for financial support. Joaquín García-Álvarez thanks the Fundación BBVA for the award of a “Beca Leonardo a Investigadores y Creadores Culturales 2017”. Conflicts of Interest: “The authors declare no conflict of interest.ʺ “The founding sponsors had no role in the Conflicts of Interest: The authors declare no conflict of interest. The founding sponsors had no role in the design design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decisionthe decision to publish to publish the results. the results”.

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