Organocatalysis and Biocatalysis Hand in Hand: Combining Catalysts

REVIEWS DOI:10.1002/adsc.201700158

Organocatalysis and Biocatalysis Hand in Hand:Combining Catalysts in One-Pot Procedures

Fabricio R. Bisogno,a,*MartínG.López-Vidal,a and Gonzalo de Gonzalob,* a Facultad de CienciasQuímicas,Instituto de Investigaciones en Físico-Química Córdoba(INFIQC-CONICET), Universidad Nacional de Córdoba, 5000 Córdoba, Argentina E-mail:[email protected] b Departamento de QuímicaOrgµnica, Universidad de Sevilla, c/ Profesor GarcíaGonzµlez 1, 41012 Sevilla, Spain E-mail:[email protected]

Received:February 8, 2017; Revised:April 5, 2017;Publishedonline:May 11, 2017

DedicatedtoProf.Vicente Gotoronthe occasion of his 70th birthday.

Abstract: Multi-stepprocesses catalysed by several 1Introduction catalysts working concurrently have been developed 2Sequential Reactions Employing Organocata- in nature,thusimproving reactionefficiency.The lysts and Biocatalysts quest for novel and improvedcatalytic systems has 3Simultaneous One-Pot ProcessesCombining led to the development of biocatalytic and later to Organocatalysts and Biocatalysts organocatalytic procedures as very valuable tools in 4One-Pot ProcessesCombining Biocatalysts and asymmetric synthesis while using mild reactioncon- Non-TraditionalOrganic Catalysts ditionsinthe absence of metal catalysts.Asatimeless 4.1 Reactions Catalysed by Enzymesand Base Cat- challenge,chemists are facing the need for process alysts designs in which different sorts of catalysts can oper- 4.2 Enzymatic Regeneration of aRedox Catalyst ate successfully in aone-pot concurrentfashion. in aOne-Pot Procedure Likewise,such designs bring about the best of each 4.3 One-Pot Catalytic CombinedRedox Processes catalyst and, in certain cases,enable us to improve Driven by Light problematic issues,such as reactivity,selectivity,solu- 5Outlook bility,inhibition, etc. Specifically, to combine these two types of catalysts in one-pot, achieving high yields and selectivity,isafascinating aspect of catalysis.Thisreview covers representativeadvancesin this field, in particular those in which biocatalysts Keywords: concurrent processes;enantioselectivity; and organocatalysts are employed either in sequen- enzyme catalysis;multistep synthesis;one-pot proce- tial reactions or in simultaneous processes. dures;organic catalysis

1Introduction of one reactionisthe substrate of the following one, avoiding intermediate accumulation and, therefore, In nature,the optimisationofagiven process is side reactions.[1] driven by evolutionary pressures.Resource- and Often, chemists employconsecutive multistep energy-savingmaximisation became evolutionary chemical synthesiswith catalytically efficientreactions pressures; hence,cellular machineries,i.e.,enzymatic thus improving the overall“atom economy” of the networks dedicated to aspecificorgeneralcellular process.[2] These methodologies have been widely task, have evolved.Inorder to improvemetabolic ef- adopted in the industrial manufacture of fine chemi- ficiency,living systems make use of several extremely cals and pharmaceutical intermediates.Inthis frame- selectivecatalysts working at the same time,thus work, strategies where multiplecatalysts simultane- forming complex biochemical networks.Toachieve ously work in “one-pot”, avoiding the costly isolation such adegree of success,aperfectregulation of the and purificationofchemical intermediates,are named different catalysts working concomitantly,often in the concurrent.[1a,3] Therefore,reactions taking place in same compartment, became of utmost importance.In the cellular environment are in fact considered as this way, for agiven biosynthetic pathway, the product concurrent. In organic chemistry,ithas been largely

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Fabricio R. Bisogno obtained Gonzalo de Gonzalo ob- his degree in biochemistry tained his Ph.D.in2003 (2004) at SanLuis National (Prof.Vicente Gotor, Univer- University(Argentina). In sity of Oviedo) working on 2007, he spent half ayear at the field of biocatalysis em- the Weizmann Instituteof ployinglipases andoxynitri- Sciences (Israel, Prof.Meir lases.Hespent his postdoc- Lahav) involved in research toral research at Consiglio on the origin of homochirali- Nazionale delle Ricerche ty.Then, he pursuedPh.D. (ICRM, Milano, Italy,Dr. studies at University of Giacomo Carrea), moving Oviedo (Spain, Prof.Ivµn back to University of Oviedo Lavandera andProf.VicenteGotor), dealing with with aJuan de la Cierva Fellowship.After aone- biocatalytic redox processes(2010). Besides,in2012 year postdoctoral stage at Universityof Groningen he obtained another Ph.D.degree at San Luis Na- (The Netherlands,Prof.Marco W. Fraaije) working tional University(Argentina,Prof.Marcela Kurina- in the research of noveloxidative biocatalysts,he Sanz) working on fungal biotransformation of bioac- spent two years at the R&D Department of the tive compounds. After postdocperiods in Oviedo pharmaceutical company Antibióticos S.A.U.(León, and Córdoba(Argentina), in 2013 he joined Prof Spain). He is currently aRamónand Cajal Re- Alicia PeÇØÇorysgroup as researcher at Córdoba searcher (MINECO) at UniversityofSevilla. His re- National Universityand INFIQC-CONICET (Ar- search is focused on asymmetric synthesis by using gentina).His research interest comprisescombina- different approaches,including biocatalytic andor- tion of biocatalysis with metal catalysisand organo- ganocatalytic procedures, as wellasthe development catalysisfor the constructionofcooperativesystems, of concurrent chemo- and biocatalytic reactions. along with exploration of novel reactivities for organo-sulfur-and organo-selenium-containingcom- pounds in enzymatic or biomimetic processes.

MartínG.López-Vidal obtained his degree in biochemistry at Córdoba National University(2014, Argentina). In 2015, he joined Prof Alicia PeÇØÇorysgroup as aPh.D. CONICET-fellow,under the guidance of Fabricio R. Bi- sogno at Córdoba National University. In 2016 he spent athree-months stay in the Laboratory of Biocatalysis at the UniversityofGraz (Austria) exploringthe reactivity of sulfur-containing compoundswith ene-reductases under the super- vision of Prof MØlanie Hall. His researchinterest is focused on the development of novel chemoenzymatic cascades for stereoselective preparation of or- ganochalcogen-compounds. demonstrated that running multiplereactions in one- agents are addedatthe beginning, thus requiring only pot, either in sequential (also known as stepwise, one operational step) mode,ischallenging to agreat when operationssuch as addition of catalysts/re- extent given the diverging reactionconditions suitable agents,temperature/atmosphere modification, etc. are for each single transformation.[4] Thus,tremendous ef- made during the course of the process to ensure the forts are made in order to find proper conditions to proper reactivity mode) or simultaneous (also known harmonically combine multiple catalytic reactions as cascade or domino reactions,inwhich conditions with no cross-spoiling effects.[5] are not modified during the process and catalysts/re-

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In abroad sense,organocatalysis can be definedas the acceleration of achemical reactionusing an or- 2SequentialReactions Employing ganic compound in substoichiometric amounts in the Organocatalystsand Biocatalysts absence of (transition) metals.[6] On the other hand, an acceptable definition of biocatalysis in organic syn- Initially,weshall deal with processes in which the or- thesis can be the employment of abiomolecule (pro- ganocatalyst andthe biocatalyst are able to catalyse tein, antibody,ribozyme) or aliving organism to carry sequential reactions in order to have multistep one- out the transformation of a(non-)natural organic pot procedures(Figure 1).[12] Theselectivity of the compound.[7] final productswhen chiral compounds are synthes- Nowadays,bothorganocatalysis and biocatalysis ised, can be induced by only the organocatalyst,by are becoming mature and amechanistic understand- only the biocatalyst or by both catalysts performing ing of enzymatic reactions alongwith catalytically- selectivereactions in the sequential process. productive organic associations have been deeply in- vestigated. It is rather remarkable that the number of examples where both sorts of catalysis working concurrently were successfully applied is limitedwhen comparedwith the far more explored combination of metal catalysed processesand biocatalysis.[8] Some reports have been published based on the combination of transition metals and organocatalysts;[9] but not so many examples are availabledealing with the combination of organocatalysis andbiocatalysis in one-pot procedures.[10] It must be takeninto account that organic substan- ces are not always soluble in aqueous media, so aproper solvent selection is usually an issue in both Figure1.Schematic representation of asequential one-pot organo- and biocatalytic systems.Notwithstanding, process using organocatalysis and biocatalysis. the use of cosolvents or additives (in the frame of a“medium engineering” concept), is acommon prac- tice in those catalytic methodologies,thus circumvent- One of the first examples described in the literature ing solubility and, in certain cases,reactivity prob- of asequential multistep one-pot process combining lems.[11] Foracombination of organo- andbiocatalytic organocatalystsand enzymes, was published in 2004 processesinone-pot procedures,the reaction medium for the synthesis of enantiomerically pure aldols,as must be carefully tailored in order to avoid cross- shown in Scheme 1.[13] spoiling. Cosolvents and additives for the organocatalysed reactionneed to be tested towards the biocatalysed reactiontoprevent inhibitory effects. From asynthetic point of view, chirality in the formed product can be installed or defined either throughthe enzymatic or the organocatalysedreac- tion or,even, both catalytic systems may define stereocentres in the same catalytic cycle,increasing the complexity of the final products. Scheme1.Synthesis of optically active aldols by combining With the settlementoftechnologiessuch as photo- an organocatalytic aldol reaction with abiocatalysed acyla- chemistry,flow chemistry,mechanochemistry,among tion in asequential one-pot process.[13] others,that can be incorporated into complex multicatalytic processes, the boundaries of combined catalysis are continuously being pushed forward. In this process,the proline-catalysedaldolreaction In this review,the focus will be placed on selected between aromatic aldehydes and acetone was com- representativeexamples that maygive ageneralidea bined with the kinetic resolution of the resulting alco- of the possibilities of combiningorganocatalysts and hols catalysed by lipases in the presence of vinyl ace- biocatalysts in one-pot including sequential and simul- tate.Aldol reactions were performed in neat acetone, taneous methodologies.Special emphasis will be as the usual solventsfor organocatalysedaldol reac- given to asymmetric processes. tions are toxic to lipases. Under these conditions,the aldol adducts were obtained with good yields and moderate selectivities.Such adducts were tested as substrates in biocatalysedacylations using vinyl ace-

Adv.Synth. Catal. 2017, 359,2026 –2049 2028 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim REVIEWS asc.wiley-vch.de tate as acyl donor. Lipase from Pseudomonascepacia and 95% ee after 2h.The entire chemoenzymatic syn- AmanoI(PS C1) led to excellent selectivities in the thesis of (R)-pantolactone was performed in what the kinetic resolutions,thus improving the ee obtained in authors claimed as a“one-pot-like” process,asthe the aldol reaction. In view of these results,the pro- volatile compoundsofthealdol reactionare removed cesses were carriedout in one-pot. Acetone was re- under vacuumprior to the bioreduction and ISPR moved from the reaction medium before the addition during the enzymatic reaction. Starting from of vinyl acetate and the lipase.Likewise,the use of 1.28 mmol of ethyl glyoxateand 2.65 mmol of isobuta- (S)-prolineand lipase PS C1 led to the formation of nal in 0.41 mL of IPA, (R)-2 was obtained with 55% the enantiopure (S)-acetates (S)-1 with moderate conversion (referredtoethylglyoxylate) and95% ee, yields (around 30–40%), These yields achieved in the as shown in Scheme 2. one-pot procedures were slightly lower than those obtained in the stepwise reactions. Other amino acids different from proline and its derivatives have been also studied as catalysts in aldol reactions.Thus,use of an l-histidine catalysed aldol reactioncombined with an alcohol dehydrogenase (ADH) catalysed reduction,[14] has been reported towards the asymmetric synthesis of (R)-pantolactone (2).[15] Firstly,the organocatalysed aldol reactionbetween isobutanal andethylglyoxylate in 2-propanol (IPA) was explored in order to obtain the enantioenriched aldol adduct.Several catalysts were studied, and among the tested amino acids and amino(thio)urea catalysts, l-histidine was chosen, displaying good activity with high enantioselectivity.Anadditional advantage of l-histidine towards more complex organocatalysts is its commercial availability in bothenantio- meric forms. In the Brønsted acid cocatalyst screen- ing, it turned out that acids with pKa valuesbetween 4.0–5.0 showed the best results and the authors adopted acetic acid as cocatalyst.Ithas been describedthat those acids couldincrease the addition yield by facili- tating the hydrolysisofthe iminium ion formed be- Scheme2.One-pot preparation of (R)-pantolactone 2 by combiningorganocatalysed aldol reaction with enzymatic tween substrate and catalyst.[16] Reactions were per- bioreductioninpresence of ADH-200.[15] formed using 2.5 Methyl glyoxylate,10mol% of l- histidine,10mol% of acetic acid in amixture water/ alcohol 1:1for 24 hat108Cleading to the formation In 2009, the sequential one-pot synthesis of chiral of the (R)-a-hydroxy ester in up to 95% conversion, 1,3-diols combininganorganocatalytic aldolreaction 85% yield and 79% ee. Further studies were focused and an enzymatic keto reductionhas been carried out on the enzymatic reductionofthe aldol adduct in aqueous media (Scheme 3).[18] Theproline-based (0.5M) and further spontaneous lactonisation of the catalyst I,developed by Singh in bothhomochiral dia- hydroxy ester, where ADH-200from Evocatal (evo- stereomeric forms,[19] has demonstrated to be an effi- 1.1.200)showed higher conversions at pH 8.0in cient catalyst for the enantioselective formation of b- buffer/2-propanol 20% v/v:upto67% conversion and hydroxy ketones with high yields and enantiomeric 95% ee. Removal of volatile compounds such as ace- excesses.For this reason, preliminary studies were fo- tone (a by-product formed in the nicotinamide cofac- cused on the optimisation of the organocatalysed tor NAD+ recycling) andnon-converted aldehydes aldol reactionusing both(S,S)-I and (R,R)-I as cata- prior to the bioreduction step,increasessignificantly lysts.Thus,employing p-chlorobenzaldehydeand ace- the conversion (64% vs. 33% without removal of vol- tone as model substrates,both enantiomeric formsof atile compounds under vacuum), probably due to the corresponding b-hydroxy ketonewere achieved competition of these compoundsfor the aldol adduct. with the same enantiomericexcess (83%). However, In order to in situ remove the acetone (In Situ Prod- the obtainedyields were lower in case of the (R)- uct Removal –ISPR),[17] acontinuous flow of air satu- isomercompared with the (S)-isomer(58 and 71%, rated with water/2-propanol (5% v/v) passing through respectively). Further studies were focused on the the bioreduction has proved to be an effective strat- bioreduction of the aldolproducts. Either (S)-ADH egy leading to 86% conversion of the aldol product from Rhodococcus sp.or(R)-ADH from Lactobacil-

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Scheme 3. One-potorganocatalysed aldol reactioncombined with biocatalysed reduction to yield the optically active diol (1R,3S)-3a.[18] lus kefir using 2-propanol as cosubstrate in asubstrate-coupled cofactorrecycling system, allowed the authors to synthesise the corresponding four possible Scheme4.Synthesis of optically active 1,3-diols by combin- isomeric 1,3-diols 3 with excellent results (>95% con- ing organocatalysed aldol reaction in the presence of (S,S)-I version, > 99% ee and 1:11 diastereomeric ratio). with bioreduction catalysed by (S)- or (R)-ADH in asequen- In ordertoexplore the substrate scope of this pro- tial one-pot processtoyield optically active diols (1R,3S)-3b cess,other substituents at the para-position of the aro- and (1R,3R)-3b.[20] matic ring were tested, where p-tolualdehyde showed similarresults with only aslight decrease in the stereoselectivity of the aldol reaction(76% ee). Once talysed aldolreactionwas optimised in saturated the individual steps were optimised, for the proof-of- aqueous NaCl solution. As expected, the catalyst concept of the whole one-pot two-stepsystem, p- loadingplays acritical role in the stereochemical out- chlorobenzaldehyde (0,5 mmol) and acetone were come of the reaction andasignificant decrease in chosen as substrates.Thus,the corresponding b-hy- enantioselectivity was observed using 5mol% of droxy ketone was obtained using (S,S)-I in 20 hours (S,S)-I after 48 h. Hence,different catalyst loadings at room temperature.After the aldol reaction, biore- were tested, resulting in ahigh enantioselectivity at ductionemployingthe (S)-ADH was carried out in 0.5 mol%, while total reactioninhibition was seen at phosphate buffer pH 7.0 (67 mM of the substrate) 10 mol% of I.The authors attributed this fact to containing2-propanol 25% v/v as cosubstrateatroom aswitch of the reactioncontrol from akinetic to temperature,affording the desired (1R,3S)-3a with athermodynamic regime. >99% ee,1:10 syn/anti diastereomeric ratio after 18 Thus,the combination of the organocatalysed aldol hours,reaching >95% conversion as shown in reactionwith bioreduction using either (S)-ADH Scheme 3. from Rhodococcus sp.or(R)-ADH from Lactobacil- Noteworthy,the generation of stereocentres is con- lus kefir under optimised conditions,enabled the trolledonly by the external catalyst, with marginal (if preparation of the corresponding opticallyactive 1,3- any) influence of the other chiral centre alreadypres- diols 3b starting from m-chlorobenzaldehyde and ace- ent in the reactant.Thus,each stereocentre is possible tone in aone-pot,two-stepfashion in 48 h. Theprod- to be definedenantioselectively by the sole modula- ucts were obtained with >95% overall conversion, tion of the organo- andthe biocatalysts. >25:1 diastereomeric ratio and >99% enantiomeric Encouraged by these initial results,expansion of excess. As already mentioned, each catalyst or set of the substrate scope to meta-substituted aromaticalde- conditions must be optimised according to the re- hydeswas attempted,asshown in Scheme 4.[20] Simi- quired performance.Inthis case,different amounts of larly,asequential one-pot multistep systemwas set up enzyme were used depending on the catalystsactivity using m-chlorobenzaldehydeaselectrophile and towards the substrate,employing 10 units/mmol> or 9equivalents of acetone.Thus,with the chemoenzy- 480 units/mmol with of (S)- or (R)-ADH, respective- matic one-pot synthesisasafinal goal, the organoca- ly.

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hyde (1.5M) as acceptor with 95% overallconversion and 95% ee after 24 h. However, 3-chlorobenzoic acid (3-CBA, 2mol%) was needed as cocatalyst in order to overcome the low activity of (S,S)-II in non-aqueous conditions,and optimal performances were found at 38Cinorder to preserve asuitable stereorecogni- tion in an organic solvent such cyclohexane. Theimmobilised catalyst wasrecycled by decanting and evaporating the organic layer before the biore- ductionstep.Likewise,chiral (1S,3R)-3b was obtained using an (S)-ADH from Rhodococcus sp.coimmobilised with its cofactor (NAD+)onto the superabsorb- ent polymer Favor SXM 9155(Evonik Industries AG).[23] Thedesired diol was obtained with high conversion (89%) andexcellent diastereo- andenantiose- lectivity (dr >35:1, > 99% ee). Moreover, the free proline derivativecatalyst II was also tested in this one-pot process and the same results were obtained in terms of activity and selectivity,making also suitable the combination in aone-pot process of anon-immobilised organocatalyst with an immobilised ADH in organic media. Scheme 5. Synthesis of (1R,3S)-3b in aone-pot procedure a-Amino-g-butyrolactones are valuablebuilding using both coimmobilised organocatalyst (S,S)-II and (S)- ADH from Rhodococcus sp.with its cofactor NAD+ in or- blocks present in aset of natural compoundsand ganic solventmedium.[21] pharmaceuticals.These compounds can be prepared by combining an l-proline-catalysed Mannich reaction to obtain an aminoketo ester, which can be fur- Very recently, by taking advantage of this sequen- ther reduced to any diastereomer alcohol by choosing tial process,the use of organic media was demonstrat- the suitableADH.[24] Theresulting amino alcohols cy- ed in asimilar one-pot process for an alternative clise,either spontaneously or under transesterification preparation of chiral 1,3-diols,asshown in conditions (HCl-MeOH), to the desired aminolac- Scheme 5.[21] Immobilised organocatalyst II in acrylic tones.The described synthesis comprises isolationof polymeric beadscatalysed the aldol reactionbetween Mannich adduct intermediates,but the authors have aromatic aldehydesand acetone in organic media also developed the one-pot reaction. with similar results to those obtained with the free As shown in Scheme 6, the starting aldimine 5 is catalyst in aqueous media.[22] Likewise,employingim- synthesised by mixing p-anisidine (0.53 mmol) with mobilised II,itwas possible to achievethe (R)-b-hy- ethyl glyoxylate (0.55 mmol) in the presenceofIPA droxy ketone(R)-4b starting from m-chlorobenzalde- (2.5 mL), which also serves as the solvent for the

Scheme 6. Synthesis of aminolactone (3S,5R)-8 in aone-pot procedure by combing an l-proline-catalysed Mannich reaction with abiocatalysed reduction of the formed ketone (S)-6.[24]

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Mannich reactioncatalysed by l-proline (0.13 mmol), tive a-oxyamination of the aldehyde (S)-9a formed in and as hydrogendonor (cosubstrate) for the reduction the first step,asshown in Scheme 7. Theone-pot re- of the formed ketone(S)-6 to the corresponding action was carriedout in aqueous medium. After 24 h amino alcohol (2S,4R)-7 in the presence of ADH-200, for the Friedel–Crafts alkylation at room temperature, after dilution of the reactionmediumwith aqueous laccase andTEMPO (2,2,6,6-tetramethylpiperidine 1- buffer. Thefinaltransesterification in the presence of oxyl radical)asmediator were added to the reaction HCl in MeOH led to the enantiopure syn-(3S,5R)-lac- mixture which was stirred for additional 24 h. When tone 8 with 47% yield and diastereomeric excess of employing 4-nitrocinnamaldehyde,the final product 72%. This value,lowerthan that obtained in the step- (2S,3S)-10a was recoveredwith a syn/anti ratio75:25 by-step synthesis,can be due to the 2-propanol em- and 96% ee for the major diastereomer, but unfortu- ployed as the solvent for the organocatalysed reac- nately with avery low conversion. Theuse of THF as tion, which might impair the selectivity of this step. reactioncosolvent (1:2 ratio with water) allowed an In asimilar one-pot approach, aldimine 5 increase of the substrate solubility,reaching a59% (1.0 mmol) was employed in the Mannich reaction yield for the final product with the same optical with acetone (5 mL) as solvent and l-proline purity. (0.25 mmol) as organocatalyst. After 16 hreaction Thereaction was then extended to other substitut- time,the solvent wasevaporated andketone(S)-6 ed indoles, to N-methylpyrrole and to 3-nitrocinna- was selectively reduced in the presence of ADH-200 maldehyde.For all the examples,the syn/anti ratios of in buffer/IPAtoamino alcohol (2S,4R)-7.Furtherhy- the final compounds (2S,3S)-10b–e were around drolysisand purification afforded aminolactone 75:25, reaching excellent optical purities for the syn (3S,5R)-8 with 51% yield. diastereomer, while the yields were between 51 and Resin-supported peptides can be employed in orga- 70%. nocatalysed reactions carriedout in aqueous environ- In 2012the first one-pot sequential three-compo- ment.[25] Thesecatalysts have been also applied to the nent reactionwas described in which two C–C bonds one-pot sequential synthesis of oxyfunctionalised in- were created.[28] In the first step,adiamineorganoca- doles,[26] in combination with the laccase from Tra- talyst IV (10 mol%) was able to performthe aldol re- metes versicolor.[27] Theresin-supported peptide III action between aglyoxylamide (0.1 mmol) and acetal- catalysed the asymmetric Friedel–Crafts alkylation of dehyde (0.1 mmol). Thesecond C–C bond formation the starting indole (0.1 mmol) with an a,b-unsaturated was carriedout by the E192N mutant of N-acetyl- aldehyde (0.15 mmol), through an iminiumintermedi- neuraminic acid lyase (NAL), which catalysed the ate,whilethe laccase was able to catalyse the selec- aldol condensation between the aldehyde formed in

Scheme 7. One-potsynthesis of indole derivatives 10a–e by combiningaresin-supported peptide-catalysed Friedel–Crafts alkylation with alaccase-catalysed a-oxyamination.[26]

Adv.Synth. Catal. 2017, 359,2026 –2049 2032 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim REVIEWS asc.wiley-vch.de the first step and pyruvate (0.1 mmol). This linear Table 1. One-pot three-component reaction catalysed by product spontaneously cyclises to achieve the hemike- proline derivative IV and E192N NAL.[28] talic final products 11a–d. As the enzymatic reactionhas to be carriedout in aqueous buffer, the organocatalysed aldolcondensa- tion was studied in this reactionmedium. It was observed that with 10 mol% IV,the reaction tookplace, but unfortunately with amodest diastereoselectivity and adrastic decrease in the enzymatic activity. Forthis reason,the one-pot,three-component reaction wascarriedout in areactionmedium that was di- luted with aqueous buffer after the first aldolreaction. Thus,aset of glyoxylamides reacted with 10 equivalents of acetaldehyde in the presence of 1 2 [a] [b] 5mol% organocatalyst in buffer pH 7.4 for 20 hours. Product R R Yield [%] cis/trans After this time, a2.5-fold dilution with buffer was 11a Pr Pr 40 78:22 performed and sodium pyruvate and E192N NAL 11b Me Pr 48 57:43 were added. Reaction mixtureswere shaken for other 11c Me Me 43 71:29 70 hat358C. Thefinal products 11a–d were recov- 11d Et Et 51 61:39 ered with yields around 40–51% and modest diaste- [a] Based on glyoxylamidestartingmaterial. reoselectivities (Table 1). These lower valuescan be [b] Determined by 1HNMR. explained by two reasons: (i)the absence of selectivity in the organocatalysed step;and (ii)the low selectivity of the NAL-catalysedreaction. Process optimization allowed the authors to obtain Aone-pot sequential organo- andbiocatalysedpro- a70% yield of anti-12 by using 2equivalents of 1,2-di- cess has been recently developed for the preparation hydrofuran and HFIP,1mol% of Schreinerscatalyst of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol()- in dichloromethane at 30 8C. Thecatalysed acetylation À 12 (bis-THF-alcohol, Scheme 8), astructural motif of of the anti-alcohol with vinyl acetate at 50 8Cwas different HIV-1 protease inhibitors such as Darunavir tested in the presence of different lipases.Best results and Brecanavir. Firstly,the organocatalysed conden- were achieved with lipase PS,recovering enantiopure sation of 1,2-dihydrofuran and glycoaldehydedimer anti-12 with a37% yield.Once the twocatalytic pro- was studied in ordertoobtain amixture of syn and cesses had been optimised, the one-pot reaction was anti diastereomers of bis-THF-alcohol.[29] Reactions performed, first by carrying out the organocatalysed were carried out in the presenceofhexafluoroiso- condensation between 1.0 mmol of dimer and propyl alcohol (HFIP) as it has been describedthat 4.0 mmol of 1,2-dihydrofuran in 2mLofCH2Cl2 in this additive could increase the condensation yield by the presence of 4.0 mmol of HFIP and2mol% of favouring the formation of glyceraldehyde monomer thiourea V at 30 8Cduring 72 hours.After this time, from its dimer.Among all the catalysts tested, vinyl acetate (2 mL)and lipase PS (260 mg) were Schreinersthiourea(V)was the most active,[30] lead- addedand the systemwas stirred at 50 8Cfor 24 h. ing to amixture of both anti-bis-THF-alcohol (the de- After the crude purification, enantiopure anti-alcohol sired one to complete the synthesis) and the syn dia- was obtained with 30% yield, while the syn-acylester stereomer with moderate yields. 13 was obtainedwith 35% yield. Scaling up of the

Scheme 8. One-potsynthesis of the valuable synthon bis-THF-alcohol 12 by combiningSchreinersthiourea V with lipase PS.[29]

Adv.Synth. Catal. 2017, 359,2026 –2049 2033 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim REVIEWS asc.wiley-vch.de process up to the gram-scale (20 mmol of starting ma- asimultaneous one-pot fashion. Moreover, this pro- terial) led to the same yield for the desired alcohol cess can be coupled with afurthersequential reduc- with 97% ee,demonstrating that this one-pot proce- tion of the aldehyde to the corresponding (R)-1,3-diol dure can be practical for the preparation of pharma- (15)inthe presenceofNaBH4 (Scheme 9), minimis- ceuticals. ing the retro-aldolreaction.

3Simultaneous One-PotProcesses Combining Organocatalysts and Biocatalysts

Apart from sequential one-pot reactions combining both organo- and biocatalysts,other designs have been performed in which all the reactioncomponents are addedatthe beginningofthe reaction(Figure 2).

Figure 2. Typical simultaneous one-pot synthesis using organo- and biocatalysts.

Thesynthesis of diol (1R,3S)-3b (Scheme 4) has been recentlyperformed by combining organocatalyst (S,S)-I and (S)-ADH from Rhodococcus sp. in asimultaneous way by adding boththe organocatalyst and the biocatalyst at the beginning of the reaction.[31] Conditionsfor both the aldol reactionand the enzymatic reductionwere optimised in order to develop an efficientprocess andtominimise possible side re- Scheme9.Synthesis of (R)-1,3-diols in aone-pot process actions such as the biocatalysedreductionofthe alde- combiningCAL-B and trifluoromethyl prolinol catalyst VI hyde,the biooxidation of diol 3b to ketone 4b,or in DES.[32] aldol condensations.Byemploying an aldehyde concentration of 500 mM, 5equiv.ofacetone and 2-propanol as cosubstrate for the ADH (28% v/v), enantio- Thus,the one-pot reactions were performed using pure (1R,3S)-3b can be obtained in 60% conversion 1.0 mmol of aldehyde,3.0 mmol of both vinylacetate after 24 hours.Scaling up to 10 mmol of 3-chloroben- and propanol and 20 mol% of trifluoromethyl-substi- zaldehyde led to 50% conversion of the desired diol. tuted diphenylprolinol (VI)asorganocatalyst. The In 2014, an aldol reactionusing an alternative deep eutectic solvent (DES) choline chloride-glycerol source of aldehydes hasbeen explored. In this con- (1:2 molar ratio;1.0 mL) was employed as reaction text, the use of vinyl esters combined with lipaseswas medium,[33] while immobilised lipase Bfrom Candida proposedtogenerate acetaldehyde that will be em- antarctica (CAL-B) carried out the acetaldehydegen- ployed in the organocatalysedsynthesis of chiral 1,3- eration. Conversions were very high after 48 h(up to diols.[32] This strategy allowsone to keep the acetalde- 92%), with reasonably high yields (up to 70%), and hyde concentration low,therefore diminishing the del- excellent enantioselectivities (up to >99%ee). Sub- eterious effects of this compound towards the enzy- strates with electron-withdrawing substituents at any matic catalyst and avoiding self-condensation of this position of the aromatic ring were tested with similar aldehyde.The lipase-catalysed transesterification of good results. vinyl acetate with 2-propanol leads to the formation Thereaction was also extended to cinnamaldehyde of acetaldehyde,which willserve as substrate in an or- derivatives such as a-bromocinnamaldehyde, with ex- ganocatalysed aldol reaction, leading to chiral b-hy- cellent ee (96%), although poor yield (14%). In addi- droxyaldehydes (R)-14.All the reactions occurred in tion, the use of aldehydeslacking electron-withdraw-

Adv.Synth. Catal. 2017, 359,2026 –2049 2034 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim REVIEWS asc.wiley-vch.de ing groups such as 4-pyridinecarboxaldehyde or cin- NAD+ and550 mM b-alanine.After degassing this namaldehyde led to disappointingly low yields (up to systemfor one hour, 100 units of the ADH were 2%) and the enantioselectivity was fully suppressed. addedtoinitiate the reaction. Thesystemwas photo- Furthermore,the mandatory use of acetaldehyde irradiated for 3hours and the crude material was ex- leads always to b-hydroxy aldehydes, therefore chiral tracted and analysed by 1HNMR,with recovered of 1,3-diols are obtained with only one stereocentre.In 1.5 mM of 16 and1.8 mM of 17. this case,the stereoselectivity is totally controlled by Theone-pot systemwas also carriedout in asyn- the organocatalyst.DES and CAL-B could be reused thetic acetone-butanol-ethanol(ABE) solution, using for up to six cycleswithout loss of enzymatic activity. 15 mM acetone,30mMbutanol and 5mMethanol. Regardingthe organocatalyst, yieldswere stable Thethree catalysts and NAD+ were added to this so- when fresh VI was addedtothe reaction medium lution.After 3hphotoirradation, the solution was ex- while aslight loss of activity wasobserved in the ab- tracted andanalysed by 1HNMR. Amixture of sence of extra organocatalyst. 1.0 mM of acetaldehyde,1.0 mM of butyraldehyde Thecombination of photo-, organo- andbiocataly- and 1.5 mM of 2-ethylhexenal was recovered. sis has recently allowed the conversion of n-butanol Resin-supported peptides (see Scheme 7) have to 2-ethylhexenal (Scheme 10). In this simultaneous been also employed in the simultaneous asymmetric a-oxyaminationofaldehydes in combination with the laccase from Trametesversicolor and TEMPO as mediator.[35] This reactioncan be regarded as aformal enolate/enamineone-electron oxidation,[36] and further radical trappingbyTEMPO.Initial studies were devoted to analyse the product outcome under different reactionconditions.Thus,the laccase-catalysed oxidation of 3-phenylpropanal in acetate buffer afforded the carboxylicacid (18)assole product. When this biocatalysed reactionwas carried out in the presence of pyrrolidine as base catalyst, the racemic a- oxyaminated carboxylic acid (19)was formed together with the a-unsubstituted carboxylic acid. Thepyrrolidine-catalysed reactionperformed in Scheme 10. Synthesis of 2-ethylhexenal 17 by combining awater/1,4-dioxanemixture led to the formation of three catalysts in aone-pot simultaneousprocedure.[34] a-unsubstituted carboxylic acid andtwo racemic oxyaminated products,the chiral aldehyde (R)-20 and the carboxylic acid (R)-19.The use of the resin-supported one-pot process the ADHfrom Saccharomyces cerevi- peptide VII as catalyst (Scheme 11) in water allowed sae catalysed the oxidation of n-butanol to n-butyral- the formation of (R)-a-oxyaminated carboxylic acid dehyde (16)using NAD+ as cofactor. Thephotocata- (65% conversion) with 63% ee alongwith asmaller lyst platinium-seeded cadmium sulfide (Pt@CdS) amount of 18 (35%). In view of these results,the one- QuantumDot was employed for the cofactor regener- pot reactioninthe presence of VII and the enzymatic ation. n-Butyraldehyde was converted to 2-ethylhexe- systemwas extended to 4-arylbutanals.Thus,oxida- nal (17)inanaldolcondensation catalysed by b-ala- tion of 4-phenylbutanal led only to the a-oxyaminated nine.[34] Thesingle reactionwas performed by mixing aldehyde with 71% yield and 82% ee. Similarly,com- 50 mM of n-butanol with 25 mM Pt@CdS,3mM plete conversion (53% yield) and80% ee were ach-

Scheme 11. Peptide-supported VII/laccase-catalysedsimultaneous one-pot a-oxyamination of aldehydes to obtain the correspondingchiral (R)-a-oxyaminated carboxylic acids (19)and aldehydes (20).[35]

Adv.Synth. Catal. 2017, 359,2026 –2049 2035 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim REVIEWS asc.wiley-vch.de ieved in the reactionof4-(4-methoxyphenyl)butanal. reactionfeatures laccase-catalysed oxidation of the This yield could be improved by performing the reac- hydroquinone reagent giving rise to radical species tion in acetate buffer (74%), while the addition of the that further addtothe chiral enamine double bond. surfactant Tween 80 to the reaction mixture after 2 Reaction optimization was performed for the reaction hours resultedinthe a-oxyaminated carboxylicacid between 3-methylbutanal and 1,4-dihydroxybenzene as major product (81%) with 64% yield and 91% ee. in the presence of (S)-2-[diphenyl(trimethylsilyloxy)- Taking into account these encouraging results,the methyl]pyrrolidine (S)-VIII as organocatalyst andthe asymmetric oxidation of different aldehydeswith lac- laccase from Agaricus bisporus. Theinitial reaction case and VII was performed in the absence andinthe was carriedout with 0.25 mmol of 1,4-dihydroxyben- presence of Tween 80. Reactions were carriedout zene in 0.5 mL buffer/acetonitrile pH 6.0 containing with 0.05 mmol of aldehyde andTEMPO,while using 10 mol% of (S)-VIII,15units of laccase and 5equiva- 0.01 mmol of VII and 0.5mgoflaccase in 0.5 mL of lents of aldehyde perequivalent of 1,4-dihydroxyben- acetate buffer. In the absenceofsurfactant, the oxy- zene. amination affordedthe chiral aldehydes (R)-20 in 1h After 72 hours,the final product 21a was obtained with good to moderate yields and optical purities with 76% yield and 87% ee. Theuse of 45 units of close to 90%, while the presence of Tween 80 laccase had areally positive effect on the procedure, (1.0 mL) led to the carboxylic acids (R)-19 with good as the yield increased up to 97% yield in the same re- yields andhighenantioselectivities after 5–8 h. The action time with 96% ee. Theamount of organocata- systemprovedtobehighly efficient since it was possi- lyst had no effect on the cascade system. Thereaction ble to reduce the amount of bothcatalysts to 5mol% was scaledupto2mmol of 1,4-dihydroxybenzene,re- with negligible loss of activity and selectivity. covering the finalhemiacetal with 84% yield and Aset of 3-substituted-2,3-dihydrobenzofuran-2,5- 92% ee. Another b-branched aldehyde such as 2-cy- diols (21a–f)was synthesised in aone-pot cascade clohexylacetaldehyde has been successfully tested in procedure by combininganinitial laccase-catalysed this procedure (91% yield and 92% ee for 21b). On oxidation of 1,4-dihydroxybenzenes(hydroquinone the contrary, unbranched aldehydes(for instance 21c derivatives), with the sequential aminocatalysed a-ar- and d)led to moderate to good yields(51% to 90%) ylation of aldehydes,asshown in Scheme 12.[37] The and lower optical purities.Itwas observed that shorter reactiontimes afforded higher selectivities.Studies on this line suggested that the final product tautomer- ises,and thusthe aldehyde forms an iminium ionwith the aminocatalyst, leading to an enamine after depro- tonation, which uponhydrolysis afforded again the hemiacetal. As branched aldehydesare more stable in the hemiacetalic form, this racemisation did not occur, while asignificant amount of aldehyde is observed for the unbranchedones,which induces this decrease in the optical purity. Theuse of substituted 1,4-dihydroxybenzes such as the 2,6-dichloro (21e)or the 2,6-dibromo (21f)derivatives in the reaction with 3-methylbutanal allowed the authors to obtain the final productswith good yields(around90%) and ex- cellentoptical purities (around95%). Chiral functionalised cyclopentenones have been employed as precursors of natural products and biologically active compounds.Different methodologies have been proposed to synthesise them,but all suf- fered from anumber of drawbacks.Therefore,aone- pot approach starting from apyranone to achieve the optically active cyclopentenone hasbeen recently developed. This methodology consisted in asequential process in which an initial organocatalysed rearrange- ment converts the pyranone into acyclopentenone presenting ahydroxy moiety, 22a,which then under- Scheme 12. One-pot synthesis of chiral 3-substituted2,3-di- went alipase-catalysed kinetic resolution to yield the [38] hydrobenzafuran-2,5-diols (21a–f)employingthe secondary alcohol (+)-22a and the ester (-)-23a (Scheme 13a). amine (S)-VIII as organocatalyst and laccase from Agaricus Therearrangement was optimised in ordertohave bisporus.[37] compatible conditions with the enzymatic reaction

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Scheme 13. a) One-pot simultaneoussynthesis of chiral cyclopentenones (+)-22a and (-)-23a by DABCO-catalysed rear- rangement andlipaseAK-catalysed kinetic resolution.[38] b) One-pot sequential synthesis and DKR of pyranones catalysed by DABCO and lipase AK for the preparation of acetylated cyclopentenones ( )-23a–d.[40] À and to prevent the decomposition of the obtained 22a Thus,racemisation of alcohol (+)-22a was induced into the undesiredenone (24a). Thus,after testing dif- in the presence of astrong acidic medium (pH 1.0– ferent reactionparameters,itwas possible to obtain 2.0) in the reactionmixture,but these conditions have 23a in 85% yield, with only 3% of enone side prod- anegative effectonlipase activity.Racemisation is uct, after a24h treatment of the starting material very effectiveunder the acylation conditions,which with 0.15 equivalents of the amine 4-diazabicy- can be likely due to the enzymatic activity or to the clo[2.2.2]octane(DABCO) at 50 8Cinthe presenceof production of acetic acid by hydrolysisofvinyl ace- tert-butyl alcohol as solvent. When combiningthe re- tate.Itwas also observed that the racemisation rate arrangement under the optimal conditions with the was improvedbyusing silica gel 60 (5 mg/mg of lipase enzymatic resolution of the alcohol formed in the AK), which also presents an acidic character. In order presence of vinylacetate,several lipaseswere tested, to combine in aone-pot process the conditions for the best results being achieved with lipase AK. Start- the racemisation and the biocatalysed acetylation, ing from 100 mg of pyranone,5equiv. of vinylacetate, asequential one-pot procedure wasdeveloped 30 mol% DABCOand 50 mg of lipase in 1.0mLof (Scheme 13b).[40] Thepyranone (2.35 mmol) rear- tert-butyl alcohol led to chiral acetate ( )-23a which rangement wascarriedout during 24 hwith DABCO was isolated in 55% yield and80% ee afterÀ 10 days, (0.36 mmol) in t-BuOH(2.0 mL), after which the mix- while the starting alcohol (+)-22a was recoveredin ture was neutralised with acetic acid. Then, lipase AK 35% yield and only 11% ee. Thelow optical purity of (400 mg), silica gel 60 (2.0 g) andvinyl acetate the alcohol can be explained by its racemisation (5.0 equiv.) were added and reacted for 7days in under the reactionconditions,which opens up the op- order to achieve the acetylcyclopentenone ( )-23a portunity for developing adynamic kinetic resolution with 81% yield and 95% ee,while the hydroxycyclo-À (DKR)inorder to obtain the acylated product 23a pentenone was recoveredwith only 10% ee and with ahigh yield and optical purity(see Figure 3).[39] ayield of 4%. This methodology was then extended to other ( )-cyclopentenones (23b–d)but in all cases, lower yieldsÀ and optical purities were obtained. Adifferent approachtothe organo- and biocatalysed one-pot systems hasbeenrecently described in the preparation of capsaicinanalogues,compounds with high biological interest, starting from lignin-de- rived compoundsusing amulti-step procedure.[41] The last step of this synthesisisthe biocatalysed acylation of vanillylamine (27). Theauthors have proposed several procedures for its preparation by combining dif- Figure 3. General representation for adynamic kinetic reso- ferent catalysts.One of the procedures consists in asi- lution (DKR). multaneous one-step process starting from 4-hydroxy-

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Scheme 14. One-pot simultaneoussynthesis of vanillylamine 27 employing l-alanine and aminotransferase from Chromobac- terium violaceum.[41]

4-(4-hydroxy-3-methoxyphenyl)butan-2-one (25)in hydes, by combiningthe anion exchange resin (OHÀ the presence of l-alanineasorganocatalyst and the form)-catalysed transcyanation of the aldehyde and aminotransferase from Chromobacterium violaceum cyanohydrin acetone andthe lipase-catalysed kinetic as biocatalyst using aqueous buffer. l-Alanine cata- resolution of the resulting cyanohydrin.[42] As the for- lysed the retro-aldol reactionof25 to vanillin (26) mation of the cyanohydrin is areversible process,this and is also employed as amino donor in the biotrans- compound will suffer afast racemisation. Thus,the formation of vanillin to 27 catalysed by the amino- enzymatic acylation will affordasingle enantiomer of transferase.Anenzymecascade systemwas employed the cyanohydrin acetate with high yield in aDKR. in order to regenerate the l-alanineand to increase After analysing different anion-exchangeresins, the the reactionconversions,asshown in Scheme 14. reactions were carried out with Amberlite IRA 904 During transamination of 26, l-alanineisconverted and the lipase from Pseudomonas sp.M-12-33from to l-pyruvate.Inthe presence of l-alaninedehydro- Amano, in the presence of isopropenyl acetate as acyl genase (l-AlaDH), l-alanineisregenerated using am- donor. After long reactiontimes (2–6 days), it was monia as nitrogen source.Asl-AlaDH is an NADH- possible to obtain the chiral (S)-cyanohydrin acetates dependent enzyme,glucose dehydrogenase (GDH) is with high yields and optical purities,except for the 1- requiredtoregeneratethis cofactor by converting d- naphthyl derivative. glucose into d-gluconic acid. Theoverall systemto This kind of reactionhas been exploited for the convert one equivalent of vanillin to vanillylaminere- synthesisofother chiral cyanohydrin acetates.In quires one equivalent of ammonia and one equivalent 2003, it was performed for the preparation of optically of glucose.The combination of the organocatalyst active phenylfuran-basedcyanohydrins esters,valua- (250 mM) and the enzymatic cascade systemafforded ble building blocks of biologicallyactive compounds, vanillylamine from 25 (2.5mM) substrate in HEPES using Amberlite IRA 904 and lipase PS from Pseudo- buffer (1.0mL) with complete conversion and 40% monas cepacia.[43] Thebasic exchangeresin wasable yield after90hours.The remaining 60% yield corre- to perform the catalysed transcyanation between phe- sponds to the dehydrated aldol condensation product, nylfuranaldehydes and acetone cyanohydrin, while obtained in aside reactionalso catalysed by l-alanine, the cyanohydrins formed were selectively acylated in as suggested by the authors. the presence of the biocatalyst and vinyl butanoate as acyl donor. Theone-pot process afforded the final (R)-cyanohydrin esterswith high yieldsand optical purities.The use of higher amountsofenzyme and 4One-Pot Processes Combining higher temperatures led to much shorter reaction Biocatalysts and Non-Traditional Organic times,aresult to be taken into account for the prepa- Catalysts ration of the desired products at the gram-scale.The authors have also performed the synthesis of chiral 4.1 Reactions Catalysed by Enzymes and Base (R)-benzothiazol-based cyanohydrin acetatesusing Catalysts the same procedure.[44] Forthese products, the best results were achieved again with Amberlite IRA 904 In 1991 the one-pot synthesis of opticallyactive cya- combinedwith the lipase from Candidaantarctica A nohydrin acetates was reported starting from alde- immobilised on Celite,which led to the best selectivi-

Adv.Synth. Catal. 2017, 359,2026 –2049 2038 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim REVIEWS asc.wiley-vch.de ties in the acetylation of the cyanohydrins with vinyl with alipase-catalysedacylation has been used for the acetate.The one-pot processes were carried out with preparation of aset of (R)-b-nitroalkyl acetates (29a– high selectivity and complete conversion after2–3 g)with high yields and optical purities.[47] As the days using 10 mg/mL of lipase preparation. Lower Henry reactionrequires the control of the equilibri- amountsled to longer times,while an excessof um, this reactionhas been usedfor two purposes: (i) enzyme afforded adecrease in the optical purityof synthesisofthe b-nitro alcohol, the substrate of the the (R)-cyanohydrin acetates as the racemisation step enzymatic acylation;and (ii)racemisation of the non- was not fast enough when compared with the enzy- reactive b-nitro alcohol enantiomer. matic reaction. Several organic bases have been tested as catalysts In 2002, the enantioselective synthesis of (S)-man- for the nitroaldolreaction, the best results being ach- delonitrile acetate (28a)through aDKR was devel- ieved with triethylamine.Lipases from Pseudomonas oped starting from benzaldehyde(0.8mmol), acetone led to better performance in the acylation step.This cyanohydrin (2 equiv.) andisopropenyl acetate process was optimised by employing30mgofPseudo- (3 equiv.)intoluene (8.0mL). Amberlite IRA904 monas cepacia lipase preparation (PS-CI) per (0.25 equiv., OHÀ form) and CAL-B (80 mg) were 0.05 mmol of substrate in toluene (1.0 mL) at room used in this simultaneous one-pot,three-step proce- temperature in the presence of 5equivalents of vinyl dure.[45] Amberlite is able to performthe releaseof acetate.When the one-pot DKR was conducted with cyanide hydrogen from acetone cyanohydrin as well an excessofnitroalkane,2equivalents of triethyl- as the HCN addition to benzaldehyde.Both processes amine,1equivalent of p-nitrobenzaldehyde, 5equiva- are reversible,somethingessential for the preparation lents of vinyl acetate and PS-CI, a65% yield of the and racemisation of mandelonitrile,which rapidly oc- corresponding b-nitroalkyl acetate was recovered with curred at either 40 or 60 8C. TheCAL-B-catalysed 85% enantiomeric excess.Asignificant amount of acetylation of mandelonitrileatthese temperatures is two by-products was obtained. Oneofthem is formed avery selectiveprocess,inwhich enantiopure (S)-28a by the coupling of the acetaldehyde (generated as by- was recovered. Unfortunately,when the reactionwas product in the acylation reaction) with the nitroal- carried out in aone-pot approach, it was observed kane,while the other one was achieved by the acyla- that the kinetic resolution of mandelonitrile is per- tion of this first by-product. formed without racemisation of the starting material, In order to improve the process yield, different acyl indicating that under these conditions the Amberlite donors were tested in the PS-CI-catalysed acylation. resin is deactivated. This is likely due to the presence Although p-chlorobenzyl acetate led to lower activi- of water in the reactionmedium, responsible for the ties as comparedwith vinyl acetate,noside reactions hydrolysis of isopropenyl acetate to acetic acid, which were observed, so this compound was chosen for fur- neutralises the alkaline resin.For this reason,anextra ther development (Table 2). Thesimultaneous one- amount of basic resin wasadded to the reaction pot DKR starting from 2-nitropropane (0.5 mmol) medium, but enantiopure (S)-28a was obtained with low yield (16%) after 45 h. Afurther development in order to circumvent this Table 2. Henry reaction and base-catalysed racemisation to low yield was madebyimmobilising CAL-B on obtainoptically active (R)-b-nitroalkyl acetates in the pres- Celite (CAL-Bcel), anatural silicate able to adsorb ence of Pseudomonas cepacia lipase.[47] water. Theuse of this biocatalyst preparation led to a97% yield of almostenantiopure (S)-mandelonitrile acetate after 4days reaction (Scheme 15).[46] Thecombination in asimultaneous one-pot DKR of an organocatalysednitroaldol (Henry) reaction

Product RTime [days] Yield [%][a] ee [%][b]

29a 4-O2N-C6H4 29099 29b 4-F3C-C6H4 38997 29c 3-NC-C6H4 39291 29d 4-F-C6H4 48598 29e 4-Cl-C6H4 48397 29f Ph 47991 29g 4-MeO-C H 42899 Scheme 15. One-pot, three-stepprocedure for the synthesis 6 4 of (S)-28a using CAL-B supported on Celite and the [a] Isolated yield. anion exchange resin Amberlite IRA904.[46] [b] Determined by HPLC.

Adv.Synth. Catal. 2017, 359,2026 –2049 2039 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim REVIEWS asc.wiley-vch.de and p-nitrobenzaldehyde(0.125 mmol) in the presence of trimethylamine (0.25 mmol), PS-CI (90 mg) and p-chlorobenzyl acetate (106 mg) in toluene (0.25 mL) andmolecular sieves (20 mg)at408Caf- forded (R)-29a with 90% yield andcomplete selectivity.The biocatalyst can be recovered without loss of activity.This methodology was extended to other ben- zaldehydes by slightly modifying the reagentamounts, achieving excellent yieldsand selectivities for (R)- 29b–g. In the last few years,anumber of examples have been reported regarding one-pot reactions in which an organic base catalyst promotes the racemisation of the biocatalytic reactionsubstrate,inorder to achieve DKRs. Theselective Baeyer–Villiger oxidation of racemic benzylketones ( )-30a–e (50 mg)catalysed by the Baeyer–Villiger Æmonooxygenase (BVMO)[48] 4-hy- droxyacetophenone monooxygenase (HAPMO)[49] from Pseudomonas fluorescens ACB(2.0 mM), using glucose 6-phosphate (G6P,20mM) and glucose 6- phosphate dehydrogenase (G6PDH, 50 units)as NADPH(0.2 mM) cofactorregeneration system, was combinedwith the racemisation of the starting material in the presence of the weak anion exchangeresin Dowex MWA-1 (100 mg). By using this simultaneous Scheme16. Dynamic kinetic resolution of racemic benzyl one-pot process benzylesters (S)-31a–e were obtained ketones ( )-30a–e catalysed by Baeyer–Villiger monooxyge- with good yields andoptical purities (Scheme 16).[50] nases andÆweak anion exchange resins. Theuse of strong anion exchangeresinsallowed higher racemisation rates,whereasthey negatively af- fected the enzymatic system.Reactions were per- ADYRKRhas been describedfor the preparation formed in Tris/HCl buffer pH 10.0 in order to ensure of chiral 3,4-dialkyl-3,4-dihydroisocoumarins 34 start- aracemisation rate higher than the conversion of the ing from 2-(3-oxoalkyl)benzonitriles 32 through asi- slower ketoneenantiomer. This procedure was then multaneous one-pot biocatalytic reductioncombined extended to the Baeyer–Villiger oxidations catalysed with substrate racemisation (Scheme 17a).[54] 2-(3- by the M446G mutant of phenylacetonemonooxyge- Oxobutan-2-yl)benzonitrile ( )-32a was chosen as nase (PAMO) from Thermobifida fusca.[51] Forthis model substrate,beingreducedÆ in the presence of the biocatalyst, the best results were achieved in Tris/HCl Prelogalcohol dehydrogenase ADH-A from Rhodo- buffer pH 9.0 containing 5% v/v of acosolvent while coccus ruber overexpressed in E. coli. Thebioreduc- using the weak anionexchange resin Lewatit tion carried out in Tris-HCl buffer pH 7.5 containing MP62.[52] Thespace-time yield of the reaction, ex- 5% v/v 2-propanol cosubstrate and 5% v/v hexane co- pressedasmmol of ketoneconsumed per hourand solvent and 308Caffordedthe chiral (S,S)-alcohol 33a per litre of solution, increasedupto60. Higher sub- with an excellent enantio- and diastereoselectivity strate loading led to adecrease in this parameter, and a56% conversion after 24 hours.Asracemisation with no effect on the selectivity.The final (S)-benzyl systems,two possible alternatives were studied:(i) tri- esterswere recovered with moderate to good yields ethylamine,or(ii)anion exchange resin Dowex and optical purities between 65 and86%. MWA-1. TheDYRKRprocess was studied with both ADHs have been also tested in dynamic processes. systems,achieving aslightly higher conversion with These enzymes are valuable tools for the production the anion exchange resin to obtain enantiopure (S,S)- of chiral alcohols with one or more stereocentres.The 33a with 86% conversion after92hours.This proce- racemisation of the non-reactive stereocentre is possi- dure was performed with other ketones bearing differ- ble in ordertoobtain multiple chiral centres in only ent substituents in the aromatic ring or in the stereo- one process.The epimerisable chiral centre is located centre,leading to the final enantiopure alcohols with in an adjacent position to the carbonyl moiety,con- good to excellent yields andcomplete diastereoselec- taining an acidicproton which facilitates the racemi- tivity.The process was further extended by carrying sation, in the so-called dynamic reductive kinetic res- out the one-pot acid-catalysed cyclization of the (S,S)- olutions (DYRKRs).[53] alcohols obtained by DYRKR after 72 hours,leading

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Scheme 17. a) DYRKR of 2-(3-oxoalkyl)benzonitriles to obtain dihydroisocoumarins (S,S)-34a–d using ADHs and trimethylamine as base catalyst.[54] b) DYRKR of 3-aryl-2-butanones to yield the correspondingchiral arylpropan-2-ols 36 and the iso- chroman (S,S)-37a by aone-pot process employingADHs and an anion exchange resin.[55]

to the corresponding (S,S)-3-dialkyl-3,4-dihydroiso- Substrate racemisation was studied in the presence coumarins 34 with good yields in most of cases while of anion exchangeresinssuch as DowexMWA-1and excellent enantio- and diastereoselectivities were ob- Amberlite IRA-440C. Ahigh pH was required to served. Under the reaction conditions employed to reach an effective racemisation, however, under these obtain (S,S)-34a–d,starting from 0.3 mmol of 32a–d in conditions the enzyme suffers from severe inactiva- 13 mL Tris-HCl 50 mM pH 7.5 buffer, triethylamine tion. In order to circumventthis drawback,ahigher (1% v/v) was chosen as racemisation reagent given its reactiontemperature was used (308C), while ADH-A higher reliabilityagainst Dowex MWA-1. was added stepwisetothe reactionmedium.The opti- Asimilar methodology hasbeen recently applied mal DYKRK conditions were applied for aset of rac- for the DYRKR of 3-arylalkan-2-ones 35 to obtain emic benzylketones (0.01 mmol). Bioreductions were the corresponding chiral substituted propan-2-ols carried out at 308CinTris-HCl 50 mM pH 10.0 36,[55] which are convertedtoisochromans 37,valua- (0.35 mL) using one of the exchange resins, while ble building blocks in organic synthesis (Scheme 17b). ADH-A was added in portions over 3–4 days.Excel- Theinitial tests with racemic( )-3-phenylbutan-2- lent enantio- and diastereoselectivities were observed one 35a in the presence of the PreÆlog E. coli/ADH-A for the C-2 substituted 3-arylbutan-2-ones.When Am- afforded (S,S)-36a with good selectivity valuesand berliteIRA-440Cwas employed, asignificant de- conversions close to 50% at shortreactiontimes crease in the reactivity was observedfor alkyl chains (83:17 diastereomeric ratio for the syn diastereomer). longer than methyl, while the use of Dowex MWA- This compound is transformed into the desired iso- 1led to better conversions,although with lower dia- chroman (S,S)-37a by treatment with zinc chloride in stereomeric ratios. chloromethoxymethane at room temperature.

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Experiments were also performed with twoanti- Table 3. DKR of racemic esters in the presence of CAL-B PrelogADHs:alcohol dehydrogenase from Lactoba- and BEMP as racemisation reagent to obtain the (S)-2,3-di- [56] cillus brevis (LBADH) and ADH-200, which led to hydrobenzo[b]furans 39 or 40. the corresponding (R,R)-propan-2-ols 36.Itwas observed that Amberlite IRA-440Ccaused inhibition in both biocatalysts,sothe dynamic processes were carried out in the presence of Dowex MWA-1. Forall the racemicbenzylketones tested, moderate to good conversions were measured together with excellent selectivities and high diasteroselectivitiesfor the (R,R)-alcohols obtained. Thechemoenzymatic synthesisof(S)-2,3-dihydrobenzo[b]furan-3-carboxylic acid (39)and (S)-5-chloro- 1 2,3-dihydrobenzo[b]furan-3-carboxylic acid (40), val- Product XR Time BEMP Yield ee [h] [equiv.] [%] [%][a] uable precursors in the synthesis of biologically active compounds,featuresaskey stepthe sequential one- 39 HMe261.0 95 90 pot biocatalysedhydrolysisofthe racemic methyl or 39 HMe241.5 92 >95 ethyl esters (38)combined with the substrate racemi- 40 Cl Me 24 2.0 71 >99 sation in the presence of an organic base.[56] Initial 40 Cl Et 24 1.0 82 >99 screeningonthe enzymes for the kinetic resolution [a] Measured by HPLC. was performed by an HPLC-CD selectivity assay, leading to CAL-B and Bacillus subtilis esterase (BS3) as the best biocatalysts for this process.For bothen- 4.2 Enzymatic Regeneration of aRedox Catalyst in zymes,enantioselectivities were excellent, recovering aOne-Pot Procedure both ester andacid with 50% conversion and yields higher than 46%. While CAL-B hydrolysed the (S)- Asignificant advance in organocatalysed redox reac- enantiomer of the ester (4.4mmol) to yield (S)-39 tions has been experienced lately although it cannot and (S)-40,BS3 hydrolysedthe (R)-antipode in an be compared with the explosion of organocatalysed enantiocomplementary fashion.Substrate racemisa- C–C bond forming reactions developed during the tion was studied in the presence of different organic same period. Organocatalysed redox reactions are bases.The Schwesinger base 2-tert-butylimino-2-dieth- mostly focused on alkene epoxidations,[58] thioether ylamino-1,3-dimethylperhydro-1,2,3-diazophosphorine sulfoxidations,[59] and Baeyer–Villiger oxidations[60] (BEMP)was the more convenient for this process.[57] employing (a)chiral nitrosyl radical-, dioxirane- or ox- Depending on the substrate structure,different aziridine-based catalysts,among others.Morerecent- amountsofBEMPwere required to achieve asatisfac- ly,successful organocatalytic asymmetric alkene re- tory racemisation. As BEMP can be inactivated in ductions under hydrogen transfer conditions have aqueous medium, areactionset-upfor the one-pot re- been reported.[61] action with separation of bothprocesseswas em- With this scenario and considering the vast knowl- ployed.Thus,aflaskwas connected with aperistaltic edge on biocatalysedoxidations,[62] it is reasonable to pump to acolumn containing immobilised BEMP. conceive fruitful combinations for the enzymatic re- Thereactionwas carried out in abiphasic system generation of redox organocatalysts.Indeed, examples buffer/n-heptane (60 mL, 2:1) in which the biocatalyst of such processes can be traced back to 1990.[63] and the enantiopure acid product stand in the aque- So far, two main strategies have been explored with ous phase,while the ester (kept in the organic phase) agreatdeal of success (Figure 4): (i)the hydrolase- was continuously pumped throughthe BEMP catalysed perhydrolysis of carboxylic acid/esters (the column. In this system,the ester is in acontinuous organocatalysts) giving rise to an organic peracid that racemisation while the acid accumulates in the aque- performs as direct oxidisingagent and, (ii)the versa- ous phase.Inorder to avoid BEMP leaching, which tile laccase/mediator systemfor several one- andtwo- can lead to sidereactions and biocatalyst inactivation, electronoxidation processes. the base was protected at the column with asecond In this hydrolase/carboxylic acid one-pot procedure, layer of ion-exchange resin.Asshown in Table 3, the substoichiometric quantities of carboxylic derivative use of this system at apreparative scale (500 mg, can be employed that, after peracid formation, should 2.81 mmol of the corresponding ester)led to the work as an oxo-transfer catalyst from hydrogenper- chiral acids with high optical purities andgood yields oxide to the substrate (mostly ketones,olefins and depending on the substrate structure. sulfides). Theuse of lipases in promiscuous reactions has been extensively reviewedinthe last years.[64] One of

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the enzyme redox potential is not enough for the oxidation of agiven substrate,the chemist usuallyadopts asmall organic molecule as an electronmediator, in the so-called “laccase/mediator system” (LMS).[27] This cleanreactionisreadilyemployed for the transi- ent generation of highly reactive intermediates that can act as one- and two-electron shuttlesbetween the

substrate and O2 to form H2O. In awide sense,this organic mediator employed in catalytic quantities or its reactive intermediate can be regarded as the actual organic catalyst.[67] Furthermore,these mediators can Figure 4. Biocatalysed regeneration of redox catalysts in act by different mechanisms, such as electron-transfer aone-pot fashion. (ET), radical hydrogen-atom-transfer (HAT)orpolar mechanisms,depending on its electronic nature. Several systems involving an oxidation stephave these lipase-catalysed promiscuous processes is,asal- been studied.The laccase-mediator couple has been ready mentioned, the reactionbetween an ester or shown as areliableand mild system for the N-depro- carboxylic acid with H2O2 to render the correspond- tection of p-methoxyphenyl (PMP)-protected ing peracid. When this carboxylicderivative is used in amines.[68] Thus,oxidation of the protected amine by asubstoichiometric quantity,acatalytic oxidation re- the laccases from Trametes versicolor or Agaricus bi- action can be coupled to the enzymatic perhydrolysis sporus leads to formation of the p-benzoquinone reaction. imine,which spontaneously hydrolysesinthe aqueous Remarkably,already in 1990 it was reported that reactionmedium,furnishing the free amine and p-qui- immobilised CAL-B and octanoic acid (10% mol) in none,asshown in Scheme18, using 0.92 mmol of the the presence of aslight molar excess of H2O2 (added PMP-protected amine.Althoughhigh yields were ob- in portions), results in the epoxidation of several al- tained by employingthe sole laccase,the use of cata- kenesunder solvent-free conditions.The reactions lytic amounts of mediators could expand the scope of were stoppedat15h with almostfull conversion in this methodology, as demonstratedinthe deprotec- most cases.[63] Tenyears later, asimilar system was set tion of N-PMP-protected 4-phenylbutan-2-amine (41), up but taking place in ionicliquids,thusobtaining the anon-benzylic amine,where no conversion was ob- cyclohexene oxide with high selectivity and 83% con- served without amediator. Best results were attained version.[65] using violuric acid as amediator after 48 h, achieving As expected, several reports have dealt with lipase- 88% conversion. catalysed generation of percarboxylic acid to carry Another example of amine deprotection involves out reactions other than epoxidation.[66] However, in alaccase-mediator systeminasimilar fashion,but in the vast majority of these cases, the carboxylic acid this case employing TEMPO as organic electronme- (here considered as the organocatalyst) is added in diator.[69] In this work, N-benzylamines can be depro- overstoichiometric quantities,thus,the sulfoxidation tected in high chemo- and regioselectivity.Thus,oxi- or the Baeyer–Villiger ketone oxidation are not strict- dation of the amine transiently affords the corre- ly catalytic and therefore are beyond the scope of this sponding imine,which is spontaneously hydrolysed, review. delivering the free amine.Hence, using laccase of Tra- On the other hand, laccases are able to oxidise sub- metes versicolor andTEMPO,the reactionwith N,N’- strates using O2 as terminal electron acceptor. When dibenzyl-4-aminopiperidine was highly regioselective

Scheme 18. Laccase-mediator (violuric acid) catalysed N-deprotectionofN-PMP-protected amines.[68]

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Scheme 19. Synthesis of aset of disulfides 42 employing laccase from T. versicolor in the presence of ABTS as mediator.[70] to the secondary amine,obtainingasonly product the 4.3 One-Pot Catalytic Combined Redox Processes corresponding free primary amine with complete con- Driven by Light version.Likewise,( )-trans-N,O-dibenzyl-2-hydroxy- cyclohexylamine waÆssuccessfully N-deprotectedin In certain cases,chromophoric organic redox media- achemoselective fashion,yielding the O-benzylderiv- tors (here considered as organocatalysts) can be read- ative as sole product. ily employed in biocatalysed processesunder light ir- Taking advantage of laccases as mild andgreen oxi- radiation. Photostimulationprovidesthe chromophor- dants,the synthesisofdifferent disulfides 42 hasbeen ic organocatalyst with asuitable redox potential to explored by homocoupling of heterocyclic thiols accept/donate electrons from/to molecules that other- (Scheme 19).[70] Thus,employingcatalytic ABTS as wise wouldbedifficult or even impossible.Inthis the organic mediator and the laccase from Trametes way,flavin and analogues have been successfully used versicolor,one-electron oxidation leads to athiyl radi- as excitable organocatalystswith fair turnover when cal, which collapses into the corresponding disulfide. coupled to oxidative enzymatic transformations. Reactions were carriedout in acetate bufferpH4.4 Likewise,ithas been recently reported that pyrimi- containingMeOH(10% v/v). Disulfides were formed dine cofactor regeneration to the oxidised form with yields ranging from 50 to 95% depending on the [NAD(P)+]isfeasible employing Myceliophthora ther- substrate structure, without formation of overoxida- mophila laccase,(Mtlac), O2 as final electron acceptor tion side products. and dyes (methylene blue,methylene green and azure This kind of laccase/mediator system has been also B) as mediators,asshowninScheme 20.[72] In this involvedinalcohol oxidation. Theoxidation of pri- report,the authors were able to demonstrate that, mary alcohols has been pursued in order to couple upon visiblelight irradiation, the NADH oxidation is asecondary reactionemploying in-situ the newly three orders of magnitude faster than the obscure formed aldehyde.[71] A1,4-diol or 1,5 diol can be oxi- counterpart. Theauthors coupled this NAD(P)+ re- dised by laccase/TEMPO,leading to ahydroxyalde- generation system with two enzymes,namely Thermus hyde,that immediately cyclises affording ahemiacetal. sp.ATN1 ADH, and acommercially availableglucose Furtheroxidation by the same system allowsthe for- dehydrogenase (GDH) to successfully obtain more mation of stable butyro-and valerolactones in aone- than 30% conversion in twohours of cyclohexanone pot, one-stepfashion. (44)from cyclohexanol (43)and gluconicacid from

Scheme 20. Use of abienzymatic system laccase-ADH coupled with dyes as mediators for the photooxidation of cyclohexanol to cyclohexanone.[72]

Adv.Synth. Catal. 2017, 359,2026 –2049 2044 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim REVIEWS asc.wiley-vch.de glucose,respectively.Inthe latter case,methylene replacedbythe systemEDTA/flavinso, electrons blue was employed as organocatalyst showing are- coming from the sacrificialdonor, pass to the diffus- markable TTN of 2500. ing excited flavin. Then, electrons are delivered to the Asimilar approachhas been shown in the Caldar- BVMO-bound flavin to trigger formationofan iomyces fumago chloroperoxidase (CPO)-catalysed enzyme-bound peroxyflavin, the actual oxo-transfer sulfoxidationofthioanisole to enantiopure (R)- catalyst that finally introduces oxygen into the sub- methylphenyl sulfoxide employing FMN as chromo- strate.Byusing this methodology, aset of enantioen- phoric organocatalyst,EDTAaselectron donor and riched (>96% ee) g-and e-lactones was successfully molecular oxygen under photostimulation.[73] Hence, prepared from the corresponding prochiral ketones. EDTAsuccessively transferselectrons to the photoex- On the contrary,reductive enzymatic reactions cited FMN organocatalyst to be delivered to the combinedwith light-driven organocatalysed electron heme prosthetic group of CPO.The authors improved supply are evenless explored than the already de- biocatalyst stability and mass transfer issuesbyadopt- scribedoxidative counterparts.Arepresentative ex- ing abiphasic surfactant-stabilised system which per- ample is the use EDTA/flavininthe presence of light mits an increase in substrate concentrationand sulf- for the reductionofelectron-deficient olefins into the oxide productivity. corresponding saturated productsbythe action of an Similarly,EDTA/flavininthe presence of light has ene-reductase from Bacillus subtilis YqjM been employed in the preparation of lactones starting (Scheme 22).[75] In this case,under light irradiation, from cyclic ketones catalysed by BVMOs the excited flavin transferstwo protons and two elec- (Scheme 21).[74] In this way,the NADPH cofactor is trons from EDTAtothe enzyme-bound flavin(pros-

Scheme 21. EDTA/flavin system employedincombination with BVMOs to catalyse Baeyer–Villiger oxidations.The scheme shows the oxidation of bicyclo[3.2.0]hept-2-en-6-one (45)tothe corresponding lactone 46.[74]

Scheme 22. Reduction of ketoisophorone 47 catalysed by the ene-reductase from Bacillus subtilis YqjM in the presence of EDTAand light.[75]

Adv.Synth. Catal. 2017, 359,2026 –2049 2045 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim REVIEWS asc.wiley-vch.de thetic group). Thus,YqjM with the prosthetic group cional de Córdoba (UNC) and thank CONICET and in its reducedform is able to deliver ahydride to the FONCyT for funding. MLVacknowledges CONICET for his beta position of the C=CbondinaMichael-type ad- doctoral fellowship. dition reaction. In this report,ketoisophorone (47) was chosenasmodel substrate and the reduction to diketone 48 took place with asimilar stereoselectivity as for the standard reactionusing NADPH and References anormal cofactor regeneration system. [1] a) E. García-Junceda, I. Lavandera, D. Rother, J. H. Schrittwieser, J. Mol. Catal. B: Enzym. 2015, 114,1–6; 5Outlook b) S. F. Mayer, W. Kroutil, K. Faber, Chem. Soc.Rev. 2001, 30,332–339;c)F.R.Bisogno,I.Lavandera, V. Gotor, Biocatalytic Concurrent Processes,in: Kirk- Already organocatalysis and biocatalysis have Othmer Encyclopedia of Chemical Technology,John reached ahigh degree of sophistication, as shown in Wiley &Sons,Hoboken, 2011,pp1–20;d)D.L. the examples described in the present review.The in- Nelson, M. Cox, Lehninger:Principles of Biochemistry, terplayofbothworlds,and therefore virtuesfrom W. H. Freeman, NewYork, 2004;e)H.Curtis,N.S. both sides,need further exploitation. Theadvance- Barnes, Biology,W.H.Freeman, NewYork, 1989. ment in this area of catalysis shall necessarily come [2] a) R. A. Sheldon, Pure Appl. Chem. 2000, 72,1233– about by adopting interdisciplinary research, in which 1246;b)B.M.Trost, Science 1991, 254,1471–1477. enzyme engineering willprovide biocatalysts with en- [3] See:a)F.R.Bisogno, A. Rioz-Martínez, C. Rodríguez, hancedrobustness towards organic solventsand reac- I. 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