Combination of Metal-Catalyzed Cycloisomerizations and Biocatalysis

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COMBINATION OF METAL-CATALYZED CYCLOISOMERIZATIONS AND BIOCATALYSIS IN AQUEOUS MEDIA: ASYMMETRIC CONSTRUCTION OF CHIRAL ALCOHOLS, LACTONES AND #-HYDROXY-CARBONYL COMPOUNDS María Jesus Rodríguez-Álvarez, Nicolas Ríos-Lombardía, Sören Schumacher, David PérezIglesias, Francisco Morís, Victorio Cadierno, Joaquín García-Álvarez, and Javier Gonzalez-Sabin ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02183 • Publication Date (Web): 06 Oct 2017 Downloaded from http://pubs.acs.org on October 7, 2017

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Combination of Metal-Catalyzed Cycloisomerizations and Biocatalysis in Aqueous Media: Asymmetric Construction of Chiral Alcohols, Lactones and -Hydroxy-Carbonyl Compounds María J. Rodríguez-Álvarez,a,+ Nicolás Ríos-Lombardía,b,+ Sören Schumacher,a David Pérez-Iglesias,a Francisco Morís,b Victorio Cadierno,a Joaquín García-Álvarez*,a and Javier González-Sabín*,b a

Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC). Departamento de Química Orgánica e Inorgánica (IUQOEM), Centro de Innovación en Química Avanzada (ORFEOCINQA), Facultad de Química, Universidad de Oviedo, E-33071, Oviedo, Spain. b

EntreChem SL, Edificio Científico Tecnológico, Campus El Cristo, 33006 Oviedo, Spain.

[+] These authors contributed equally to the work.

*Corresponding Authors: e-mail: [email protected]; [email protected]

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ABSTRACT The combination of the metal-catalyzed cycloisomerization of alkynes containing a tethered nucleophile as substituent in aqueous media (followed by the spontaneous hydrolysis, hydroalkoxylation or aminolysis of the transiently formed 5-membered heterocycles), with the subsequent enantioselective ketone bioreduction (mediated by KREDs) has been achieved. The overall transformations, which formally involve a three-step one-pot reaction, provide a variety of enantiopure valuable molecules [e.g., 1,4-diols, lactones and hydroxy-carbonyl compounds (carboxylic acids, esters and amides)] with high conversions and enantioselectivities and under mild reaction conditions, disclosing the concept of integrated metal-catalyzed cycloisomerizations of alkynes and enzymatic catalysis in water. KEYWORDS: One-pot Processes, Cascade Reactions, Metal-Catalysis, Biocatalysis, Enantioselective. INTRODUCTION In recent years chemists have tried to emulate Nature by the development of one-pot asymmetric multicatalytic reactions to construct enantiomerically enriched molecules,1 also fulfilling important Green Chemistry Principles2 related with the minimization of waste-production and time-consuming and tedious purification steps associated with traditional multistep processes.3 In particular, two different catalytic worlds (metal-catalysis4 and bio-catalysis5) have recently converged in the development of new methodologies merging the advantages of both areas.6 However, this assembly has been mainly reported in volatile organic compounds (VOCs) as solvents [e.g., dynamic kinetic resolutions (DKRs) by combining a racemizing metal catalyst with a biotransformation].7 Recently, the combination of organometallic compounds and enzymes in aqueous media has crossed the frontiers between well-established metal-catalyzed organic reactions (Pd-catalyzed C-C coupling, Wacker oxidation and C-H activation; Cu(I)-catalyzed click chemistry; Ru-catalyzed olefin metathesis; or Aucatalyzed cyclization of allenes) and several biocatalyzed transformations of organic functional groups (enzymatic reduction, halogenation, ester hydrolysis or epoxidations).8 In this sense, we previously ACS Paragon Plus Environment

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developed a one-pot process for the direct transformation of racemic allylic alcohols into the corresponding saturated chiral alcohols or amines in water by combining the Ru(IV)-catalyzed redox isomerization of allylic alcohols with the bioreduction (ketoreductases, KREDs) or bioamination (ωtransaminases, ω-TAs) of the transiently formed prochiral ketones (see Scheme 1).9

Scheme 1 Ru-catalyzed allylic alcohol isomerization combined with an enantioselective enzymatic reduction/amination in a one-pot process in aqueous media. Although isomerization reactions always proceed with a total mass transfer from substrates to products (a very attractive point for Green Chemistry),10 they often lack practical applications, since an increase in structural complexity is not always achieved. As an alternative, the formal metal-catalyzed hydration of alkynes, through the initial intramolecular cyclization of a pendant nucleophile (NuH),11 facilitates the desired increase in the functionalization under reaction conditions (aqueous media, mild temperature, absence of methanol as co-catalyst) compatible with a further biocatalytic step (Scheme 2).

Scheme 2 One-pot conversion of alkynols, -alkynoic acids or alkynyl amides into enantiopure molecules through the combination of metal- and biocatalyzed reactions in water. Thus, we now present the one-pot combination of the following three reactions in aqueous media: i) metal-catalyzed cycloisomerization of alkynols, -alkynoic acids or alkynyl amides;12 ii)


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concomitant hydrolysis, hydroalkoxylation or aminolysis of the three different 5-membered heterocycles formed during the cycloisomerization; and iii) the enantioselective bioreduction of the transiently formed prochiral carbonyl compounds (Scheme 2). This integrated methodology, which allows the assembly of three valuable synthetic tools in a one-pot procedure, represents a sustainable and enantioselective route for a variety of chiral molecules (e.g., diols, lactones and -hydroxy-carbonyl compounds) under mild and standard bench conditions. RESULTS AND DISCUSSION As part of our ongoing interest in the study of metal-catalyzed organic reactions in aqueous media,9,12a,d,13 we started our investigations by evaluating the catalytic activity of four different palladium(II) complexes (1-4) in the cycloisomerization of alkynols using, as a model reaction, the cycloisomerization of the commercially available 4-pentyn-1-ol (5a). In a typical experiment, the reactions were performed in water, at 30 ºC and under aerobic conditions with a metal loading of 5 mol% (i.e., 2.5 mol% of dimers 1-2).12a However, and instead of the expected 5-methyl-2,3dihydrofuran (6), the formal hydrated product 7 (5-hydroxy-2-pentanone) was cleanly obtained in quantitative yield when complex 1 was used as catalyst (entry 1, Table 1). At this point, it is important to note that the vast majority of reported examples for metal-catalyzed hydrations of alkynes usually required high temperatures and/or methanol as co-catalyst,14 which could deactivate the enzyme in the subsequent biotransformation. A similar formal hydration process was previously observed by Atwood et al. in a closely related example of Pt(II)-catalyzed cycloisomerization of pentynols in water.15 In this seminal work, the authors demonstrated that the reaction proceeds through a 5-exo-dig rearrangement, leading to the transiently formation of 6 (see Table 1), which suffers the concomitant nucleophilic attack of water to afford the corresponding hydroxyl-ketone 7. We also discarded the formation of this carbonyl product by direct hydration of 5a, since under the reaction conditions employed (5 mol%, 30 ºC) complex 1 is not able to hydrate terminals alkynes, such as 1-pentyne or 1-hexyne. Moreover, we found that: i) the use of lower catalytic loadings slowed down the reaction considerably [as an example, ACS Paragon Plus Environment

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by using 1 mol% in Pd (i.e., 0.5 mol% of dimer 1) no quantitative conversion was achieved even after 24 h; entry 5, Table 1]; and ii) the presence of catalytic amounts of palladium complexes is essential, as in its absence, no reaction was observed (entry 6, Table 1). Finally, this catalytic system was also active with internal alkynes (3-pentyn-1-ol, 5b) giving rise again to the expected hydroxyl-ketone 7 at room temperature and in the presence of air after 17 h (entry 7, Table 1). The mechanism for this hydration is very similar to that of 4-pentyn-1-ol (5a), the major difference being that now proceeds through a 5endo-dig mechanism.15 Table 1 Optimization of the cycloisomerization and concomitant hydrolysis of 4-pentyn-1-ol (5a) and 3-pentyn-1-ol (5b) catalyzed by the palladium complexes 1-4 in water.a

Entry

Substrate

Catalyst

Mol% [Pd]

Time (h)

Conversionb

1

5a

1

5

9

99%

2

5a

2

5

24

57%

3

5a

3

5

9

88%

4

5a

4

5

24

12%

5

5a

1

1

24

75%

6

5a

-

-

24

1%

7

5b

1

5

17

99%

a

General Conditions: Reactions performed under air, at 30 ºC using 1 mmol of 4-pentyn-1-ol (5a) or 3pentyn-1-ol (5b) and 1-5 mol% in Pd of catalysts 1-4 in 1 mL of water. b Determined by GC.

Inspired by these preliminary results, which suggest the possibility to promote the hydration of 5a or its internal counterpart 5b in a reaction medium compatible with a second biocatalytic step in a potential one-pot process (aqueous media, mild temperature and in the absence of methanol as coACS Paragon Plus Environment

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catalyst), we studied the bioreduction of the hydroxyl-ketone 7 utilizing the ketoreductases from the Codex® KRED Screening Kit, but employing directly the reaction media coming from the metalcatalyzed cycloisomerization/hydrolysis reaction of both 5a and 5b, with a previous 4 times dilution (250 mM substrate concentration). Pleasantly, the impact of the Pd(II)-catalyst 1 was negligible in the enzymatic system as quantitative conversions were always observed.16 Thus, the one-pot approach was achieved furnishing, in both cases, the corresponding 1,4-pentanediol (8) in good yields (up to 90%) after 24 h at 30 ºC (see Scheme 3). Regarding the enantioselectivities, we were able to identify KREDs which afforded both enantiomers with excellent ee values (up to >99%).

Scheme 3 Chemoenzymatic one-pot sequential process for the enantioselective synthesis of 1,4pentadienol (8) in aqueous media and at room temperature. Next, and trying to push further our methodology, we explored the possibility of coupling a further step, namely the laccase-catalyzed oxidation of the resulting enantiopure 1,4-pentanediol (8) (Scheme 3) towards -valerolactone (GVL, 9) in a three-step metal-bio-organo/bio-catalyzed reaction sequence (Scheme 4).17 Remarkably, using the commercially available laccase from Trametes versicolor and TEMPO, the oxidation of the primary alcohol took place selectively, generating an enantioenriched hydroxyl aldehyde intermediate, which suffer the concomitant cyclization and oxidation of the second hydroxyl group, giving rise to chiral valerolactone 9. However, we observed experimentally a detrimental effect of KRED on the laccase/TEMPO system. The only required setting to solve this drawback was removing the insolubles (e.g., precipitated protein) by centrifugation after the bioreduction step, and adding to the supernatant a citrate buffer medium pH 5.0 containing the laccase and TEMPO. Under this new experimental conditions we were able to produce both antipodes ACS Paragon Plus Environment

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of 9 in quantitative conversion and excellent ee for each enantiomer [>99% for (R)-9; 98% for (S)-9], as the oxidation process took place with retention of the configuration.18,19 In this sense, and contrasting with the racemic approaches which employ biomass as starting material, there are only limited methodologies to deliver optically active GVL.20

Scheme 4 Chemoenzymatic one-pot synthesis of 1,4-pentadienol (8) and subsequent catalytic oxidation promoted by the laccase/TEMPO system to obtain enantiopure -valerolactone (GVL, 9). In

order

to

demonstrate

the

feasibility

of

our

one-pot

protocol

(cycloisomerization/hydrolysis/bioreduction of alkynes), we decided to study the inclusion of other tethered nucleophile substituents to accomplish the hydration of alkynes under mild reaction conditions and in pure water as solvent. In this sense, the metal-catalyzed cycloisomerization of -alkynoic acids is a plausible candidate,21 as this route gives access to the corresponding 5-membered enol-lactones which can suffer the corresponding hydrolysis reaction to form the desired keto-acids (see Table 2).22 Thus, we firstly evaluated the catalytic activity of the palladium complex 1 in the cycloisomerization/hydrolysis process of 4-pentynoic acid (10) to generate the corresponding levulinic acid (12),23 under the previously optimized reaction conditions employed for alkynols 5a,b (30 ºC, 5 mol% of palladium). However, under this catalytic setting we observed the selective formation of the corresponding enollactone intermediate (11) in quantitative yield as the sole reaction product (12 was not detected; entry 1, Table 2). By employing other commercially available palladium(II) complexes like [PdCl2(COD)] (3) or [PdCl2(PPh3)2] (4), we found in both cases the formation of mixtures containing 11 and the desired levulinic acid (12) in different ratios (entries 2-3, Table 2) after long reaction times (3-7 h). To tackle this hurdle, we explored the Au(III)-catalyzed cycloisomerization/hydrolysis of 4-pentynoic acid (10), ACS Paragon Plus Environment

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as it has been previously reported that different Au(III)-precursors are able to promote this reaction in 3alkynoates.24 Initially, when KAuCl4 was used as catalyst (5 mol%) at 30 ºC, we observed once more the formation of a reaction mixture containing 11 and 12 (entry 4, Table 2). Nevertheless, we were delighted to find that just by increasing the temperature from 30 to 50 ºC, we achieved the complete conversion of 10 into 12 in only 45 minutes, under air and in aqueous media (entry 5, Table 2).25 Finally, we observed that: i) the efficiency and the selectivity of the reaction was strongly lowered when a gold(I)-complex was employed as catalyst (i.e., [AuCl(SMe2)] (14); entry 6, Table 2); and ii) the catalytic reaction did not took place in the absence of a gold catalyst (entry 7, Table 2). Table 2. Optimization of the cycloisomerization and concomitant hydrolysis of 4-pentynoic acid (10) catalyzed by palladium or gold complexes in water.a

Entry

Catalyst

Mol% [M]

Temp (ºC)

Time

1

1

5

30

2

3

5

3

4

4

Product ratio (%)b 10

11

12

1h

1

99

-

30

3h

-

75

25

5

30

7h

-

80

20

13

5

30

1h

-

65

35

5

13

5

50

45 min

-

1

99

6

14

5

50

45 min

9

20

71

7

-

-

50

1h

99

1

-

a

General Conditions: Reactions performed under air, at 30-50 ºC using 0.5 mmol of the 4pentynoic acid (10) and 5 mol% in [Pd] or [Au] in 0.5 mL of water. b Determined by GC.


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Once we have found the optimized reaction conditions for the cycloisomerization/hydrolysis of 4-pentynoic acid (10) in water, we turned our efforts towards developing a one-pot process in which the obtained levulinic acid (12) could be subsequently reduced (without isolation or purification steps) by KREDs, employing the reaction medium coming from the metal-catalyzed reaction to feed the subsequent biotransformation. In this case, catalyst 13 exerted partial inhibition on the enzyme activity leading to incomplete bioreductions (c up to 50%). Fortunately, this drawback could be circumvented just by adding 5% v/v of DMSO, allowing the quantitative synthesis of enantiopure -hydroxyvaleric acid (-HVA, 15) in a one-pot procedure in aqueous media in 24 h (Scheme 5).26,27 Both enantiomers were obtained with excellent ee values (up to >99%) simply by choosing the adequate biocatalyst.28

Scheme 5 Chemoenzymatic one-pot conversion of 4-pentynoic acid (10) into enantiopure hydroxyvaleric acid (15) in aqueous media, through the combination of metal- and biocatalyzed reactions. So far we have been able to promote the metal-catalyzed cycloisomerization/hydrolysis of 4pentynoic acid (10) by employing water as nucleophile to accomplish the opening of the transiently formed 5-membered enol-lactone 11. In theory a similar class of reaction, the formal metal-catalyzed intermolecular hydroalkoxylation of alkynes (a challenging reaction from a regioselectivity standpoint),21b could be also proposed as strategy to convert 10 into the desired levulinate just by using the corresponding alcohol as both nucleophile and reaction media (see Scheme 6). Taking into account the fact that propan-2-ol (iPrOH) is the hydrogen donor employed to recycle the NADP+ cofactor during the bioreduction, we decided to use iPrOH as solvent. In this sense, and by employing KAuCl4 as catalyst (5 mol%) for this formal intermolecular hydroalkoxylation reaction,24 we observed the ACS Paragon Plus Environment

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conversion of 4-pentynoic acid (10) into the corresponding isopropyl levulinate (16a) in quantitative yield (99%), at 50 ºC and in the presence of air (see Scheme 6). At this point it is important to note that under these conditions, the formation of the hydrated product (levulinic acid) was not observed. Finally, not only aliphatic (iPrOH) but also aromatic alcohols (like phenol), can also be successfully employed in this hydroalkoxylation reaction, leading to the formation of the corresponding aromatic levulinate 16b (see Scheme 6).

Scheme 6 Chemoenzymatic one-pot conversion of 4-pentynoic acid (10) into enantiopure valerolactone (9) through the combination of metal-catalyzed hydroalkoxylation and bioreduction. Bearing in mind that the KREDs-mediated bioreduction of prochiral -keto esters (i.e., levulinates 16a-b) can also give rise to enantiopure -valerolactone (GVL, 9), through the spontaneous cyclization of the transitorily formed -hydroxy esters (17a-b, see Scheme 6),18 we decided to focus our attention on the bioreduction of the levulinates 16a-b by adding directly the KREDs to the reaction media of the formal gold catalyzed hydroalkoxylation of 10, in a stepwise fashion (previous dilution to 250 mM substrate concentration). In this sense, we were delighted to find that complete conversion was achieved in all cases after 8 h of reaction giving rise to both enantiomers of 9 with excellent enantioselectivity (ee up to >99%).29 As a result, this two-step metal-bio reaction sequence towards


10

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enantiopure GVL starting from 4-pentynoic acid (10) enables us to cut short the previous one using pentynols (5a,b, three-step metal-bio-organo/bio- reaction sequence, see Scheme 4). Finally, and to extend even further our one-pot combination, we turned our attention to the metal-catalyzed cycloisomerization of alkynyl amides, in which the intramolecular addition of a N-H bond across the carbon-carbon triple bond facilitates the formation of the corresponding alkylidene lactams (see Scheme 7).30 In principle, this transformation opens access to the desired -keto amides through the hydrolysis of the corresponding 5-membered lactam intermediate.31 Thus, we studied the cycloisomerization/hydrolysis of N-tosyl-pent-4-yn-amide (18) as a model reaction, in the conditions previously optimized for 4-pentynoic acid (10) in aqueous media (5 mol% of KAuCl4, 50 ºC, see Scheme 7). As expected, longer reaction time (5 h) was needed to achieve full conversion of 18 into the corresponding 4-oxo-N-tosylpentanamide (19a). In this sense, we should highlight that the cycloisomerization of alkynyl amides is more challenging than that of their corresponding carboxylic acid counterparts and usually needs prolonged reaction times and/or higher temperatures.32

Scheme 7 Chemoenzymatic one-pot conversion of N-tosyl-pent-4-yn-amide (18) into the enantiopure hydroxy amide 20a through the combination of metal- and biocatalyzed organic reactions in water. As we have previously demonstrated with pentynols 5a,b (Scheme 4) and 4-pentynoic acid (10, Schemes 5-6), the crude reaction mixture of the gold-catalyzed cycloisomerization/hydration of N-tosyl-


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pent-4-yn-amide (18) could be directly used (without isolation or purification steps) for a further bioreduction of the produced 4-oxo-N-tosylpentanamide (19a) promoted by KREDs. From the corresponding parametric study (see Table S5 in the Supporting Information), KRED P2-H07 emerged as the only effective biocatalyst, leading to high conversion (96%) and excellent stereoselectivity (>99% ee) for the one-pot synthesis of the -hydroxy amide 20a. On the contrary, the rest of the essayed KREDs led to low conversions and ee up to 40%. Bearing in mind: i) the excellent activities displayed by the KREDs towards compounds 7, 12 and 16a-b; and ii) their structural resemblance with 19a, we propose that a bulkier group such as tosyl seems to exceed the steric requirements of these biocatalysts towards this kind of substrates. To try to solve this problem, and taking into account several reported cascade cyclization processes involving -alkynoic acids and amines33 (via initial cycloisomerization of the alkynoic acid and concomitant aminolysis of the enol-lactone 11), we decided to explore this methodology for the synthesis of the corresponding -keto amides 19b-h (see Table 3). To this end, we selected as a model the intermolecular reaction between 10 and aniline working in neat conditions (to avoid competing hydrolysis processes) and under air. This mixture containing the gold catalyst KAuCl4 (1 mol%) was warmed at 50 ºC (entry 1, Table 3) to yield the desired 4-oxo-N-phenylpentanamide (19b) in almost quantitative yield (99%) after 3 h. At this point, it is important to note that the nature of the catalyst is crucial as lower conversions were for example obtained when PdCl2 was used as catalyst (compare odd and even entries in Table 3). Moreover, this methodology offers excellent substrate scope, showing similar conversion with other secondary aromatic amines containing both electron-donating (Me, entries 3-4; MeO, entries 5-6) or electron-withdrawing groups (F, entries 7-8; Cl, entries 9-10; Br, entries 11-12; I, entries 13-14).


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Table 3. Optimization of the cycloisomerization/aminolysis of 4-pentynoic acid (10) with secondary aromatic amines catalyzed by gold or palladium compounds under neat conditions.a

Entry

Catalyst

R-C6H4-NH2

Product

Conversionb

1

KAuCl4

H

19b

99%

2

PdCl2

H

19b

90%

3

KAuCl4

Me

19c

99%

4

PdCl2

Me

19c

75%

5

KAuCl4

MeO

19d

99%

6

PdCl2

MeO

19d

90%

7

KAuCl4

F

19e

99%

8

PdCl2

F

19e

85%

9

KAuCl4

Cl

19f

99%

10

PdCl2

Cl

19f

90%

11

KAuCl4

Br

19g

99%

12

PdCl2

Br

19g

83%

13

KAuCl4

I

19h

99%

14

PdCl2

I

19h

87%

a

General Conditions: Reactions performed under air, at 50 ºC using 0.5 mmol of the 4pentynoic acid (10), 0.5 mmol of the corresponding aromatic amine R-C6H4-NH2 and 1 mol% in [Pd] or [Au]. b Determined by GC.

Having identify KAuCl4 as an efficient catalyst for the conversion of 10 into the corresponding

-keto amides 19b-h (quantitative yields after 3 h), we next extended our studies to the desired one-pot conversion to the corresponding enantiopure -hydroxy amides 20b-h (see Scheme 8), to prove our previous assumption on the bulkiness of tosyl group, which exceed the steric requirements of our biocatalysts. Thus, once the cycloisomerization/aminolysis reaction was completed (GC), the reaction mixture was diluted to 250 mM with the aqueous buffer of the bioreduction (containing iPrOH, DMSO and NADP+), the corresponding KRED added, and the mixture stirred at 30 ºC for 24 h. As can be seen


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in Scheme 8 and Tables S6-S12 (Supporting Information), the majority of the KREDs were active and reached complete conversion using -keto amides containing either electron-withdrawing or electrondonating substituents on the aryl moiety. Regarding enantioselectivities, results depended on the biocatalyst and to lesser degree on the substrate. Nevertheless, it was possible to identify KREDs [P1A04 and P1-B02 for (R)-enantiomers; P3-B03 for (S)-enantiomers] which afforded both enantiomers of 20b-h with ee values in 99->99% range.

Scheme 8 Chemoenzymatic one-pot conversion of 4-pentynoic acid (10) into enantiopure -hydroxy amides 20b-h, through the combination of metal- and biocatalyzed reactions. CONCLUSIONS In summary, we have designed an efficient, stereoselective and operationally simple one-pot protocol for the synthesis of a variety of enantiopure molecules [e.g., diols, lactones, and -hydroxycarbonyl compounds (carboxylic acids, esters and amides)], through the combination of: i) metalcatalyzed cycloisomerization of alkynols, -alkynoic acids or alkynyl amides; ii) concomitant hydrolysis, hydroalkoxylation or aminolysis of the transiently formed heterocycles; and iii) the enantioselective bioreduction of the corresponding prochiral carbonyl compounds, demonstrating the feasibility of this chemoenzymatic sequential one-pot procedure. In all cases, the desired final compounds were isolated in high yields and with excellent enantiomeric excess. At this point, it is


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important to note that we employed a one-pot methodology, in which the aqueous reaction media coming from the metal-catalyzed reaction was used directly to feed the enzymatic bioreduction, resulting in simplified downstream operations relative to classical multistep reactions. This methodology, which exploits the possibility of merging the advantages of chemical catalysts and biocatalysis will open up new avenues for further exploration of this effective catalytic dual systems. SUPPORTING INFORMATION The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.xxxxxxxxx. Experimental procedures, characterization data, copies of NMR spectra of all compounds (PDF). Enzymatic screenings, analytical data (GC and HPLC analysis) and copies of GC and HPLC chromatograms (PDF). ACKNOWLEDGEMENTS We are indebted to the MINECO of Spain (CTQ2013-40591-P, CTQ2016-81797-REDC and CTQ2016-75986-P) and the Gobierno del Principado de Asturias (Project GRUPIN14-006) for financial support. J.G.-A. thanks: i) MINECO and the European Social Fund for the award of a “Ramón y Cajal” contract; and ii) the Fundación BBVA for the award of a “Beca Leonardo a Investigadores y Creadores Culturales 2017”. S.S. (from the University of Heidelberg, Germany) thanks the Erasmus Program. N.R.-L. acknowledges MINECO for funding under Torres-Quevedo program (PTQ-12-05 407). REFERENCES 1 (a) Bruggink, A.; Schoevaart, R.; Kieboom, T. Org. Process Res. Dev. 2003, 7, 622-640; (b) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302-312; (c) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197-201. ACS Paragon Plus Environment

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13 (a) García-Álvarez, J.; Díez, J.; Gimeno, J. Green Chem. 2010, 12, 2127-2130; (b) García-Álvarez, J.; Gimeno, J.; Suárez, F. J. Organometallics 2011, 30, 2893-2896; (c) García-Álvarez, J.; Díez, J.; Gimeno, J.; Suárez, F. J.; Vicent, C. Eur. J. Inorg. Chem. 2012, 5854-5863; (d) García-Álvarez, J.; Díez, J.; Vidal, C.; Vicent, C. Inorg. Chem. 2013, 52, 6533-6542. 14 (a) Grotjahn, D. B.; Lev, D. A. J. Am. Chem. Soc. 2004, 126, 12232-12233; (b) Marion, N.; Ramon, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448-449; (c) Fujita; K.-i.; Kujime, M.; Muraki, T. Bull. Chem. Soc. Jpn. 2009, 82, 261-266; (d) Cabrero-Antonino, J. R.; Leyva-Pérez, A.; Corma, A. Chem. Eur. J. 2012, 18, 11107-11114; (e) Li, X.; Hu, G.; Luo, P.; Tang, G.; Gao, Y.; Xu, P.; Zhao, Y. Adv. Synth. Catal. 2012, 354, 2427-2432; (f) Liang, S.; Hammond, G. B.; Xu, B. Chem. Commun. 2015, 51, 903-906; (g) Ebule, R. E.; Malhotra, D.; Hammond, G. B.; Xu, B. Adv. Synth. Catal. 2016, 358, 1478-1481. For a general review in metal-catalyzed hydration of alkynes, see: (h) Hintermann, L.; Labonne, A. Synthesis 2007, 1121-1150. 15 Lucey, D. W.; Atwood, J. D. Organometallics 2002, 21, 2481-2490. 16 The Codex® KRED Screening Kit (Codexis) contains 24 ketoreductases. For a parametric study of the catalytic activity of the full panel of enzymes in the presence of metal catalyst 1, see Table S1 (Supporting Information). 17 For a recent and seminal example in the field of oxidation of pentanediols for the synthesis of lactones using a laccase/TEMPO catalytic system in aqueous medium, see: Díaz-Rodríguez, A.; Lavandera, I.; Kanbak-Aksu, S.; Sheldon, R. A.; Gotor, V.; Gotor-Fernández, V. Adv. Synth. Catal. 2012, 354, 3405-3408. 18 -valerolactone can be also obtained through a tandem protocol which combines the bioreduction of

-keto esters and spontaneous cyclization: Díaz-Rodríguez, A.; Borzęcka, W.; Lavandera, I.; Gotor, V. ACS Catal. 2014, 4, 386-393. Likewise, and starting from levulinic acid, -valerolactone was reached by a three step chemo-bio-bio reaction sequence employing a carbonyl reductase and a ACS Paragon Plus Environment

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lipase: Götz, K.; Liese, A.; Ansorge-Schumacher, M.; Hilterhaus, L. Appl. Microbiol. Biotechnol. 2013, 97, 3865-3876. 19 Lactones are very important structural motifs in biological active molecules and in the field of flavour and aroma. (a) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem. Int. Ed. 2009, 48, 9426-9451; (b) Ghosh, A. K.; Shurrush, K.; Kulkarni, S. J. Org. Chem. 2009, 74, 45084518; (c) Albrecht, L.; Albrecht, A.; Janecki, T. α-Alkylidene-γ- and δ-Lactones and Lactams, In Natural Lactones and Lactams: Synthesis, Occurrence and Biological Activity; Janecki, T. Ed.; Wiley-VCH: Weinheim, 2014; pp 147-192. 20 Tukacs, J. M.; Fridrich, B.; Dibó, G.; Székely, E.; Mika, L. T. Green Chem. 2015, 17, 5189-5195. This methodology is only able to achieve moderate values of ee (up to 82%). 21 (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127-2198; (b) Alonso, F.; Belestkaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079-3160; (c) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem. Int. Ed. 2004, 43, 3368-3398; (d) Patil, N. T.; Kavthe, R. D.; Shinde, V. S. Tetrahedron 2012, 68, 8079-8146. 22 Hydrolysis of lactones is a well-known process: Olson, A. R.; Hyde, J. L. J. Am. Chem. Soc. 1941, 63, 2459-2461. 23 Levulinic acid is one of the most important biomass-derived chemicals that may serve as a starting material for a number of useful chemicals. Geilen, F. M. A.; Engendahl, B.; Harwardt, A.; Marquardt, W.; Klankermayer, J.; Leitner, W. Angew. Chem. Int. Ed. 2010, 49, 5510-5514. 24 (a) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729-3731; (b) Wang, W.; Xu, B.; Hammond, G. B. J. Org. Chem. 2009, 74, 1640-1643; (c) Jeong, J.; Ray, D.; Ho Oh, C. Synlett 2012, 897-902.


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25 The possible catalysis mediated by the potential acid released after dissolving KAuCl4 in water can be ruled out, as the same catalytic activity was observed even in the presence of a base (2,6-lutidine, 5 mol%) in the reaction medium. 26 We propose that DMSO acts as a ligand, giving rise to the in situ formation of the corresponding Au(III)-solvate complex [AuCl2(DMSO)2]Cl, which prevents the inhibition effect of the metallic salt KAuCl4 on the enzyme. Milovanović, M.; Djeković, A.; Volarević, V.; Petrović, B.; Arsenijević, N.; Bugarčić, Ž. D. J. Inorg. Biochem. 2010, 104, 944-949. However, other coordinating solvents (i.e., CH3CN or THF) were not able to prevent this inhibition effect. 27 The incompatibility problems usually associated with the combination of metal- and bio-catalysts may be also overcome by implementing a compartmentalization of the catalysts. For recent examples, see: (a) Heidlindemann, M.; Rulli, G.; Berkessel, A.; Hummel, W.; Gröger, H. ACS Catal. 2014, 4, 1099-1103; (b) Sperl, J. M.; Carsten, J. M.; Guterl, J.-K.; Lommes, P.; Sieber, V. ACS Catal. 2016, 6, 6329-6334. See also ref. 8g. 28 A parametric study of the catalytic activity of the full panel of enzymes in the reduction of levulinic acid is available in Table S2 (Supporting Information). 29 For a parametric study of the catalytic activity of the full panel of enzymes in the bioreduction of levulinates 16a-b see Table S3-S4 (Supporting Information). 30 For a recent review covering the field of metal-catalyzed hydroamidation of alkynes, see: Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Chem. Rev. 2015, 115, 2596-2697. 31 Hydrolysis of lactams is also a well-known phenomena: Cox, R. A. Can. J. Chem. 1998, 76, 649656. 32 For selected examples of metal-catalyzed cycloisomerization of alkynyl amides, see: (a) Khan, M. W.; Kundu, N. G. Synlett 1997, 12, 1435-1437; (b) Sashida, H.; Kawamukai, A. Synthesis 1999, 7, ACS Paragon Plus Environment

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1145-1148; (c) Patil, N. T.; Huo, Z.; Bajracharya, G. B.; Yamamoto, Y. J. Org. Chem. 2006, 71, 3612-3614; (d) Varela-Fernández, A.; Varela, J. A.; Saá, C. Adv. Synth. Catal. 2011, 353, 19331937; (e) Espinosa-Jalapa, N. Á.; Ke, D.; Nebra, N.; Le Goanvic, L.; Mallet-Ladeira, S.; Monot, J.; Martín-Vaca, B.; Bourissou, D. ACS Catal. 2014, 4, 3605-3611; (f) Belger, K.; Krause, N. Org. Biomol. Chem. 2015, 13, 8556-8560; (g) Ke, D.; Espinosa, N. Á.; Mallet-Ladeira, S.; Monot, J.; Martín-Vaca, B.; Bourissou, D. Adv. Synth. Catal. 2016, 358, 2324-2331. 33 (a) Yang, T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007, 129, 12070-12071; (b) Feng, E.; Zhou, Y.; Zhang, L.; Sun, H; Jiang, H.; Liu, H. J. Org. Chem. 2010, 75, 3274-3282; (c) Feng, E.; Zhou, Y.; Zhao, F.; Chen, X.; Zhang, L.; Jiang, H.; Liu, H. Green Chem. 2012, 14, 1888-1895; (d) Ji, X.; Zhou, Y.; Wang, J.; Zhao, L.; Jiang, H.; Liu, H. J. Org. Chem. 2013, 78, 4312-4318.


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FOR TABLE OF CONTENTS USE ONLY

Combination of metal-catalyzed cycloisomerizations and biocatalysis in aqueous media: asymmetric construction of chiral alcohols, lactones and -hydroxy-carbonyl compounds.

María J. Rodríguez-Álvarez, Nicolás Ríos-Lombardía, Sören Schumacher, David Pérez-Iglesias, Francisco Morís, Victorio Cadierno, Joaquín García-Álvarez* and Javier González-Sabín*

Two catalytic worlds (metal and bio) better than one! A new one-pot metal- and bio-catalyzed protocol for the enantioselective synthesis of a variety of chiral molecules (diols, lactones, and -hydroxy-carbonyl compounds) in water is reported. The overall transformations, which formally involve a three-step one-pot reaction, establish a new bridge between metal- and bio-catalyzed reactions in aqueous media.


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Combination of Metal-Catalyzed Cycloisomerizations and Biocatalysis

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