Reaction Design for the Compartmented Combination of

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Reaction Design for the Compartmented Combination of Heterogeneous and Enzyme Catalysis Josef M. Sperl, Joerg M. Carsten, Jan-Karl Guterl, Petra Lommes, and Volker Sieber ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01276 • Publication Date (Web): 12 Aug 2016 Downloaded from http://pubs.acs.org on August 25, 2016

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Reaction Design for the Compartmented Combination of Heterogeneous and Enzyme Catalysis Josef M. Sperl, Jörg M. Carsten, Jan-Karl Guterl, Petra Lommes and Volker Sieber* Chair of Chemistry of Biogenic Resources, Technical University of Munich, Straubing Center of Science, Schulgasse 16, 94315 Straubing (Germany) E-mail: [email protected]

ABSTRACT: The combination of a heterogeneously catalyzed reaction with a biotransformation as one-pot cascade process is an important strategy to reduce costs, time, and labor efforts in the production of chemicals from biogenic resources. Although one-pot cascade type approaches generally result in more efficient chemical processes by reducing the number of work-up operations needed and time consumed, the combination of different types of catalysts, both chemical and enzymatic, into a single reaction vessel often remains challenging. During our study aimed at the direct synthesis of 2-keto-3-deoxy sugar acids as one intermediate towards biobased building blocks starting from the corresponding sugars by combining heterogeneous inorganic catalysis with enzyme catalysis we encountered several incompatibility problems. These were overcome by a chemo-enzymatic method in different compartments, which involves the gold-catalyzed direct oxidation by molecular oxygen and the subsequent conversion of the sugar acids through an enzymatic dehydration step. The described procedure represents an efficient synthesis route towards four different 2-keto-3-deoxy sugar acids and serves as a proof of concept for the combination of one-pot-incompatible catalysts under continuous flow.

chemo-enzymatic synthesis • 2-keto-3-deoxy sugar acids • continuous flow • gold catalysis • dihydroxyacid dehydratase The combination of the two worlds of heterogeneous metal catalysis and biocatalysis into one-pot type processes can be regarded as a key issue for the conversion of biomass into chemicals and the development of a more sustainable chemical industry.1-3 Such processes avoid time- and capacity-consuming and waste-producing steps like workup, purification and isolation of intermediates and are thus superior in terms of sustainability and economic feasibility.4-6 Despite their advantages, examples of the combination of biocatalysis and chemical catalysis in aqueous reaction media are still rare.5-13 This fact can be attributed to issues of incompatibility that need to be overcome for a successful integrated approach. The combination into one-pot processes usually requires a tradeoff between the optimal conditions for each catalyst alone (e.g. temperature, pH value) and also raises problems like deactivation and poisoning.1, 14-16 We were interested in the conversion of carbohydrates as major constituents of biomass by the combination of chemical oxidation and enzymatic dehydration (Scheme 1). Dehydration is an important reaction when utilizing biomass. Whereas the petrochemical production of chemicals relies on hydrocarbons to which heteroatom functionality is added, the conversion of carbohydrates requires deoxygenation for further use. Enzymatic dehydration is the major biochemical strategy to reduce the num-

ber of functional groups and to remove excess oxygen atoms from biomass-derived carbohydrates. It yields an improved carbon to oxygen ratio and when combined with a ketoreduction results in an overall deoxygenation. Scheme 1. Two-step process for the chemo-enzymatic synthesis of KDS.

Focusing at the first steps of possible carbohydrate conversion routes, we wanted to generate a one-pot two-step process for the synthesis of 2-keto-3-deoxy sugar acids (KDS) from different aldoses. KDS contain one methylene group instead of a hydroxymethylene group, and such represent a first partially defunctionalized intermediate in the production of biobased building blocks such as adipic acid, muconic acid, succinic acid or 1,4 butanediol.17-18 In addition, the conversion of a vicinal diol into a ketogroup and an adjacent methylene group leads to elements more suitable for organic synthesis by exchanging chemically indifferent hydroxymethylene groups against a vicinal electrophilic and nucleophilic carbon pair. In the case of carbohydrates with an adjacent hydroxyl group present 1

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at the beta-position to the keto group also a generic aldol building block is formed. Accordingly, the availability of an easy and general process route to produce different KDS and derivatives is of high interest and our approach might serve as a model towards this direction. For this we were especially interested in replacing the existing protocols by a chemo-enzymatic reaction sequence in which a heterogeneous chemical and a biocatalytic reaction step are coupled, as these have proven to be powerful tools, because they combine the strengths of both approaches.19 Accordingly, we designed a two-step procedure in which the corresponding sugars are first converted to sugar acids by the gold catalyzed action of molecular oxygen. The derived sugar acids are then directly converted to KDS in an enzymatic dehydration. During our studies towards a one-pot process, we encountered several incompatibility problems associated with the combination of the heterogeneous gold catalyst and the dehydratase enzyme. Finally, we could overcome these hurdles by implementing a novel fed-batch continuous flow process with compartmentalization of the catalysts. To the best of our knowledge, this study represents the first integrated process involving heterogeneous chemical oxidation and subsequent biocatalytic deoxygenation in a compartmented continuous flow chemical setting. In order to produce several 2-keto-3-deoxy sugar acids (KDS) directly from their corresponding sugars we aimed at using a catalyst that accepts a wide range of different sugars and converts them with a very high selectivity of almost 100 %. This led us to the adaptation of a previously published method,20 describing the gold-catalyzed aqueous phase oxidation of different aldoses to the corresponding aldonic acids with a remarkable selectivity of higher than 99.5 % together with a high catalyst activity. Thus, this method should be ideally suited for our purpose and readily adoptable to our reaction scheme. We started our work studying the chemical oxidation of different sugars with a 0.5 % Au/Al2O3 catalyst at conditions suitable for the subsequent enzymatic dehydration and were able to selectively oxidize D-glucose, D-galactose, Larabinose and D-xylose to their aldonic acids (Figure 1). Encouraged by these results, which were comparable to previous conversions,20 we focused on the establishment of a two-step process including a second conversion based on dehydratase enzymes. Several different enzyme classes of dehydratases act on different α,β-dihydroxy acids, most important being aldonate dehydratases and dihydroxyacid dehydratases (DHAD; EC 4.2.1.9). Among these are the enolase-like gluconate dehydratase and the iron-sulfur cluster dehydratase DHAD, which have previously been used for biofuel or KDS production via cell-based and cell-free reaction systems.21-23

Figure 1. Reaction scheme and typical curves of Au catalyzed sugar oxidation to the corresponding aldonic acids. csugar = 50 mM.

The DHAD from Sulfolobus solfataricus (SsDHAD) had been described as being very promiscuous with activity for a broad range of sugar acids.24 Moreover, SsDHAD is a thermostable enzyme with a half-life of 17 h at 50 °C and its FeS cluster is oxygen-tolerant and stable.22 After successfully achieving the chemical oxidation in our lab, we were now interested in the direct SsDHAD-mediated dehydration of the produced sugar acids. SsDHAD was expressed in the soluble fraction and purified by heat precipitation and size exclusion chromatography. By this method 15 mg of SsDHAD per g of wet cell weight were obtained with a specific activity for D-gluconate of 2.9 U/mg at 50 °C in 100 mM HEPES pH 7.0 (50 °C). We further analyzed the enzymatic activity of SsDHAD on three different sugar acids as substrate via our HPLCbased method. D-xylonate and L-arabonate are converted best with specific activities of 7.1 and 6.0 U/mg. The activity using D-galactonate is comparable to D-gluconate with 3.7 U/mg (Figure 2). In order to understand the stereochemical preference of the SsDHAD we are currently performing studies on its substrate scope using rare and unnatural sugar acids. Nevertheless, our present results showed a very broad catalytic promiscuity of SsDHAD with activity on D-xylonate and L-arabonate as well as D2


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gluconate and D-galactonate and encouraged us to further evaluate a chemo-enzymatic synthesis approach to KDS. Preliminary tests of the gold catalyst showed a negative effect of protein buffer salts on the oxidation activities. Thus, we were concerned about finding a suitable buffer system for the combination of both reactions. We assumed that an appropriate concentration of substrate (e.g. D-gluconate) at pH values around 7 should have enough ionic strength to ensure SsDHAD activity and solubility. To test this, we exchanged the HEPES buffer against 50 mM D-gluconate (pH 7) and analyzed the activity of SsDHAD at 50 °C by diluting the resulting enzyme preparation into fresh substrate solution (pH 7). We found, that SsDHAD is able to convert sugar acids in the absence of buffer salts and that its activity is almost the same as in the presence of 100 mM HEPES pH 7.0 (50 °C) (2.5 U/mg compared to 2.9 U/mg in HEPES) (Figure 2).

Figure 2. Specific activities for the SsDHAD catalyzed dehydration of different sugar acids.

In order to combine the chemical approach of gold catalyzed oxidation of sugars with the catalytic potential of SsDHAD we first aimed at the development of a one-pot process. Thus, we needed to find a trade-off between the ideal conditions for each single step, still allowing high overall activity for the two-step process. From our previous work we knew the pH and temperature profiles of SsDHAD for D-gluconate25 and compared the enzymatic properties to the pH and temperature dependence of the gold catalyzed oxidation. The activity of SsDHAD for its substrate D-gluconate is highest at pH values around 6.2 with still high activity in the pH range from 6 to 7.5. It decreases with increasing pH values and at a pH of 9 almost all the activity is lost. The temperature profile suggests high temperatures for the enzymatic reaction (good activity in the range from 50 to 80 °C). The optimal temperature for the conversion of D-gluconate is 77 °C.25 Activity and selectivity of the gold-catalyst are best at medium alkaline conditions (pH 9 to 10). Reduction of the pH results in lower activity. Increasing the tempera-

ture promotes activity, although temperatures above 60 °C are not recommended as unwanted reactions such as isomerization and degradation reactions might occur and are favored at relatively high temperatures.26 Thus, to set up a combined chemo-enzymatic conversion we needed to find a compromise to reach highest possible total activity for the two-step process. We decided to start our experiments with a relatively low pH value of 7 and a temperature of 50 °C. In a first attempt, we added purified SsDHAD directly to the D-glucose oxidation reaction with the result of an abrupt stop of NaOH consumption due to an immediate inactivation of the gold catalyst (Figure 3A). We assumed that cystein residues and/or leaked ironsulfur-cluster of the SsDHAD enzyme bind to the Au surface of the catalyst and thus abolish the transfer of the substrates D-glucose and oxygen to the catalytic center. In further reaction setups we tried to prevent the catalyst from being poisoned by using mechanical barriers between the enzyme and the Au surface. To this end, we put either enzyme solution or catalyst into a dialysis membrane, which was then immersed into the reaction solution. In another attempt, we immobilized the catalyst in alginate capsules, which were then added to a solution of D-glucose containing SsDHAD. None of these trials gave satisfactory results. The Au catalyst was deactivated in all cases, albeit at a lower rate. We attribute this to the decelerated diffusion process of iron-sulfur-cluster or other low molecular weight contaminants towards the catalyst surface as well as to prohibited binding of enzyme to the catalyst surface. Further analyses would be necessary to delineate the contribution of each factor to the inactivation. However, in each attempt the activity of immobilized Au catalyst in the absence of enzyme was lower compared to experiments with free catalyst presumably due to mass transfer limitations. As all one-pot attempts failed, we decided to completely separate the heterogeneous catalyst reaction from the enzymatic conversion, inspired by a previously described continuous flow reactor system27 for the oxidation of D-glucose and the recently published first demonstration of a compartmentation strategy5 with the advantages of catalyst separation and avoidance of compatibility problems. We chose a cross flow filtration cartridge instead of the previously used ultrasonic separator due to our significantly lower reactor volume (50 ml instead of 1000 ml). Using this approach, we could directly separate 100 % of the catalyst from the reaction solution. We envisioned a combination of a continuous stirred tank reactor with a continuous flow system, so we aimed at using the SsDHAD in its immobilized form. This was achieved by loading SsDHAD onto a Nisepharose column, which was connected to the oxidation reactor and the cross flow device (Figure 3B). This scheme should allow for a fed-batch continuous flow process. The reaction sequence was started by adding Au catalyst to a solution of L-arabinose. The pH was kept at a value of 7 as the solution should directly flow to the column (heated to 50 °C in a temperature controlled compartment) and so activity of SsDHAD should be ensured. After a conversion 3


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Figure 3. One-pot (A) and compartmented setups for the chemo-enzymatic synthesis of KDS. B: Direct transfer of sugar acid solution onto immobilized SsDHAD. C: Adjustment of pH and removal of H2O2 by catalase treatment before loading sugar acid solution onto immobilized SsDHAD and downstream purification of KDS via anion and cation exchange chromatography. Sym28 bols and drawings are used in accordance to literature.

of 90 % was reached according to NaOH consumption, we started to pass the filtrate at a flow rate of 1 ml/min over to the SsDHAD column and simultaneously started to feed the reaction vessel with a 50 mM L-arabinose solution at the same flow rate. However, running of filtrate solution over the column caused an immediate loss of the brownish SsDHAD color and HPLC measurements showed that L-arabonate was not converted to L-KDA. We assumed that hydrogen peroxide which is formed from molecular oxygen on the catalyst surface during the catalytic oxidation reaction was responsible for the degradation of the iron-sulfur cluster of the SsDHAD (loss of brownish color) and thus abolished the catalytic activity. Subsequent measurements showed that hydrogen peroxide was present in the reaction mixture at concentrations

up to 10 mg/L. Although both catalysts were located in separate compartments, the biotransformation as second step still had to be compatible with the reaction solution of the heterogeneously catalyzed reaction. Having solved the incompatibility issues of the gold catalyst in presence of SsDHAD we now encountered problems with a reaction intermediate of the heterogeneous catalyst. In order to circumvent the problem of SsDHAD inactivation by hydrogen peroxide, we decided to change the reaction setup again with the advantage of optimized conditions for each individual reaction step (Figure 3C). The filtrate from the catalytic oxidation was now collected in a second reaction vessel to which catalase was added to remove hydrogen peroxide. This setup gave us the opportunity to change parameters for each reaction individually 4


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and we decided to use a pH value of 9 for the oxidation in order to enhance the activity of the gold catalyst. Another automatic titrator was then used to set the pH to 6.5 with HCl titration in the second vessel to ensure working of the catalase and the SsDHAD. With this setup, we were able to also enhance the overall reaction velocity as we could approach optimal pH values for both reactions. The hydrogen peroxide free solution was pumped over the SsDHAD column at the same flow rate as the filtrate flow and sugar feeding. The final step was to translate this procedure to a combined fed-batch and continuous flow environment. Catalytic oxidation of L-arabinose was performed up to a conversion of about 90 % after which the catalyst was separated by the cross flow filtration and the filtrate solution collected into a second reaction vessel at a flow rate of 1 ml/min. Accordingly, L-arabinose was fed to the oxidation reactor at the same flow rate. The pH was automatically titrated to a value of 6.5 in the second continuous stirred tank reactor and an excess of catalase (2000 U) was added to ensure complete removal of hydrogen peroxide even after dilution by further substrate feeding (in our setup catalase is not immobilized and gets removed over time). The resulting solution was then pumped to an SsDHAD column heated to 50 °C. 10 ml fractions were collected for a total of 100 ml and subsequently analyzed via HPLC. Full conversion of Larabonate to L-KDA was observed by HPLC. Pure L-KDA (58 % yield after purification) was then obtained by two fast purification steps over an anion and a cation exchange column. The identity of the product was subsequently confirmed by NMR29 and MS measurements. As a proof of concept we could show the direct conversion of L-arabinose via L-arabonate to L-KDA in a two-step compartmented continuous process. The yield was constant during a total volume of 100 ml with an average product concentration of 38 mM L-KDA (Figure 4).

Figure 4. L-arabonate and L-KDA concentrations during the continuous process.

To demonstrate the application of our continuous mode process for the synthesis of other KDS we additionally performed the transformation for three other sugars. Four different KDS can be prepared by the described process (Table 1). For D-gluconate and D-galactonate the activity of SsDHAD is lower and we recognized that the activity of the SsDHAD is further reduced by substrate flow over the column, presumably caused by partial leaking of the FeS cluster. Due to this behavior, the flow rate had to be decreased accordingly to get full conversion of these sugar acids during the continuous flow process. Also the amount of KDS that can be synthesized with one preparation of SsDHAD is limited due to this inactivation. Alternatively a larger volume of Ni-sepharose could be used or the column could be loaded with fresh SsDHAD after the activity is too low to ensure full conversion. We are currently performing studies to overcome this inactivation which also include tests of further dehydratases. Table 1. Continuous flow transformation of different sugars to KDS. substrate

flow rate -1 (ml min )

av. conc. (mM)

yield 1 b.p.(%)

yield 1 a.p. (%)

L-arabinose

1.0

38

84

58

D-xylose

1.0

31

69

n.d.

D-galactose

0.5

39

87

n.d.

D-glucose

0.3

41

91

86

1 1

1

D-KDX and D-KDGal showed degradation during the ion exchange purification step. b.p. before purification, a.p. after purification

Nevertheless, the described method presents a more economic approach to reach KDS compared to synthetic chemical procedures. Our results show that the catalytic oxidation is applicable to a range of sugars thus enabling an easy access to the corresponding sugar acids. In order to reach technical relevance it will be necessary to use higher substrate concentrations and to reach higher productivity rates. This should be feasible as the activity of the gold catalyst is enhanced and the activity of the SsDHAD is not affected by higher substrate concentrations. The productivities reached vary according to the specific activities of the SsDHAD for different substrates. An upscaling of the enzymatic step as well as enzyme engineering to enhance the specific activities should lead to improved productivity rates. The promiscuous nature of SsDHAD together with the broad substrate range of the gold catalyst might enable us to synthesize even more KDS variants. Furthermore, our continuous-flow combination of heterogeneous and enzyme catalysis should be applicable to a wide range of other alliances of heterogeneous catalysts and enzymes. In summary, we wanted to generate a one-pot two-step process for the synthesis of KDS, but encountered several incompatibility problems associated with the combination of the heterogeneous gold catalyst and the enzyme SsDHAD. Finally, we could 5


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overcome these hurdles by using a fed-batch continuous flow process with compartmentalized combination of catalysts. Although this approach required individual optimization to our reaction scheme, we believe that it is generally applicable to a broad spectrum of combinations of heterogeneous and enzyme catalysts with distinct pH value preferences in water.

ASSOCIATED CONTENT Supporting Information Available:

Experimental procedures, KDS synthesis data and compound characterization are provided (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Phone: +499421187301.

Author Contributions All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT Part of this work was kindly supported by the German Federal Ministry of Education and Research (BMBF) through grant No. 031A177B. We thank Evonik Industries for supplying us with gold catalyst and Dr. Broder Rühmann for assistance in recording and analysis of mass spectra.

ABBREVIATIONS KDS 2-keto-3-deoxy sugar acid.

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Reaction Design for the Compartmented Combination of

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