One-Pot, Two-Module Three-Step Cascade To Transform Phenol

Letter pubs.acs.org/acscatalysis

One-Pot, Two-Module Three-Step Cascade To Transform Phenol Derivatives to Enantiomerically Pure (R)- or (S)‑p‑Hydroxyphenyl Lactic Acids Eduardo Busto,†,§ Robert C. Simon,† Nina Richter,†,‡ and Wolfgang Kroutil*,† †

Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010-Graz, Austria Austrian Centre of Industrial Biotechnology (ACIB), Petersgasse 14, 8010 Graz, Austria

‡

S Supporting Information *

ABSTRACT: Readily available phenol derivatives were substituted in para-position via a C−C bond formation to give enantiomerically pure (R)- or (S)-3-(para-hydroxyphenyl) lactic acids. The transformation was achieved by designing a biocatalytic cascade consisting of three linear steps, namely, (i) the C−C coupling of the phenol and pyruvate in the presence of ammonia to afford the corresponding L-tyrosine derivative, followed by (ii) oxidative deamination and (iii) enantioselective reduction. Compatibility analysis showed that the reaction rate of the first step is slowed in the presence of the product of the third step; consequently, the three-step cascade was subdivided in two modules (module 1 = step 1; module 2 = steps 2 and 3), which were run in one pot sequentially. Because of the exquisite selectivity achieved in the C−C coupling step, para-isomers were obtained exclusively. By choosing the appropriate alcohol dehydrogenase, the (R)- as well as the (S)-isomer were isolated in enantiopure form. Preparative transformations of 2-, 3-, and 2,3-disubstituted phenols (23−96 mM) afforded the corresponding (R)- and (S)-para-hydroxyphenyl lactic acids in high yield (58%−85%) and enantiopure form (ee > 97%). KEYWORDS: cascade, C−C coupling, deamination, bioreduction, enantiopure aryl lactic acids

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INTRODUCTION α-Hydroxy acids are part of numerous natural products, as well as of pharmaceuticals1 and particularly depsipeptides, that mimic the natural amino acids.2 Among them, 3-(4-hydroxyphenyl) lactic acid derivatives represent privileged scaffolds found in a broad range of natural products as Aeruginosins3 with potent inhibitory activity toward serine proteases. Moreover, naturally occurring halogenated derivatives have also been demonstrated to be strong inhibitors of trypsin.4 Structurally related Rosmarinic acid and its derivatives display a wide variety of biological activities, such as anti-inflammatory, antioxidant, or neuroprotective effects.5 The synthetic analogue Saroglitazar has been recently approved for the treatment of the diabetic dyslipidemia.6 We have recently reported a concurrent redox biocatalytic two-step cascade for the transformation of L-tyrosine to (R)- or (S)-p-hydroxyphenyl lactic acid under very mild reaction conditions.7 However, the preparation of highly interesting aryl-substituted derivatives is restricted by the limited commercial availability of derivatives of L-tyrosine. Therefore, a cascade for the direct transformation of substituted phenols to the optically pure p-hydroxyphenyl lactic acid is desired.

materials for the preparation of 3-(4-hydroxyphenyl) lactic acids. In detail, a linear three-step cascade was designed based on the combination of four enzyme-catalyzed reactions (Scheme 1). Although artificial two-step cascades involving enzymes from different organisms have become broadly investigated for the preparation of non-natural products,9−18 the combination of three or more steps is even more appealing.19−22 In the first step, the C−C coupling between pyruvate/ ammonia and different phenol derivatives should afford substituted tyrosine derivatives using a tyrosine phenol lyase (TPL) (Scheme 1).12,23 Tyrosine derivatives might also be obtained from coumaric acid derivatives, using a tyrosine ammonia lyase.24 Subsequently, oxidation of the L-amino acid substrate by an amino acid deaminase at the expense of molecular oxygen should give the prochiral α-keto acid in the second step.25 Note that the L-amino acid deaminase does not lead to the formation of hydrogen peroxide according to the literature, although acting like an oxidase.25 In the final and third step, the keto acid is stereoselectively reduced either to the (R)- or (S)-α-hydroxy acid, depending on the stereopreference of the selected dehydrogenase.7

RESULTS AND DISCUSSION A biocatalytic retro-synthetic analysis8 revealed that paraunsubstituted phenols 1 and pyruvate (2) are suitable starting

Received: January 5, 2016 Revised: February 23, 2016

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© XXXX American Chemical Society

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ACS Catalysis Scheme 1. Linear Three-Step Biocatalytic Cascade for the Transformation of Phenols 1a−g into the Corresponding Enantiomerically Pure p-Hydroxyphenyl Lactic Acids (R)- or (S)-5a−ga

The cascade was finally performed in a one-pot, two-module, three-step fashion; thus, module 2, consisting of two biocatalytic steps, was started when module 1 (one reaction step) was completed. Reaction conditions: phenol 1a−g (23−92 mM), pyruvate (2, 2 equiv), NH4+ (5 equiv), NAD+ (1 mM), NH4HCOO (3 equiv), TPL from Citrobacter freundii (41 U/mmol), L-AAD from Proteus myxofaciens (40 U/mmol), Hic (114 U/mmol for D-Hic, 68 U/mmol for L-Hic), FDH (76 U/mmol), 21 °C, 170 rpm, 24 h for module 1 and 3 h for module 2. a

In an initial study, the two-step subcascade from the amino acid tyrosine 3 to the corresponding α-hydroxy acid 5thus, the oxidation and reduction stepswere run simultaneously, using commercially available L-3-chlorotyrosine (3a) as a model substrate. The L-amino acid deaminase (L-AAD) from Proteus myxofaciens,7,25 and stereocomplementary L- and D-isocaproate reductases (HicDHs) from L. paracasei DSM 20008 (L-Hic)26 and L. confuses DSM 20196 (D-Hic)27 were recombinantly expressed in E. coli and used as freeze-dried cell catalysts. Cofactor recycling of NADH was performed using a commercially available FDH preparation.28 The reaction was completed at 25 mM substrate concentration within a short time (8 h), affording enantiomerically pure (R)- or (S)-4a (>97% ee), depending on the preference of the Hic reductase. Thus, the two-step redox cascade can be efficiently applied for 3-chlorotyrosine 3a. Next, the simultaneous three-step cascade was evaluated performing the C−C coupling, the oxidation, and the reduction steps in a simultaneous fashion to establish a straightforward route for the preparation of p-hydroxyphenyl lactic acids from phenols (Scheme 1). As a catalyst for the first step, the variant M379 V of the recombinant tyrosine phenol lyase (TPL) from Citrobacter freundii used as a cell free extract was selected, since it was reported to possess a broad substrate scope.19,23c Using phenol 3a as a substrate at a concentration of 25 mM, the cascade resulted in 24% of the desired lactic acid (S)-5a, whereby the remaining 76% was unconverted phenol 1a. The intermediates amino acid (S)-2a or the keto acid 3a were not detected, thus the oxidation and the reduction steps are perfectly coupled; however, the bottleneck of the cascade seemed to be located at the C−C coupling step. Interestingly, running only the first step for 1a to 3a, conversions of >90% were reached within 24 h. Consequently, it was deduced that a reagent required for step 2 or step 3, or compounds formed during these steps, led to reduced conversion of the first step. To analyze the reason for the bottleneck, an compatibility analysis was performed for the first step; thus, the first step of the reaction was tested in the presence of reagents/compounds of steps 2 and 3 (see Table 1). Oxygen pressure or formate (added as ammonium formate) did not affect the conversion of

Table 1. Compatibility Analysis of the C−C Coupling Step (1a, Pyruvate) and Subsequent Cascade Steps

entry

additive

concadditive

c (%)a,b

1 2 3 4 5 6 7

− O2 NH4 formate (S)-5a (R)-5a (S)-5a (R)-5a

− 1 bar 150 mM 5 mM 5 mM 25 mM 25 mM

93 94 93 8 15 3 10

a

Determined by HPLC on a reverse phase. bReaction conditions: phenol 1a (23 mM), KPi (pH 8, 50 mM, 0.64 mL), pyruvate (2, 2 equiv), NH4Cl (150 mM), TPL from Citrobacter freundii (4 mg, 1.2 U), 21 °C, 170 rpm, 24 h.

the C−C coupling reaction (entries 2 and 3 in Table 1). However, a strong effect was observed for the final products of the cascade (R)- or (S)-5a (entries 4−7 in Table 1). Both enantiomers of 5a resulted in low conversion for the TPLcatalyzed step, even at low concentrations (5 mM), although even lower conversion was found for the (S)-isomer. To circumvent the reduced activity of the first step in the presence of the final product, the cascade was performed in a one-pot sequential mode, thus separating the three-step cascade in two modules. The first module encompasses the C−C coupling step to provide the amino acid (S)-3a and was run until completion in the absence of the catalysts and reagents required for steps 2 and 3. Subsequently, in module 2, the oxidation/reduction cascade of (S)-3a into the phenyl lactic acids (R)- or (S)-5a was performed by the addition of the catalysts/reagents of step 2/3 to the reaction mixture of the completed first step without intermediate workup (Scheme 1). 2394

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ACS Catalysis This modular cascade was studied at a substrate concentration between 23 and 92 mM. The two modules were efficiently coupled at 23−46 mM, affording the target (R)- or (S)-5a in enantiopure form, depending on the choice of the Hic enzyme (Table 2, entries 1, 2, 4, and 5). Reactions on

Table 3. Substrate Scope and Preparative Yields of the Modular Cascade Transforming Phenol and Pyruvate To Optically Pure Para-Hydroxyphenyl Lactic Acids entrya

R

Hica

1 2 3 4 5 6 7 8 9 10 11 12

2-Br (b) 2-Br (b) 2-Me (c) 2-Me (c) 2-F (d) 2-F (d) 3-F (e) 3-F (e) 3-Cl (f) 3-Cl (f) 2,3-diF (g) 2,3-diF (g)

L-Hic

Table 2. Sequential One-Pot Biocatalytic Cascade for the Preparation of (R)- or (S)-5a at Different Substrate Concentrations entry 1 2 3 4 5 6

a

a

Hic

1a [mM]

1a (%)

L-Hic

23 46 92 23 46 92

7 3 31 6 3 28

L-Hic L-Hic D-Hic D-Hic D-Hic

b

2a (%) 97 >97 >97 >97 >97 >97 >97 >97 96 >97 >97

(S) (R) (S) (R) (S) (R) (S) (R) (S) (R) (S) (R)

a

Reaction conditions: phenol 1a−g (23−92 mM), pyruvate (2, 2 equiv), NH4+ (5 equiv), NAD+ (1 mM), NH4HCOO (3 equiv), TPL from Citrobacter freundii (41 U/mmol), L-AAD from Proteus myxofaciens (40 U/mmol), Hic (114 U/mmol for D-Hic, 68 U/ mmol for L-Hic), FDH (76 U/mmol), 21 °C, 170 rpm, 24 h for module 1 and 3 h for module 2. bDetermined by HPLC. cIsolated yields in brackets. dDetermined by HPLC on a chiral phase.

dichroism spectra31 with the CD spectra of a related compound such as (R)- and (S)-para-hydroxyphenyl lactic acid (5h)7 (see Figures S28−S36 in the Supporting Information). As expected, the hydroxy acids obtained with L-Hic have (S)-configuration, while D-Hic afforded the (R)-isomers. In conclusion, p-unsubstituted phenol derivatives were transformed to the corresponding para-hydroxyphenyl lactic acids through a three-step biocatalytic cascade comprised of C− C coupling, oxidative deamination, and enantioselective reduction. As reagents, just pyruvate, molecular oxygen (O2), and ammonium formate were required. Both (R)- and (S)enantiomers were produced, depending on the choice of the appropriate reductase. Compatibility analysis revealed that a product of a later step reduced the rate of the first step, which was required to perform the three-step cascade in a one-pot, two-module fashion. Transformations were conducted at substrate concentrations of 23−92 mM, leading to good isolated yields (58%−85%) and without requiring chromatographic purification within a short reaction time (27 h). As a consequence, this approach extends the toolbox of C−C bond formation32 and provides a mild and environmentally friendly route for the preparation of para-hydroxyphenyl lactic acids, which are present in a broad range of natural products and pharmaceuticals. Representative Procedure for the Synthesis of pHydroxyphenyl Lactic Acids (R)- or (S)-5a−g. The corresponding phenol (1a−g, 23−92 mM) was added over a period of 1 h to a solution of sodium pyruvate (2, 2 equiv) and lyophilized cell free extract (C. freundii M379 V TPL, 126 mg, 38 U) in a potassium phosphate buffer [50 mM, pH 8, 5 eqs NH4+, 0.04 mM PLP] and the reaction was incubated for 24 h at 21 °C and 170 rpm. After this time, NAD+ (1 mM), NH4formate (3 equiv), L-AAD (40 U/mmol), L- or D-Hic (68 U/ mmol for L-Hic, 114 U/mmol for D-Hic), and FDH (76 U/ mmol) were added, and the reactions were shaken for additional 3 h under 1 bar of O2. The reaction was stopped with aqueous HCl (4 M), extracted with EtOAc (3 × 30 mL), the combined organic phases were washed with aqueous HCl 4

preparative scale (1a, 0.44 mmol, 56.6 mg, 46 mM) afforded the enantiopure hydroxy acids with up to 97% product formation and in high isolated yields [(R)-5a, 69.6 mg, 73% and (S)-5a, 73.4 mg, 77%] after a simple extraction step without requiring chromatographic purification. At higher substrate concentration of 1a (92 mM), the C−C coupling step did not reach completion under the reaction conditions employed; subsequently, it turned out that, at a certain concentration of 1a (>25 mM), the oxidation step was slowed because the L-AAD was not able to oxidize the amino acid (S)3a. Most likely, the FAD-dependent enzyme L-AAD was inhibited by the formation of a charge-transfer complex between phenol and flavin, as reported in the literature.29 Interestingly, other phenols were transformed more efficiently than 1a (see below). Finally, the scope of the biocascade was investigated for a panel of 2- and 3-substituted phenols at the optimal substrate concentration for each phenol (Table 3). Besides the model substrate 2-chlorophenol 1a, also phenols possessing a bromo (1b), a methyl (1c), or a fluorine (1d) in 2-position were successfully transformed into the corresponding para-hydroxy phenyl lactic acids 5 at useful substrate concentrations (46−92 mM). The cascade, was also successfully performed for 3substituted phenols (23−92 mM) containing a fluoro (1e) or a chloro (1f) group. In addition, 2,3-difluorophenol 1g (46 mM) was also successfully transformed into the corresponding (R)or (S)-5g. In all cases, both (R)- and (S)-isomers were isolated in enantiopure form (>97% ee, HPLC) at up to >99% product formation and excellent isolated yield (up to 85%) without requiring chromatographic purification. Note that, exclusively, (S)-5a30 and (S)-5b30 have been described previously, while the para-hydroxyphenyl lactic acids 5c−g have not been described at all, neither in racemic nor in optically enriched or pure form, to the best of our knowledge. This clearly shows that the presented methodology provides an efficient access a range of novel para-hydroxyphenyl lactic acids. The absolute configuration of the para-hydroxyphenyl lactic acids 5a−g was determined by comparing their circular 2395

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ACS Catalysis M (3 × 30 mL) dried over Na2SO4 and the solvent was evaporated under reduced pressure. The product was washed with n-heptane (2 × 10 mL) and dried under high vacuum, affording the corresponding hydroxy acids (R)- or (S)-5a-g in high chemical purity, good to excellent isolated yields (58%− 85%), and in enantiopure form (>97% ee). Reaction Scale and Isolated Yields. 1a: (56.6 mg, 0.44 mmol, 46 mM); Isolated yields: (R)-5a, (69.6 mg, 73%) and (S)-5a, (73.4 mg, 77%). 1b: (76.1 mg, 0.44 mmol, 46 mM); Isolated yields: (R)-5b, (66.6 mg, 58%) and (S)-5b, (68.9 mg, 60%). 1c: (71.4 mg, 0.66 mmol, 69 mM); Isolated yields: (R)5c (96.9 mg, 75%) and (S)-5c (99.6 mg, 77%). 1d: (98.6 mg, 0.88 mmol, 92 mM); Isolated yields: (R)-5d (135.6 mg, 77%) and (S)-5d (140.9 mg, 80%). 1e: (98.6 mg, 0.88 mmol, 92 mM); Isolated yields: (R)-5e (140.7 mg, 80%) and (S)-5e (142.4 mg, 81%). 1f: (28.3 mg, 0.22 mmol, 23 mM). Isolated yields: (R)-5f (30.0 mg, 63%) and (S)-5f (30.3 mg, 63%). 1g: (57.2 mg, 0.44 mmol, 46 mM). Isolated yields: (R)-5g (81.6 mg, 85%) and (S)-5g (76.7 mg, 80%).

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(5) Kim, G.-D.; Park, Y. S.; Jin, Y. H.; Park, C. S. Appl. Microbiol. Biotechnol. 2015, 99, 2083−2092. (6) Agrawal, R. Curr. Drug Targets 2014, 15, 151−155. (7) (a) Gourinchas, G.; Busto, E.; Killinger, M.; Richter, N.; Wiltschi, B.; Kroutil, W. Chem. Commun. 2015, 51, 2828−2831. (b) Busto, E.; Richter, N.; Grischek, B.; Kroutil, W. Chem.Eur. J. 2014, 20, 11225− 11228. (8) Turner, N. J.; O’Reilly, E. Nat. Chem. Biol. 2013, 9, 285−288. (9) Köhler, V.; Turner, N. J. Chem. Commun. 2015, 51, 450−464. (10) Muschiol, J.; Peters, C.; Oberleitner, N.; Mihovilovic, M. D.; Bornscheuer, U. T.; Rudroff, F. Chem. Commun. 2015, 51, 5798−5811. (11) Zhang, J.; Wu, S.; Wu, J.; Li, Z. ACS Catal. 2015, 5, 51−58. (12) Dennig, A.; Busto, E.; Kroutil, W.; Faber, K. ACS Catal. 2015, 5, 7503−7506. (13) Wu, S.; Chen, Y.; Xu, Y.; Li, A.; Xu, Q.; Glieder, A.; Li, Z. ACS Catal. 2014, 4, 409−420. (14) Schrittwieser, J. H.; Groenendaal, B.; Resch, V.; Ghislieri, D.; Wallner, S.; Fischereder, E.-M.; Fuchs, E.; Grischek, B.; Sattler, J. H.; Macheroux, P.; Turner, N. J.; Kroutil, W. Angew. Chem., Int. Ed. 2014, 53, 3731−3734. (15) Sattler, J. H.; Fuchs, M.; Tauber, K.; Mutti, F. G.; Faber, K.; Pfeffer, J.; Haas, T.; Kroutil, W. Angew. Chem., Int. Ed. 2012, 51, 9156− 9159. (16) Xu, Y.; Li, A.; Jia, X.; Li, Z. Green Chem. 2011, 13, 2452−2458. (17) Xu, Y.; Jia, X.; Panke, S.; Li, Z. Chem. Commun. 2009, 2009, 1481−1483. (18) Voss, C. V.; Gruber, C. C.; Faber, K.; Knaus, T.; Macheroux, P.; Kroutil, W. J. Am. Chem. Soc. 2008, 130, 13969−13972. (19) Busto, E.; Simon, R. C.; Kroutil, W. Angew. Chem., Int. Ed. 2015, 54, 10899−10902. (20) (a) Wagner, N.; Bosshart, A.; Failmezger, J.; Bechtold, M.; Panke, S. Angew. Chem., Int. Ed. 2015, 54, 4182−4186. (b) Both, P.; Busch, H.; Kelly, P. P.; Mutti, F. G.; Turner, N. J.; Flitsch, S. L. Angew. Chem., Int. Ed. 2016, 55, 1511−1513. (21) Schmidt, S.; Scherkus, C.; Muschiol, J.; Menyes, U.; Winkler, T.; Hummel, W.; Gröger, H.; Liese, A.; Herz, H.-G.; Bornscheuer, U. T. Angew. Chem., Int. Ed. 2015, 54, 2784−2787. (22) Sattler, J. H.; Fuchs, M.; Mutti, F. G.; Grischek, B.; Engel, P.; Pfeffer, J.; Woodley, J. M.; Kroutil, W. Angew. Chem., Int. Ed. 2014, 53, 14153−14157. (23) (a) Phillips, R. S.; Ravichandran, K.; Von Tersch, R. L. Enzyme Microb. Technol. 1989, 11, 80−83. (b) Kim, K.; Cole, P. A. Bioorg. Med. Chem. Lett. 1999, 9, 1205−1208. (c) Gloge, A.; Zón, J.; Kövári, Á .; Poppe, L.; Rétey, J. Chem.Eur. J. 2000, 6, 3386−3390. (c1) Seisser, B.; Zinkl, R.; Gruber, K.; Kaufmann, F.; Hafner, A.; Kroutil, W. Adv. Synth. Catal. 2010, 352, 731−736. (d) de Lange, B.; Hyett, D. J.; Maas, P. J. D.; Mink, D.; van Assema, F. B. J.; Sereinig, N.; de Vries, A. H. M.; de Vries, J. G. ChemCatChem 2011, 3, 289−292. (e) Yu, Y.; Zhou, Q.; Wang, L.; Liu, X.; Zhang, W.; Hu, M.; Dong, J.; Li, J.; Lv, X.; Ouyang, H.; Li, H.; Gao, F.; Gong, W.; Lu, Y.; Wang, J. Chem. Sci. 2015, 6, 3881−3885. (24) (a) Kyndt, J. A.; Meyer, T. E.; Cusanovich, M. A.; Van Beeumen, J. J. FEBS Lett. 2002, 512, 240−244. (b) Pilbák, S.; Farkas, O.; Poppe, L. Chem.Eur. J. 2012, 18, 7793−7802. (c) A related enzyme is the phenylalanine ammonia lyase; see: Parmeggiani, F.; Lovelock, S. L.; Weise, N. J.; Ahmed, S. T.; Turner, N. J. Angew. Chem., Int. Ed. 2015, 54, 4608−4611. (25) (a) Alexandre, F. R.; Pantaleone, D. P.; Taylor, P. P.; Fotheringham, I. G.; Ager, D. G.; Turner, N. J. Tetrahedron Lett. 2002, 43, 707−710. (b) Pantaleone, D. P.; Geller, A. M.; Taylor, P. P. J. Mol. Catal. B: Enzym. 2001, 11, 795−803. (26) Schütte, H.; Hummel, W.; Kula, M.-R. Appl. Microbiol. Biotechnol. 1984, 19, 167−176. (27) Hummel, W.; Schütte, H.; Kula, M. R. Appl. Microbiol. Biotechnol. 1985, 21, 7−15. (28) The crude preparation from FDH was purchased from Evocatal. (29) Winkler, C. K.; Clay, D.; van Heerden, E.; Faber, K. Biotechnol. Bioeng. 2013, 110, 3085−3092.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b00030. Catalyst preparation, analytical data (HPLC traces, LCMS, 1H, 13C and 19F-NMR, CD spectra) for isolated compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Present Address §

Department of Organic Chemistry I, Universidad Complutense de Madrid, 28040 Madrid, Spain. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding

E.B. received funding from the European Commission by a Marie Curie Actions-Intra-European Fellowship (IEF) in the project “BIOCASCADE” (FP7-PEOPLE-2011-IEF). N.R. and W.K. were supported by the Austrian BMWFJ, BMVIT, SFG, Standortagentur Tirol and ZIT, through the Austrian FFGCOMET-Funding Program. COST Action CM1303 “Systems Biocatalysis” is acknowledged. Notes

The authors declare no competing financial interest.

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REFERENCES

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