Chemoenzymatic Dynamic Kinetic Resolution of Amines in Fully

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Chemoenzymatic Dynamic Kinetic Resolution of Amines in Fully Continuous-Flow Mode Emese Farkas,† Maŕ k Olah́ ,† Attila Földi,† Jań os Kot́ i,‡ Jań os É les,‡ Joź sef Nagy,† Cristian Andrei Gal,§ Csaba Paizs,§ Gab́ or Hornyań szky,*,†,∥ and Laś zló Poppe*,†,§,∥

Org. Lett. Downloaded from pubs.acs.org by UNIV OF OTAGO on 12/13/18. For personal use only.

†

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Mű egyetem rkp. 3, H-1111 Budapest, Hungary ‡ Gedeon Richter Plc., P.O. Box 27, H-1475 Budapest, Hungary § Biocatalysis and Biotransformation Research Centre, Faculty of Chemistry and Chemical Engineering, Babeş-Bolyai University of Cluj-Napoca, Arany János str. 11, RO-400028 Cluj-Napoca, Romania ∥ SynBiocat LLC., Szilasliget u. 3, H-1172 Budapest, Hungary S Supporting Information *

ABSTRACT: In this study, lipase-mediated dynamic kinetic resolution (DKR) of various benzylic amines (1a−g) is presented which is realized in a so far unprecedented fully continuous-flow system. The DKR process applying sol−gel immobilized lipase B from Candida antarctica as biocatalyst, palladium on 3-aminopropyl-functionalized silica as racemization catalyst, isopropyl 2ethoxyacetate as acylating agent, ammonium formate as hydrogen and nitrogen sources, and 2-methyl-2-butanol as solvent under regulated pressure provided the desired products in moderate to good yields with excellent enantiomeric excesses.

E

usually immobilized to enable their recovery and to enhance their stability.6 The racemization process, in turn, is often catalyzed by homogeneous catalystssuch as transition metal−ligand complexes (Ru, Ir)which can be cumbersome to recover.7 The first chemoenzymatic DKR of an amine utilized a lipase and Pd on charcoal.8 Although this process has been followed by numerous further examples,9 improvement of DKR processes of amines is still a hot field of interest as exemplified by the efforts toward continuously operated implementation.7d,10 Generally, racemization of amines is more difficult than that of alcohols and requires harsher conditions.2b,d,11 Purification of the product from a DKR process could be simplified by using heterogenized racemization catalyst (e.g., Pd, Ni, Co).12 The studies on effectivity of racemization revealed that acid−base properties of catalyst support significantly influenced the process, and supports of basic character were more beneficial than the acidic ones.2c,10,11 Furthermore, heterogeneous catalysts to be used under

nantiopure amines and their derivatives are important ingredients of natural and industrial products.1 In the enantiomer or enantiotope selective step of the synthesis of enantiopure compounds, chiral catalysts2 or enzymes (foremost lipases)3 are often used. Catalytic processes avoiding stoichiometric components result in higher productivity and in lower level of byproducts related to the chiral component. When the key step in a catalytic procedure is enantiomer selectivee.g., the enzymatic step in kinetic resolution (KR)a major drawback of the process starting from a racemate is the maximal 50% yield of the desired enantiomeric product.4 A dynamic kinetic resolution (DKR) process combining the enantiomer selective step with an in situ racemization of the nonreacting enantiomer overcomes this limitation and enables a yield from a racemate close to 100%.5 Various solutions such as changing the enantiopreference of the KR step or application of enantiodivergent synthetic strategies from the DKR product to the target compound can be applied if the opposite enantiomeric form of the target compound is required.5c The enantiomer selective KR step of a chemoenzymatic DKR process is catalyzed by enzymes which are © XXXX American Chemical Society

Received: November 17, 2018

A

DOI: 10.1021/acs.orglett.8b03676 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. Substrates Tested for Racemization and DKR in Fully Continuous Mode

reactors were applied.17 Such systems, enabling enzymatic reactions and racemization at significantly different temperatures, however, suffered from unit-number-dependent limitations in conversion.17 Based on these considerations, the key for development of a fully continuous-flow DKR process of an amine without conversion limitations is to find an optimal combination of an enzymatic process (usually requiring relatively mild conditions) and a suitable racemization process (usually needing elevated temperature).7g,13c A racemization process suitable for a DKR should be sufficiently active and selective in the temperature range enabled by the thermal stability of the enzyme. Furthermore, due to the homogeneity requirement of a fully continuous-flow DKR, the limited solubility of the extra hydrogen and ammonia source in organic solvents should be remedied. After having found that the solubility of ammonium formate in 2-methyl-2-butanol (tert-amyl alcohol)being also compatible with enzymatic reactionwas suitably high, racemization and further DKR experiments with various amines were performed in this solvent (Scheme 1). In addition to the commercially available 10% Pd/C, six further heterogeneous palladium catalysts were prepared and studied as racemization catalysts [Pd/BaSO4, Pd/BaCO3,10,18 Pd/Al(O)OH;13c,19 Pd/AMP-D, Pd/AEAP-D, and Pd/AMPKG on in-house prepared 3-aminopropyl- and 3-(2aminoethylamino)propyl-modified silica20 carriers (for further details, see SI)]. For the racemization tests in continuous-flow mode, the above seven heterogeneous Pd catalysts were packed into stainless steel columns.

continuous-flow conditions in packed-bed systems should have high mechanical and thermal stability, high surface-to-volume ratio, and suitable particle size. Redox racemization of amines proceeds via an imine intermediate.13 In the metal-catalyzed racemization process, side reactions besides the reduction of the imine may generate byproducts such as further imines, secondary amines, hydrocarbons, and ketones.13 Such undesired side reactions can be suppressed by additional hydrogen and ammonia sources.11 Ammonium formate has proven to be a suitable, green, and easy-to-handle hydrogen and ammonia source in reactions involving imine reduction (DKR, reductive amination).14 However, its poor solubility in solvents commonly used for DKR of amines enabled only semicontinuously operated DKR so far, which included a fully continuous-flow enzymecatalyzed step combined with a semicontinuous racemization step requiring filtration.14b Since amines are stronger nucleophiles than secondary alcohols,12 minimization of the competition between enzymatic and chemical acylation in the KR step is an additional challenge. Selection of an acylating agent with a proper, slightly activated acid moiety15,16 could be a solution to avoid undesired nonselective chemical acylation parallel to the selective biocatalytic N-acylation. Due to the enhanced rate of enzymatic reaction and the lowered rate of nonselective chemical acylation, isopropyl 2-ethoxyacetate was found to be a suitable acylating agent for KR of amines.3i To avoid compatibility issues between the different temperature requirements of the enzymatic KR and the racemization process in fully continuous-flow operated systems, systems comprising an alternating sequence of serially connected B

DOI: 10.1021/acs.orglett.8b03676 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters In the first series of racemization experiments, microreactors were packed with various Pd catalysts, and a solution of (S)-1phenylethylamine (S)-1a containing ammonium formate (1.2 equiv) as hydrogen source was pumped through the microreactor at elevated temperatures (60, 90, and 120 °C). In all cases, enantiomeric composition of 1a [ee(S)‑1a] and selectivity (sel(R,S)‑1a) were determined from the effluents. At 120 °C the Pd catalysts converted (S)-1a mostly to byproducts (sel(R,S)‑1 < 5%). At 90 °C appropriate degree of racemization was achieved (Table S3: ee(S)‑1a < 15%) but only with moderate selectivity (sel(R,S)‑1a = 2−74%). Because only temperatures below 70 °C were found to be compatible with the long-term thermostability of immobilized Candida antarctica (CaLB),21 the most detailed racemization studies were performed at 60 °C (Table 1, entries 1−7).

AMP-KG is proven to be the most appropriate racemization catalyst at 60 °C (ee(S)‑1a = 2%) with good selectivity (sel(R,S)‑1a = 94%; Table 1, entry 7). Next, the mixture of a robust sol−gel immobilized form of lipase B from Candida antarctica (CaLB-TDP10)21 and the most promising Pd/AMP-KG in a mixed-bed reactor (column B) was tested, in order to test the compatibility of the racemization with the biocatalyst. In this set of experiments, the racemization of (S)-1a and two nonbenzylic amines (S)-1h and (S)-1i were tested. The tests revealed smooth and efficient racemization of benzylic amine (S)-1a with Pd/AMP-KG even in the presence of CaLB-TDP10 (ee(S)‑1a = 3% with sel(R,S)‑1a = 95%: entry 8 in Table 1), while the nonbenzylic amines could not be racemized at all (ee(S)‑1 ≥ 99%: entries 9 and 10 in Table 1). Because Pd catalysts could mediate reductive amination of nonbenzylic amines with the aid of ammonium formate at even 40 °C,22 hindered oxidation may be the reason for noneffective racemization of nonbenzylic amines. To address all issues aroused during the preliminary experiments for continuous-flow DKR of 1-phenylethaneamine rac-1a (see Section 3.5.6 in SI), the following key elements were applied in our final DKR system [n = 1 or 2 in Scheme 1, panel b)]: (i) isopropyl 2-ethoxyacetate 3 was selected as an efficient amine acylating agent3i in the enzyme-catalyzed step; (ii) a KR column (column A, filled only with CaLB-TDP-10) was introduced to minimize the amount of forming 2ethoxyacetamide 4; (iii) Pd/AMP-KG was used (as the most efficient racemization catalyst); (iv) 2-methyl-2-butanol was replaced with a 2-methyl-2-butanol/toluene 1:1 (v/v) mixture (to enhance the solubility of the more hydrophilic amines rac1c−e in solution A); (v) back pressure was applied at the outlet of column B; (vi) the Pd/AMP-KG in column B was preactivated by a flow of ammonium formate solution (30 min). In this system, the KR column (column A: CaLB-TDP-10) was fed with solution A of rac-1a and 3, and the outlet stream containing almost equimolar amounts of the amide (R)-2a and the unreacted amine (S)-1a was unified with solution B (ammonium formate in dry 2-methyl-2-butanol) in a three-way valve and fed to a mixed-bed column (column B: Pd/AMP-KG + CaLB-TDP10). After investigating the effect of imidazolium formate as hydrogen source (Table S4) and equivalency of ammonium formate on DKR of rac-1a (Table S5), the most efficient setup for DKR of rac-1a (temperature: 60 °C; flow rate: 5 μL min−1 in all pumps, 0.6 equiv of ammonium formate) provided amide

Table 1. Racemization Results for (S)-1a, (S)-1h, and (S)-1i by Supported Pd Catalysts in Packed-Bed Continuous-Flow Reactor Using Ammonium Formate As the Hydrogen Sourcea entry

amine

catalystb

ee(S)‑1 (%)c

sel(R,S)‑1 (%)c,d

1 2 3 4 5 6 7 8 9 10

(S)-1a (S)-1a (S)-1a (S)-1a (S)-1a (S)-1a (S)-1a (S)-1a (S)-1h (S)-1i

10% Pd/C Pd/AlO(OH) Pd/AEAP-D Pd/BaCO3 Pd/BaSO4 Pd/AMP-D Pd/AMP-KG Pd/AMP-KGe Pd/AMP-KGe Pd/AMP-KGe

>99 57 36 6 1 5 2 3 99 99

13 99 95 66 68 90 94 95 93 90

a Entries 1−7: (S)-1a (69 mM), ammonium formate (1.0 equiv, 69 mM) in dry 2-methyl-2-butanol at 60 °C with 20 μL min−1 flow rate. Entries 8−10: (S)-amine [(S)-1a, (S)-1h, or (S)-1i (69 mM)], ammonium formate (1.2 equiv, 83 mM) in dry 2-methyl-2-butanol at 60 °C with 10 μL min−1 flow rate. bSee in SI the Sections 3.1 and 3.2 for catalysts and Section 3.5.3 on filling weights. cDetermined by GC (see SI). dsel(R,S)‑1= amount of (R,S)-1/amount of detectable compounds in reaction mixture × 100 (%). eEntries 8−10: see Section 3.5.4.2 for filling weight of catalyst and experimental details.

At 60 °C, 10% Pd/C converted (S)-1a mostly to byproducts (sel(R,S)‑1a= 13%) without racemization (ee(S)‑1a > 99%; Table 1, entry 1), while various degrees of racemization (ee(S)‑1a= 1− 57%) and selectivity (sel(R,S)‑1a = 66−99%) could be achieved with six other Pd catalysts (Table 1, entries 2−7). Overall, Pd/

Table 2. Chemoenzymatic DKR of Seven Benzylic Amines and rac-1a−g in Fully Continuous-Flow Modea entrya 1 2 3 4 5 6 7

amine rac-1a rac-1b rac-1c rac-1d rac-1e rac-1f rac-1g

n (−) 1 1 2 1 2 1 0e

T (°C) 60 60 60 60 60 60 70

P (psi)

ee(S)‑1a−f (%)b

ee(R)‑2a−f (%)b

conv. (%)b

yield (%)

30 30 30 30 30 30 100

c

99.9 99.5 98.9 99.3 99.2 99.9 99.1(99.3)g

>99 61.9 63.5 96.7 65.0 72.0 63(75)h

96 60 60 86 57d 67 n.i.i

n.d. 92.0 63.3 8.3 74.4 9.7 98(59)f

Entries 1−6: Solution A: rac-1a−f (138 mM) and 3 (2 equiv, 138 mM) in dry 2-methyl-2-butanol/toluene 1:1 (v/v) at 5 μL min−1. Solution B: ammonium formate (0.6 equiv) in 2-methyl-2-butanol at 5 μL min−1. bDetermined by GC (for details, see SI). cNot detected. d4-Ethyl-1,1′byphenyl was isolated as byproduct. eEntry 7 (n = 0): no column A, rac-1g (138 mM), 3 (2 equiv, 138 mM), and ammonium formate (0.6 equiv) in dry 2-methyl-2-butanol were fed directly to column B at 10 μL min−1. fee(S)‑1g (the value of ee(S)-1a is between parentheses). gee(S)‑2g (the value of ee(S)-2a is between parentheses). hc(S)‑2g (conversion to (S)-2g + (S)-2a is between parentheses). in.i.: not isolated. a

C

DOI: 10.1021/acs.orglett.8b03676 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters (R)-2a in high isolated yield (96%) with excellent enantiomeric excess (>99%) (Table 2, entry 1). Next, in addition to the continuous-flow DKR with rac-1a, this system was investigated with several further benzylic amines having different electronic and steric properties to evaluate the functional group tolerance of the process (Scheme 1). The most apparent limitation of this type of DKR process was the presence of functional groups reducible by transfer hydrogenation with the racemization catalyst. Preliminary experiments with 4-chloro-, 4-bromo-, and 4-nitro-substituted phenylethan-1-amines revealed reduction of such groups under the racemization conditions, rendering such compounds to be incompatible with this type of DKR process. Afterward, the DKR process was studied with a set of six further valuable benzylic amines rac-1b−g. The KR process with amines rac-1a−f revealed nearly 50% conversions with a single CaLB-TDP10-filled column (n = 1 for column A in Scheme 1), but in the case of bulkier amines rac-1c and rac-1e the single KR column provided unsatisfactory conversions (n = 1:34% from rac-1c and 25% from rac-1e). Thus, to achieve near to 50% conversion in the KR part (column A) of the DKR systems for transformation of rac-1c and rac-1e, a two KR column system was applied (n = 2, column A in Scheme 1). The efficiency of racemization could be concluded from the enantiomeric composition of the residual amine (ee(S)‑1a−g). Quite efficient racemization happened in the DKR of rac-1a (no 1a remained, Table 2, entry 1), of rac-1d (ee(S)‑1d = 8.3%, Table 2, entry 4), and of rac-1f (ee(S)‑1f = 9.7%, Table 2, entry 6). Accordingly, good to excellent conversions and yields could be achieved by the DKR from these substrates (Table 2, entries 1, 4, and 5). The slightly enhanced positive inductive effect of the ethyl group attached to the benzylic position (rac1f) did not prevent racemization. The lower conversion of DKR from rac-1f was due to the decreased rate of the enzymic KR from this substrate as compared to the KR from rac-1a. Expectedly, in the case of amines with electron-donating substituents, such as rac-1c with 3,4-methoxy substituents or rac-1e with 4-phenyl substituent, the racemization was not quite efficient (ee(S)‑1c = 63.3% and ee(S)‑1e = 74.4%; Table 2, entries 3 and 5). Unexpectedly, the 4-fluoro substituent in rac1b had significant negative impact on racemization (ee(S)‑1b = 92.0%, Table 2, entry 2). Due to the lowered efficiency of racemization, only moderate isolated yields (57−60%) but excellent enantiomeric purities (ee ≥ 98.9%) could be achieved in the DKRs from rac-1b,c,e. DKR of rac-1g showed that a fluorine even at aliphatic position was partially reducible by the racemization catalyst under the DKR process conditions (0.6 equiv of HCOO−NH4+, 100 psi, 70 °C: Table 2, entry 7). Enantiomeric purities of the fluorine-containing product (R)-2g and of the dehalogenated byproduct (R)-2a were excellent (ee(S)‑1g and ee(S)‑1g > 99%), but the enantiomeric composition of the residual halogenated substrate (ee(S)‑1g = 59%) indicated moderate efficiency of racemization of (S)-1g. The robustness of a catalytic system under continuous-flow conditions can be characterized by its operation stability. Therefore, the DKR system of rac-1a to (R)-2a was operated and monitored at 60 °C for 48 h, revealing excellent operational stability (Figure 1). The system was stable for at least 2 days, producing enantiopure (R)-2a (ee(S)‑1a > 99.8%) with a space time yield of 103 kg m−3 day−1.

Figure 1. Operational stability of the continuously operated Pd/ AMP-KG−CaLB-TDP10 DKR system converting 1-phenylethan-1amine rac-1a [GC conversion (●: dark red) is shown for the DKR system operated under conditions of Table 2 for 48 h].

In conclusion, a novel system enabling fully continuous-flow mode DKR of racemic benzylic amines (rac-1a−f) is described for the first time. The DKR system involving a robust lipase (CaLB-TDP10) for kinetic resolution and a mild racemization with palladium on aminopropyl-grafted silica (Pd/AMP-KG) and ammonium formate fully dissolved in 2-methyl-2-butanol as hydrogen source could be operated at moderately high temperature (60−70 °C). Our study revealed that this racemization process was effective for benzylic amines without easily reducible functions. The optimized DKR system comprising a KR unit (1 or 2 packed-bed columns filled with CaLB-TDP10) and a mixed-bed DKR unit (a column filled with Pd/AMP-KG + CaLB-TDP10) could be applied successfully for conversion of six valuable benzylic amines rac1a−f to amides (R)-2a−f in medium to high isolated yields (57−96%) with excellent enantiomeric purity (>98.8%).

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03676. Catalyst synthesis and characterization, experimental procedures for racemization, and DKR (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

*Tel.: +36-1-463-3299. Fax: +36-1-463-3697. E-mail: poppe@ mail.bme.hu. *E-mail: [email protected]. ORCID

László Poppe: 0000-0002-8358-1378 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Thanks to Dr. Diána Balogh-Weiser (BME, Budapest Hungary) for SEM measurements and Prof. Mihály Nógrádi (BME, Budapest, Hungary) for helpful discussions. This work was supported by CELSA (BME-KU Leuven, ConSolid project), by the National Research, Development and Innovation Fund of Hungary (FIEK_16-1-2016-0007), by the Higher Education Excellence Program of the Ministry of D

DOI: 10.1021/acs.orglett.8b03676 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

(9) (a) Parvulescu, A. N.; Jacobs, P. A.; De Vos, D. E. Chem. - Eur. J. 2007, 13, 2034−2043. (b) Andrade, L. H.; Silva, A. V.; Pedrozo, E. C. Tetrahedron Lett. 2009, 50, 4331−4334. (c) Xu, G.; Lan, S.; Fu, S.; Wu, J.; Yang, L. Tetrahedron Lett. 2015, 56, 2714−2719. (d) Gustafson, K. P. J.; Lihammar, R.; Verho, O.; Engström, K.; Bäckvall, J.-E. J. Org. Chem. 2014, 79, 3747−3751. (e) Parvulescu, A. N.; Jacobs, P. A.; De Vos, D. E. Appl. Catal., A 2009, 368, 9−16. (f) Kim, Y.; Park, J.; Kim, M.-J. Tetrahedron Lett. 2010, 51, 5581− 5584. (g) Busto, E.; Gotor-Fernández, V.; Gotor, V. J. Org. Chem. 2012, 77, 4842−4848. (h) Choi, Y. K.; Kim, M. J.; Ahn, Y.; Kim, M.-J. Org. Lett. 2001, 3, 4099−4101. (i) Parvulescu, A. N.; Van der Eycken, E.; Jacobs, P. A.; De Vos, D. E. J. Catal. 2008, 255, 206−212. (j) Ma, G.; Xu, Z.; Zhang, P.; Liu, J.; Hao, X.; Ouyang, J.; Liang, P.; You, S.; Jia, X. Org. Process Res. Dev. 2014, 18, 1169−1174. (k) Engström, K.; Johnston, E. V.; Verho, O.; Gustafson, K. P. J.; Shakeri, M.; Tai, C.W.; Bäckvall, J.-E. Angew. Chem., Int. Ed. 2013, 52, 14006−14010. (l) Han, K.; Kim, Y.; Park, J.; Kim, M.-J. Tetrahedron Lett. 2010, 51, 3536−3537. (10) Miranda, de A. S.; Miranda, L. S. M.; Souza, de R. O. M. A. Biotechnol. Adv. 2015, 33, 372−393. (11) Turner, N. J.; Truppo, M. D. In Chiral Amine Synthesis; Nugent, T. C., Ed.; Wiley-VCH: Weinheim, 2010; pp 431−478. (12) (a) Jiang, C.; Cheng, G. Curr. Org. Chem. 2013, 17, 1225− 1234. (b) Parvulescu, A.; De Vos, D.; Jacobs, P. Chem. Commun. 2005, 5307−5309. (c) Shakeri, M.; Tai, C.; Göthelid, E.; Oscarsson, S.; Bäckvall, J.-E. Chem. - Eur. J. 2011, 17, 13269−13273. (d) Parvulescu, A. N.; Jacobs, P. A.; De Vos, D. E. Adv. Synth. Catal. 2008, 350, 113−121. (e) Geukens, I.; Plessers, E.; Won Seo, J.; De Vos, D. E. Eur. J. Inorg. Chem. 2013, 2013, 2623−2628. (f) Xia, B.; Cheng, G.; Lin, X.; Wu, Q. Eur. J. Org. Chem. 2014, 2014, 2917− 2923. (13) (a) Kim, Y.; Park, J.; Kim, M.-J. ChemCatChem 2011, 3, 271− 277. (b) Lee, J. H.; Han, K.; Kim, M.-J.; Park, J. Eur. J. Org. Chem. 2010, 2010, 999−1015. (c) Kim, M.-J.; Kim, W.-H.; Han, K.; Choi, Y. K.; Park, J. Org. Lett. 2007, 9, 1157−1159. (14) (a) de Miranda, A. S.; de Souza, R. O. M. A.; Miranda, L. S. M. RSC Adv. 2014, 4, 13620−13625. (b) Falus, P.; Boros, Z.; Hornyánszky, G.; Nagy, J.; Darvas, F.; Ü rge, L.; Poppe, L. Tetrahedron Lett. 2011, 52, 1310−1312. (15) Zhang, S.; Baker, J.; Pulay, P. J. Phys. Chem. A 2010, 114, 432− 442. (16) Schmid, A.; Dordick, J. S.; Hauer, B.; Kiener, A.; Wubbolts, M.; Witholt, B. Nature 2001, 409, 258−268. (17) (a) Poppe, L.; Tomin, A.; Boros, Z.; Varga, E.; Ü rge, L.; Darvas, F. Hung. Pat. Appl. HU 2009-720, 2011. (b) Falus, P.; Cerioli, L.; Bajnóczi, G.; Boros, Z.; Weiser, D.; Nagy, J.; Tessaro, D.; Servi, S.; Poppe, L. Adv. Synth. Catal. 2016, 358, 1608−1617. (18) Mozingo, R. Org. Synth. 1946, 26, 77. (19) (a) Kwon, M. S.; Kim, N.; Park, C. M.; Lee, J. S.; Kang, K. Y.; Park, J. Org. Lett. 2005, 7, 1077−1079. (b) Kwon, M. S.; Kim, N.; Seo, S. H.; Park, I. S.; Cheedrala, R. K.; Park, J. Angew. Chem., Int. Ed. 2005, 44, 6913−6915. (20) Boros, Z.; Weiser, D.; Márkus, M.; Abaháziová, E.; Magyar, Á .; Tomin, A.; Koczka, B.; Kovács, P.; Poppe, L. Process Biochem. 2013, 48, 1039−1047. (21) Weiser, D.; Nagy, F.; Bánóczi, G.; Oláh, M.; Farkas, A.; Szilágyi, A.; László, K.; Gellért, Á .; Marosi, Gy.; Kemény, S.; Poppe, L. Green Chem. 2017, 19, 3927−3937. (22) Falus, P.; Boros, Z.; Hornyánszky, G.; Nagy, J.; Darvas, F.; Ü rge, L.; Poppe, L. Tetrahedron Lett. 2011, 52, 1310−1312.

Human Capacities of Hungary (BME FIKP-BIO), and by the Romanian Ministry for European Funds, through the National Authority for Scientific Research and Innovation and cofunded by the European Regional Development Fund (NEMSyB, ID P37_273, Cod MySMIS 103413 POC). E.F. thanks Gedeon Richter Plc. Centennial Foundation for scholarship and support. C.A.G. thanks Collegium Talentum 2018 Programme of Hungary for support.

■

REFERENCES

(1) (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827−10852. (b) Kaschani, F.; van der Hoorn, R. Curr. Opin. Chem. Biol. 2007, 11, 88−98. (c) Turner, N. J. Curr. Opin. Chem. Biol. 2011, 15, 234−240. (d) Wolf, C. Dynamic stereochemistry of chiral compounds: principles and applications; The Royal Society of Chemistry: Cambridge, 2008. (2) (a) Steinreiber, J.; Faber, K.; Griengl, H. Chem. - Eur. J. 2008, 14, 8060−8072. (b) Pellissier, H. Tetrahedron 2011, 67, 3769−3802. (c) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem. Rev. 2008, 252, 647−658. (d) Pellissier, H. Tetrahedron 2008, 64, 1563−1601. (e) Ahmed, M.; Kelly, T.; Ghanem, A. Tetrahedron 2012, 68, 6781− 6802. (3) (a) Kapoor, M.; Gupta, M. N. Process Biochem. 2012, 47, 555− 569. (b) Höhne, M.; Bornscheuer, U. T. ChemCatChem 2009, 1, 42− 51. (c) Gotor-Fernández, V.; Fernández-Torres, P.; Gotor, V. Tetrahedron: Asymmetry 2006, 17, 2558−2564. (d) Guo, J.; Chen, C.-P.; Wang, S.-G.; Huang, X.-J. Enzyme Microb. Technol. 2015, 71, 8−12. (e) Gotor-Fernández, V.; Busto, E.; Gotor, V. Adv. Synth. Catal. 2006, 348, 797−812. (f) Hietanen, A.; Lundell, K.; Kanerva, L. T.; Liljebad, A. Arkivoc 2012, 5, 60−74. (g) Pilissão, C.; Carvalho, P. de O.; Nascimento, M.; da, G. Process Biochem. 2009, 44, 1352−1357. (h) Päivio, M.; Perkiö, P.; Kanerva, L. T. Tetrahedron: Asymmetry 2012, 23, 230−236. (i) Oláh, M.; Boros, Z.; Hornyánszky, G.; Poppe, L. Tetrahedron 2016, 72, 7249−7255. (j) Weiser, D.; Nagy, F.; Bánóczi, G.; Oláh, M.; Farkas, A.; Szilágyi, A.; László, K.; Gellért, Á .; Marosi, Gy.; Kemény, S.; Poppe, L. Green Chem. 2017, 19, 3927− 3937. (4) Faber, K. Biotransformations in organic chemistry, 6th ed.; Springer: Berlin, 2011. (5) (a) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475−1490. (b) Faber, K. Chem. - Eur. J. 2001, 7, 5004−5010. (c) Poppe, L.; Nagy, J.; Hornyánszky, G.; Boros, Z. Stereochemistry and Stereoselective Synthesis − An Introduction; Poppe, L., Nógrádi, M., Eds.; Wiley-VCH Verlag KGaA: Weinheim-New York, 2016. (6) (a) Bornscheuer, U. T. Angew. Chem., Int. Ed. 2003, 42, 3336− 3337. (b) Barbosa, O.; Ortiz, C.; Berenguer-Murcia, Á .; Torres, R.; Rodrigues, R. C.; Fernandez-Lafuente, R. Biotechnol. Adv. 2015, 33, 435−456. (c) Rodrigues, R. C.; Ortiz, C.; Berenguer-Murcia, Á .; Torres, R.; Fernández-Lafuente, R. Chem. Soc. Rev. 2013, 42, 6290− 6307. (d) Tran, D. N.; Balkus, K. J., Jr. ACS Catal. 2011, 1, 956−968. (e) Garcia-Galan, C.; Berenguer-Murcia, Á .; Fernandez-Lafuente, R.; Rodrigues, R. C. Adv. Synth. Catal. 2011, 353, 2885−2904. (7) (a) Pamiès, O.; Ell, A. H.; Samec, J. S. M.; Hermanns, N.; Bäckvall, J.-E. Tetrahedron Lett. 2002, 43, 4699−4702. (b) Paetzold, J.; Bäckvall, J.-E. J. Am. Chem. Soc. 2005, 127, 17620−17621. (c) Leijondahl, K.; Borén, L.; Braun, R.; Bäckvall, J.-E. Org. Lett. 2008, 10, 2027−2030. (d) Veld, M. A. J.; Hult, K.; Palmans, A. R. A.; Meijer, E. W. Eur. J. Org. Chem. 2007, 32, 5416−5421. (e) Mavrynsky, D.; Leino, R. J. Organomet. Chem. 2014, 760, 161−166. (f) Hoben, C. E.; Kanupp, L.; Bäckvall, J.-E. Tetrahedron Lett. 2008, 49, 977−979. (g) Stirling, M.; Blacker, J.; Page, M. I. Tetrahedron Lett. 2007, 48, 1247−1250. (h) Martín-Matute, B.; Bäckvall, J.-E. Curr. Opin. Chem. Biol. 2007, 11, 226−232. (i) Thalén, L. K.; Bäckvall, J.-E. Beilstein J. Org. Chem. 2010, 6, 823−829. (j) Rodríguez-Mata, M.; GotorFernández, V.; González-Sabín, J.; Rebolledo, F.; Gotor, V. Org. Biomol. Chem. 2011, 9, 2274−2278. (8) Reetz, M. T.; Schimossek, K. Chimia 1996, 50, 668−669. E

DOI: 10.1021/acs.orglett.8b03676 Org. Lett. XXXX, XXX, XXX−XXX