Biocatalytic Route to Chiral 2-Substituted-1,2,3,4

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Biocatalytic Route to Chiral 2-Substituted-1, 2, 3, 4tetrahydroquinolines Using Cyclohexylamine Oxidase Muteins Peiyuan Yao, Peiqian Cong, Rui Gong, Jinlong Li, Guangyue Li, Jie Ren, Jinhui Feng, Jianping Lin, Peter Lau, Qiaqing Wu, and Dunming Zhu ACS Catal., Just Accepted Manuscript • Publication Date (Web): 11 Jan 2018 Downloaded from http://pubs.acs.org on January 11, 2018

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Biocatalytic Route to Chiral 2-Substituted-1, 2, 3, 4tetrahydroquinolines Using Cyclohexylamine Oxidase Muteins Peiyuan Yao,1,‡ Peiqian Cong,1,2,‡ Rui Gong,1,2,‡ Jinlong Li,1 Guangyue Li,1 Jie Ren,1 Jinhui Feng,1 Jianping Lin,1 Peter C. K. Lau,1,* Qiaqing Wu,1,* and Dunming Zhu1,*

1

National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research

Center of Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 Xi Qi Dao, Tianjin Airport Economic Area, Tianjin 300308, PR China.

2

University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District,

Beijing 100049, PR China *Email: [email protected], [email protected], [email protected]

ABSTRACT

Chiral 2-substituted-1, 2, 3, 4-tetrahydroquinolines (2-substituted-THQs) can serve as invaluable building blocks for certain pharmaceutical agents. This study was conducted to expand the biocatalytic repertoire of a bacterial cyclohexylamine oxidase (CHAO) to include rare access to some key enantiomers. Principal results of this work are the generation of six key 2-substituted-

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THQs derivatives with high ee values (up to 99%) and isolated yield in the range of 58% - 92%. Synthesis of these compounds was made possible by derived muteins of CHAO by directed evolution and in combination with the Turner-deracemization strategy. Interestingly, the L225A mutein for 2-isopropyl-THQ and 2-cyclopropyl-THQ reversed the enantiopreference relative to other muteins. Four structural models were built for variant L225A and Q233A rendering (R)cyclopropyl-THQ and (S)-cyclopropyl-THQ and computational results provided support for the experimentally observed stereoselectivity.

KEYWORDS: amine oxidase, 2-substituted-1, 2, 3, 4-tetrahydroquinoline, biocatalysis, chiral amine, directed evolution, deracemization, chemical building blocks

INTRODUCTION

The 1, 2, 3, 4-tetrahydroquinoline (THQ) nucleus has been described as a “privileged” scaffold or substructure in many biologically active natural products and therapeutic agents. Optically active 2-substituted-THQs and derivatives represent one of the most important heterocyclic compounds, and they exist widely in natural products, pharmacologically relevant therapeutic agents and act as chiral ligands.1,2 Numerous methods for the synthesis of these compounds have been studied. Asymmetric ring-construction reactions were used for the synthesis of polysubstituted THQ and 2-aryl THQ with high enantioselectivity, but low enantioselectivity was observed with 2-alkyl THQ.3-7 Various transition metal complexes, such as iridium,8-10 ruthenium,11-13 rhodium,14 and palladium15 have been reported to catalyze the asymmetric


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transfer hydrogenation of quinoline derivatives in high ee values and yields. However, harsh conditions such as high pressure and flammable hydrogen were used. To avoid using hydrogen, chiral phosphoric acids catalyst system was developed for asymmetric transfer hydrogenation of 2-aryl quinoline in high ee values and yields, but the enantioselectivity toward 2-alkyl quinoline was less than 66% ee.16-17

By virtue of mild reaction conditions, non-toxicity, and the recyclable nature of the enzymes, biocatalysis deserves special attention. But biocatalytic methods for the synthesis of chiral 2substituted-THQ derivatives are limited. Recently, Chen and coworkers reported whole cells of Pseudomonas monteilii ZMU-T01 that mediated the oxidative resolution of various racemic 2substituted-THQs. Although the enantiomeric excess (ee) was >99%, the maximum theoretical yield of this method was only up to 50%.18

Turner et al. reported a strategy to prepare enantiomerically pure primary, secondary and tertiary amines by employing engineered entities of monoamine oxidase from Aspergillus niger (MAO-N) in combination with a nonselective chemical reducing agent or imine reductases.19-25 In this context, deracemization of 2-methyl-THQ (1) to (R)-2-methyl-THQ ((R)-1) (Scheme 1) resulting in 98% ee and 76% yield had been achieved in our laboratory using a mutein (T198F/L199S/M226F) of cyclohexylamine oxidase (CHAO) of Brevibacterium oxydans IH35A origin.26 However, the enzyme activity towards large steric 2-substituted-THQs was relatively low (Scheme 1).


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N H 1

N H

N H

2

3

N H

N H

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N H 4

N H

N H

Cl 5

6

N H OMe

7

9

OMe

N H

N H

8

O

N H

O

OMe 10

11

12

Scheme 1. 2-Substituted-THQs used in this study.

Herein, we expand the biocatalytic repertoire of CHAO by creating a new library of diverse mutants and assayed towards various 2-substituted-THQs (Scheme 1). The mutants which showed obvious enhanced activity were selected for kinetic resolution to identify their enantioselectivity in search of effective biocatalysts to access potential building blocks for alkaloid synthesis.

RESULTS AND DISCUSSION

According to the crystal structure of CHAO-FAD-Cyclohexanone (PDB ID: 4I59), 27 13 amino acid residues (F88, T198, L199, L225, M226, Q233, Y321, F351, L353, I366, F368, P422, and Y459) located within a distance of 6Å of the product cyclohexanone were selected and mutated to amino acids with different properties to create a library of 71 designed mutants, of which 34 are presented in Table S1 in the Supporting Information. All the genetic variants were produced


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as soluble proteins with the expected molecular mass (50 kDa) in the recombinant host Escherichia coli at 25 °C (see Figure S1 in the Supporting Information). Equal amount of the wild type CHAO (wt CHAO) or the respective muteins were assayed against 10 selected substrates with the exception of compound 1 and 11 in Scheme 1. We were particularly interested in (S)-5, (R)-11 and (R)-12 since no enzymatic method has been reported to prepare these compounds which are key intermediates for the preparation of naturally occurring alkaloids (+)-angustureine, (+)-cuspareine, and (+)-galipinine.28-30

The wt CHAO had no or trace activity toward all the selected substrates except 4 which showed 3.6% activity relative to (S)-1-phenylethanamine (Figure S2 in the Supporting Information, first panel in graphs A - M ). With the exception of F88Y, almost all mutants of F88, Y321, L353, I366, F368, and P422 also exhibited low activity toward the selected substrates but substrate 4 although only 1.2 fold higher than that of the wt CHAO. On the other hand, nine of the mutants (T198F, L199F, L199Y, L225A, L225I, M226F, Q233A, F351Y, and Y459T) had an obvious enhanced activity toward most of the substrates except compounds 7, 8, and 9, the latter of which both the wt CHAO and its muteins had no activities.

Thus, we proceeded to investigate the enantioselectivity of the beneficial mutants (T198F, L199F, L199Y, L225A, L225I, M226F, Q233A, F351Y, and Y459T) in the oxidation of racemic 2-substituted-THQs. Whole cells expressing the enzyme were incubated with the substrates for 2 hours in the absence of a reducing agent, and the ee of the remaining substrate were determined


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by HPLC analysis. As shown in Figure 1, almost all mutants had the same enantiopreference toward the selected 2-substituted-THQs except mutant L225A which showed opposite enantiopreference toward substrates 1, 2, 3 and 12. This is a significant result, because thus far 2substituted-THQs could be obtained only as one enantiomer, as shown by catalysis using the previously evolved CHAO variants26 or Pseudomonas monteilii ZMU-T01 strains,18 while the enantiocomplementarity of CHAO toward 2-substituted-THQs was achieved by inverting the enantiopreference of the enzyme through a single residue mutation. Regarding the enantiocomplementarity of amine oxidases, the monoamine oxidase MAO-N and mutants from Aspergillus niger were shown to be highly S-selective as reported by Turner et al. Recently, they reported an enantiocomplementary R-selective amine oxidase engineered from 6-hydroxy-Dnicotine oxidase (6-HDNO).25, 31 Another R-stereoselective amine oxidase had been obtained by molecular evolution from a D-amino acid oxidase.32 The substrate profiles of these two enzymes were expanded without inverting their enantiopreference. Similarly, the substrate range of MAON was extended to access (S)-1, 2, 3, 4-tetrahydro-1-substituted-isoquinolines and reversal of enantiopreference was observed for 1-aminotetraline with 94% and 11% ee for R- and Senantiomer, respectively, and the mutants have 3 or 5 mutated residues.33

The wt CHAO and some mutants that showed higher activity were expressed in Escherichia coli BL21 (DE3) at 25 °C and purified to near homogeneity in one chromatographic step using a DEAE FF crude column (see Figure S3 in the Supporting Information). Their kinetic parameters


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were also obtained by measuring the initial velocities of the enzymatic reaction and curve-fitting according to the Michaelis−Menten equation using GraphPad Prism 5 software (see Table S3 in the Supporting Information). In the majority of cases, mutein L225A displayed the highest catalytic efficiency toward the indicated substrates followed by mutein Y459T. Despite the relatively poor kinetics of muteins L225A and Q233A toward substrate 3, the product yield in subsequent chemosynthesis was not impacted (Tables 1 and S3).

Figure 1. Results of kinetic resolution by using CHAO and mutants against various 2substituted-THQs. The negative numbers refer to the (R)-1 and the same enantiopreference. 1(■), 2(●), 3(▲), 4(▼), 5(□), 6(○), 10(◇), 11(★), 12(×).


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In order to shed light on possible reasons for reversed stereoselectivity of L225A mutation, two structural models were built for variant L225A harboring (R)-3 and (S)-3, respectively, using the Schrodinger program (Supporting Information). Based on the previously proposed and generally accepted mechanism,

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docking conformations were selected. A distance constraint (2.5 Å, 50

kcal/mol) between the coordinating N-atom of FAD and the H-atom of the stereogenic C-atom in the two enantiomers was applied in the first 5 ns of molecular dynamics (MD), thereby simulating the induced-fit process of substrate binding. This corresponds to a pose close to the transition state. The molecular mechanics generalized Born surface area (MM-GBSA) method implemented in AMBER16 was used to calculate binding free energies of the L225A-complexes of (R)-3 and (S)-3. The decomposed binding free energies shows that the binding free energy between (R)-3 and (S)-3 with FAD were -1.01 kcal/mol and -3.35 kcal/mol, respectively. With the aim of exploring the conformational changes at the catalytic active site, the entire systems were equilibrated without any constraints by MD for 50 ns at 300 K after 5 ns constrained MD simulations. The MD trajectory was aligned and clustered into three clusters for each system based on the backbone atoms of variant L225A complex to identify the most representative conformations of the sampled phase space. The representative structures of catalytic domain from three highly clustered conformations of MD simulation trajectory are shown in Figure 2 and Figure S4 in the Supporting Information. The results of the simulations showed that in the L225A (S)-3 complex, the interatomic distance between the N-atom of FAD and the H-atom of the stereogenic carbon in (S)-3 is constant at a distance of ~2.5 Å (Figure 2A), a feature which


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supports catalysis. We did not find the similar phenomenon in the L225A (R)-3 complex (Figure 2B (2.9 Å), Figure S4C (3.2 Å), Figure S4D (3.5 Å)). Other L225A (S)-3 complex clusters are characterized by long distances as shown in Figure S4A (3.7 Å) and Figure S4B (5.0 Å). In addition, it is notable that the computed binding energy of FAD with (S)-3 is approximately 2.34 kcal/mol smaller than the FAD with (R)-3. It makes (S)-3 more approachable to FAD. This is possibly the reason why (S)-3 had a more frequency close to FAD (~2.5 Å). Moreover, all the interatomic distance between the N-atom of FAD and the H-atom of the stereogenic carbon in substrate 3 is less than or equal to 2.5 Å, calculated in the last 50 ns of MD trajectory. And this distance occurs almost 40 times more frequently for (S)-3 than for (R)-3.

We also applied the MD and analysis to mutein Q233A complexes with (S)-3 and (R)-3 to see how L225A and Q233A exhibited different enantiopreferences toward substrate 3. Representative structures of the catalytic domain from three highly clustered conformations of MD simulation trajectory are shown in Figure 2 and Figure S4 in the Supporting Information. The results of the simulations showed that in the Q233A (R)-3 complex, the interatomic distance between the N-atom of FAD and the H-atom of the stereogenic carbon in (R)-3 is constant at a distance of ~2.5 Å (Figure 2C). We did not find an equivalent phenomenon in the Q233A (S)-3 complex [Figure 2D (3.0 Å), Figure S4G (5.2 Å), Figure S4F (5.9 Å)]. Other Q233A (R)-3 complex clusters are characterized by long distances as shown in Figure S4E (2.9 Å) and Figure S4F (3.6 Å). Likewise, all the interatomic distance between the N-atom of FAD and the H-atom


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of the stereogenic carbon in substrate-3 is less than or equal to 2.5 Å, calculated in the last 50 ns of MD trajectory. And this distance occurs almost 10 times more frequently for (R)-3 than for (S)-3 in the Q233A system. The distance between FAD and substrate of less than or equal to 2.5 Å constitutes the active conformation for catalysis. As such, the computational results are in line with the experimentally observed stereoselectivity.

Figure 2. Representative conformations of three clusters in MD simulations. (A) and (C) Catalytically active conformations of L225A-(S)-3 and Q233A-(R)-3. (B) and (D) Conformations of L225A-(R)-3 and Q233A-(S)-3 which severely restrict catalytic activity, there are no representative catalytically active conformations of L225A-(R)-3 and Q233A-(S)-3.


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We then applied the Turner-deracemization protocol19, 20, 22, 24, 35-37 to racemic 2-substitutedTHQs by using E. coli whole cells of CHAO mutants that showed good activity. Biotransformations were carried out at 5 mM concentration in 50 mM sodium phosphate buffer (pH = 6.5) using the nonselective chemical reducing agent (NH3.BH3). The results shown in Table 1 demonstrated that compounds 2, 3, 4, 5, 10, and 11 can be deracemized using L225A, Q233A or Y459T variants, providing the optically enriched products in good to excellent ee, and comparable to high isolated yields. Mutant L225A was also applied to deracemization reactions of 1 and 6, but the ee values were only 28% and 50%, respectively indicating low enantioselectivity.

Table 1. Chemoenzymatic Synthesis of 2-Substituted-THQs employing CHAO mutantsa Substrate

Mutant

ee (%)b

Yield(%)c

2

L225A

97.2(R)

80.0

2

Q233A

95.6(S)

89.0

3

L225A

91.3(R)

79.8

3

Q233A

>99.0 (S)

92.4

4

L225A

93.8(R)

57.7

5

L225A

>99.0 (S)

78.7

10

L225A

98.8(R)

74.4

11

Y459T

94.2(R)

90.8


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a

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Reaction conditions: 2 mL substrate in DMSO (250 mM, 5 mM of final concentration), 50

mg/ mL wet cells of CHAO mutant, 40 mM borane–ammonia complex, 98 mL sodium phosphate buffer (50 mmol/L, pH 6.5), 30 oC, 200 rpm, 24 h. bee value was determined by Chiral HPLC analysis, cisolated yield.

CONCLUSIONS

In summary, the scope of chemo-enzymatic deracemization by combining muteins of CHAO and ammonia-borane has been extended to large steric 2-substituted-THQs, thereby establishing an alternative biocatalytic route to the synthesis of this important class of compounds. Significantly, the complementary enantiomeric 2-isopropyl-THQ and 2-cyclopropyl-THQ were obtained in high ee values and isolated yields, via the chemo-enzymatic deracemization catalyzed by L225A and Q233A, respectively. It is worthy to note that highly effective asymmetric transfer hydrogenation of 2-alkyl THQ is still a great challenge for metal and organic catalysis. The enantiocomplementarity of CHAO toward 2-substituted-THQs is achieved through various mutants and the MD studies shed some insight into the mechanism of enantioselectivity. Further protein engineering of CHAO is underway in our laboratory to access the enantiocomplementary mutants of the enzyme toward other amines, and to further extend its application in chiral amine synthesis.

ASSOCIATED CONTENT


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Supporting Information

The experimental details, list of mutants and their substrate specificities, kinetic data of selected mutants, primers used for site mutagenesis, preparation of whole cells for kinetic resolution of 2substituted-THQs, and the HPLC spectra of the reaction mixtures. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*Fax: +86 22 84861996. E-mail: [email protected] (D. Zhu).

*Fax: +86 22 24828703. E-mail: [email protected] (Q. Wu).

*Fax: +86 22 24828703. E-mail: [email protected] (P. C. K. Lau)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally.

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT


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This work was financially supported by Youth Innovation Promotion Association of the Chinese Academy of Sciences (Grant No. 2016166) and the National Natural Science Foundation of China (Grant No. 21302215). Support by Tianjin “Thousand Talents” Program for Senior International Scientists to P.C.K. Lau is gratefully acknowledged.

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Biocatalytic Route to Chiral 2-Substituted-1,2,3,4

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