Enzyme-catalyzed direct three-component aza-Diels-Alder reaction using lipase from Candida sp. 99-125
Dong-Hang Yin , Wei Liu , Zhi-Xiang Wang , Xin Huang , Jing Zhang , De-Chun Huang
Nitrogen-containing six-numbered heterocycles have attracted great attention due to their widespread biological effects [1]. Azabicyclo[2.2.2]octane derivatives, which are one kind of nitrogen-containing six-numbered heterocycles, have been reported to be several agonists and antagonists of many receptors [2-4]. Meanwhile, it has been reported that azabicyclo [2.2.2] octane derivatives displayed obvious inhibitory effects toward enzymes [5, 6].
Since the first aza-Diels-Alder cycloaddition reaction of imine was reported in 1943 [7], aza-Diels-Alder reaction has been an important contribution to construct Azabicyclo [2.2.2] octane derivatives. Initially, electron-rich dienes, such as Danishefsky?ˉs diene [8] were used in the cycloaddition reaction. In recent years, performed dienes have been substituted with cyclohexanone derivatives. The resulting azabicyclo [2.2.2] octan-5-one derivatives have shown promising activity in the inhibition of AChE activity, as well as the inhibition of amyloid β fibrillogeneis [9]. Generally, the reaction is activated by Lewis and Br?nsted acids and proline derivatives [10, 11]. In recent years, some other catalysts, such as [Emim][Pro] [12] and 1-(2-hydroxynaphthalen-1-yl) naphthalene-2-ol (BINOL) derivatives [13] have been employed in the cycloaddition, producing high efficiency and enantioselectivity. However, these catalysts suffer several disadvantages such as expensiveness, multistep synthesis and lower reusability, especially toxicity to the environment and humans. Thus, it is necessary to explore sustainable, effective and environment-friendly catalysts.
Recently enzymatic promiscuity [14] has been regarded as one of the most outstanding concepts in biocatalysis [15-17]. Despite lower activities toward promiscuous substrates compared with their native activity, the importance of promiscuity concept in biocatalysis is noteworthy, resulting in new insights on the existing enzymes and extensive application of biocatalysts in organic synthesis [18]. For example, lipase from Candida antarctica, whose native activity is lipid hydrolysis, can promote the formation of C-C, C-N and C-S bonds [19]. Moreover, Penicillin G acylase is also capable of Markovnikov addition of allopurinol to vinyl ester [20], apart from accelerating the synthesis of β-lactam antibiotics.
He et al. reported the first example of enzyme-catalyzed direct aza-Diels-Alder reaction in 2012 [21]. The direct three-component aza-Diels-Alder reaction was catalyzed by hen egg white lysozyme. However, no documents concerning direct three-component aza-Diels-Alder reaction catalyzed by lipases has been reported. Among various lipases, lipases from Candida sp. have been widely used in organic synthesis, such as the synthesis of long carbon chain esters and optical resolution of chiral compounds [22, 23]. Lipase from Candida sp. 99-125 established by Tan?ˉs group [24] has been successfully used in the esterification reaction and acylation reaction [25-27]. Herein we wished to report a novel discovery that the readily available lipase from Candida sp. 99-125 efficiently promoted the one-pot, three-component aza-Diels-Alder reaction of aromatic aldehyde, aromatic amine and 2-cyclohexen-1-one (Fig. 1), leading to moderate to excellent yields. In this study, lipase was first used to catalyze direct aza-Diels-Alder reaction although several enzymes have been employed in the aza-Diels-Alder reaction. It may provide a novel case of enzyme promiscuity and a potential synthetic way for nitrogen-containing heterocycles.
All chemicals were purchased from Aladdin Industrial Corporation. Lipase from Candida sp. 99-125 was supplied by Tan?ˉs group in Beijing University of Chemical Technology. 1H NMR spectra were recorded on a Bruker-300 (300 MHz) in CDCl3 solution. Mass spectrometry was recorded on accurate-mass Q-TOF LC/MS (Agilent 6520).
Lipase (150 mg) from Candida sp. 99-125 was added to a 25 mL round-bottom flask containing aromatic aldehyde (1, 4.9 mmol), aromatic amine (2, 7.7 mmol), 2-cyclohexen-1-one (3, 10.3 mmol), MeCN (1.8 mL) and deionized water (0.2 mL). The reaction mixture was stirred at 35?? for certain time. Upon completion, the reaction was terminated by filtering the enzyme. The filtrate was diluted with ethyl acetate and washed with distilled water. The crude product was concentrated under vacuum and purified by preparative chromatography (MeOH/H2O). The endo/exo ratios were determined by HPLC (Agilent 1260 Infinity) equipped with Eclipe XDB-C18 chromatographic column. Mobile phase A was pure water containing 0.1% formic acid; while mobile phase B was methanol. The volume flow rate of mobile A was 0.3 mL/min; while the volume flow rate of mobile B was 0.7 mL/min. The total volume flow rate was 1 mL/min.
3-endo-Phenyl-2-phenyl-2-azabicyclo-[2.2.2] octan-5-one: Colorless solid; 1H NMR (300 MHz, CDCl3): β 7.25-7.31 (m, 5H), 7.14-7.20 (m, 2H), 6.73 (t, 1H, J=7.2), 6.66 (d, 2H, J=8.4), 4.66 (bd, 1H, J=1.8 Hz), 4.54 (s, 1H), 2.79-2.80 (m, 1H), 2.73-2.79 (m, 1H), 2.42-2.49 (m, 1H), 2.23-2.32 (m, 1H), 1.98-2.18 (m, 2H), 1.68-1.78 (m, 1H); 13C NMR (75 MHz, CDCl3): β 129.2, 128.9, 128.3, 128.0, 127.7, 127.5, 127.1, 125.6, 117.8, 117.4, 113.7, 113.3, 77.4, 77.0, 76.6, 65.9, 56.0, 52.2, 48.6, 46.4, 46.0, 41.1, 40.0, 38.0, 29.7, 26.7, 22.7; HRMS (ESI+) calcd. for C19H20NO (M+H+) 278.1539, found 278.1537.
3-exo-Phenyl-2-phenyl-2-azabicyclo-[2.2.2] octan-5-one: Colorless solid; 1H NMR (300 MHz, CDCl3): β 7.31-7.40 (m, 6H), 7.02-7.07 (m, 2H), 6.65-6.70 (m, 1H), 6.55 (d, 1H, J=7.8), 4.61 (d, 1H, J=8.7 Hz), 4.13-4.17 (m, 1H), 3.20-3.27 (m, 1H), 2.76-2.84 (m, 1H), 2.56-2.62 (m, 1H), 2.25-2.46 (m, 2H), 1.81-1.93 (m, 1H), 1.67-1.78 (m, 1H); 13C NMR (75 MHz, CDCl3) β 210.3, 143.2, 128.8, 128.3, 128.0, 127.7, 127.1, 122.2, 117.4, 113.7, 77.4, 77.0, 76.6, 55.9, 46.4, 38.0, 26.7; HRMS (ESI+) calcd. for C19H20NO (M+H+) 278.1539, found 278.1539.
3-endo-(4-Methoxyphenyl)-2-(4-methoxyphenyl)-2-azabicyclo-[2.2.2] octan-5-one: White crystals; 1H NMR (300 MHz, CDCl3): β 7.21 (d, 2H, J=8.5 Hz), 6.84 (d, 2H, J=8.6 Hz), 6.77 (m, 2H), 6.63 (m, 2H), 4.54 (s, 1H), 4.42 (s, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 2.73 (m, 2H), 2.51-2.39 (m, 1H), 2.23 (m, 1H), 2.12 (m, 1H), 2.07-1.93 (m, 1H), 1.79-1.70 (m, 1H).
3-endo-(4-Chlorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo-[2.2.2] octan-5-one: White crystals; 1H NMR (300 MHz, CDCl3): β 7.31-7.24 (m, 4H), 6.79 (m, 2H), 6.62 (m, 2H), 4.57 (s, 1H), 4.44 (s, 1H), 3.74 (s, 3H), 2.74 (m, 2H), 2.55-2.42 (m, 1H), 2.25 (m, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.77 (m, 1H).
3-endo-(3-Chlorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo-[2.2.2] octan-5-one: White crystals; 1H NMR (300 MHz, CDCl3): β 7.29-7.15 (m, 4H), 6.78 (m, 2H), 6.61 (m, 2H), 4.55 (s, 1H), 4.43 (s, 1H), 3.73 (s, 3H), 2.74 (m, 2H), 2.48 (m, 1H), 2.24 (m, 1H), 2.13 (m, 1H), 2.07-1.95 (m, 1H), 1.76 (m, 1H).
3-endo-(2-Chlorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo-[2.2.2] octan-5-one: Yellow oil; 1H NMR (300 MHz, CDCl3) β 7.38 (m, 2H), 7.17 (m, 2H), 6.76 (m, 2H), 6.57 (m, 2H), 4.96 (s, 1H), 4.46 (s, 1H), 3.71 (s, 3H), 2.84 (m, 2H), 2.50 (m, 1H), 2.22 (s, 1H), 2.03 (m, 1H), 1.97 (s, 1H), 1.81 (m, 1H).
3-endo-(4-Methylphenyl)-2-(4-methoxyphenyl)-2-azabicyclo-[2.2.2] octan-5-one: White crystals; 1H NMR (300 MHz, CDCl3): β 7.18 (d, 2H, J=8.1 Hz), 7.11 (d, 2H, J=8.0 Hz), 6.77 (m, 2H), 6.63 (m, 2H), 4.55 (s, 1H), 4.42 (s, 1H), 3.72 (s, 3H), 2.74 (m, 2H), 2.51-2.38 (m, 1H), 2.30 (s, 3H), 2.20 (m, 1H), 2.16-2.07 (m, 1H), 2.08-1.92 (m, 1H), 1.74 (m, 1H).
Generally, enzymes work well at the appropriate temperature. Too low temperature results in low catalytic efficiency, while high temperature may accelerate the inactivation of enzymes. Thus, a temperature screening was performed. The yield increased from 30.2% to 53.2% when the temperature increased from 25?? to 40?? (Table 1). However, with further increase in temperature, the yield decreased. The inactivation of lipase caused by higher temperature might be the main cause. Interestingly, the concentration of endo product decreased gradually when the temperature increased from 25?? to 50??. Based on the results revealed by He et al. [28], higher temperature was favorable for overcoming the energy barrier between raw materials and exo products, which could promote the formation of exo products.
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As described above, appropriate temperature is necessary for the natural fold of lipase. Similarly, pH also plays an important role in stabilizing the natural fold of lipase. Therefore, the effect of pH on the enzyme activity was also investigated. In the optimization process, the deionized water was substituted with phosphate buffer solution (pH from 6.5 to 9.5). As shown in Table 2, the increase in pH resulted in higher yield. On the contrary, when phosphate buffer solution with a pH of 6.5 was used, the yield was only 44.1%. Hence, it can be seen that weak basicity favored the reaction, resulting in a relatively higher yield. Maybe lipase from Candida sp. 99-125 is more stable under weak alkaline environment than acidic conditions. Moreover, pH also had obvious effect on the ratio of endo and exo products. When phosphate buffer solution with a pH of 8.5 was used, the highest yield and selectivity was obtained. Interestingly, the same results were observed when deionized water and phosphate buffer solution (pH 7.0) were used, which demonstrated that ions in the phosphate buffer solution, such as sodium ions and phosphate anions, had no obvious effect on the enzyme activity.
Typically, enzyme activity was likely to be improved obviously by adding some additives into the enzyme solutions. Thus, metal ions and surfactants were employed in the lipase-catalyzed aza-Diels-Alder reaction. The data in Table 3 displayed that addition of Mg2+, Cu2+ and Fe2+ went against the formation of azabicyclo [2.2.2] octan-5-one. On the contrary, Ca2+ promoted the increase of enzyme activity, leading to more products. However, only a slight increase in yield was observed. Thus, no calcium ions were added in the subsequent experiments. Compared with control experiment, the yield obtained in the presence of most surfactants was almost equal to the reaction conducted without surfactants. When sodium dodecyl sulfonate was added into the reaction mixture, a decrease in yield was observed. It might be due to the inactivation of lipase caused by the addition of sodium dodecyl sulfonate. Meanwhile, ethylene diamine tetraacetic acid showed no obvious effect on the yield and selectivity, which demonstrated that lipase from Candida sp. 99-125 was not one kind of metalloenzyme. Considering the fact that no obvious improvement was observed with the addition of metal ions and surfactants, therefore no additives were added into the reaction mixture in the subsequent study.
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In order to obtain enhanced stability, several solvents were employed in the lipase-catalyzed aza-Diels-Alder reaction [29]. As could be seen in Table 4, solvent played a vital role in the synthesis of azabicyclo [2.2.2] octan-5-one. The reaction performed in MeCN gave the yield of 68.7%, while, the reaction in ethyl acetate, toluene and DMSO provided the product in yields 41.9%-53.7%. The other used solvents including DMF and hexane gave lower yields. Moreover, the reaction was also conducted without organic solvents and water, resulting in the product in a yield of 61.8%. Interestingly, higher selectivity was observed when the reaction was conducted in DMF and DMSO. On the contrary, obvious decrease in selectivity was detected with toluene as the solvent. The difference inyield and selectivity in different solvents might be attributed to the specific interactions between the solvent and lipase.
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In order to obtain more products, the molar ratio of substrates was investigated. The detailed results were displayed in Table 5. Initially, more aniline led to higher yield. When the molar ratio was set to 1:3:2, the product was obtained in a yield of 80.8% with 87/12 (endo/exo). Further increase in the dosage of 2-cyclohexen-1-one resulted in more products. When the molar ratio was 1:3:4, the yield reached 89.8%. However, increase in aniline and 2-cyclohexen-1-one did not show any improvement in the selectivity. Hence, the molar ratio (1/2/3=1:3:4) was chosen as the optimal molar ratio for subsequent study on the basis of the results in Table 5.
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The effect of enzyme concentration on the yield and selectivity was also studied. When the enzyme concentration was 50mg/mL, the reaction onlygave a yield of 67.1%. With the increase in enzyme concentration, more products were detected. The enzyme concentration of 100mg/mL led to the best yield of 93.3% (Table 6). However, further increase in enzyme concentration did not promote the reaction, providing a constant yield and selectivity. Therefore, the optimal enzyme concentrationwas set to 100mg/mL in consideration of the effectiveness and economic efficiency.
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Next, the effect of reaction time on the yield and selectivity was also investigated. Initially, the reaction conducted at 40?? for 8h gave the yield of 47.2%. Increasing the reaction time led to higher yield. When the reaction was performed for 32h, the best yield of 96.7% was obtained. However, further increase in reaction time did not result in more products. On the contrary, a constant yield was observed. Interestingly, the data in Table 7 showed that the selectivity was significantly influenced by the reaction time. In the initial stage of the reaction, the exo products were obtained as the major product. However, as the reaction progressed, the endo/exo ratio increased and the endo products occupied the dominant position. A possible explanation was that exo products were the products of kinetic control, while the endo products were the products of thermodynamic control. With extended reaction time, exo products formed were gradually transformed into endo products which were more stable.
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Water plays an important role in the enzyme-catalyzed organic reaction [30]. Conformational flexibility and increased hydration were obtained by adding appropriate amount of water into the nonaqueous solvent, leading to higher enzyme activity. When the water content was 10%, the yield was 96.7% (Table 8). More water led to decreased yield. Notably, the selectivity was also influenced by the water content. When the reaction was conducted in anhydrous MeCN, endo products were the major product. Increasing the water content favored the formation of exo products.
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With the optimized reaction conditions in hand, other aromatic aldehydes were employed in the lipase-catalyzed aza-Diels-Alder reaction to confirm the generality and scope of this new enzymatic promiscuity. As shown in Table 9, the yields greatly depended on the substituents in aromatic aldehydes. Aromatic aldehydes with electron-withdrawing substituents gave better yields, while electron-donating groups in the aromatic aldehydes led to worse yields. Moreover, the effect of steric hindrance of substituents on the yield and selectivity was also investigated in detail. 4-Chlorobenzaldehyde and 3-chlorobenzaldehyde gave the yield of 98.9% and 98.3%, respectively. However, when 2-chlorobenzaldehyde was employed in the reaction, only a yield of 81.1% was obtained. Furthermore, the data in Table 9 showed that substituents in aromatic aldehydes had little effect on the selectivity.
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Based on the catalytic mechanism of lipases revealed by CasasGodoy et al., we hypothesized the mechanism of the lipasecatalyzed direct aza-Diels-Alder reaction (Fig. 2). The active site of lipase from Candida sp. 99-125 is composed of aspartate, histidine, and serine residues [31]. Under the action of amino acid residues and oxyanion hole, the enol and imine were synthesized. The oxyanion hole stabilizes the charge distribution and reduces the state energy of the tetrahedral intermediate by forming at least two hydrogen bonds. Next, enol reacts with intermediates formed by imines and amino acid residues via a Mannich-Michael process to give the final product with the aid of lipase from Candida sp. 99-125.
In conclusion, the first lipase-catalyzed direct three-component aza-Diels-Alder reaction was developed. The lipase from Candida sp. 99-125 as an economical, effective and environmental friendly catalyst could catalyze the reactionwith a wide range of substrates, leading to moderate to excellent yields. This novel enzymatic process will widen the application of lipases in organic synthesis.
This research was supported in part by the Natural Science Foundation of Jiangsu Province (No. BK2012763) and the Fundamental Research Funds of the Central Universities from the Ministries of Education and Finance of China (No. ZD2014YX0027).
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2016.10.015.
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