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Article

Chemoenzymatic One-Pot Process for the Synthesis of Tetrahydroisoquinolines

by
Andreas Sebastian Klein
1,
Anna Christina Albrecht
1 and
Jörg Pietruszka
1,2,*
1
Institute of Bioorganic Chemistry, Heinrich Heine University Düsseldorf, Forschungszentrum Jülich, Stetternicher Forst, Building 15.8, 52426 Jülich, Germany
2
Institute of Bio- and Geosciences (IBG-1: Bioorganic Chemistry), Forschungszentrum Jülich, 52428 Jülich, Germany
*
Author to whom correspondence should be addressed.
Catalysts 2021, 11(11), 1389; https://doi.org/10.3390/catal11111389
Submission received: 27 October 2021 / Revised: 10 November 2021 / Accepted: 11 November 2021 / Published: 17 November 2021
(This article belongs to the Special Issue Biocatalytic Cascade Reactions)
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Abstract

:
1,2,3,4-Tetrahydroisoquinolines form a valuable scaffold for a variety of bioactive secondary metabolites and commercial pharmaceuticals. Due to the harsh or complex conditions of the conventional chemical synthesis of this molecular motif, alternative mild reaction pathways are in demand. Here we present an easy-to-operate chemoenzymatic one-pot process for the synthesis of tetrahydroisoquinolines starting from benzylic alcohols and an amino alcohol. We initially demonstrate the oxidation of 12 benzylic alcohols by a laccase/TEMPO system to the corresponding aldehydes, which are subsequently integrated in a phosphate salt mediated Pictet–Spengler reaction with m-tyramine. The reaction conditions of both individual reactions were analyzed separately, adapted to each other, and a straightforward one-pot process was developed. This enables the production of 12 1,2,3,4-tetrahydroisoquinolines with yields of up to 87% with constant reaction conditions in phosphate buffer and common laboratory glass bottles without the supplementation of any additives.

Graphical Abstract

1. Introduction

1,2,3,4-Tetrahydroisoquinolines (1, THIQs) form the backbone of numerous plant-derived and mammalian bioactive alkaloids and their derivatives [1,2]. Their potential pharmacological applications include their use as antidepressants, antitumor, anti-HIV and antimalarial drugs [3,4,5,6]. THIQs 1 available on the market include the antihypertensive quinapril and the antitussive noscapine [7,8]. The pharmacological and structural diversity of natural and synthetic THIQs 1 makes them a relevant motive for the synthesis of compound libraries in drug development (Scheme 1) [9].
Different strategies for obtaining THIQs 1 have been developed. In addition to the extraction of alkaloids from higher plants, which provides insufficient amounts of the target compounds and complex product mixtures, application of biocatalysts (Pictet–Spenglerases) of the corresponding biosynthetic pathways is the focus of current research [10]. One of the best-studied examples is norcoclaurine synthases (NCS) catalyzing the formation of a THIQ 1 between dopamine and 4-hydroxyphenylacetaldehyde in plants [11,12,13,14,15,16]. A major limitation of the use of these biocatalysts, however, is their narrow substrate spectrum, which is constantly being expanded by examining the protein structures and reaction mechanisms coupled with enzyme engineering [17,18,19,20,21,22].
In classical synthetic processes, either the Pictet–Spengler reaction, starting from β-arylethylamines and aldehydes, or the Bischler-Napieralski reaction combined with a subsequent reduction provide access to the corresponding THIQ 1 scaffolds (Scheme 1) [23,24]. However, the use of these reactions is accompanied by harsh reaction conditions such as high reaction temperatures (>100 °C) and the use of strong acids as well as Lewis acids [25,26,27,28]. They are therefore not suitable for use in chemoenzymatic cascades. Another alternative is the synthetic application of calcium hexafluoroisopropoxide complexes, which is a mild variant for the synthesis of THIQs 1 from β-arylethylamines and aldehydes, but these catalysts are not commercially available, and the reactions can only be carried out under inert conditions [29].
In recent years, the use of phosphate salts and buffers for the production of THIQs 1 by the Pictet–Spengler reaction involving a wide range of substrates including aliphatic, aromatic, and heterocyclic aldehydes and ketones has been reported (Scheme 1) [20,30,31,32,33]. These low-cost phosphate salts allow mild reaction conditions and are also compatible with chemoenzymatic reaction cascades. In the recent literature, there is a considerable number of reviews focusing on in vitro chemoenzymatic and biocatalytic cascades, their great benefits in synthesis routes of complex molecules, and the potential for their optimization [34,35,36].
Another critical aspect in the synthesis of THIQs 1 is the dependence on aldehydes. This functional group is characterized by its reactivity and tends to oxidize into the corresponding carboxylic acid when stored; one of the best-known examples is the autoxidation of benzaldehyde to benzoic acid [37]. Therefore, the in situ generation of aldehydes from their corresponding primary alcohols could provide an appropriate solution in cascade reactions. Several methods for this kind of oxidation, such as the application of inorganic metal salts, are known in chemistry, but they still cause problems due to environmental pollution or safety aspects.
As a biocompatible method, the use of the multi-copper enzyme laccase together with the air-stable organocatalyst (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (2, TEMPO) has been described in literature in recent years and was also implemented in cascade reactions [38,39,40,41,42,43,44,45,46,47,48,49,50,51]. The oxidation of the primary alcohol is catalyzed by the mediator TEMPO (2), which is in turn recycled in a second catalytic cycle by the primary oxidant oxygen and the multicopper oxidase (Scheme 2).
Here, we develop a straightforward one-pot chemoenzymatic process for the production of 1-phenyl-1,2,3,4-THIQs 1 using benzylic alcohols 3 and the ß-arylethylamine m-tyramine (4). Based on the reaction conditions for the phosphate salt-mediated Pictet–Spengler reaction, first a suitable laccase/TEMPO (2) system was investigated for the oxidation of benzylic alcohols 3 to their corresponding benzaldehydes 5. Subsequently, the two reactions were combined in a one-pot process.

2. Results and Discussion

For the development of an easy-to-operate one-pot chemoenzymatic process towards THIQs 1, the following objectives were initially defined: The entire process should be performed in a standard glass vessel in potassium phosphate (KPi) buffer with minimal or no supplementation of additives (no co-solvents and antioxidants) at constant reaction conditions (temperature, constant pH and ionic strength of the buffer) in a common device (incubator shaker, oxygen atmosphere).

2.1. Oxidation of Benzylic Alcohols 3 via the Laccase/TEMPO (2) System

Studies on the laccase-catalyzed oxidation of alcohols to the corresponding aldehydes or ketones using TEMPO (2) as a mediator have been published in recent years. Common to most publications is the use of the fungal laccase from Trametes versicolor, which has a pH optimum at pH 4.5–5.0 in acetate buffer (usually with the addition of co-solvents like toluene, acetonitrile or MTBE) [40,41,42,43,44,45,46]. As the subsequent phosphate salt-mediated Pictet–Spengler reaction was to take place in KPi buffer, the acetate buffer was not compatible. In addition, computer-based DFT and MP2 calculations of the phosphate-mediated reaction with formaldehyde and 3-hydroxyphenylethylamines showed that an alkaline pH value of 8–9 represents an energetic minimum for the reaction. In this pH range both HPO42− and H2PO4− ions are present, which are necessary for the abstraction of protons (for a suggested mechanism see S4.2.3, Scheme S1) [32]. Therefore, the two-domain laccase Ssl1 (Streptomyces sviceus laccase 1) from a mesophilic source organism was introduced as an alternative. Depending on suitable substrates, this laccase shows an alkaline activity profile with a pH optimum around pH 8–9 and also exhibits high stability over a wide pH range (pH 5–11) and elevated temperatures [52,53,54].
The heterologous expression of the laccase gene ssl1 was performed in Escherichia coli BL21 (DE3) at 25 °C in Terrific Broth (TB) medium supplemented with 2 mm copper sulfate and 40 µm IPTG for induction. Higher concentrations of IPTG led to a reduction of the active enzyme amount. The cell lysates (either from frozen cell pellets or freeze-dried cells) were treated with heat at 65 °C for 20 min to deactivate non-specific enzyme activities. The determination of the laccase activity of the clarified cell supernatants was then performed in a colorimetric assay using 2,6-dimethoxyphenol (2,6-DMP) as the substrate (for further information on expression, preparation and activity determination see S3.1–S3.3). As a result of the heat treatment, the clarified cell supernatants could be directly used in the oxidation reactions without the requirement of time-consuming enzyme purification.
The substrate benzyl alcohol (3a), which was initially chosen for the standard reaction, proved to be unsuitable for closer analysis of the oxidation reaction towards benzaldehyde (5a), as no variation of the reaction conditions allowed a complete conversion to be achieved. Therefore, 2-bromobenzyl alcohol (3b) and its corresponding aldehyde 2-bromobenzaldehyde (5b) were applied as alternative substrates for all analyses of the laccase/TEMPO (2) system and the subsequent Pictet–Spengler reaction. Furthermore, the use of a halogenated substrate allows for a future entry point of chemical derivatizations.
The oxidation was carried out in KPi buffer with a concentration of 0.2 m and a pH value of 8 (activity optimum of laccase) at 37 °C without any addition of a co-solvent. These reaction conditions represented a compromise between previously published parameters: studies on the laccase Ssl1 were mainly performed at room temperature, whereas for the phosphate salt-mediated Pictet–Spengler reaction temperatures ranging from 50 to 70 °C and phosphate concentrations between 0.1 and 1.0 m were reported [20,30,33,52,55]. In analytical approaches in glass vials, the oxidation of 2-bromobenzyl alcohol (3b, c = 0.12 m; batch size 1 mL) was initially investigated as a function of the volumetric activity of the laccase Ssl1 and the equivalents of TEMPO (2) as the mediator (Figure 1).
It could be observed that complete conversion of the starting material was achieved at a laccase activity of >0.5 U/mL and a TEMPO (2) quantity of > 0.15 equivalents (referring to 1 equiv of 2-bromobenzyl alcohol (3b)). A subsequent upscaling on a semi-preparative batch with 2-bromobenzyl alcohol (3b, c = 0.12 m; batch size 10 mL) also showed complete conversion under these conditions without the formation of the possible over-oxidized product 2-bromobenzoic acid. In contrast, in control studies without TEMPO (2) or laccase (buffer only or heat-treated clarified cell supernatants of E. coli bearing an empty vector) no conversion could be detected. This proved that a specific purification of the laccase via protein tags is therefore not essential for the preparative application in biocatalytic reactions. Likewise, no co-solvents are obligatory, despite the reaction being a heterogeneous mixture. Regarding different molarities of the KPi buffer, an increase of the concentration had a negative effect on conversion. A significant reduction to only 50% is apparent at the concentration of 1 m, as previously applied in the literature for the subsequent phosphate salt-mediated Pictet–Spengler reaction with aldehydes.
The conditions of the analytical approaches with 2-bromobenzyl alcohol (3b) were transferred to benzyl alcohol (3a) and 10 additional benzyl alcohol derivatives 3c–l containing substitutions at the ortho and para positions with electron withdrawing (EWG) and electron donating (EDG) groups (Scheme 3 and Table 1). While hydroxylated benzylic alcohols (compounds not shown; R=OH) were also tested, there was—as expected—a considerable formation of side product as seen from the discoloration of the reaction solution to dark brown, hinting to the formation of oligo-/polymers. As a trend, a slightly adverse effect of activating EDG groups was observed in both positions. Except for benzyl alcohol (3a), all substrates applied in the laccase/TEMPO (2) system demonstrated a conversion of at least 72%—a considerable number of them even a complete conversion. For consistency, the conditions of the oxidation of benzylic alcohols 3 were applied unchanged to the subsequent cascade development.

2.2. Phosphate Salt-Mediated Pictet–Spengler Reaction

In recent years it has been shown that phosphate compounds (KH2PO4, NaH2PO4, Na4P2O7, glucose-1-phosphate, uridine monophosphate) can be used as mediators in the Pictet–Spengler reaction [30,33]. The application of the low-cost KPi buffer avoids the aforementioned harsh reaction conditions and the use of metals as Lewis acids or complex catalysts. For the evaluation of the parameters of the selected standard reaction with 2-bromobenzaldehyde (5b) and m-tyramine hydrobromide (4·HBr), the previously published reactions of Erdmann et al. were referred to, in which the phosphate salt-mediated Pictet–Spengler reaction between 2-bromobenzaldehyde (5b) and metaraminol—an m-tyramine (4) derivative—was performed [20]. Erdmann et al. implemented their reaction in a 1:10 (v/v) mixture of KPi buffer (0.2 m or 1.0 m, pH 7) and the co-solvent DMSO supplemented with the antioxidant sodium ascorbate (0.5 eq.) under an inert gas atmosphere at 60 °C for 18 h (54% yield). Taking the previous optimizations for the oxidation of the benzylic alcohols 3a–l in the laccase/TEMPO (2) system into account, KPi buffer (0.2 m) was chosen as the reaction medium without the addition of a co-solvent for the Pictet–Spengler reaction. By omitting the co-solvent (beside DMSO, acetonitrile, ethanol, and methanol are mentioned in literature) the product precipitates during the reaction and is therefore removed from a possible equilibrium. With the chosen reaction parameters, the corresponding THIQ 1b was formed in 74% yield as a racemic mixture at pH 7 and 60 °C (Scheme 4 and Table 2).
With the envisioned goal of a straightforward one-pot process, the temperature and pH were adjusted to the established reaction conditions of the benzylic alcohol 3 oxidation in the laccase/TEMPO (2) system (37 °C, pH 8; yield 67%, Table 2). The slightly alkaline pH value thus also corresponds to the aforementioned optimum of the phosphate salt-mediated Pictet–Spengler reaction and the activity optimum of the laccase Ssl1 [32,52]. The high influence of an alkaline pH is also confirmed by a control experiment at pH 5 (optimum of the fungal laccase from T. versicolor), resulting in a yield of only 2%. By choosing these reaction conditions the following predefined objectives of the one-pot process were already considered: constant temperature, pH, and ionic strength of the buffer; no co-solvents. In a second series of experiments, the requirement for the additive sodium ascorbate and reaction handling under inert gas atmosphere to avoid possible oxidation side reactions were evaluated. However, no significant influence of these parameters could be determined, enabling the reaction to be carried out under oxygen atmosphere and avoiding additives completely (Scheme 4). In addition, the reaction can be carried out with the same efficiency both in glass flasks with magnetic stirring bars and glass vials in an incubator shaker. Furthermore, the downstream process for the extraction and purification of THIQs 1 was also improved compared to the methods currently described in the literature for semi-preparative and preparative reaction scales [20,30,33]. The extracted raw material could be effectively purified from remaining aldehyde 5 by substituting aqueous HCl to HCl dissolved in diethyl ether resulting in the precipitation of only the final THIQ 1 and a single by-product (which will be discussed later).
The newly defined conditions for the phosphate salt-mediated Pictet–Spengler reaction with 2-bromobenzaldehyde (5b) and m-tyramine hydrobromide (4·HBr) were then implemented for benzaldehyde (5a) and the 10 additional derivatives 5c–l already produced in the laccase/TEMPO (2) system. For the 1-phenyl-1,2,3,4-THIQs 1a,c–l, yields between 52–93% were achieved, but no trend was observed for the substitutions in ortho and para position and their attributed electronic effects (Scheme 5 and Table 3). Due to the use of m-tyramine (4) as the amino alcohol, all products were obtained as racemic mixtures.
In all reactions, the formation of a strongly yellow-colored and fluorescent under UV light (Figure S9) by-product was observed, which was analyzed in the standard reaction containing 2-bromobenzaldehyde (5b) and m-tyramine hydrobromide (4·HBr). The evaluation of mass and NMR data of the by-product 6 confirmed the in situ reaction of the produced THIQ 1b with a second molecule of 2-bromobenzaldehyde (5b); under basic conditions the dihydroisoquinolinone 6 is formed via a contingent imine tautomerism (Scheme 6; for a detailed suggested reaction mechanism, see S4.2.4, Scheme S2).
A direct correlation between the amount of the by-product 6 and the increase in aldehyde 5b concentration in the Pictet–Spengler reaction could be identified, providing a further opportunity for optimization with regard to increasing yields.

2.3. Chemoenzymatic One-Pot Process

The final easy-to-operate chemoenzymatic one-pot process is designed as a consecutive reaction sequence. First, the oxidation of the benzylic alcohols 3 to the corresponding aldehydes 5 takes place in the laccase/TEMPO (2) system and subsequently the formation of the THIQs 1 is initiated by adding the amino alcohol m-tyramine hydrobromide (4·HBr) (Scheme 7 and Table 4).
The results of first reaction setups containing 0.20 equiv of TEMPO (2) suggest that the components of the first reaction step of the cascade have an influence on the phosphate salt-mediated Pictet–Spengler reaction. Therefore, the second reaction step was investigated with 2-bromobenzaldehyde (5b) as substrate in the presence of different amounts of TEMPO (2). In the presence of 0.2 equiv TEMPO (2), a 57% yield of THIQ 1b was obtained, whereas a reduction to 0.1 equiv increased the yield to 73%. Continued reduction of TEMPO (2) to 0.067 equiv did not result in a further increase in yield (71%).
As decreasing the amount of TEMPO (2) in the cascade reaction should simply lead to slightly increased reaction times in the chemoenzymatic oxidation step (see Figure 1), the equivalents were reduced to 0.15 in further cascade reactions and samples taken for GC measurement to follow the reaction progress. Following this reasoning, the volumetric activity of laccase was also reduced to 0.6 U/mL in an effort to facilitate workup with ethyl acetate. The cascade reaction starting with the oxidation of, e.g., 3e was performed for 44 h, resulting in a conversion of 93%. For more detailed reaction times and conversions of the first step in the reaction cascade, see Supplementary Table S1. As expected based on the literature and confirmed by measuring the optical rotation, the presence of laccase during the Pictet–Spengler reaction did not result in any asymmetric induction [56].
It was found that in the consecutive cascade with respect to all benzyl alcohols 3 the intended THIQs 1 could be isolated after column chromatography with yields ranging from 32–87%. Again, no clear trend based on the electronic effects of the substituents in ortho and para position was observed. When compared to the theoretical yield (calculated by the multiplication of the conversion and yield of the individual steps), it was observed that the yield of all but three cascade reactions was within 16% of the theoretical yield. The cascades resulting in 1a and 1j even slightly exceeded expectations (Scheme 8 and Table 5).
The reaction sequence is carried out under constant conditions and can be performed using standard laboratory equipment, with the following parameters allowing an easily parallelized experiment setup:
  • Laccase Ssl1 from S. sviceus (heat-treated clarified cell supernatant, prepared as a batch, aliquoted, thawed as needed).
  • 1.00 equiv benzylic alcohol 3, 0.15 equiv TEMPO (2), 0.33 equiv m-tyramine hydrobromide (4·HBr).
  • KPi buffer (0.2 m, pH 8).
  • Glass bottle, constant shaking in incubator at 37 °C, oxygen atmosphere, no additives.

3. Materials and Methods

All materials and methods are given in detail in the Supplementary Materials. The procedure for the chemoenzymatic one-pot process as a combination of both single reaction steps is described in the following:
The chemoenzymatic one-pot process was performed in a 100 mL Schott® flask fitted with a PTFE/silicon septum perforated with a cannula for oxygen exchange under constant shaking at 400 rpm on an orbital shaker for culture flasks at 37 °C.
The benzylic alcohol 3 (1.38 mmol, 1.00 equiv) and TEMPO (2, 32 mg, 0.21 mmol, 0.15 equiv) were added to a freshly thawed laccase solution (0.6 U/mL) in KPi buffer (10 mL, 200 mm, pH 8.0) with 0.3 mm CuSO4. The reaction mixture was shaken for 20−45 h at 37 °C. Afterwards, m-tyramine hydrobromide (4·HBr, 100 mg, 0.46 mmol, 0.33 equiv) in KPi buffer (10 mL, 200 mm, pH 8.0) was added to the reaction mixture and shaken for another 18−24 h. The solution was then cooled to room temperature (25 °C) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The THIQs 1a–l were precipitated by adding small amounts of cold HCl solution in diethyl ether (1 m) to the residue. The resulting solid was washed with cold diethyl ether, filtered, and resuspended in MeOH. The solvent was removed under reduced pressure and the THIQs 1a–l were purified via column (length = 10−16 cm, diameter = 3 cm) chromatography on silica with dichloromethane/MeOH [4% (v/v)]/ammonia in MeOH (7 n) [1% (v/v)] providing the THIQs 1a–l as free amines and racemic mixtures. The yields are related to the quantity of m-tyramine hydrobromide (4·HBr) used.

4. Conclusions

In summary, we successfully developed an easy-to-operate chemoenzymatic one-pot process for the synthesis of tetrahydroisoquinoline libraries with yields of up to 87% starting from benzylic alcohols and an amino alcohol. The reaction conditions of the individual processes, the oxidation of benzylic alcohols and the phosphate salt-mediated Pictet–Spengler reaction, were adapted to each other and, furthermore, a by-product of the latter reaction was identified. After demonstrating the feasibility of this cascade, future studies could focus on expanding the library by substituting m-tyramine with different β-arylethylamines or combining the chemoenzymatic oxidation with a stereoselective Pictet–Spengler reaction.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/catal11111389/s1, S1: Overview of compounds (including numbers); S2: General methods (materials and analytics); S3: Methods in biology [S3.1–S3.3: strains, vectors, protein production, laccase activity assay; S3.4: oxidation of benzylic alcohols 3a–l using the laccase/TEMPO (2) system]; S4: Chemical syntheses [S4.1: synthesis and analysis (NMR, IR, LC-MS) of m-tyramine∙HBr (4∙HBr); S4.2: phosphate salt mediated Pictet–Spengler reaction + suggested mechanism (Scheme S1), analysis of by-product 6 (NMR, IR, HRMS) + suggested mechanism (Scheme S2)]; S5: Chemoenzymatic one-pot cascade towards THIQs 1a–l; S6: Compound characterization of THIQs 1a–l (NMR, IR, LC-MS, HRMS); S7: Reaction monitoring (Supplementary Table S1).

Author Contributions

Conceptualization, A.S.K. and J.P.; methodology, A.S.K.; validation, A.C.A., A.S.K. and J.P.; investigation, A.C.A., A.S.K.; writing—original draft preparation, A.S.K.; writing—review and editing, A.C.A., ASK, and J.P.; visualization, A.S.K.; supervision, A.S.K. and J.P.; project administration, J.P.; funding acquisition, J.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Culture and Science within the framework of the NRW-Strategieprojekt Bioeconomy Science Center (BioSC, no. 313/323-400-002 13).

Data Availability Statement

The data presented in this study are available in the Supplementary Materials of this article.

Acknowledgments

The authors thank Kevin Bochinsky (Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich) for his help with NMR analysis and Beatrix Paschold for her support concerning heterologous expression.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 11 01389 sch001 550
Scheme 1. Access to 1,2,3,4-Tetrahydroisoquinolines 1 by the Pictet–Spengler reaction or Bischler-Napieralski reaction with subsequent reduction.
Scheme 1. Access to 1,2,3,4-Tetrahydroisoquinolines 1 by the Pictet–Spengler reaction or Bischler-Napieralski reaction with subsequent reduction.
Catalysts 11 01389 sch001
Catalysts 11 01389 sch002 550
Scheme 2. Catalytic cycles of a laccase/TEMPO (2) system for the oxidation of primary alcohols to their corresponding aldehydes (adapted from Tromp et al.) [41]. THIQs 1 are formed by the consecutive Pictet–Spengler reaction with the amino alcohol m-tyramine (4).
Scheme 2. Catalytic cycles of a laccase/TEMPO (2) system for the oxidation of primary alcohols to their corresponding aldehydes (adapted from Tromp et al.) [41]. THIQs 1 are formed by the consecutive Pictet–Spengler reaction with the amino alcohol m-tyramine (4).
Catalysts 11 01389 sch002
Catalysts 11 01389 g001 550
Figure 1. Analysis of the laccase/TEMPO (2) system for the oxidation of 2-bromobenzyl alcohol (3b, c = 0.12 m) to the corresponding 2-bromobenzaldehyde (5b). (A) To determine the conversion for individual volumetric activities of Ssl1 a constant amount of TEMPO (2, 0.175 equiv) was chosen; (B) in order to determine the conversion for individual amounts of TEMPO (2), a constant volumetric activity of Ssl1 of 1 U/mL was chosen. (The rel. conversion is derived from the ratio (benzylic alcohol:benzaldehyde) by GC; the data was analyzed by a logistic regression.).
Figure 1. Analysis of the laccase/TEMPO (2) system for the oxidation of 2-bromobenzyl alcohol (3b, c = 0.12 m) to the corresponding 2-bromobenzaldehyde (5b). (A) To determine the conversion for individual volumetric activities of Ssl1 a constant amount of TEMPO (2, 0.175 equiv) was chosen; (B) in order to determine the conversion for individual amounts of TEMPO (2), a constant volumetric activity of Ssl1 of 1 U/mL was chosen. (The rel. conversion is derived from the ratio (benzylic alcohol:benzaldehyde) by GC; the data was analyzed by a logistic regression.).
Catalysts 11 01389 g001
Catalysts 11 01389 sch003 550
Scheme 3. Oxidation of benzylic alcohols 3a–l towards their corresponding benzaldehydes 5a–l in the laccase/TEMPO (2) system; for results see Table 1.
Scheme 3. Oxidation of benzylic alcohols 3a–l towards their corresponding benzaldehydes 5a–l in the laccase/TEMPO (2) system; for results see Table 1.
Catalysts 11 01389 sch003
Catalysts 11 01389 sch004 550
Scheme 4. Analysis of the reaction parameters for the phosphate salt-mediated Pictet–Spengler reaction with 2-bromobenzaldehyde (5b) and m-tyramine hydrobromide (4·HBr) towards the THIQ 1b; for results see Table 2.
Scheme 4. Analysis of the reaction parameters for the phosphate salt-mediated Pictet–Spengler reaction with 2-bromobenzaldehyde (5b) and m-tyramine hydrobromide (4·HBr) towards the THIQ 1b; for results see Table 2.
Catalysts 11 01389 sch004
Catalysts 11 01389 sch005 550
Scheme 5. Phosphate salt-mediated Pictet–Spengler reaction with benzaldehydes 5a–l and m-tyramine hydrobromide (4·HBr) towards 1-phenyl-1,2,3,4-THIQs 1a–l; for results see Table 3.
Scheme 5. Phosphate salt-mediated Pictet–Spengler reaction with benzaldehydes 5a–l and m-tyramine hydrobromide (4·HBr) towards 1-phenyl-1,2,3,4-THIQs 1a–l; for results see Table 3.
Catalysts 11 01389 sch005
Catalysts 11 01389 sch006 550
Scheme 6. Side reaction of the phosphate salt-mediated Pictet–Spengler reaction towards the by-product dihydroisoquinolinone 6 under alkaline conditions.
Scheme 6. Side reaction of the phosphate salt-mediated Pictet–Spengler reaction towards the by-product dihydroisoquinolinone 6 under alkaline conditions.
Catalysts 11 01389 sch006
Catalysts 11 01389 sch007 550
Scheme 7. Chemoenzymatic one-pot process with benzylic alcohols 3a–l and m-tyramine hydrobromide (4·HBr) towards 1-phenyl-1,2,3,4-THIQs 1a–l; for results see Table 4.
Scheme 7. Chemoenzymatic one-pot process with benzylic alcohols 3a–l and m-tyramine hydrobromide (4·HBr) towards 1-phenyl-1,2,3,4-THIQs 1a–l; for results see Table 4.
Catalysts 11 01389 sch007
Catalysts 11 01389 sch008 550
Scheme 8. Comparison of obtained and theoretical yields of the chemoenzymatic one-pot process with benzylic alcohols 3a–l and m-tyramine hydrobromide (4·HBr) towards 1-phenyl-1,2,3,4-THIQs 1a–l; for results see Table 5.
Scheme 8. Comparison of obtained and theoretical yields of the chemoenzymatic one-pot process with benzylic alcohols 3a–l and m-tyramine hydrobromide (4·HBr) towards 1-phenyl-1,2,3,4-THIQs 1a–l; for results see Table 5.
Catalysts 11 01389 sch008
Table
Table 1. Conversion of laccase-mediated oxidation.
Table 1. Conversion of laccase-mediated oxidation.
Benzylic
Alcohol		BenzaldehydeRConversion [%] 1
3a5aH28
3b5b2-Br100
3c5c2-F73
3d5d2-NO2100
3e5e2-OMe72
3f5f4-Br100
3g5g4-Cl92
3h5h4-F98
3i5i4-CF3100
3j5j4-NO284
3k5k4-Me100
3l5l4-OMe90
1 The conversion was derived from the ratio (benzylic alcohol; benzaldehyde) by GC.
Table
Table 2. Parameters influencing the Pictet-Spengler reaction.
Table 2. Parameters influencing the Pictet-Spengler reaction.
pHT [°C]Sodium
Ascorbate		AtmosphereYield [%] 1
560+N22
760+N274
737+N265
837+N267
837-N265
837-O268
1 The yields are related to the quantity of m-tyramine hydrobromide (4·HBr) used.
Table
Table 3. Yields of phosphate salt-mediated Pictet-Spengler reaction.
Table 3. Yields of phosphate salt-mediated Pictet-Spengler reaction.
THIQRYield [%] 1
1aH93
1b2’-Br76
1c2’-F92
1d2’-NO276
1e2’-OMe86
1f4’-Br79
1g4’-Cl84
1h4’-F88
1i4’-CF352
1j4’-NO291
1k4’-Me60
1l4’-OMe65
1 The yields are related to the quantity of m-tyramine hydrobromide (4·HBr) used.
Table
Table 4. Yields of sequential one-pot process.
Table 4. Yields of sequential one-pot process.
Benzylic AlcoholRTHIQYield [%] 1
3aH1a322
3b2-Br1b493
3c2-F1c64
3d2-NO21d473
3e2-OMe1e572
3f4-Br1f70
3g4-Cl1g552
3h4-F1h71
3i4-CF31i37
3j4-NO21j872
3k4-Me1k583
3l4-OMe1l43
1 The yields are related to the quantity of m-tyramine hydrobromide (4·HBr) used. 2 First reaction was shaken for 40–45 h. 3 0.20 equiv TEMPO (2), Laccase SSL1 1 U/mL.
Table
Table 5. Obtained and theoretical yields of chemoenzymatic one-pot process.
Table 5. Obtained and theoretical yields of chemoenzymatic one-pot process.
RConversion 1
1st step [%]		Yield 2
2nd step		Theor. Yield 3
Cascade [%]		Yield [%] 1THIQ
H289326321a
2-Br1007676491b
2-F739267641c
2-NO21007676471d
2-OMe728662571e
4-Br1007979701f
4-Cl928477551g
4-F988886711h
4-CF31005252371i
4-NO2849176871j
4-Me1006060581k
4-OMe906559431l
1 The conversion is derived from the ratio (benzylic alcohol:benzaldehyde) by GC. 2 The yields are related to the quantity of m-tyramine hydrobromide (4·HBr) used. 3 The theoretical yield is calculated by the multiplication of the conversion and yield of the individual steps.
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Klein, A.S.; Albrecht, A.C.; Pietruszka, J. Chemoenzymatic One-Pot Process for the Synthesis of Tetrahydroisoquinolines. Catalysts 2021, 11, 1389. https://doi.org/10.3390/catal11111389

AMA Style

Klein AS, Albrecht AC, Pietruszka J. Chemoenzymatic One-Pot Process for the Synthesis of Tetrahydroisoquinolines. Catalysts. 2021; 11(11):1389. https://doi.org/10.3390/catal11111389

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Klein, Andreas Sebastian, Anna Christina Albrecht, and Jörg Pietruszka. 2021. "Chemoenzymatic One-Pot Process for the Synthesis of Tetrahydroisoquinolines" Catalysts 11, no. 11: 1389. https://doi.org/10.3390/catal11111389

APA Style

Klein, A. S., Albrecht, A. C., & Pietruszka, J. (2021). Chemoenzymatic One-Pot Process for the Synthesis of Tetrahydroisoquinolines. Catalysts, 11(11), 1389. https://doi.org/10.3390/catal11111389

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