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. 2023 Feb 15;145(8):4431–4437. doi: 10.1021/jacs.2c09176

One-Pot Chemoenzymatic Cascade for the Enantioselective C(1)-Allylation of Tetrahydroisoquinolines

Jack J Sangster 1, Rebecca E Ruscoe 1, Sebastian C Cosgrove 1, Juan Mangas-Sánchez 1, Nicholas J Turner 1,*
PMCID: PMC9983016  PMID: 36790859

Abstract

graphic file with name ja2c09176_0010.jpg

Herein, we report a one-pot, chemoenzymatic process for the synthesis of enantioenriched C(1)-allylated tetrahydroisoquinolines. This transformation couples a monoamine oxidase (MAO-N)-catalyzed oxidation with a metal catalyzed allylboration, followed by a biocatalytic deracemization to afford allylic amine derivatives in both high yields and good to high enantiomeric excess. The cascade is operationally simple, with all components added at the start of the reaction and can be used to generate key building blocks for further elaboration.

Introduction

Enantiopure amines comprise an important class of organic compounds, in particular heterocyclic amines, which constitute a large number of bioactive molecules.1 The prevalence of chiral amine containing compounds in active pharmaceutical ingredients (APIs) is estimated to compromise 40–45% of all drug candidates, which has driven developments in this area.2 Traditionally, the main approaches for the stereoselective synthesis of chiral amines involves deracemization,3 imine/enamine reduction,4,5 transfer hydrogenation,6 N–H insertion,7,8 reductive amination,9 hydroamination,10 and nucleophilic addition to imines.11 Despite the high atom economy of these catalytic approaches, the requirement for precious metal catalysts, high molecular weight ligands, solvents, and high pressures all adversely impact the overall sustainability.12 As more emphasis has been placed on sustainable manufacturing, biocatalysis has emerged as a pre-eminent method for the preparation of chiral amines due to the unique regio-, chemo-, and stereoselectivity conferred by enzymes under benign reaction conditions.13 A range of different enzymes have been developed for chiral amine synthesis including amine oxidases (AOs),14 imine reductases (IREDs),14−18 reductive aminases (RedAms),19−21 transaminases (TAs),14 amine dehydrogenases (AmDHs),20,22 and cytochrome P450 variants (P411s).23,24 However, only a small number of enzymes have been characterized which generate chiral amines via nucleophilic addition to an imine intermediate, namely, norcoclaurine synthases (NCSs)25 and berberine bridge enzymes (BBEs),26 both of which are highly substrate dependent.

Although the enantioselective allylation of carbonyls and acyclic imines has been widely reported in the literature,27,28 the analogous enantioselective allylation of cyclic imines has received little interest.29 Scaffolds such as C(1)-substituted 1,2,3,4-tetrahydroisoquinolines (THIQs) provide compounds with a variety of biological properties, which is highlighted in their use in the pharmaceutical industry (Figure 1).

Figure 1.

Figure 1

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Biologically active compounds containing THIQ core structures.

One such strategy to prepare these compounds involves the oxidative functionalization of N-substituted tetrahydroisoquinolines (THIQs) at the C(1) position. Oss et al., reported a mild method for the C(1)-functionalization of tetrahydroisoquinolines.30 The group exploited the tropylium ion to generate an N-benzyl/alkyl iminium intermediate, which was quenched by a range of carbon nucleophiles. This approach enabled access to a range of C(1)-substituted products in good to excellent conversion; however, the necessity for N-functionalized substrates could limit its application. The work by Yan and co-workers also exploited the oxidative functionalization of N-substituted THIQs for the preparation of 1-allyl THIQs.31 The group used triphenylcarbenium tetrafluoroborate to generate the N-acyl iminium intermediate, which was intercepted with allyl trimethylsilane. Using this method, several N-acyl 1-allyl substituted were prepared in excellent yields. However, the requirement for the stochiometric oxidant negatively impacts the sustainability of this work. Currently, few approaches have been outlined for the stereoselective allylation of tetrahydroisoquinolines. The main approach involves the allylation of cyclic imines through nucleophilic addition of preformed chiral boronates.32 A further approach exploits a transition metal catalyst and a chiral ligand to catalyze the allylation stereoselectively.33 Although these reports demonstrate enantioselective allylation, they are limited by the requirements of organic solvents, high temperatures, chiral ligands, and preformed imine substrates.

Biocatalytic approaches toward C(1)-functionalized THIQs remain largely unexplored. Norcoclaurine synthases (NCSs) have been exploited by Roddan et al., to access (S)-1-aryl tetrahydroisoquinolines.34 This simple one-step approach generates the 1-aryl products in good to excellent yield and ee, without the need for N-functionalization. Erdmann and co-workers also used NCSs in a multi-enzyme cascade toward highly functionalized 1-benzyl/aryl THIQ derivatives.35 The three enzyme cascade starting from cheap starting materials furnished either enantiomer of the C(1)-substituted products in excellent yield and ee. Currently, only one chemoenzymatic cascade has been reported for the C(1)-functionalization of THIQs. The cascade was developed by Odachowski et al., and involves a MAO-N catalyzed oxidation followed by gold-catalyzed propargylation.36 The one-pot approach afforded a range of N-methyl-1-propargyl THIQs in good to excellent yields, under mild reaction conditions.

Results and Discussion

Following on from our previous work, we envisaged initially employing an enzymatic oxidation reaction to gain access to achiral 3,4-dihydroisoquinolines 2, which would be utilized in a subsequent chemical C–C bond forming step, to form racemic C(1)-substituted THIQs 3 (Scheme 1). Re-oxidation of this substrate, followed by an enzymatic stereoselective reduction, would allow access to the desired enantio-enriched scaffolds 4.

Scheme 1. Retrosynthetic Analysis of Proposed Cascade.

Scheme 1

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To establish the feasibility of the cascade we initially focussed on the model substrate 1,2,3,4-tetrahydroisoquinoline 1a which has previously been shown to be oxidized to 3,4-dihydroisoquinoline 2a using variants of monoamine oxidase (MAO-N).37−46 For the allylation step involving allylBPin we screened a range of organic solvents and buffers (see Supporting Information for details) and found that the conversion of 2a to 3a proceeded well in 100 mM KPi pH 7.8 buffer.

Next, we combined the enzyme catalyzed oxidation and subsequent chemical allylation steps into a one-pot procedure (Table 1). We initially selected four amine oxidases, which included three variants of MAO-N from Aspergillus niger along with the 6-hydroxy-d-nicotine oxidase (6-HDNO) from Arthrobacter nicotinovorans. The MAO-N variants are all (S)-selective enzymes which have been engineered toward the oxidation of pharmaceutically relevant amines. The D5 variant was engineered in our lab to achieve increased activity with both secondary and tertiary amines by increasing the volume of the active site.47 Using molecular modeling and saturated mutagenesis, a new variant, MAO-N D9, was developed which showed a 990-fold increase in activity toward Crispine A.48 The final MAO-N variant, D11, was engineered toward the oxidation of bulky diaryl chiral amines by increasing the volume of the hydrophobic pocket.2 The 6-HDNO variant was developed in our group for the (R)-selective oxidation of a broad range of 1, 2, and 3° amines.49

Table 1. Optimization of Conversion of 1a to 2aa.

graphic file with name ja2c09176_0008.jpg

entry enzyme AllylBPin (equiv) LA (10 mol %) 1a (%)b 2a (%)b (rac)-3a (%)b
1 D5c 2.5   >99 0 0
2 D9c 2.5   21 43 36
3 D9d 2.5   27 44 29
4 D9 2.5   0 51 49
5 D9 2.0   0 55 45
6 D9 3.0   0 48 52
7 D9 8.0   0 43 57
8 D9 8.0 InCl3 >99 0 0
9 D9 8.0 ZnBr 0 40 60
10 D9 8.0 Cu(OAc)2 98 0 2
11 D9 8.0 CuCl2 1 0 94
12 D9 8.0 Ag(OTf)3 0 50 50
13 D9 8.0 Yb(OTf)3 0 <1 >99
14 6-HDNO 8.0 Yb(OTf)3 >99 0 0
15 D11 8.0 Yb(OTf)3 1 0 99e
16   8.0 Yb(OTf)3 >99 0 0
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a

Biotransformations were carried out using 5 mM 1,2,3,4-tetrahydroisoquinoline, 2 mg mL–1 purified amine oxidase variant, and 10 mol % of Lewis Acid (LA), and reactions were made up to 500 μL with 5% v/v DMSO and 100 mM KPi buffer corrected to pH 7.8. If not stated enzymes were purified.

b

Conversions were based on GCMS data compared to analytic standards.

c

50 mg mL–1 MAO-N cell lysate.

d

500 mg mL–1 MAO-N whole cell.

e

The allylic imine intermediate is not observed in the GCMS. Using chiral HPLC, the conversion of rac-3a is 72 with 26% for the allylic imine intermediate.

Although MAO-N D5 showed no activity, the D9 variant gave 36% conversion to the desired product (rac)-3a (Table 1, entry 2) and 43% of intermediate imine 2a. Carrying out the reaction using lyophilized whole cells proved detrimental (Table 1, entry 3), with a decreased conversion to (rac)-3a of 29%. However, using purified enzyme improved the yield significantly (Table 1, entry 4). Increasing the amount of allylBPin (Table 1, entries 5–7, see Supporting Information for further optimization), improved the conversion to 3a to 57%.

It has been shown that nucleophilic addition to imines (including allylation reactions) can benefit from the addition of a Lewis acid (LA) leading to higher conversions.50 Therefore, we screened a series of water stable LAs (Table 1, entries 8–13) and found that both CuCl2 and Yb(OTf)3 gave >90% conversion (entries 11 and 13) with no remaining starting material or imine intermediate observed with Yb(OTf)3. No product was observed with the (R)-selective 6-HDNO (Table 1, entry 14). However, purified MAO-N D11 gave excellent conversions (entry 15). A control experiment in the absence of enzyme (Table 1, entry 16 see Supporting Information for further details) resulted in no conversion to 3a.

We next turned our attention toward the deracemization of (rac)-3a.26,41,51 which we envisaged could be achieved via stereoselective oxidation coupled with either selective or non-selective reduction to enantioenriched-3a.

Unfortunately, both the MAO-N D5 and D9 variants were unable to oxidize the racemic product 3a (Table 2, entries 1 and 2). The (R)-selective oxidase, 6-HDNO was also not able to oxidize (rac)-3a (Table 2, entry 3) which currently limits the cascade to accessing only (R)-products. Enzyme engineering could potentially be used to address this issue. Fortunately, the D11 variant succesfully oxidized (rac)-3a to the corresponding allylic imine intermediate in 26% conversion, favoring formation of (S)-3a in 36% ee via kinetic resolution (Table 2, entry 4). These results for the oxidation of (rac)-3a using the three MAO-N variants agree with previous reports, where the large hydrophobic site of D11 compared to D5 and D9 is better able to accommodate the bulky bicyclic amine.43 Exploiting the activity of MAO-D11, we then investigated a range of chemical and enzymatic reductants (Table 2, entries 4–15). Non-selective chemical reducing agents (entries 5 and 6) showed poor to moderate enantioselectivity for this deracemization process (NH3BH3, 30% ee and NaBH3CN, 72% ee) with significant amounts of the side-product 4a being formed. To effectively develop an enzymatic deracemization of the racemic product, the selectivity of the enzymatic oxidation and the IRED catalyzed reduction must be complementary. Thus, we exploited the (S)-selective oxidase, MAO-N D11, coupled with a panel of (R)-selective IREDs for the reduction step (Table 2, entries 714). The small panel comprised previously characterized and metagenomic IREDs which had displayed high (R)-selectivity for the reduction of 2-phenylpiperidine.16,52 Pleasingly with R-IRED, we observed full conversion to the desired (R)-enantiomer (entry 14), with no formation of the fully reduced side-product 4a, and therefore moved forward with these as our optimal conditions. The absolute configuration of 3a was confirmed as (R)-, as expected, by comparison of the optical rotation value with the previously reported (S)-3a (see Supporting Information 7.1). All subsequent products were assigned as (R)- by analogy, as predicted from the combined use of (S)-MAO-N and (R)-IRED.

Table 2. Screening of Reducing Agents From (rac)-3aa.

graphic file with name ja2c09176_0009.jpg

entry MAO-N variant reducing agent 3a (%)d 3a (R/S)e 4a (%)d
1 D5 none 100 50:50 0
2 D9 none 100 50:50 0
3 6-HDNO none 100 50:50 0
4 D11 none 74f 68:32 0
5 D11 NH3·BH3b 59 65:35 41
6 D11 NaBH3CNb 71 86:14 29
7 D11 pIRED 229c >99 68:32 <1
8 D11 pIRED 255c 81 76:24 19
9 D11 pIRED 282c >99 64:36 <1
10 D11 pIRED 357c 98 70:30 2
11 D11 pIRED 170c 95 76:24 5
12 D11 pIRED 180c 94 75:25 6
13 D11 pIRED 224c 99 63:37 1
14 D11 R-IREDc >99 >99:1 <1
15 D11 AdRedAm 86 95:5 14
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a

Biotransformations were carried out using 5 mM 1,2,3,4-tetrahydroisoquinoline and 2 mg mL–1 purified amine oxidase variant, and reactions were made up to 500 μL with 5% v/v DMSO and 100 mM KPi buffer corrected to pH 7.8.

b

Biotransformations where chemical reducing agents were used required 2 mg mL–1 purified MAO-N D11 and 40 mM of reducing agent.

c

Biotransformations where IREDs enzymes were used required 2 mg mL–1 purified MAO-N D11 and 6 mg mL–1 IRED lysate, 40 mM d-glucose, 0.4 mM NADP+, and 1 mg mL–1 CDX-GDH.

d

Conversions were based on GCMS data compared to analytical standards.

e

Measured by chiral HPLC and compared to racemic standards.

f

Rest of material observed is oxidized 3a to the imine intermediate.

Next, we explored the substrate scope of the reaction with respect to the tetrahydroisoquinoline (Scheme 2). Subtrates with halogens in the 6-position proceeded well in the reaction, furnishing the desired products in excellent yields and enantioselectivity (3b–d), with the fluoro-analogue 3d providing the best yield and enantioselectivity (94%, 84% ee). Electron-donating groups were also compatible under the reaction conditions (3e), with the 6-methoxy derivative produced in high yields and enantioselectivity. Unfortunately, the same conversions were not observed when incorporating a methoxy group at the 7-position (Scheme 2, 3f), with D11 unable to perform the initial oxidation of 1f. We also attempted the reaction with the 7-bromo-substrate and similarly saw no initial oxidation.

Scheme 2. Exploring the Substrate Scope With Respect to the THIQ Starting Material.

Scheme 2

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Biotransformations were carried out using 5 mM cyclic amine, 40 mM allylBPin, 10 mol % Yb(OTf)3, 2 mg mL–1 purified MAO-N D11, 6 mg mL–1, R-IRED lysate, 40 mM d-glucose, 0.4 mM NADP+, and 1 mg/mL CDX-GDH; reactions were made up to 500 μL with 5% v/v DMSO and 100 mM KPi buffer corrected to pH 7.8. Yields given are determined by GCMS analysis compared to analytical standards. Enantiomeric excess (ee) was determined by chiral HPLC analysis and compared to racemic standards.

Substitution was tolerated in the 6-7-dimethoxy derivative 3g, giving rise to the desired product in excellent yields and very good enantioselectivity (91%, 86% ee). Compound 3g is a key intermediate in a synthetic route to (+)-crispine A, a natural alkaloid that has been shown to have anti-tumour activity.53 Utilizing this method to synthesize 3g would avoid the need to use precious metals, which have been published previously.54−61 Substitution in the 8-position on the ring were investigated, with a methyl group furnishing the desired product (R)-3i; however, the enantioselectivity was low (32%). Pleasingly, the 8-bromo product (R)-3j worked well under the reaction conditions, giving rise to the desired product in excellent yields; however, enantioselectivity remained low (99%, 38% ee). The indoline derivative 3k was formed in good yields (78%) although low enantioselectivity (30% ee). This compound is a key intermediate for the synthesis of harmacine.62 To address the poor enantioselectivity of 3k, a broader panel of IREDs was screened in the cascade; however, this had no effect on the ee. As the enantioselectivity of the cascade is set through the deracemization, this means the activity and selectivity of both the oxidase and IRED need to be optimal to achieve greater ee. As R-IRED is a broad and highly selective enzyme, the cascade is currently limited by the D11 variant, further engineering of which will be required to enhance ee values.

We then examined the substrate scope with respect to the boryl component (Scheme 3). Pleasingly, when a methyl- or ethyl-group was substituted at R2, the reaction proceeded well giving rise to the desired products 3l and 3m, respectively. When a phenyl group was substituted at R2, the reaction progressed well to give a yield of 72% and very good ee (82%) (3n). Replacing R1 with a methyl group produced the desired product 3o in excellent yield (96%), moderate enantioselectivity (54%), and gave a mixture of diastereoisomers. When R4 is a methyl group (3p), the desired product is formed in excellent yield, with excellent diastereo- and enantioselectivity. Introducing two methyl groups at these positions (R3 = R4 = Me) probed the limit of this reaction with product 3q being produced in low yields (19%). We were able to incorporate a propargyl group into the products by submitting a simple allene BPin into the reaction, to give compound 3r in excellent yield (97%); however, the enantioselectivity was moderate. However, the racemic product 3r has been shown as a key intermediate for the synthesis of reserpine alkaloids that are used to treat hypertension.63

Scheme 3. Exploring the Substrate Scope With Respect to the Boryl Reagent.

Scheme 3

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Biotransformations were carried out using 5 mM cyclic amine, 40 mM allylBPin derivative, 10 mol % Yb(OTf)3, 2 mg mL–1 purified MAO-N D11, 6 mg mL–1, R-IRED lysate, 40 mM d-glucose, 0.4 mM NADP+, and 1 mg mL–1 CDX-GDH; reactions were made up to 500 μL with 5% v/v DMSO and 100 mM KPi buffer corrected to pH 7.8. Yields given are determined by GCMS analysis compared to analytical standards. Enantiomeric excess (ee) was determined by chiral HPLC analysis and compared to racemic standards.

To improve our understanding of the reaction, we carried out a series of time course experiments, where we monitored the conversion and enantioselectivity of the formation of 1-allyl-1,2,3,4-tetrahydroisoquinoline 3a from 1,2,3,4-tetrahydroisoquinoline 1a over time (see Supporting Information). After only 6 h, the conversion reached 90% with 90% ee, and after 12 h, only the desired product and (R)-3a could be observed (>99% ee). The proposed catalytic cycle is shown in Scheme 4.

Scheme 4. Proposed Catalytic Cycle.

Scheme 4

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Initial oxidation of the tetrahydroisoquinoline 1 catalyzed by MAO-N is followed by nucleophilic addition of allylboronic acid pinacol ester, in the presence of a Lewis acid, to form a racemic mixture of product 3. MAO-N then selectively oxidizes the (S)-enantiomer of 3 to the corresponding dihydroisoquinoline 5, which is subsequently reduced selectively to the desired product, (R)-3. Once formed, either via the initial allylation reaction or the oxidation/reduction pathway, the desired R-enantiomer remains untouched by MAO-N.

Finally, to demonstrate the practical utility of this chemo-enzymatic allylation process, we carried out preparative scale reactions. Products (R)-3a and (R)-3m were successfully isolated from scaled-up reactions in 59 and 64% yield, respectively (98% ee) (Scheme 5).

Scheme 5. Preparative Scale Reactions.

Scheme 5

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Biotransformations were carried out using 15 mM cyclic amine, 120 mM allylBPin derivative, 10 mol % Yb(OTf)3, 2 mg mL–1 purified MAO-N D11, 6 mg mL–1 R-IRED lysate, 40 mM d-glucose, 0.4 mM NADP+, and 1 mg mL–1 CDX-GDH; reactions were made up to 50 mL with 5% v/v DMSO and 100 mM KPi buffer corrected to pH 7.8. Conversion given are determined by GCMS analysis compared to analytical standards. Enantiomeric excess (ee) was determined by chiral HPLC analysis and compared to racemic standards.

In summary, we have developed a one-pot chemo-enzymatic cascade process that employs two different biocatalysts, namely, a monoamine oxidase (MAO-N) and an imine reductase (IREDs), to enable enantioselective C(1)-allylation of tetrahydroisoquinolines. The cascade has been shown to work with a range of substituted tetrahydroisoquinolines as well as various allylBPin reagents. This report is a major advancement over our previous work on chemoenzymatic cascades toward C(1)-substituted THIQs.36 In our earlier approach, N-alkylation of the THIQ substrate was required to generate the more reactive iminium intermediate, limiting further downstream modification. Our current approach goes via the imine intermediate and thus does not require N-alkylation or acylation. However, the key advancement is the ability of this cascade to deracemize the racemic product, obtaining high enantioselectivities. The method offers an alternative approach to access these privileged scaffolds without the requirement of precious metals, organic solvents, and high temperatures.

Acknowledgments

We wish to thank the ERC (Advanced Grant BIO-H-BORROW—grant no. 742987), and J.J.S. is grateful to the Industrial Affiliates of CoEBio3 for a PhD studentship.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.2c09176.

  • Details of experimental procedures, HPLC traces, and NMR spectra (PDF)

Author Present Address

† Lennard-Jones Laboratory, School of Chemical and Physical Sciences, Keele University, Keele, Staffordshire, ST5 5BG, U.K

Author Present Address

‡ Aragonese Foundation for Research & Development (ARAID). Institute of Chemical Synthesis and Homogeneous Catalysis (ISQCH-CSIC). Pedro Cerbuna 12, 50009 Zaragoza, Spain.

The authors declare no competing financial interest.

Supplementary Material

ja2c09176_si_001.pdf (2.6MB, pdf)

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