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One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo- and heterogeneous Lewis acids

One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo- and heterogeneous Lewis acids Continuous flow chemistry holds great potential for the production of biologically relevant molecules. Herein, we present an approach for the continuous synthesis of cannabidiol and tetrahydrocannabinol in a one-flow system. The designed route consists of a reaction cascade involving Friedel-Crafts alkylation, subsequent ring opening and cyclisation in up to 45% yield. The reactions were successfully performed using both hetero- and homogeneous Lewis acids in continuous flow and provide yields that are similar to comparable batch processes. . . . Keywords Cannabinoids Heterocycles Flow chemistry Heterogeneous Lewis acid catalysis Introduction increasingly applied for safer, scalable and more efficient re- actions in academic and industrial settings. An ongoing challenge in organic synthesis is the optimisation The preparation of APIs in a continuous flow process is of isolated yield in chemical transformations for the produc- desirable as it increases safety, scalability, reproducibility tion of biologically relevant molecules. A practical approach and efficiency. Multistep cascade reactions, which can be for reaction optimisation is offered by flow chemistry, which carried out in a single flow system (One-Flow) are particu- allows efficient and even automated screening for reaction larly attractive for the synthesis of pharmaceutically active conditions and faster analysis [1–6]. In addition, during the small molecules [9]. Within the framework of our EU last decade flow chemistry has emerged as a viable approach FETOPEN ONE-FLOW project [10], in which cascade for the larger scale preparation of fine chemicals and active one-flow approaches are being developed for the synthesis pharmaceutical ingredients (APIs) [7, 8]. Hence, while batch of APIs, we aimed to implement this strategy for producing reactions are still commonly used, flow chemistry is cannabinoids. A class of molecules that are typically prepared in batch are synthetic (phyto-)cannabinoid derivatives. These cannabinol Highlights mimetics are derived from naturally occurring molecules that � Development of heterogeneous Lewis acid catalysts for in flow Friedel- have been isolated from various genera of Cannabis [11]. Crafts alkylation � Implementation of homo- and heterogeneous Lewis acids for the prep- Chemists and biologists have shown great interest in unveiling aration of cannabinoids in a one-flow system the function of the endogenous cannabinoid receptors (CB and CB ) as they play a major role in health and disease [12]. * Floris P. J. T. Rutjes Up till now, a plethora of (ant-)agonists have been identified Floris.Rutjes@ru.nl; https://www.ru.nl/syntheticorganicchemistry/ for both cannabinoid receptors, and are prepared on large scale Jan C. M. van Hest through batch chemistry [13]. Many of these synthetic routes J.C.M.v.Hest@tue.nl; https://www.tue.nl/en/research/research- are experimentally challenging, poorly scalable and afford groups/bio-organic-chemistry/ overall yields up to 40%. Recently, however, Giorgi and co- workers reported the flow synthesis of racemic ortho-tetrahy- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525, AJ Nijmegen, The Netherlands drocannabinols (THC) in flow using multiple heterogeneous catalytic steps (Scheme 1a)[14]. A sequence of citral oxida- Bio-organic chemistry, Eindhoven University of Technology, P.O. Box 513 (STO 3.31), 5600 MB Eindhoven, The Netherlands tion with gold nanoparticles, Friedel-Crafts alkylation and a 100 J Flow Chem (2021) 11:99–105 internal H-NMR standard to allow reaction monitoring by NMR (see: Supporting information I). The flow reactions with triflic acid (TfOH) gave promising results affording appreciable amounts of olivetylverbenyl (5) and THC product 6. Unfortunately, the use of TfOH also resulted in the formation of a precipitate, which hampered the flow process (Table 1,entries 1–6). The insoluble precip- itate was hypothesised to consist of PEEK polymers formed through degradation of the polymer by TfOH. In contrast, use of the homogeneous Lewis acid BF ·OEt did not give pre- 3 2 cipitation, and showed similar yield. Surprised by the smaller residence time, using BF ·OEt we were able to selectively 3 2 tune the system to afford either more olivetylverbenyl (5)or Scheme 1 a One-flow synthesis of a diastereomeric mixture of racemic 8 (−)-trans-Δ -THC (6,entries 7–9and 14–18, respectively). 8 9 ortho- Δ -and Δ -THC using citral (1) and olivetol (2)by Giorgi et al. b 8 9 After more extensive optimisation, we reached yields of up Our enantio- and diastereoselective one-flow synthesis of Δ -and Δ - THC to 47% into olivetylverbenyl (5) or 45% into (−)-trans-Δ - THC (6) (entries 8 and 15, respectively), which is in line with final cyclisation using titanium-doped montmorillonite (Ti/ reported maximum yields in batch reactions [17, 28]. A fur- ther increase in yield could not be achieved, most likely due to MMT) afforded a variety of THCs, albeit without stereoselectivity and low regioselectivity. side product formation (in particular olivetyldiverbenyl) and further degradation of (−)-verbenol [16, 29]. Purification of Alternatively, enantiopure tetrahydrocannabinols can be these complex mixtures was conducted using silica gel col- synthesised using various chiral pool approaches in a limited number of synthetic steps [15–24]. To the best of our knowl- umn chromatography and resulted also in partial recovery of olivetol, indicating that Friedel-Crafts alkylation did not go to edge, the application of flow chemistry for the stereoselective synthesis of THC has not yet been reported (Scheme 1b). We completion. herewith report a straightforward one-flow system to efficient- 8 9 ly prepare both (−)-trans-Δ -and Δ -THCs using homoge- 8 9 Heterogeneous flow synthesis of CBD, Δ -and Δ -THC neous and heterogeneous Lewis acids. Prompted by the results of homogeneous Lewis acids, we set out to investigate a variety of heterogeneous Lewis acids as Results and discussion well. While homogeneous catalysts are fast and effective on mmol laboratory scale, industry shows more interest in het- Homogeneous flow synthesis of olivetylverbenyl and erogeneous catalysts which generally reach higher turnover Δ -THC numbers and can be more easily recycled [30]. Our attention was drawn to metal-coordinated Amberlyst resins, which can Inspired by the chiral pool approach of Mechoulam [16], be readily prepared and were shown to be effective in Lewis which we initially used in a batch approach to make THC acid catalysis [31–33]. Six different Lewis acids were selected derivatives, we now set out to use this strategy in a one-flow (Zn(OTf) ,Sn(OTf) ,Cu(OTf) ,Yb(OTf) ,Sc(OTf) and 2 2 2 3 3 system to synthesise (−)-trans-Δ -THC [25, 26]. Since our In(OTf) ) and immobilised on Amberlyst-15® (Scheme 2). group previously investigated such chiral pool approach Since BF ·OEt appeared very effective under homogeneous 3 2 [27], we were keen to implement the proven batch process reaction conditions, we also included silica-supported boron into a continuous flow process. In line with our previous batch trifluoride (Silica-BF ) and polyvinylpyrrolidone-supported experiments we initially investigated the flow synthesis of boron trifluoride (PVP-BF ) as heterogeneous catalysts. thermodynamically favoured Δ -THC using homogeneous The setup consisted of syringe pumps, perfluoroalkoxy Brønsted catalysts. More specifically, this involved the reac- (PFA) tubing (OD 1/8″,ID 1/16″ or 1/25″), Super tion of (−)-verbenol (3) and olivetol (2), which in a sequence Flangeless fittings and a Omnifit packed bed reactor of Brønsted acid-mediated Friedel-Crafts alkylation, rear- (6.6 × 10 mm) (see: Supporting information II). We rangement and cyclisation in a one-flow reactor afforded started the screening with commercially available 8 + + 8 (−)-trans-Δ -THC (6) via the intermediate product DOWEX-H and Amberlyst-H in the synthesis of Δ - olivetylverbenyl (5). The setup consisted of syringe pumps, THC. Only small amounts of olivetylverbenyl (5)were + 8 perfluoroalkoxy (PFA) tubing (OD 1/8″,ID 1/16″ or 1/25″), observed with DOWEX-H ,while Δ -THC was not ob- Super Flangeless fittings, while biphenyl was used as an served at all (Table 2,entry 1). Inversely,Amberlyst-H J Flow Chem (2021) 11:99–105 101 Table 1 Homogeneous flow synthesis of olivetylverbenyl (5)and (−)-trans-Δ -THC (6) entry Brønsted or t yield (%) Lewis acid (mol%) (s) olivetylverbenyl (5)Δ -THC (6) 1 TfOH (0.25) 30 41 9 26026 11 32408 17 4 TfOH (0.50) 30 25 11 56030 17 62406 41 7BF ·OEt (0.10) 30 42 0 3 2 86047 0 924041 0 10 BF ·OEt (0.25) 30 37 11 3 2 11 60 30 15 12 240 7 32 13 BF ·OEt (0.50) 30 11 28 3 2 14 60 0 38 15 240 0 45 16 BF ·OEt (1.00) 30 0 41 3 2 17 60 0 41 18 240 0 40 Conditions: A stock solution of olivetol and (−)-verbenol (0.25 M) in DCM and a stock solution of Brønsted or Lewis acid (0.25 M) in DCM were a 1 pumped through a PFA reactor (200 μL) and quenched directly using saturated aqueous NaHCO ; crude yield based on H-NMR using biphenyl as internal standard did provide small amounts of (−)-trans-Δ -THC (6), but resins gave poor dispersion of the reactants because of the interestingly the intermediate product 5 was not observed resin particle size, which hampered the reproducibility (entry 2). We hypothesised that DOWEX-H was not ef- and catalytic activity of the resins (see also: Supporting ficient in Friedel-Crafts alkylation and cyclisation and information II). To increase yields of the low reactive −1 Amberlyst not acidic enough to obtain higher yields of resins we decreased flow rates to 0.01 mL·min ,but 6. We then shifted our focus to the Lewis acidic did not obtain the desired tetrahydrocannabinols. Amberlyst-metal complexes and observed quantitative amounts of Friedel-Crafts product 5, but no formation of In an attempt to further raise the yields, we changed to the (−)-trans-Δ -THC (6,entries 3–8). The lack of (−)- boron trifluoride resins, as the corresponding catalyst is trans-Δ -THC (6) production was attributed to a lower known to be effective in homogeneous flow reactions Lewis acid strength compared to conventional BF ·OEt [33–35]. Interestingly, while pumping the substrate solution 3 2 used for cannabinoid synthesis. In addition, all Amberlyst through the reactor, a red colour was observed (see: supporting information II). We were delighted to see the for- mation of small amounts of (−)-trans-Δ -THC (6) in the crude product, and also observed an increase in yield of 6 by increas- ing residence time (entries 9 and 10). The PVP-BF resin resulted in a smaller amount of product, and showed faster Scheme 2 The incorporation of metal triflate Lewis acids on Amberlyst- 15® 102 J Flow Chem (2021) 11:99–105 Table 2 Screening of the heterogeneous catalysts for Δ -THC (6) formation entry catalyst yield (%) olivetylverbenyl (5)Δ -THC (6) t 100 s 1000 s 100 s 1000 s 1Dowex-H 17 21 0 0 2Amberlyst-Zn 31 49 0 0 3Amberlyst-Sn 43 51 0 0 4Amberlyst-Cu 29 n.d. 00 5Amberlyst-Yb 31 61 0 0 6Amberlyst-Sc 36 46 0 0 7Amberlyst-In 41 55 0 0 8Amberlyst-H 00 12 14 9PVP-BF 00 28 40 10 Silica-BF 00 34 39 Conditions: a stock solution of olivetol and p-mentha-2,8-dien-1-ol (0.25 M) in DCM was pumped over a packed bed reactor filled with Lewis acid a 1 b c (approximately 500 mg resin); crude yield based on H-NMR using biphenyl as internal standard; not determined; residence time of 100 and 1000 s −1 corresponds to a flow rate of respectively 0.10 and 0.01 mL·min loss of catalytic activity than the Si-BF resin upon prolonged among the highest yields reported for this one-pot multistep use (over 15 mL solution) [36–41]. sequence into the Δ -isomer [28]. In addition, this synthetic Stimulated by this result, we aimed to prepare the synthet- procedure is also scalable due to the continuous character of ically more challenging cannabidiol (CBD, 7)and (−)- the reaction setup. Finally, a further increase in residence time 9 9 8 trans-Δ -THC (8) using Si-BF as well. In batch chemistry, afforded mixtures of CBD (7), Δ -THC (8)and Δ -THC (6) the formation of 8 is hard to optimise, since it readily and did not provide any selectivity (entries 4 and 5). isomerises to its thermodynamically more stable Δ -isomer 6 [17, 26]. The application of this reaction in a one-flow sys- tem, however, allows for more precise control of reaction Conclusion parameters, and is better suited for optimisation. The flow system yielding Si-BF was applied to p-mentha-2,8-dien-1- In conclusion, we developed a synthetically versatile flow 9 8 9 ol (4) and olivetol to successfully afford (−)-trans-Δ -THC system to synthesise CBD, Δ -and Δ -THC in up to 45% with minimal amounts of Δ -THC (Table 3)[17]. yield. The studied cascade reaction was effective in homoge- neous systems using BF OEt or TfOH as the catalyst, but 3 2 The flow reactor containing silica-supported boron also in a heterogeneous setup using silica-supported boron trifluoride provided a variety of cannabinoid products and trifluoride. In the search for heterogeneous solid-supported was successful in the Friedel-Crafts alkylation and cyclisation Lewis acids, we assessed a small variety of Amberlyst-metal reaction. At high flow speeds, thus shorter residence times, complexes to conduct the final chemical transformations of mixtures of CBD (7)and Δ -THC (8) were obtained (entries the cascade reaction. The various flow conditions were eval- 1 and 2). In both entries, we did not observe transformation uated using H-NMR and internal standards and seemed to be into the thermodynamic Δ -THC isomer (6). Both CBD and experimentally feasible for the continuous flow production of Δ -THC were isolated in small amounts after silica gel puri- cannabinoids. We envision that this hands-on flow system fication. The yield into Δ -THC (8) was effectively increased will be highly valuable for organic chemists aiming to prepare by going to longer residence times, affording up to 40% of enantiopure CBD- and THC-like scaffolds using a chiral pool yield on NMR and 30% of isolated yield (entry 3). Although approach. A follow-up study to investigate the applicability of there was some isomerisation to the Δ -THC isomer (6)vis- the system to a wider range of synthetic cannabinoid deriva- ible in the crude NMR spectra, the 30% isolated yield ranks tives is currently ongoing in our laboratories. J Flow Chem (2021) 11:99–105 103 Table 3 Heterogeneous flow synthesis of CBD (7)and (−)-trans-Δ -THC (8) c a entry t (s) yield (isolated) 9 8 CBD (7)Δ -THC (8)Δ -THC (6) 1 5 20 (12) 20 (8) 0 2 10 26 (12) 20 (14) 0 3 20 10 (7) 40 (30) 7 (n.i.) 4 100 9 (2) 41 (19) 10 (10) 5 200 4 (n.i.) 37 (14) 23 (27) Conditions: a stock solution of olivetol and p-mentha-2,8-dien-1-ol (0.25 M) in DCM was pumped over a packed bed reactor filled with catalyst (500 mg a 1 silica-supported boron trifluoride) and quenched directly using saturated aqueous NaHCO solution; crude yield percentage (%) based on H-NMR b c using biphenyl as internal standard; not isolated; residence time of 5, 10, 20, 100 and 200 s corresponds to flow rates of respectively 2.00, 1.00, 0.50, −1 0.10 and 0.05 mL·min Experimental section (for 1/16″), Low-pressure PEEK T-pieces and crosses (1/4–28 thread, flat bottomed) were used to design homogeneous flow General information experiments. Heterogeneous experiments used same materials and utilised an adjustable Omnifit® glass reactor (ID 6.6 mm, NMR spectra were recorded on a Bruker Avance III 400 MHz or length 1–50 mm, 006SCC-06-05-AA) (See also: Supporting a Bruker 500 MHz spectrometer and the compounds were information III). 1 13 11 19 assigned using HNMR, C NMR, B NMR, F NMR, COSY, HSQCED and HMBC spectra. Chemical shifts were Preparation of Amberlyst-metal catalysts reported in parts per million (ppm.) relative to reference 1 13 1 (CDCl : H: 7.26 ppm. and C 77.16 ppm.; CD OD: H: 3 3 Amberlyst® 15 (hydrogen form, 1.00 g) was added in a poly- 13 1 3.31 ppm. and C 49.00 ppm.; (CD ) SO: H: 2.50 ppm. and propylene vessel with frit (25 mL) and mixed with saturated 3 2 C 39.52 ppm.) NMR data are presented in the following way: aqueous Na SO solution (15 mL). The vessel was closed, mixed 2 4 chemical shift, multiplicity (s = singlet, bs = broad singlet, d = for 10 min, filtered using vacuum suction, and washed with doublet, t = triplet, dd = doublet of doublets, ddd = doublet of saturated aqueous Na SO solution (3 × 15 mL). The pH of the 2 4 doublet of doublets, dtd = doublet of triplet of doublets h = filtration was measured, and when the pH >6.0 the Amberlyst- heptet, m = multiplet and/or multiple resonances) and coupling Na was dried in a vacuum oven (50 °C) for 4 h. The obtained constants J in Hz. Reactions were monitored using TLC F Amberlyst-Na was mixed with EtOH (20 mL), the metal triflate (Merck KGaA) using UV absorption detection (254 nm) and (1 mmol/g of resin) was added and the mixture was shaken by spraying them with cerium ammonium molybdate stain overnight at r.t. The resin was filtered using vacuum suction, (Hannesian’s stain) followed by charring at ca 300 °C. Mass EtOH (20mL) wasaddedand shaken for1hatr.t.The resin spectra were recorded on a JEOL AccuTOF CS JMS-T100CS was filtered using vacuum suction and finally dried in a vacuum (ESI) mass spectrometer. Melting points (m.p.) were determined oven (50 °C) for 4 h. to afford the Amberlyst-metal resin. using a Büchi Melting Point B-545. Automatic flash column chromatography was executed on a Biotage Isolera Spektra Preparation of PVP-BF One using SNAP or Silicycle cartridges (Biotage, 30–100 μm, 60 Å) 4–50 g. Reactions under protective atmosphere were per- Polyvinylpyrrolidone (PVP, MW 40.000, 1.50 g) was added in a formed under positive Ar/N flow in flame-dried flasks. Syringe flask and stirred in dry DCM (15 mL). BF OEt (2.88 g, 3 2 pumps, Chemyx Fusion 100, were obtained from Chemyx. Flow 20.2 mmol, 2.50 mL) was dissolved in dry DCM (10 mL) and chemistry equipment was obtained from Inacom instruments, added to a dripping funnel. The BF OEt solution was added 3 2 Screening Devices and VWR Scientific. Perfluoroalkoxy dropwise to the PVP solution, and stirred for 1 h at r.t. The (PFA) tubing (OD 1/16″,ID1/50″), Super flangeless fittings stirring bar was removed, and the suspension was filtered and 104 J Flow Chem (2021) 11:99–105 washed with DCM (2 × 25 mL) to afford a white powder. The MgSO , concentrated in vacuo and analysed directly. (See also: white powder was dried overnight under high vacuum at r.t. to Supporting information V). afford PVP-BF resin which was used freshly within two weeks. Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s41981-020-00133-2. Preparation of Si-BF Authors’ contributions Not applicable. Silica gel 60H (4.11 g, 68.4 mmol) was added in a flask which was evacuated and backfilled thrice with Ar. Dry MeOH Funding We kindly acknowledge funding by the H2020-FETOPEN- 2016-2017 programme of the European Commission (Grant agreement (90 mL) was added, and the mixture was stirred to obtain a number: 737266-ONE FLOW). cloudy suspension. BF OEt (58.1 mmol, 7.18 mL, 0.85 3 2 equiv) was added dropwise, and the mixture was stirred for Data availability The raw data will be accessible on the Radboud 2 h at r.t. The stirring bar was removed, and the solvent care- University depository. fully evaporated in vacuo to afford a white powder. The white powder was dried overnight under high vacuum at r.t. to af- Compliance with ethical standards ford Si-BF resin which was used freshly within two weeks. Conflicts of interest/competing interests There are no conflicts of interest. Homogeneous flow synthesis of cannabinoids Code availability Not applicable Olivetol (1 equiv), (−)-verbenol or p-mentha-2,8-dien-1-ol (1 Open Access This article is licensed under a Creative Commons equiv) and biphenyl (0.25 equiv, H-NMR standard) were added Attribution 4.0 International License, which permits use, sharing, in a flask which was evacuated and backfilled thrice with Ar. The adaptation, distribution and reproduction in any medium or format, as reactants were dissolved in dry DCM at r.t. to obtain a 0.25 M long as you give appropriate credit to the original author(s) and the reactant solution. Brønsted or Lewis acid (1 equiv) was added in source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article a second flask, and dissolved in dry DCM at r.t. to obtain a are included in the article's Creative Commons licence, unless indicated 0.25 M catalyst solution. Both solutions were loaded in glass otherwise in a credit line to the material. If material is not included in the syringes, placed in syringe pumps and connected to a T-piece article's Creative Commons licence and your intended use is not (PEEK). The PFA tubing reactor was connected to the T-piece permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a and the syringe pumps were set to the according speed. At least copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. (1,5 × t ) was waited for the system to equilibrate after which obtained samples could be obtained. The reactor outlet was led into a stirred solution of saturated aqueous NaHCO . The crude References mixture was extracted with DCM, and the organic layers were combined, dried with MgSO , concentrated in vacuo and 1. 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Petrzilka T, Sikemeier C (1967) Synthesis of (−)-Δ6, 1-3, 4-trans- tetrahydrocannabinol, as well as (+)-Δ6, 1-3, 4-trans-tetrahydro- Publisher’snote Springer Nature remains neutral with regard to jurisdic- cannabinol. Helv Chim Acta 50(2):1416–1419 tional claims in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Flow Chemistry Springer Journals

One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo- and heterogeneous Lewis acids

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Springer Journals
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Copyright © The Author(s) 2020
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2062-249X
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2063-0212
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10.1007/s41981-020-00133-2
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Abstract

Continuous flow chemistry holds great potential for the production of biologically relevant molecules. Herein, we present an approach for the continuous synthesis of cannabidiol and tetrahydrocannabinol in a one-flow system. The designed route consists of a reaction cascade involving Friedel-Crafts alkylation, subsequent ring opening and cyclisation in up to 45% yield. The reactions were successfully performed using both hetero- and homogeneous Lewis acids in continuous flow and provide yields that are similar to comparable batch processes. . . . Keywords Cannabinoids Heterocycles Flow chemistry Heterogeneous Lewis acid catalysis Introduction increasingly applied for safer, scalable and more efficient re- actions in academic and industrial settings. An ongoing challenge in organic synthesis is the optimisation The preparation of APIs in a continuous flow process is of isolated yield in chemical transformations for the produc- desirable as it increases safety, scalability, reproducibility tion of biologically relevant molecules. A practical approach and efficiency. Multistep cascade reactions, which can be for reaction optimisation is offered by flow chemistry, which carried out in a single flow system (One-Flow) are particu- allows efficient and even automated screening for reaction larly attractive for the synthesis of pharmaceutically active conditions and faster analysis [1–6]. In addition, during the small molecules [9]. Within the framework of our EU last decade flow chemistry has emerged as a viable approach FETOPEN ONE-FLOW project [10], in which cascade for the larger scale preparation of fine chemicals and active one-flow approaches are being developed for the synthesis pharmaceutical ingredients (APIs) [7, 8]. Hence, while batch of APIs, we aimed to implement this strategy for producing reactions are still commonly used, flow chemistry is cannabinoids. A class of molecules that are typically prepared in batch are synthetic (phyto-)cannabinoid derivatives. These cannabinol Highlights mimetics are derived from naturally occurring molecules that � Development of heterogeneous Lewis acid catalysts for in flow Friedel- have been isolated from various genera of Cannabis [11]. Crafts alkylation � Implementation of homo- and heterogeneous Lewis acids for the prep- Chemists and biologists have shown great interest in unveiling aration of cannabinoids in a one-flow system the function of the endogenous cannabinoid receptors (CB and CB ) as they play a major role in health and disease [12]. * Floris P. J. T. Rutjes Up till now, a plethora of (ant-)agonists have been identified Floris.Rutjes@ru.nl; https://www.ru.nl/syntheticorganicchemistry/ for both cannabinoid receptors, and are prepared on large scale Jan C. M. van Hest through batch chemistry [13]. Many of these synthetic routes J.C.M.v.Hest@tue.nl; https://www.tue.nl/en/research/research- are experimentally challenging, poorly scalable and afford groups/bio-organic-chemistry/ overall yields up to 40%. Recently, however, Giorgi and co- workers reported the flow synthesis of racemic ortho-tetrahy- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525, AJ Nijmegen, The Netherlands drocannabinols (THC) in flow using multiple heterogeneous catalytic steps (Scheme 1a)[14]. A sequence of citral oxida- Bio-organic chemistry, Eindhoven University of Technology, P.O. Box 513 (STO 3.31), 5600 MB Eindhoven, The Netherlands tion with gold nanoparticles, Friedel-Crafts alkylation and a 100 J Flow Chem (2021) 11:99–105 internal H-NMR standard to allow reaction monitoring by NMR (see: Supporting information I). The flow reactions with triflic acid (TfOH) gave promising results affording appreciable amounts of olivetylverbenyl (5) and THC product 6. Unfortunately, the use of TfOH also resulted in the formation of a precipitate, which hampered the flow process (Table 1,entries 1–6). The insoluble precip- itate was hypothesised to consist of PEEK polymers formed through degradation of the polymer by TfOH. In contrast, use of the homogeneous Lewis acid BF ·OEt did not give pre- 3 2 cipitation, and showed similar yield. Surprised by the smaller residence time, using BF ·OEt we were able to selectively 3 2 tune the system to afford either more olivetylverbenyl (5)or Scheme 1 a One-flow synthesis of a diastereomeric mixture of racemic 8 (−)-trans-Δ -THC (6,entries 7–9and 14–18, respectively). 8 9 ortho- Δ -and Δ -THC using citral (1) and olivetol (2)by Giorgi et al. b 8 9 After more extensive optimisation, we reached yields of up Our enantio- and diastereoselective one-flow synthesis of Δ -and Δ - THC to 47% into olivetylverbenyl (5) or 45% into (−)-trans-Δ - THC (6) (entries 8 and 15, respectively), which is in line with final cyclisation using titanium-doped montmorillonite (Ti/ reported maximum yields in batch reactions [17, 28]. A fur- ther increase in yield could not be achieved, most likely due to MMT) afforded a variety of THCs, albeit without stereoselectivity and low regioselectivity. side product formation (in particular olivetyldiverbenyl) and further degradation of (−)-verbenol [16, 29]. Purification of Alternatively, enantiopure tetrahydrocannabinols can be these complex mixtures was conducted using silica gel col- synthesised using various chiral pool approaches in a limited number of synthetic steps [15–24]. To the best of our knowl- umn chromatography and resulted also in partial recovery of olivetol, indicating that Friedel-Crafts alkylation did not go to edge, the application of flow chemistry for the stereoselective synthesis of THC has not yet been reported (Scheme 1b). We completion. herewith report a straightforward one-flow system to efficient- 8 9 ly prepare both (−)-trans-Δ -and Δ -THCs using homoge- 8 9 Heterogeneous flow synthesis of CBD, Δ -and Δ -THC neous and heterogeneous Lewis acids. Prompted by the results of homogeneous Lewis acids, we set out to investigate a variety of heterogeneous Lewis acids as Results and discussion well. While homogeneous catalysts are fast and effective on mmol laboratory scale, industry shows more interest in het- Homogeneous flow synthesis of olivetylverbenyl and erogeneous catalysts which generally reach higher turnover Δ -THC numbers and can be more easily recycled [30]. Our attention was drawn to metal-coordinated Amberlyst resins, which can Inspired by the chiral pool approach of Mechoulam [16], be readily prepared and were shown to be effective in Lewis which we initially used in a batch approach to make THC acid catalysis [31–33]. Six different Lewis acids were selected derivatives, we now set out to use this strategy in a one-flow (Zn(OTf) ,Sn(OTf) ,Cu(OTf) ,Yb(OTf) ,Sc(OTf) and 2 2 2 3 3 system to synthesise (−)-trans-Δ -THC [25, 26]. Since our In(OTf) ) and immobilised on Amberlyst-15® (Scheme 2). group previously investigated such chiral pool approach Since BF ·OEt appeared very effective under homogeneous 3 2 [27], we were keen to implement the proven batch process reaction conditions, we also included silica-supported boron into a continuous flow process. In line with our previous batch trifluoride (Silica-BF ) and polyvinylpyrrolidone-supported experiments we initially investigated the flow synthesis of boron trifluoride (PVP-BF ) as heterogeneous catalysts. thermodynamically favoured Δ -THC using homogeneous The setup consisted of syringe pumps, perfluoroalkoxy Brønsted catalysts. More specifically, this involved the reac- (PFA) tubing (OD 1/8″,ID 1/16″ or 1/25″), Super tion of (−)-verbenol (3) and olivetol (2), which in a sequence Flangeless fittings and a Omnifit packed bed reactor of Brønsted acid-mediated Friedel-Crafts alkylation, rear- (6.6 × 10 mm) (see: Supporting information II). We rangement and cyclisation in a one-flow reactor afforded started the screening with commercially available 8 + + 8 (−)-trans-Δ -THC (6) via the intermediate product DOWEX-H and Amberlyst-H in the synthesis of Δ - olivetylverbenyl (5). The setup consisted of syringe pumps, THC. Only small amounts of olivetylverbenyl (5)were + 8 perfluoroalkoxy (PFA) tubing (OD 1/8″,ID 1/16″ or 1/25″), observed with DOWEX-H ,while Δ -THC was not ob- Super Flangeless fittings, while biphenyl was used as an served at all (Table 2,entry 1). Inversely,Amberlyst-H J Flow Chem (2021) 11:99–105 101 Table 1 Homogeneous flow synthesis of olivetylverbenyl (5)and (−)-trans-Δ -THC (6) entry Brønsted or t yield (%) Lewis acid (mol%) (s) olivetylverbenyl (5)Δ -THC (6) 1 TfOH (0.25) 30 41 9 26026 11 32408 17 4 TfOH (0.50) 30 25 11 56030 17 62406 41 7BF ·OEt (0.10) 30 42 0 3 2 86047 0 924041 0 10 BF ·OEt (0.25) 30 37 11 3 2 11 60 30 15 12 240 7 32 13 BF ·OEt (0.50) 30 11 28 3 2 14 60 0 38 15 240 0 45 16 BF ·OEt (1.00) 30 0 41 3 2 17 60 0 41 18 240 0 40 Conditions: A stock solution of olivetol and (−)-verbenol (0.25 M) in DCM and a stock solution of Brønsted or Lewis acid (0.25 M) in DCM were a 1 pumped through a PFA reactor (200 μL) and quenched directly using saturated aqueous NaHCO ; crude yield based on H-NMR using biphenyl as internal standard did provide small amounts of (−)-trans-Δ -THC (6), but resins gave poor dispersion of the reactants because of the interestingly the intermediate product 5 was not observed resin particle size, which hampered the reproducibility (entry 2). We hypothesised that DOWEX-H was not ef- and catalytic activity of the resins (see also: Supporting ficient in Friedel-Crafts alkylation and cyclisation and information II). To increase yields of the low reactive −1 Amberlyst not acidic enough to obtain higher yields of resins we decreased flow rates to 0.01 mL·min ,but 6. We then shifted our focus to the Lewis acidic did not obtain the desired tetrahydrocannabinols. Amberlyst-metal complexes and observed quantitative amounts of Friedel-Crafts product 5, but no formation of In an attempt to further raise the yields, we changed to the (−)-trans-Δ -THC (6,entries 3–8). The lack of (−)- boron trifluoride resins, as the corresponding catalyst is trans-Δ -THC (6) production was attributed to a lower known to be effective in homogeneous flow reactions Lewis acid strength compared to conventional BF ·OEt [33–35]. Interestingly, while pumping the substrate solution 3 2 used for cannabinoid synthesis. In addition, all Amberlyst through the reactor, a red colour was observed (see: supporting information II). We were delighted to see the for- mation of small amounts of (−)-trans-Δ -THC (6) in the crude product, and also observed an increase in yield of 6 by increas- ing residence time (entries 9 and 10). The PVP-BF resin resulted in a smaller amount of product, and showed faster Scheme 2 The incorporation of metal triflate Lewis acids on Amberlyst- 15® 102 J Flow Chem (2021) 11:99–105 Table 2 Screening of the heterogeneous catalysts for Δ -THC (6) formation entry catalyst yield (%) olivetylverbenyl (5)Δ -THC (6) t 100 s 1000 s 100 s 1000 s 1Dowex-H 17 21 0 0 2Amberlyst-Zn 31 49 0 0 3Amberlyst-Sn 43 51 0 0 4Amberlyst-Cu 29 n.d. 00 5Amberlyst-Yb 31 61 0 0 6Amberlyst-Sc 36 46 0 0 7Amberlyst-In 41 55 0 0 8Amberlyst-H 00 12 14 9PVP-BF 00 28 40 10 Silica-BF 00 34 39 Conditions: a stock solution of olivetol and p-mentha-2,8-dien-1-ol (0.25 M) in DCM was pumped over a packed bed reactor filled with Lewis acid a 1 b c (approximately 500 mg resin); crude yield based on H-NMR using biphenyl as internal standard; not determined; residence time of 100 and 1000 s −1 corresponds to a flow rate of respectively 0.10 and 0.01 mL·min loss of catalytic activity than the Si-BF resin upon prolonged among the highest yields reported for this one-pot multistep use (over 15 mL solution) [36–41]. sequence into the Δ -isomer [28]. In addition, this synthetic Stimulated by this result, we aimed to prepare the synthet- procedure is also scalable due to the continuous character of ically more challenging cannabidiol (CBD, 7)and (−)- the reaction setup. Finally, a further increase in residence time 9 9 8 trans-Δ -THC (8) using Si-BF as well. In batch chemistry, afforded mixtures of CBD (7), Δ -THC (8)and Δ -THC (6) the formation of 8 is hard to optimise, since it readily and did not provide any selectivity (entries 4 and 5). isomerises to its thermodynamically more stable Δ -isomer 6 [17, 26]. The application of this reaction in a one-flow sys- tem, however, allows for more precise control of reaction Conclusion parameters, and is better suited for optimisation. The flow system yielding Si-BF was applied to p-mentha-2,8-dien-1- In conclusion, we developed a synthetically versatile flow 9 8 9 ol (4) and olivetol to successfully afford (−)-trans-Δ -THC system to synthesise CBD, Δ -and Δ -THC in up to 45% with minimal amounts of Δ -THC (Table 3)[17]. yield. The studied cascade reaction was effective in homoge- neous systems using BF OEt or TfOH as the catalyst, but 3 2 The flow reactor containing silica-supported boron also in a heterogeneous setup using silica-supported boron trifluoride provided a variety of cannabinoid products and trifluoride. In the search for heterogeneous solid-supported was successful in the Friedel-Crafts alkylation and cyclisation Lewis acids, we assessed a small variety of Amberlyst-metal reaction. At high flow speeds, thus shorter residence times, complexes to conduct the final chemical transformations of mixtures of CBD (7)and Δ -THC (8) were obtained (entries the cascade reaction. The various flow conditions were eval- 1 and 2). In both entries, we did not observe transformation uated using H-NMR and internal standards and seemed to be into the thermodynamic Δ -THC isomer (6). Both CBD and experimentally feasible for the continuous flow production of Δ -THC were isolated in small amounts after silica gel puri- cannabinoids. We envision that this hands-on flow system fication. The yield into Δ -THC (8) was effectively increased will be highly valuable for organic chemists aiming to prepare by going to longer residence times, affording up to 40% of enantiopure CBD- and THC-like scaffolds using a chiral pool yield on NMR and 30% of isolated yield (entry 3). Although approach. A follow-up study to investigate the applicability of there was some isomerisation to the Δ -THC isomer (6)vis- the system to a wider range of synthetic cannabinoid deriva- ible in the crude NMR spectra, the 30% isolated yield ranks tives is currently ongoing in our laboratories. J Flow Chem (2021) 11:99–105 103 Table 3 Heterogeneous flow synthesis of CBD (7)and (−)-trans-Δ -THC (8) c a entry t (s) yield (isolated) 9 8 CBD (7)Δ -THC (8)Δ -THC (6) 1 5 20 (12) 20 (8) 0 2 10 26 (12) 20 (14) 0 3 20 10 (7) 40 (30) 7 (n.i.) 4 100 9 (2) 41 (19) 10 (10) 5 200 4 (n.i.) 37 (14) 23 (27) Conditions: a stock solution of olivetol and p-mentha-2,8-dien-1-ol (0.25 M) in DCM was pumped over a packed bed reactor filled with catalyst (500 mg a 1 silica-supported boron trifluoride) and quenched directly using saturated aqueous NaHCO solution; crude yield percentage (%) based on H-NMR b c using biphenyl as internal standard; not isolated; residence time of 5, 10, 20, 100 and 200 s corresponds to flow rates of respectively 2.00, 1.00, 0.50, −1 0.10 and 0.05 mL·min Experimental section (for 1/16″), Low-pressure PEEK T-pieces and crosses (1/4–28 thread, flat bottomed) were used to design homogeneous flow General information experiments. Heterogeneous experiments used same materials and utilised an adjustable Omnifit® glass reactor (ID 6.6 mm, NMR spectra were recorded on a Bruker Avance III 400 MHz or length 1–50 mm, 006SCC-06-05-AA) (See also: Supporting a Bruker 500 MHz spectrometer and the compounds were information III). 1 13 11 19 assigned using HNMR, C NMR, B NMR, F NMR, COSY, HSQCED and HMBC spectra. Chemical shifts were Preparation of Amberlyst-metal catalysts reported in parts per million (ppm.) relative to reference 1 13 1 (CDCl : H: 7.26 ppm. and C 77.16 ppm.; CD OD: H: 3 3 Amberlyst® 15 (hydrogen form, 1.00 g) was added in a poly- 13 1 3.31 ppm. and C 49.00 ppm.; (CD ) SO: H: 2.50 ppm. and propylene vessel with frit (25 mL) and mixed with saturated 3 2 C 39.52 ppm.) NMR data are presented in the following way: aqueous Na SO solution (15 mL). The vessel was closed, mixed 2 4 chemical shift, multiplicity (s = singlet, bs = broad singlet, d = for 10 min, filtered using vacuum suction, and washed with doublet, t = triplet, dd = doublet of doublets, ddd = doublet of saturated aqueous Na SO solution (3 × 15 mL). The pH of the 2 4 doublet of doublets, dtd = doublet of triplet of doublets h = filtration was measured, and when the pH >6.0 the Amberlyst- heptet, m = multiplet and/or multiple resonances) and coupling Na was dried in a vacuum oven (50 °C) for 4 h. The obtained constants J in Hz. Reactions were monitored using TLC F Amberlyst-Na was mixed with EtOH (20 mL), the metal triflate (Merck KGaA) using UV absorption detection (254 nm) and (1 mmol/g of resin) was added and the mixture was shaken by spraying them with cerium ammonium molybdate stain overnight at r.t. The resin was filtered using vacuum suction, (Hannesian’s stain) followed by charring at ca 300 °C. Mass EtOH (20mL) wasaddedand shaken for1hatr.t.The resin spectra were recorded on a JEOL AccuTOF CS JMS-T100CS was filtered using vacuum suction and finally dried in a vacuum (ESI) mass spectrometer. Melting points (m.p.) were determined oven (50 °C) for 4 h. to afford the Amberlyst-metal resin. using a Büchi Melting Point B-545. Automatic flash column chromatography was executed on a Biotage Isolera Spektra Preparation of PVP-BF One using SNAP or Silicycle cartridges (Biotage, 30–100 μm, 60 Å) 4–50 g. Reactions under protective atmosphere were per- Polyvinylpyrrolidone (PVP, MW 40.000, 1.50 g) was added in a formed under positive Ar/N flow in flame-dried flasks. Syringe flask and stirred in dry DCM (15 mL). BF OEt (2.88 g, 3 2 pumps, Chemyx Fusion 100, were obtained from Chemyx. Flow 20.2 mmol, 2.50 mL) was dissolved in dry DCM (10 mL) and chemistry equipment was obtained from Inacom instruments, added to a dripping funnel. The BF OEt solution was added 3 2 Screening Devices and VWR Scientific. Perfluoroalkoxy dropwise to the PVP solution, and stirred for 1 h at r.t. The (PFA) tubing (OD 1/16″,ID1/50″), Super flangeless fittings stirring bar was removed, and the suspension was filtered and 104 J Flow Chem (2021) 11:99–105 washed with DCM (2 × 25 mL) to afford a white powder. The MgSO , concentrated in vacuo and analysed directly. (See also: white powder was dried overnight under high vacuum at r.t. to Supporting information V). afford PVP-BF resin which was used freshly within two weeks. Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s41981-020-00133-2. Preparation of Si-BF Authors’ contributions Not applicable. Silica gel 60H (4.11 g, 68.4 mmol) was added in a flask which was evacuated and backfilled thrice with Ar. Dry MeOH Funding We kindly acknowledge funding by the H2020-FETOPEN- 2016-2017 programme of the European Commission (Grant agreement (90 mL) was added, and the mixture was stirred to obtain a number: 737266-ONE FLOW). cloudy suspension. BF OEt (58.1 mmol, 7.18 mL, 0.85 3 2 equiv) was added dropwise, and the mixture was stirred for Data availability The raw data will be accessible on the Radboud 2 h at r.t. The stirring bar was removed, and the solvent care- University depository. fully evaporated in vacuo to afford a white powder. The white powder was dried overnight under high vacuum at r.t. to af- Compliance with ethical standards ford Si-BF resin which was used freshly within two weeks. Conflicts of interest/competing interests There are no conflicts of interest. Homogeneous flow synthesis of cannabinoids Code availability Not applicable Olivetol (1 equiv), (−)-verbenol or p-mentha-2,8-dien-1-ol (1 Open Access This article is licensed under a Creative Commons equiv) and biphenyl (0.25 equiv, H-NMR standard) were added Attribution 4.0 International License, which permits use, sharing, in a flask which was evacuated and backfilled thrice with Ar. The adaptation, distribution and reproduction in any medium or format, as reactants were dissolved in dry DCM at r.t. to obtain a 0.25 M long as you give appropriate credit to the original author(s) and the reactant solution. Brønsted or Lewis acid (1 equiv) was added in source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article a second flask, and dissolved in dry DCM at r.t. to obtain a are included in the article's Creative Commons licence, unless indicated 0.25 M catalyst solution. Both solutions were loaded in glass otherwise in a credit line to the material. If material is not included in the syringes, placed in syringe pumps and connected to a T-piece article's Creative Commons licence and your intended use is not (PEEK). The PFA tubing reactor was connected to the T-piece permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a and the syringe pumps were set to the according speed. At least copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. (1,5 × t ) was waited for the system to equilibrate after which obtained samples could be obtained. The reactor outlet was led into a stirred solution of saturated aqueous NaHCO . The crude References mixture was extracted with DCM, and the organic layers were combined, dried with MgSO , concentrated in vacuo and 1. 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