Synthesis of C 3 -Symmetric Cinchona-Based Organocatalysts and Their Applications in Asymmetric Michael and Friedel–Crafts Reactions

: In this work, anchoring of cinchona derivatives to trifunctional cores (hub approach) was demonstrated to obtain size-enlarged organocatalysts. By modifying the cinchona skeleton in different positions, we prepared four C 3 -symmetric size-enlarged cinchona derivatives (hub-cinchonas), which were tested as organocatalysts and their catalytic activities were compared with the parent cinchona (hydroquinine) catalyst. We showed that in the hydroxyalkylation reaction of indole, hydroquinine provides good enantioselectivities (up to 73% ee), while the four new size-enlarged derivatives resulted in signiﬁcantly lower values (up to 29% ee) in this reaction. Anchoring cinchonas to trifunctional cores was found to facilitate nanoﬁltration-supported catalyst recovery using the PolarClean alternative solvent. The C 3 -symmetric size-enlarged organocatalysts were completely rejected by all the applied membranes, whereas the separation of hydroquinine was found to be insufﬁcient when using organic solvent nanoﬁltration. Furthermore, the asymmetric catalysis was successfully demonstrated in the case of the Michael reaction of 1,3-diketones and trans - β -nitrostyrene using Hub 3 -cinchona (up to 96% ee) as a result of the positive effect of the C 3 -symmetric structure using a bulkier substrate. This equates to an increased selectivity of the catalyst in comparison to hydroquinine in the latter Michael reaction.


Introduction
Over the years, catalysis has been widely explored for the more economical and often more selective production of high-value products [1]. As the preparation of enantiopure organic compounds is of great interest, asymmetric catalysis has developed into a dynamic, rapidly evolving field [2]. Compounds with rotational symmetry have gained increased attention in asymmetric synthesis because they are believed to be able to improve enantioselectivity by decreasing the number of possible transition states during the reaction [3][4][5]. Due to their beneficial effect on enantioselectivity, C 2 -and C 3 -symmetric molecules have been the focus of extensive research and, as a result, C 3 -symmetric compounds have been successfully applied as catalysts, ligands, molecular receptors, supra-and macromolecular constructs, gelators, metal-organic materials (MOMs), etc. [6][7][8][9][10][11].

Results
During our work, we prepared and explored two types of C3-symmetric cinchona organocatalysts with varied H-bond donor properties ( Figure 1). Compounds belonging to Type A are structurally the simplest as they have no H-bond donor units due to the derivatization of the hydroxyl group (9-OH, see Figure 1c) of the cinchona skeleton during the immobilization process. On the contrary, the mono H-bond donor 9-OH has been reserved in the case of Type B compounds as the cinchona motif was anchored to the hub, either through the aromatic quinoline (Williamson ether formation) or through the quinuclidine unit using copper(I) catalyzed azide-alkyne cycloaddition (CuAAC). As a hub, we used 1,3,5-triethynylbenzene, 1,3,5-tris(bromomethyl)benzene, or tripropargylamine.

Synthesis of New C3-Symmetric Hub-Cinchona Catalysts
First, we prepared Hub 1,2 -cinchona (Type A) organocatalysts using a common intermediate (3, Scheme 1). Cinchona azide 3 was obtained in two steps: mesylation of hydroquinine (1), followed by substitution with azide anion applying NaN3. Then, azide 3 was reacted with either 1,3,5-triethynylbenzene (4), or tripropargylamine (5) in a CuAAC reaction, which gave Hub 1 -and Hub 2 -cinchona, respectively, with moderate yields. Having been functionalized at the secondary hydroxyl group of the cinchona moiety, these compounds contain no H-bond donor units. However, other non-covalent interactions can still be formed through the protonated quinuclidine N-atom (ionic) or the aromatic quinoline ring (π-π stacking). Furthermore, the triazole-rings formed by the CuAAC reaction are good electron pair donors, which could interact with metallic species, combining the advantageous catalytic qualities of organocatalysts and transition metals to promote new chemical transformations [42,43].
Next, cinchona derivatives with mono H-bond donor units (Type B) have been prepared. Hydroquinine (1) was demethylated using BBr3 (1M in DCM) to obtain dihydrocupreine 6 that bears a free phenolic hydroxyl group (Scheme 2). Then, using Cs2CO3, as a base, the phenolate of 6 was formed, which could react with 1,3,5-tris(bromomethyl)benzene (7) in a Williamson ether formation reaction to give the size-enlarged organocatalyst Hub 3 -cinchona with a good yield. Consequently, we connected the cinchona motif to the core through a stable ether bond, and the H-bond donor hydroxyl group remained intact.

Synthesis of New C 3 -Symmetric Hub-Cinchona Catalysts
First, we prepared Hub 1,2 -cinchona (Type A) organocatalysts using a common intermediate (3, Scheme 1). Cinchona azide 3 was obtained in two steps: mesylation of hydroquinine (1), followed by substitution with azide anion applying NaN 3 . Then, azide 3 was reacted with either 1,3,5-triethynylbenzene (4), or tripropargylamine (5) in a CuAAC reaction, which gave Hub 1 -and Hub 2 -cinchona, respectively, with moderate yields. Having been functionalized at the secondary hydroxyl group of the cinchona moiety, these compounds contain no H-bond donor units. However, other non-covalent interactions can still be formed through the protonated quinuclidine N-atom (ionic) or the aromatic quinoline ring (π-π stacking). Furthermore, the triazole-rings formed by the CuAAC reaction are good electron pair donors, which could interact with metallic species, combining the advantageous catalytic qualities of organocatalysts and transition metals to promote new chemical transformations [42,43].
Next, cinchona derivatives with mono H-bond donor units (Type B) have been prepared. Hydroquinine (1) was demethylated using BBr 3 (1M in DCM) to obtain dihydrocupreine 6 that bears a free phenolic hydroxyl group (Scheme 2). Then, using Cs 2 CO 3, as a base, the phenolate of 6 was formed, which could react with 1,3,5-tris(bromomethyl)benzene (7) in a Williamson ether formation reaction to give the size-enlarged organocatalyst Hub 3cinchona with a good yield. Consequently, we connected the cinchona motif to the core through a stable ether bond, and the H-bond donor hydroxyl group remained intact.

Application of Hub-Cinchona Catalysts in Hydroxyalkylation of Indole and Michael Addition Reactions
We started our organocatalytic reactions with the hydroxyalkylation of indole. First, the optimal solvent and reaction time were chosen using 5 mol% hydroquinine (1), the parent catalytic unit of the hub-cinchona derivatives. As solvents, 11 conventional and Symmetry 2021, 13, 521 4 of 16 alternative agents were used (Table 1). In general, ether-type solvents showed better enantioselectivities in this reaction, while the protic ethanol gave a practically racemic product. An explanation for this solvent effect could be the formation of competing Hbonds between the solvent and the catalyst/substrates. Regarding the yield, in toluene and ethanol we achieved almost complete transformation, while the other solvents also gave good results (>67%). For the subsequent experiments, cyclopentyl methyl ether (CPME) was chosen, because this solvent provided the best enantioselectivity (73% ee) and the yield was still good after 24 h stirring at 0 • C (82%). Based on the 19 F NMR spectra, the yield did not change significantly when the reaction time was reduced to 1 h. Organocatalyst Hub 4 -cinchona was prepared via convergent synthesis (Scheme 3), utilizing an alternative anchoring method. We converted the commercially available quinine (8) into didehydroquinine (9) using a Br2 addition-HBr elimination reaction. In a separate reaction, we reacted 1,3,5-tris(bromomethyl)benzene (7) with NaN3 in a mixture of water:acetone (1/100) to give the triazido-derivative 10. Finally, alkyne 9 and triazide 10 Scheme 1. Syntheses of the size-enlarged C 3 -symmetric Hub 1 -and Hub 2 -cinchona organocatalysts (Type A) by CuAAC using a common cinchona azide intermediate (3) and trifunctional alkynes (4 or 5) with different chemical and structural properties. TEA: triethylamine; MsCl: methanesulfonyl chloride; DIPEA: N,N-diisopropylethylamine. Organocatalyst Hub 4 -cinchona was prepared via convergent synthesis (Scheme 3), utilizing an alternative anchoring method. We converted the commercially available quinine (8) into didehydroquinine (9) using a Br2 addition-HBr elimination reaction. In a separate reaction, we reacted 1,3,5-tris(bromomethyl)benzene (7) with NaN3 in a mixture of

Application of Hub-Cinchona Catalysts in Hydroxyalkylation of Indole and Michael Addition Reactions
We started our organocatalytic reactions with the hydroxyalkylation of indole. First, the optimal solvent and reaction time were chosen using 5 mol% hydroquinine (1), the parent catalytic unit of the hub-cinchona derivatives. As solvents, 11 conventional and alternative agents were used (Table 1). In general, ether-type solvents showed better enantioselectivities in this reaction, while the protic ethanol gave a practically racemic product. An explanation for this solvent effect could be the formation of competing H-bonds between the solvent and the catalyst/substrates. Regarding the yield, in toluene and ethanol we achieved almost complete transformation, while the other solvents also gave good results (>67%). For the subsequent experiments, cyclopentyl methyl ether (CPME) was chosen, because this solvent provided the best enantioselectivity (73% ee) and the yield was still good after 24 h stirring at 0 °C (82%). Based on the 19 F NMR spectra, the yield did not change significantly when the reaction time was reduced to 1 h.

Application of Hub-Cinchona Catalysts in Hydroxyalkylation of Indole and Michael Addition Reactions
We started our organocatalytic reactions with the hydroxyalkylation of indole. First, the optimal solvent and reaction time were chosen using 5 mol% hydroquinine (1), the parent catalytic unit of the hub-cinchona derivatives. As solvents, 11 conventional and alternative agents were used (Table 1). In general, ether-type solvents showed better enantioselectivities in this reaction, while the protic ethanol gave a practically racemic product. An explanation for this solvent effect could be the formation of competing H-bonds between the solvent and the catalyst/substrates. Regarding the yield, in toluene and ethanol we achieved almost complete transformation, while the other solvents also gave good results (>67%). For the subsequent experiments, cyclopentyl methyl ether (CPME) was chosen, because this solvent provided the best enantioselectivity (73% ee) and the yield was still good after 24 h stirring at 0 °C (82%). Based on the 19 F NMR spectra, the yield did not change significantly when the reaction time was reduced to 1 h. With the best solvent and reaction time in hand, we used our newly prepared hubcinchona organocatalysts in the hydroxyalkylation reaction (Table 2). While the yield was only slightly lower (~10% difference), the size-enlarged catalysts showed significantly lower enantioselectivities in comparison to hydroquinine (1). The highest enantiomeric excess was achieved with Hub 4 -cinchona (29% ee), while Hub 2 -cinchona practically provided the hydroxyalkylated product as a racemic mixture (2% ee). Due to the tripropargylamine hub, the latter catalyst (Hub 2 -cinchona) contains a competitive basic unit with the quinuclidine N-atom, which can explain the lack of enantioselectivity. Comparing the structural features of the other catalysts, we can conclude that Hub 1 -and Hub 4 -cinchonas have more rigid structures, which can be attributed to the triazole rings that also serve as spacers between the hub and the catalytically active motifs. Therefore, the cinchona units in these cases are more separated from each other. Still, the formation of non-covalent interactions between the individual catalytic motifs within the hub-cinchonas can explain, in general, the significantly lower enantioselectivity and why Hub 1,4 -cinchonas gave better results than the structurally more flexible Hub 3 -cinchona. The Structures, NMR spectra, MS spectra and HPLC chromatograms of the prepared C 3 -symmetric hub-cinchonas (Hub1-4cinchonas) are shown in Supplementary Materials. Table 2. Hydroquinine (1) and Hub 1-4 -cinchonas catalyzed indole hydroxyalkylation reaction 1 . lower enantioselectivities in comparison to hydroquinine (1). The highest enantiomeric excess was achieved with Hub 4 -cinchona (29% ee), while Hub 2 -cinchona practically provided the hydroxyalkylated product as a racemic mixture (2% ee). Due to the tripropargylamine hub, the latter catalyst (Hub 2 -cinchona) contains a competitive basic unit with the quinuclidine N-atom, which can explain the lack of enantioselectivity. Comparing the structural features of the other catalysts, we can conclude that Hub 1 -and Hub 4 -cinchonas have more rigid structures, which can be attributed to the triazole rings that also serve as spacers between the hub and the catalytically active motifs. Therefore, the cinchona units in these cases are more separated from each other. Still, the formation of non-covalent interactions between the individual catalytic motifs within the hub-cinchonas can explain, in general, the significantly lower enantioselectivity and why Hub 1,4 -cinchonas gave better results than the structurally more flexible Hub 3 -cinchona. The Structures, NMR spectra, MS spectra and HPLC chromatograms of the prepared C3-symmetric hub-cinchonas (Hub1-4-cinchonas) are shown in Supplementary Materials. As the solvent can significantly alter the formation of non-covalent interactions, we performed the complete solvent screen with Hub 3 -cinchona (Table 3). While no higher enantioselectivity was achieved, the previously observed trend was still recognizable: ether-type solvents gave good results, but the protic ethanol promoted the formation of the racemic product. Interestingly, in some cases (toluene, DCM, and MeCN) the other antipode of 13 was found to be present in excess.

Catalyst
Yield ( Considering that these two catalysts (1 and Hub 3 -cinchona) are structurally very similar in regard to the catalytical motif(s), the higher selectivity clearly suggests that the C3symmetric structural feature of the size-enlarged Hub 3 -cinchona has a positive effect on Considering that these two catalysts (1 and Hub 3 -cinchona) are structurally very similar in regard to the catalytical motif(s), the higher selectivity clearly suggests that the C 3 -symmetric structural feature of the size-enlarged Hub 3 -cinchona has a positive effect on the enantioselectivity. This advantageous outcome can be attributed either to the formation of a sterically more hindered space during the transition state or to an alternative catalyst-substrate interaction layout including two or more cinchona motifs.
Next, using Hub 3 -cinchona, the Michael addition reaction was also performed with a structurally bulkier and electronically more favorable Michael donor, 1,3-diphenylpropane-1,3-dione (17, Scheme 4). The applied reaction conditions were based on our previous work [45]. Although only 1 mol% of catalyst was used, the enantioselectivity observed was significantly higher regardless of the solvent (2 mL), e.g., DCM (53% ee), EtOAc (64% ee), MeCN (71% ee), or toluene (80% ee). The best result was achieved by using MTBE. In this case, the selectivity reached 93% ee and the yield was 69% after purification by preparative thin-layer chromatography (TLC). In comparison, the reaction catalyzed by hydroquinine (1) gave only 6% ee with an 84% preparative yield. the enantioselectivity. This advantageous outcome can be attributed either to the formation of a sterically more hindered space during the transition state or to an alternative catalyst-substrate interaction layout including two or more cinchona motifs. Next, using Hub 3 -cinchona, the Michael addition reaction was also performed with a structurally bulkier and electronically more favorable Michael donor, 1,3-diphenylpropane-1,3-dione (17, Scheme 4). The applied reaction conditions were based on our previous work [45]. Although only 1 mol% of catalyst was used, the enantioselectivity observed was significantly higher regardless of the solvent (2 mL), e.g., DCM (53% ee), EtOAc (64% ee), MeCN (71% ee), or toluene (80% ee). The best result was achieved by using MTBE. In this case, the selectivity reached 93% ee and the yield was 69% after purification by preparative thin-layer chromatography (TLC). In comparison, the reaction catalyzed by hydroquinine (1) gave only 6% ee with an 84% preparative yield. To conclude, the Michael addition reaction showed increased selectivity for the sizeenlarged Hub 3 -cinchona catalysts compared to its cinchona unit (hydroquinine, 1), which indicates the positive effect of the C3-symmetric structure. Furthermore, a Michael adduct prepared from the bulkier substrate was obtained with excellent enantioselectivities (up to 93% ee) with Hub 3 -cinchona size-enlarged organocatalyst.

Membrane Rejection of Hub-Cinchona Organocatalysts
Given the bulky nature of the size-enlarged catalysts, they were fully retained on all the tested membranes with rejection values of 100% (Figure 2a). It is important to achieve 100% rejection in order to avoid the loss of any valuable catalyst during the recovery process. The rejections of indole (11) and the hydroxyalkylated product 13 vary between 5% and 55% depending on both the membrane and the molecular weight (MW). For efficient catalyst recovery, the rejection gap between the catalyst and the other solutes needs to be To conclude, the Michael addition reaction showed increased selectivity for the sizeenlarged Hub 3 -cinchona catalysts compared to its cinchona unit (hydroquinine, 1), which indicates the positive effect of the C 3 -symmetric structure. Furthermore, a Michael adduct prepared from the bulkier substrate was obtained with excellent enantioselectivities (up to 93% ee) with Hub 3 -cinchona size-enlarged organocatalyst.

Membrane Rejection of Hub-Cinchona Organocatalysts
Given the bulky nature of the size-enlarged catalysts, they were fully retained on all the tested membranes with rejection values of 100% (Figure 2a). It is important to achieve 100% Symmetry 2021, 13, 521 8 of 16 rejection in order to avoid the loss of any valuable catalyst during the recovery process. The rejections of indole (11) and the hydroxyalkylated product 13 vary between 5% and 55% depending on both the membrane and the molecular weight (MW). For efficient catalyst recovery, the rejection gap between the catalyst and the other solutes needs to be as large as possible. Consequently, one can conclude that the best membrane for hub-cinchona organocatalyst recovery is DM900. This membrane exhibited substrate solute rejections below 30%, while still maintaining complete retention of the catalysts. Moreover, DM900 is the most open membrane with the highest flux of 6.7 ± 0.24 L m −2 h −1 (Figure 2b). It is important to maximize the flux in order to achieve an efficient catalyst recovery process. Comparing the membrane rejections of the hub-cinchonas with hydroquinine (1), the advantage of molecular size-enlargement can be clearly seen. Due to the similar rejection values of hydroquinine (1) and product 13, membrane recovery of 1 from the reaction mixture would be inadequate.

General Information
Starting materials were purchased from commercially available sources (Sigma-Aldrich, Merck, and Alfa Aesar). Infrared spectra were recorded on a Bruker Alpha-T FT-IR spectrometer (Bruker, Ettlingen, Germany). Optical rotations were measured on a Perkin-Elmer 241 polarimeter (Perkin-Elmer, Waltham, MA, USA) that was calibrated by measuring the optical rotations of both enantiomers of menthol. Silica gel 60 F254 (Merck) and aluminum oxide 60 F254 neutral type E (Merck) plates were used for TLC. Aluminum oxide (neutral, activated, Brockman I) and silica gel 60 (70-230 mesh, Merck) were used for column chromatography. Ratios of solvents for the eluents are given in volumes (mL mL −1 ). Melting points were taken on a Boetius micro-melting point apparatus (VEB Dresden Analytik, Dresden, Germany) and they were uncorrected. N,N-Dimethylacetamide (DMAc) solution of polybenzimidazole (PBI, 26 wt%) was purchased from PBI Performance Products (USA). The previously reported 20PBI.X membrane was obtained based on Schaepertoens et al. [46]. PBI was selected as it is an emerging polymer for OSN [47,48]. Du-raMem solvent-resistant membranes (DM500 and DM900) can be obtained from Evonik (Germany). PolarClean solvent is produced by Solvay (Italy). NMR spectra were recorded either on a Bruker DRX-500 Avance spectrometer (at 500 MHz for 1 H, at 125 MHz for 13 C, and at 376 MHz for 19 F spectra) or on a Bruker 300 Avance spectrometer (at 300 MHz for 1 H, at 75 MHz for 13 C, and at 222.5 MHz for 19 F spectra) or on a Bruker Avance III HD (at 600 MHz for 1 H and at 150 MHz for 13 C spectra). HPLC-MS was performed on an HPLC system using Agilent Technologies 1200 Series-Agilent Technologies 6130 Quadrupole; column: Phenomenex Kinetex C18 100A (2.6 μm, 50 × 3.00 mm); A eluent: water (1% HCOONH4); B eluent: MeCN (8% water, 1% HCOONH4); gradient: 20%-100%. In case of

General Information
Starting materials were purchased from commercially available sources (Sigma-Aldrich, Merck, and Alfa Aesar). Infrared spectra were recorded on a Bruker Alpha-T FT-IR spectrometer (Bruker, Ettlingen, Germany). Optical rotations were measured on a Perkin-Elmer 241 polarimeter (Perkin-Elmer, Waltham, MA, USA) that was calibrated by measuring the optical rotations of both enantiomers of menthol. Silica gel 60 F 254 (Merck) and aluminum oxide 60 F 254 neutral type E (Merck) plates were used for TLC. Aluminum oxide (neutral, activated, Brockman I) and silica gel 60 (70-230 mesh, Merck) were used for column chromatography. Ratios of solvents for the eluents are given in volumes (mL mL −1 ). Melting points were taken on a Boetius micro-melting point apparatus (VEB Dresden Analytik, Dresden, Germany) and they were uncorrected. N,N-Dimethylacetamide (DMAc) solution of polybenzimidazole (PBI, 26 wt%) was purchased from PBI Performance Products (USA). The previously reported 20PBI.X membrane was obtained based on Schaepertoens et al. [46]. PBI was selected as it is an emerging polymer for OSN [47,48]. DuraMem solvent-resistant membranes (DM500 and DM900) can be obtained from Evonik (Germany). PolarClean solvent is produced by Solvay (Italy). NMR spectra were recorded either on a Bruker DRX-500 Avance spectrometer (at 500 MHz for 1 H, at 125 MHz for 13 C, and at 376 MHz for 19 F spectra) or on a Bruker 300 Avance spectrometer (at 300 MHz for 1 H, at 75 MHz for 13 C, and at 222.5 MHz for 19 F spectra) or on a Bruker Avance III HD (at 600 MHz for 1 H and at 150 MHz for 13 C spectra). HPLC-MS was performed on an HPLC system using Agilent Technologies 1200 Series-Agilent Technologies 6130 Quadrupole; column: Phenomenex Kinetex C18 100A (2.6 µm, 50 × 3.00 mm); A eluent: water (1% HCOONH 4 ); B eluent: MeCN (8% water, 1% HCOONH 4 ); gradient: 20-100%. In case of indole hydroxyalkylation, HPLC-MS was performed using a Shimadzu LCMS-2020 (Shimadzu Corp., Kyoto, Japan) device, equipped with a Reprospher (Altmann Analytik Corp., München, Germany) 100 C18 (5 µm, 100 × 3 mm) column and a positive/negative double ion source (DUIS±) with a quadrupole MS analyzer in a range of 50-1000 m/z. The samples were eluted with gradient elution, using eluent A (0.1% formic acid in water) and eluent B (0.1% formic acid in MeCN). The flow rate was set to 1.5 mL min −1 . The initial condition was 5% eluent B, followed by a linear gradient to 100% eluent B by 1.5 min; from 1.5 to 4.0 min, 100% eluent B was retained, and from 4 to 4.5 min, it went back by a linear gradient to 5% eluent B, which was retained from 4.5 to 5 min. The column temperature was kept at room temperature, and the injection volume was 1-10 µL. The purity of the compounds was assessed by HPLC with UV detection at 215 and 254 nm. High resolution mass measurements were performed on a Thermo Exactive plus EMR Orbitrap mass spectrometer, which was used with a Thermo Ultimate 3000 UHPLC with 100% methanol as the mobile phase, or on a Thermo Velos Pro Orbitrap Elite (Thermo Fisher Scientific) system. The ionization method was ESI operated in positive ion mode. The samples were dissolved in methanol. Data acquisition and analysis were accomplished with Xcalibur software version 4.0 (Thermo Fisher Scientific). The enantiomeric ratios of the samples were determined by chiral high-performance liquid chromatography (HPLC) measurements using either reversed-phase mode (Thermo Finnigan Surveyor LC System, Thermo Fisher Scientific, Waltham, MA, USA) or normal phase mode (PerkinElmer Series 200 LC System, PerkinElmer, Inc, Shelton, CT, USA), and the exact conditions are indicated in the correspondent asymmetric reaction in the Experimental Section. This compound was prepared based on the description in the literature [49]. A solution of hydroquinine (1, 3.00 g, 9.19 mmol, 1.0 eq) in dry tetrahydrofuran (THF, 55 mL) was stirred under Ar at 0 • C. Triethylamine (TEA, 6.2 mL, 44.1 mmol, 4.8 eq) was added to this solution, followed by dropwise addition of methanesulfonyl chloride (2.9 mL, 36.8 mmol, 4.0 eq). Next, the reaction mixture was allowed to warm up to room temperature, and it was stirred for 4 h. The solvent was evaporated under reduced pressure. The residue was dissolved in a mixture of DCM (50 mL) and sat. aqueous solution of NaHCO 3 (50 mL). The aqueous phase was extracted with DCM (2 × 50 mL). The combined organic phase was dried over anhydrous MgSO 4 , filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, MeOH/toluene 1:6) to obtain hydroquinine mesylate (2, 2.20 g, 73%) as a yellow solid. Compound 3 was prepared based on the description in the literature [49]. A solution of mesylate 2 (2.00 g, 4.94 mmol, 1.0 eq) in dry dimethylformamide (DMF, 55 mL) was stirred under Ar atmosphere at room temperature. NaN 3 was then added (1.45 g, 22.3 mmol, 4.5 eq) to this solution. Next, the reaction mixture was warmed up to 45 • C and it was stirred at this temperature until the reaction was completed. The solvent was evaporated under reduced pressure, then, water was added to the residue, and this aqueous mixture was extracted with Et 2 O (3 × 15 mL). The combined organic phase was evaporated to obtain azido-hydroquinine as a yellow oil (3, 1.44 g, 83%) and used without further purification.  [44,51].

Dihydrocupreine (6):
Hydroquinine (1, 1.00 g, 3.06 mmol, 1.0 eq) was dissolved in DCM (90 mL) under an Ar atmosphere, then this solution was cooled to 0 • C. Next, BBr 3 (1 M DCM solution, 26.0 mL, 26.0 mmol, 8.5 eq) was added dropwise. Next, the reaction mixture was left to slowly warm up to room temperature, and it was stirred overnight. After complete consumption of the starting material (TLC, silica gel, DCM/MeOH/NH 4 OH 5:1:0.01), a solution of 10% NaOH (aq., 40 mL) was added to the mixture. Following the separation of the two phases, the aqueous phase was washed with DCM (3 × 50 mL). Next, cc. HCl (aq.) was added to neutralize the aqueous phase, followed by extraction with DCM (3 × 50 mL). The combined organic phase was dried over anhydrous MgSO 4 , filtered, and the solvent was evaporated under reduced pressure to yield 6 (860 mg, 90%) as a brown solid. To a solution of quinine (8,5.00 g, 15.4 mmol, 1.0 eq) in DCM (150 mL), a mixture of Br 2 (1.70 mL, 30.9 mmol, 2.0 eq) and DCM (7 mL) was added at 0 • C. The reaction mixture was stirred at 0 • C for 1 h while a yellow solid precipitated. After stirring the reaction mixture for an additional hour at room temperature, hexane (300 mL) was added, stirred for 10 min, and filtered. The filtrate was washed with hexane and dried under infrared lamp for 1 h. The yellow solid was dissolved in THF (150 mL), and tetrabutylammonium iodide (TBAI, 550 mg, 1.71 mmol, 0.1 eq) was added to this solution. Then, finely powdered potassium hydroxide (KOH, 5.00 g, 89.1 mmol, 5.8 eq) was added to the mixture, and stirred at 45 • C for 1 h when an additional batch of KOH (5.00 g, 89.1 mmol, 5.8 eq) was added to it. The reaction mixture was stirred for 12 h at room temperature. After complete consumption of the starting materials (TLC, silica gel, MeOH/DCM/TEA 1:10:0.2), the mixture was filtered, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The crude product was purified by dry column vacuum chromatography (silica gel, EtOAc/NH 4 OH 20:1, EtOAc/NH 4 OH/MeOH 95:5-45:55) to yield 9 (4.25 g, 85%) as a brown solid.

1,3,5-Tris(azidomethyl)benzene
R f : 0.65 (silica gel, EtOAc/hexane 1:2). Spectroscopic data are fully consistent with those reported in the literature [54]. Although the tris(azidomethyl)benzene is reported to be relatively insensitive to heat and shock, special care was taken during its synthesis and application to avoid accidents [55,56].

Nanofiltration
Membrane separation was carried out in a crossflow nanofiltration rig with 53 cm 2 effective area (A), as described in the literature [62]. PolarClean, as a green solvent [63], was used for the filtration, and the applied pressure was 10 bar. Two independent measurements were carried out, and the presented results are mean values. Equations (1) and (2) were used to calculate the rejection and permeance after 24 h recirculation in the rig, respectively.
where C p and C f are the permeate and feed concentrations of the solutes, respectively; V is the permeate volume, while t is the time of solvent permeation through the membrane with certain membrane area (A).

Conclusions
Four structurally different C 3 -symmetric cinchona organocatalysts were prepared, in which the catalytic units are covalently anchored to a trifunctional central core (hub). Depending on the immobilization site, we obtained compounds either containing or lacking mono H-bond donor groups on the cinchona skeleton.
The catalytic activities of these size-enlarged molecules were tested in the hydroxyalkylation of indole and Michael addition reaction. While the parent hydroquinine was found to be an efficient catalyst for the Friedel-Crafts reaction of indole (up to 73% ee), the hub-cinchona catalysts showed significantly lower enantioselectivities, regardless of the solvent applied. The structure-selectivity correlations revealed that catalysts with more rigid and extensive spacers performed better, suggesting a disadvantageous interaction of the individual cinchona units. On the contrary, in the Michael addition reaction, the hub-cinchona catalyst showed increased selectivity compared to hydroquinine, which indicates the positive effect of the C 3 -symmetric structure. Furthermore, Hub 3 -cinchona was also shown to provide enantioselectivities up to 96% ee, in the case of a bulkier substrate. Finally, membrane recovery of the size-enlarged organocatalysts using the PolarClean alternative solvent was found to be straightforward thanks to their~four-fold increase in size compared to hydroquinine.