Synthesis of chiral polymers containing thioetherified cinchonidinium repeating units and their application to asymmetric catalysis

Tetrahedron: Asymmetry 25 (2014) 1309–1315

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Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy

Synthesis of chiral polymers containing thioetherified cinchonidinium repeating units and their application to asymmetric catalysis Md. Robiul Islam, Parbhej Ahamed, Naoki Haraguchi, Shinichi Itsuno ⇑ Department of Environmental & Life Sciences, Toyohashi University of Technology, Toyohashi 441-8580, Japan

a r t i c l e

i n f o

Article history: Received 10 July 2014 Accepted 13 August 2014

a b s t r a c t A thiol-ene reaction of dithiol and two equivalents of cinchonidine afforded a thioetherified cinchonidine dimer. The dimer was treated with benzyl bromide to give a quaternary ammonium dimer. An ion exchange reaction of the cinchonidinium dimer and disodium disulfonate gave polymers containing chiral quaternary ammonium repeating units in their main-chain structures. Another type of chiral polymer was synthesized by quaternization polymerization. Repeated quaternization reactions between the thioetherified cinchonidine dimer and dihalides yielded chiral polymers containing cinchonidinium structures in their main chains. Both of these chiral polymers were successfully used as catalysts for the asymmetric alkylation of N-diphenylmethylene glycine tert-butyl ester. The chiral cinchonidinium polymers explored in this study showed excellent catalytic activity in asymmetric alkylation reactions and were reused several times without loss of activity. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction Cinchona alkaloid-based quaternary ammonium salts are some of the most widely investigated and most effective chiral organocatalysts for asymmetric transformations.1 Cinchona alkaloids possess various functionalities in spite of their relatively low molecular weights of less than 300. For example, cinchonidine has functional groups such as a vinyl group, a hydroxyl group, quinuclidine nitrogen, and quinoline ring. Suitable chiral catalyst designs for asymmetric organocatalysts can be realized by utilizing these functionalities.2 Indeed, a large number of quaternary ammonium salts based on cinchona alkaloids have been developed for chiral organocatalysis applications.3 Recently, highly active catalysts have been also reported.4 However, compared to transition metal catalyzed reactions, organocatalyst-mediated reactions require a relatively large amount of the catalyst.5 The quaternary ammonium salts are amphiphilic, which is an essential property of these types of catalysts regarding their performance as phase transfer catalysts.6 The amphiphilicity of such catalysts usually hinders their separation from the reaction mixture. If a reaction requires a large amount of such an amphiphilic catalyst, a decrease in the product yield may occur during the product isolation process. ⇑ Corresponding author. +81 (0)532 44 6813. E-mail address: [email protected] (S. Itsuno). http://dx.doi.org/10.1016/j.tetasy.2014.08.013 0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

One of the more efficient methodologies to avoid such problems is to use polymer-immobilized organocatalysts.7 Several approaches to immobilize chiral organocatalysts onto polymers have been reported.8 Cross-linked polystyrene is the most frequently used polymer support for the immobilization of a catalyst.9 Unfortunately, most of them lead to lowering of the catalytic activity and enantioselectivity, mainly because of their insolubility caused by the crosslinkage and randomly attached chiral catalyst molecules onto random polymer chains. Several approaches to immobilize cinchona-derived organocatalysts onto polymers have also been reported. In most cases, the immobilization strategy employed involves the attachment of cinchona-derived catalysts onto the side chains of the polymers, resulting in chiral polymers containing randomly attached cinchona moieties on the crosslinked polymer supports.10 We have recently concentrated on the synthesis of chiral polymers containing repeating units of an organocatalyst in their mainchain structures.11 In this study, we have developed novel types of chiral polymers containing cinchonidinium salt structures in their main-chain repeating units. These chiral polymers were prepared by two methods, ion exchange polymerization12 and quaternized polymerization.13 For these polymerizations, cinchonidinium dimers were required as the repeating units. The vinyl groups of the cinchonidine were utilized for thiol-ene reactions.14 The reaction of dithiol and cinchonidine was useful for the synthesis of cinchonidine dimers, which were successfully used for the

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synthesis of polymers having main-chain chirality. We found that these chiral thioetherified cinchonidinium polymers are excellent organocatalysts for asymmetric alkylation reactions. Details of the cinchonidine dimer synthesis followed by polymerization and asymmetric benzylation of N-diphenylmethylene glycine tert-butyl ester by using the chiral polymers are discussed in this article.

to prepare the polymers 12. During the polymerization, polymers 12 were precipitated in the solution. The isolated yields, molecular weights, molecular weight distributions, and the specific rotation values of chiral polymers 12 are summarized in Table 1. Chiral ionic polymers having molecular weights of 4600–14,000 were synthesized by this method. Another group of polymers containing chiral quaternary ammonium structures in their main chains was synthesized by using quaternization polymerization (Scheme 4).17 Thioetherified dimer 6 was allowed to react with dihalides 13 to give chiral quaternized polymers 14 in high yields (Table 2). The isolated yields, molecular weights, molecular weight distributions, and the specific rotation values of the chiral polymers 14 are summarized in Table 2. Chiral quaternized polymers 14 having molecular weights of 3400– 17,300 were synthesized by this method. We then used the chiral quaternary ammonium dimers and polymers as catalysts for the asymmetric benzylation of N-diphenylmethylene glycine tert-butyl ester 1518 (Scheme 5). Results with dimeric catalysts 7 are summarized in Table 3. Compared with unmodified cinchonidinium salt 8 (entry 1), thioetherified cinchonidinium salt 4 showed somewhat higher enantioselectivity (entry 2). The same reaction also smoothly occurred with the dimeric catalysts 7 to give 16 (entries 3 and 4). The dimeric catalysts 7 showed even higher enantioselectivities in the same reaction. The linker structure of dimer 7 affected the enantioselectivity. Chiral ionic polymers 12 were easily synthesized from quaternized dimers 7 and disodium disulfonate 11 (Scheme 3). By using 7a and 7b, chiral ionic polymers 12 were synthesized and used as catalysts for the asymmetric benzylation reaction. Table 4 summarizes the results of asymmetric reactions with 12. In the presence of the chiral ionic polymer 12, the reactions took place smoothly to give chiral products with high levels of enantioselectivity. Using 12a, slightly higher enantioselectivities (82–85% ee, entries 1–4) were obtained than using the corresponding dimeric catalyst 7a (81% ee (Table 3, entry 3)). When the reaction temperature was decreased to 20 °C, 90% ee was obtained with 12ad (entry 5).

2. Results and discussion Of the various kinds of vinyl group reactions, thiol-ene reactions have recently attracted the attention of researchers owing to the recognition of their click characteristics.14b The thiol-ene reactions are generally rapid and tolerant of the presence of oxygen and moisture.15 The reactions proceed with quantitative conversion to give the corresponding thioether in a regioselective manner. As a model reaction, tert-butylthiol 2 was allowed to react with cinchonidine 1 (Scheme 1). In the presence of AIBN, the thioetherification reaction occurred smoothly to give 3. Quaternization of 3 with benzyl bromide gave N-benzyl derivative 4 in high yield. Chiral polymer synthesis requires the preparation of a dimer of a cinchona alkaloid. We have prepared thioether-linked dimers 6 of cinchonidine (Scheme 2). Two equivalents of cinchonidine were allowed to react with dithiol 5 to give thioether linked dimeric compounds 6. A subsequent quaternization reaction of the dimers 6 was carried out with benzyl bromide at 80 °C in a mixed solvent of ethanol, DMF, and chloroform (5:6:2).16 The quaternized dimers 7 were obtained in quantitative conversion (Scheme 2). We used the quaternary ammonium dimers 7 for the synthesis of chiral ionic polymers 12 as shown in Scheme 3. An ion exchange reaction between quaternary ammonium bromide 8 and sodium sulfonate 9 occurred smoothly to give the quaternary ammonium sulfonate 10 in a quantitative conversion. The model reaction of 8 and 9 prompted us to apply the ion exchange reaction for the synthesis of chiral polymers. Repeated ion exchange reactions between dimers 7 and disodium disulfonate 11 gave chiral ionic polymers 12. Various kinds of disodium disulfonates 11 were used

S

SH

S

2 N

N

AIBN CHCl3 60 oC, 24 h

OH N

OH N

PhCH2Br (1.1 equiv.) EtOH:DMF:CHCl3 =5:6:2 80 oC, 6 h

Ph

OH N

3

1

Br

N

4

Scheme 1. Synthesis of thioetherified cinchonidinium salt 4.

N HS

R

SH

5

N N

HO

OH

AIBN 1

CHCl3 70 oC, 12h

N

HO

S

N

EtOH:DMF:CHCl3 = 5:6: 2 80 oC, 6h

Ph N

Br

6

5a:

Ph

S

R

N

PhCH2Br (2.1 equiv.)

SH

HS SH

5b: HS

Scheme 2. Synthesis of thioether linked dimeric catalysts 7.

R S 7

S

OH

Br

N

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M.R. Islam et al. / Tetrahedron: Asymmetry 25 (2014) 1309–1315 Me

O3S

Br N

NaO3S

N

+ OH

Me

N

OH

9

8

N

N NaO3S

R

SO3Na

10

Ph

Br

O3S HO

N

11

R

SO3 Na

OH

7 MeOH / H2O

Ph

N

R

Br

S

S

N n 12

NaO3S

NaO 3S SO3Na

SO3Na 11c

11a NaO 3S

SO3Na

NaO 3S

SO3Na

12aa: 7a + 11a 12ab: 7a + 11b 12ac: 7a + 11c 12ad : 7a + 11d 12ae: 7a + 11e 12ba: 7b + 11a 12bb: 7b + 11b 12bd: 7b + 11d 12be: 7b + 11e

11d 11b

SO 3Na NaO3S 11e

Scheme 3. Synthesis of chiral ionic polymers 12.

Table 1 Synthesis of chiral ionic polymer 12 from quaternized dimer 7 and disulfonate 11

a b

Entry

Dimer

Disulfonate

Polymer

1 2 3 4 5 6 7 8 9

7a 7a 7a 7a 7a 7b 7b 7b 7b

11a 11b 11c 11d 11e 11a 11b 11d 11e

12aa 12ab 12ac 12ad 12ae 12ba 12bb 12bd 12be

Yield (%) 92 94 95 92 87 87 87 85 72

Mna

Mw/Mna

14,000 7400 7000 7200 5900 5400 9000 6500 4600

1.13 1.42 1.22 1.94 2.57 1.50 2.05 1.87 1.58

[a]25b D 106.1 101.3 99.1 94.7 100.1 75.9 78.5 75.6 80.1

Determined by SEC measurement using DMF as a solvent at a flow rate of 1.0 mL/min at 40 °C. Specific rotation values were measured for the DMSO solution at concentration of c 1.0.

Reusability of polymeric catalysts is always an important issue from a green chemical point of view. Polymeric catalysts 12 were insoluble in both the organic and aqueous phases. After the reaction was complete, the polymeric catalyst could be easily separated from the reaction mixture. The recovered polymers can be reused for the same reactions. We demonstrated the use of the recycled polymeric catalyst 12bd. For entries 9 to 12, the same polymer 12bd was reused. These experiments revealed that the polymeric catalyst can be reused at least several times without any significant loss of catalytic activity. Next, we examined the catalytic activity of another type of polymer 14 having chiral quaternary ammonium structures in their main-chain structures. From thioetherified dimers 6 and various kinds of dihalides 13, chiral polymers 14 were prepared as shown in Scheme 4. We found that these polymers also showed high catalytic activity in the asymmetric benzylation reaction. The results

obtained by using polymeric catalysts 14 are summarized in Table 5. In most cases, these polymeric catalysts 14 showed somewhat higher enantioselectivities compared with those obtained from the corresponding dimeric ones 7. For example, the use of 14aa resulted in 85% ee (entry 1), which was higher than that obtained with 7a (81% ee). All other polymers 14a showed higher enantioselectivities except for 14ae (entry 5). Polymers 14b also showed similar tendencies. In particular, the use of 14bc afforded the chiral product 16 in 92% ee (entry 9). Lowering the reaction temperature resulted in increases of the enantioselectivities (entries 11–13), as expected. Although a longer reaction time was required at 40 °C, the reaction still occurred to give the product in high yield with 95% ee (entry 12). Almost no reaction occurred at 60 °C after 24 h (entry 12). The aqueous phase was completely frozen at 60 °C and the solid polymeric catalyst could not interact with the reagents at this temperature. This type of polymeric catalyst

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M.R. Islam et al. / Tetrahedron: Asymmetry 25 (2014) 1309–1315 N

R

X

X

HO

X

6

R N

13 N

o

DMSO, 80 C, 10h

R

X

OH

S

S N n

14 Br Br

Br

Br

14aa: 6a + 13a 14ab: 6a + 13b 14ac: 6a + 13c 14ad: 6a + 13d 14ae: 6a + 13e 14ba: 6b + 13a 14bb: 6b + 13b 14bc: 6b + 13c 14bd: 6b + 13d 14be: 6b + 13e

13a Cl

13d

Cl 13b

Cl Br Cl

Br

13e

13c

Scheme 4. Quaternization polymerization of thioetherified dimer 6 and dihalide 13.

Table 2 Synthesis of chiral quaternized polymer 14 from thioetherified dimer 6 and dihalide 13 Entry

Dimer

Dihalide

Polymer Yield

Mna

Mw/Mna

1 2 3 4 5 6 7 8 9 10

6a 6a 6a 6a 6a 6b 6b 6b 6b 6D

13a 13b 13c 13d 13e 13a 13b 13c 13d 13e

14aa 14ab 14ac 14ad 14ae 14ba 14bb 14bc 14bd 14be

7100 3900 3400 4200 4100 4700 17,300 3900 5200 3500

1.30 1.30 1.35 1.75 1.62 1.21 1.66 1.19 1.66 1.56

94 99 93 99 80 90 92 92 90 92

Table 4 Asymmetric benzylation of N-diphenylmethylene glycine tert-butyl ester by using chiral ionic polymer 12 at 0 °C

[a]25b D 102.7 125.8 41.9 100.9 152.4 90.7 94.7 160.2 125.6 55.9

a Determined by SEC measurement using DMF as a solvent at a flow rate of 1.0 mL/min at 40 °C. b Specific rotation values were measured for the DMSO solution at concentration of c 1.0.

a b c d

catalyst (10 mol%) benzyl bromide (1.2 eq.)

O

Ph N

t

O Bu

Ph

toluene : chloroform = 7:3, o 50wt % KOH, 0 C

Ph

O N

Ph

e f

O tBu Ph

15

16

Scheme 5. Asymmetric alkylation of N-diphenylmethylene glycine tert-butyl ester 15.

Table 3 Asymmetric alkylation of N-diphenylmethylene glycine tert-butyl ester 15 with dimeric catalyst Entry 1 2 3 4 a b c

Catalyst c

8 4 7a 7b

Time (h) 5 3 3 5

Yielda (%) 91 86 89 91

% eeb

Config.

71 77 81 85

(S) (S) (S) (S)

Isolated yield. The ee values were determined by HPLC using a CHIRALCEL OD-H column. See Ref. 11b.

was also recovered easily and reused as exemplified by 14bb (entries 7 and 8) and 14bc (entries 9, 10, and 13).

Entry

Catalyst

1 2 3 4 5c 6 7 8 9 10d 11e 12f 13

12aa 12ab 12ac 12ad 12ad 12ae 12ba 12bb 12bd 12bd 12bd 12bd 12be

Time (h) 4 2 7 1 7 2 1 3 2 2 4 5 2

Yielda (%) 83 85 89 89 93 85 82 87 89 89 80 80 83

% eeb

Config.

84 83 82 85 90 84 81 81 82 81 82 80 81

(S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S)

Isolated yield. The ee values were determined by HPLC using a CHIRALCEL OD-H column. Reaction was carried out at 20 °C. Catalyst 12bd used in entry 9 was reused. Catalyst 12bd used in entry 10 was reused. Catalyst 12bd used in entry 11 was reused.

3. Conclusions Dimers of cinchonidine were successfully prepared by means of thiol-ene reactions of dithiols and cinchonidine. From these dimers, we synthesized polymers 12 and 14 containing chiral quaternary ammonium repeating units in their main-chain structures by using two different approaches. The first approach involved chiral ionic polymer synthesis by ion exchange reactions between quaternized dimers of thioetherified cinchonidinium salts 7 and disodium disulfonates 11. The second approach was quaternization polymerization of thioetherified dimers of cinchonidine 6 and dihalides 13. Both polymerizations occurred smoothly to give the chiral polymers 12 and 14 containing cinchonidinium structures in their main-chain repeating units. The chiral polymers 12 and 14 were successfully applied to catalysis for the asymmetric benzylation of N-diphenylmethylene glycine tert-butyl ester 15 to give a phenylalanine derivative 16 in high yields with high levels of enantioselectivity. In most cases, using polymeric catalysts 12 and 14 resulted in higher enantiose-

M.R. Islam et al. / Tetrahedron: Asymmetry 25 (2014) 1309–1315 Table 5 Asymmetric alkylation of N-diphenylmethylene glycine tert-butyl ester by using polymeric catalysts 14

a b c d e

Entry

Catalyst

1 2 3 4 5 6 7 8c 9 10 11 12 13 14 15 16

14aa 14ab 14ac 14ad 14ae 14ba 14bb 14bb 14bc 14bcd 14bc 14bc 14bce 14bc 14bd 14be

Time (h)

Temp. (°C)

Yielda (%)

3 3 3 2 3 2 2 2 12 10 10 24 24 24 8 3

0 0 0 0 0 0 0 0 0 0 20 40 40 60 0 0

95 90 87 78 71 77 91 90 93 91 94 83 87 N.D 85 72

eeb (%)

Config.

85 87 84 82 79 84 89 88 92 92 94 95 95 N.D 84 81

(S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) — (S) (S)

Isolated yield. The ee values were determined by HPLC using a CHIRALCEL OD-H column. Compound 14bb used in entry 7 was reused. Compound 14bc used in entry 9 was reused. Compound 14bc used in entry 10 was reused at 40 °C.

lectivities than using their corresponding dimeric catalysts. Achiral repeating units in the chiral polymers such as thioetherified linkers in 12 and 14, disulfonate in 12, and dihalide in 14 influenced the catalytic activity and enantioselectivity of the polymeric catalysts. From the various combinations of linker structures and cinchonidinium salts, 12ad and 14bc gave the best results for each polymer structure. The polymeric chiral catalysts were active enough even at lower temperatures such as 40 °C to give chiral products in high yields with high enantioselectivities of up to 95% ee using 14bc. Since the cinchonidinium polymers are insoluble in both the organic and aqueous phases, polymeric catalysts 12 and 14 were easily recovered from the reaction mixtures and reused several times without any significant loss of catalytic activity. Applicability of these chiral polymer catalysts for other asymmetric reactions is now under investigation. 4. Experimental 4.1. General All solvents and reagents were purchased from Sigma–Aldrich, Wako Pure Chemical Industries, Ltd, or Tokyo Chemical Industry Co., Ltd at the highest available purity and used as was, unless noted otherwise. Reactions were monitored by thin-layer chromatography (TLC) using Merck precoated silica gel plates (Merck 5554, 60F254). Column chromatography was performed using a silica gel column (Wakogel C-200, 100–200 mesh). Melting points were recorded using a Yanaco micro melting apparatus and were uncorrected. 1H and 13C NMR (300 MHz or 400 MHz) spectra were measured in CDCl3 or DMSO-d6 on a JEOL JNM-ECS300 or JNMECX400 spectrometer. Peaks were referenced to the (CH3)4Si (TMS) peak at d = 0 (1H) or the solvent peaks [i.e., the CDCl3 peak at d = 7.26 (1H)/77.1 (13C) or the DMSO-d6 peak at d = 2.5 (1H)/39.5 (13C)]. The J values were reported in Hertz. IR spectra were recorded with a JEOL JIR-7000 FT-IR spectrometer and are reported in reciprocal centimeters (cm 1). Elemental analyses were performed at the Microanalytical Center of Kyoto University. Size exclusion chromatography (SEC) was performed with a Tosoh instrument with HLC 8020 UV (254 nm) or refractive index detection. DMF was used as a carrier solvent at a flow rate of 1.0 mL/min at 40 °C. Two polystyrene gel columns with bead sizes of 10 lm

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were used. Calibration curves were plotted to determine number-average molecular weight (Mn) and molecular weight distribution (Mw/Mn) values with polystyrene standards. HPLC analyses were performed with a JASCO HPLC system composed of a 3-line degasser DG-980, HPLC pump PV-980, column oven CO-965, equipped with a chiral column (CHIRALCEL OD-H, Daicel) using hexane/2-propanol as eluent. A UV detector (JASCO UV-975 for the JASCO HPLC system) was used for peak detection. Optical rotations were recorded with a JASCO DIP-149 digital polarimeter using a 10 cm thermostated microcell. 4.2. Procedure for the synthesis of thioetherified cinchonidine 3 A mixture of cinchonidine (1, 0.88 g, 3.00 mmol), tert-butyl mercaptan (2, 0.54 g, 6.00 mmol), and AIBN (0.02 g, 0.12 mmol) was stirred at 70 °C for 24 h. After removal of the solvent under vacuum, the residue was washed several times with hexane. The white product 3 (0.89 g, 77% yield) was used for the next reaction without further purification. Mp 158–159 °C. [a]25 63.9 (c 1.0, D = DMSO); 1H NMR (400 MHz, CDCl3): d 1.26 (s, 6H), 1.39–1.55 (m, 4H), 1.70–1.80 (m, 4H), 2.3–2.43 (t, J = 6 Hz, 2H), 2.55–2.68 (m, 1H), 3.01–3.13 (m, 2H), 3.41–3.50 (m, 1H), 3.94 (s, 1H), 5.64 (d, J = 3 Hz, 1H), 7.38–7.42 (m, 1H), 7.57 (t, J = 3 Hz, 1H), 7.63–7.67 (m, 1H), 7.95–7.97 (m, 1H), 8.08 (d, J = 6 Hz, 1H), 8.82 (d, J = 3.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.26, 25.86, 26.26, 28.12, 31.04, 34.79, 35.01, 42.03, 43.35, 58.37, 60.29, 71.77, 118.38, 123.08, 125.72, 126.71, 129.13, 130.28, 148.18, 149.65, 150.14; IR (KBr): m 1507 (C@N), 1098 (C–O), 756 (C–S); Anal. Calcd for C23H32N2OS: C 71.83, H 8.39, N 7.28. Found: C 71.74, H 8.54, N 7.98. 4.3. Procedure for the synthesis of thioetherified chiral quaternary ammonium salt 4 A mixture of 3 (0.52 g, 1.34 mmol) and benzyl bromide (0.25 g, 1.48 mmol) in EtOH/DMF/CHCl3 = 5/6/2 mixed solvent (5 mL) was stirred at 80 °C for 6 h. After cooling the reaction mixture to room temperature, the solvent was removed under vacuum and the crude product was dissolved in MeOH (2.5 mL) and poured into Et2O (100 mL). The mixture was stirred at room temperature for 1 h and filtered. The resulting solid was washed with Et2O several times to give product 4 (0.67 g, 90% yield) as a white solid. Mp 161–163 °C; [a]25 125.3 (c 1.0, DMSO); 1H NMR (400 MHz, D = DMSO-d6): d 1.15 (s, 9H), 1.49–1.56 (m, 2H), 1.84–2.07 (m, 4H), 2.34–2.38 (m, 2H), 3.03–3.19 (m, 2H), 3.48–3.51 (d, J = 9 Hz, 1H), 4.06–4.11 (t, J = 6 Hz, 1H), 4.61 (s, 1H), 5.56–5.59 (d, J = 9 Hz, 1H), 5.70–5.73 (d, J = 9 Hz, 1H), 6.52 (s, 2H), 7.10–7.19 (m, 5H), 7.61– 7.63 (m, 3H), 7.80 (d, 1H), 8.13 (t, 1H), 8.80 (d, 1H); 13C NMR (100 MHz, DMSO-d6): d 20.69, 23.86, 24.93, 30.62, 32.68, 41.72, 50.59, 61.20, 62.78, 63.95, 67.61, 120.11, 123.71, 124.36, 127.18, 127.93, 128.87, 129.34, 129.81, 133.63, 145.28, 147.62, 150.11; IR (KBr): m 1508 (C@N), 764 (C–S); Anal. Calcd for C30H39N2OS: C 64.85, H 7.08, N 5.04. Found: C 64.31, H 7.05, N 5.41. 4.4. General procedure for the synthesis of thioether linked dimer 6 A mixture of cinchonidine 1 (2.35 g, 8.00 mmol), dithiol 5 (4.00 mmol), and AIBN (12.8 mg, 0.08 mmol) in CHCl3 (12 mL) was stirred at 80 °C for 12 h. During the reaction AIBN (0.02 mmol) was added three times. The residue, after the removal of solvent under high vacuum was purified by column chromatography to give the products 6. 4.4.1. Thioether linked dimer 6a Off-white solid, yield 57%; mp 101–102 °C; [a]25 57.6 (c 1.0, D = DMSO); 1H NMR (400 MHz, CDCl3): d 1.31 (m, 3H), 1.41–1.52 (m,

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8H), 1.62 (s, 2H), 1.73–1.76 (m, 6H), 2.33–2.42 (m, 10H), 2.50 (m, 2H), 3.01–3.07 (m, 4H), 3.40–3.47 (m, 2H), 4.38 (s, 2H), 5.61–5.62 (d, J = 3 Hz, 2H), 7.40–7.43 (m, 2H), 7.53 (d, J = 3 Hz, 2H), 7.63– 7.67 (m, 2H), 7.99 (d, J = 3 Hz, 2H), 8.10 (d, J = 3 Hz, 2H), 8.77 (d, J = 3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 20.92, 25.72, 28.05, 28.41, 29.43, 30.09, 32.15, 34.62, 43.25, 58.27, 60.22, 71.45, 118.38, 123.05, 125.63, 126.67, 129.09, 129.97, 147.94, 149.91, 150.25; IR (KBr): m 1507 (C@N), 1,098 (C–O), 760 (C–S); Anal. Calcd for C44H58N4O2S2: C 71.50, H 7.91, N 7.58. Found: C 71.11, H 8.02, N 7.54. 4.4.2. Thioether linked dimer 6b Off-white solid, yield 24%; mp 108–110 °C; [a]25 35.4 (c 1.0, D = DMSO); 1H NMR (400 MHz, CDCl3): d 1.37–1.41 (m, 6H), 1.68–1.71 (m, 8H), 2.22–2.26 (m, 6H), 2.49–2.53 (m, 2H), 2.98–3.01 (m, 4H), 3.40 (m, 2H), 3.49–3.59 (m, 6H), 4.26 (s, 2H), 5.60 (d, J = 3 Hz, 2H), 7.08 (m, 4H), 7.51–7.52 (m, 4H), 7.64–7.67 (m, 2H), 8.04–8.09 (m, 4H), 8.78 (d, J = 3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 21.29, 25.76, 28.11, 29.27, 34.28, 34.82, 36.02, 43.26, 58.26, 60.29, 71.71, 118.40, 123.17, 125.80, 126.81, 128.95, 129.19, 130.30, 137.20, 148.23, 149.76, 150.12; IR (KBr): m 1507 (C@N), 759 (C–S); Anal. Calcd for C46H54N4O2S2: C 72.78, H 7.17, N 7.38. Found: C 72.98, H 7.26, N 7.21. 4.5. General procedure for the synthesis of thioether linked dimeric catalyst 7 A mixture of 6 (1.00 mmol) and benzyl bromide (0.36 g, 2.1 mmol) in EtOH/DMF/CHCl3 = 5/6/2 mixed solvent (10 mL) was stirred at 80 °C for 6 h. After cooling the reaction mixture to room temperature, the solvent was removed under vacuum and dissolved in MeOH (3 mL) and poured into Et2O (250 mL). The mixture was stirred at room temperature for 1 h and filtered. The resulting solid was washed with Et2O several times and then with hexane to give the products 7. 4.5.1. Thioether linked dimeric catalyst 7a Off white solid, yield 99%; mp 163–165 °C; [a]25 105.9 (c 1.0, D = DMSO); 1H NMR (400 MHz, DMSO-d6): d 1.13–1.15 (m, 3H), 1.29– 1.43 (m, 10H), 1.72–1.75 (m, 2H), 1.94–2.02 (m, 8H), 2.28–2.32 (m, 8H), 3.17–3.18 (m, 2H), 2.46–2.49 (d, J = 6 Hz, 2H), 3.93–3.96 (t, J = 4 Hz, 2H), 4.23–4.28 (t, J = 6 Hz, 2H), 4.87–4.90 (d, J = 9 Hz, 2H), 5.12–5.15 (d, J = 9 Hz, 2H), 6.55 (d, 2H), 6.73–6.74 (d, J = 3 Hz, 2H), 7.56–7.57 (m, 6H), 7.69–7.76 (m, 6H), 7.80–7.84 (m, 4H), 8.09–8.10 (d, J = 6 Hz, 2H), 8.27–8.30 (d, J = 9 Hz, 2H), 8.98– 8.99 (d, J = 3 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 20.67, 23.86, 24.66, 27.62, 28.32, 28.80, 30.77, 32.62, 50.57, 61.26, 62.77, 63.99, 67.55, 119.04, 120.09, 123.71, 124.36, 127.17, 127.93, 128.87, 129.33, 129.81, 133.68, 145.29, 147.62, 150.10; IR (KBr): m 1508 (C@N), 762 (C–S); Anal. Calcd for C58H72Br2N4O2S2: C 64.43, H 6.71, N 5.18. Found: C 64.78, H 6.81, N 5.16.

4.6. General procedure for the synthesis of main-chain chiral ionic polymer 12 A solution of disodium disulfonate salt 11 (0.5 mmol) in water (5 mL) was added dropwise to a solution of dimeric quaternary ammonium salt 7 (0.5 mmol) in MeOH (5 mL). This mixture was stirred vigorously at room temperature for 24 h. After removing the MeOH under high vacuum, the suspension was filtered and washed with water and hexane to obtain the resulting ionic polymer 12. Yield, molecular weight, molecular weight distribution, and the specific rotation value are described in Table 1. 4.7. General procedure for the synthesis of main-chain chiral quaternary ammonium polymer 14 A mixture of cinchonidine dimer 7 (0.500 mmol) and dihalide 13 (0.500 mmol) in DMSO (2 mL) was stirred at 80 °C for 10 h. The residue, after the removal of the solvent under high vacuum, was dissolved in MeOH (5 mL) and poured into Et2O (200 mL). After filtration of the mixture, the solid was washed with hexane and ethyl acetate, and was dried under high vacuum to give the polymer 14. Yield, molecular weight, molecular weight distribution, and the specific rotation value are described in Table 2. 4.8. General procedure for enantioselective alkylation of Ndiphenylmethylene glycine tert-butyl ester 15 using chiral polymeric catalyst 14aa Chiral polymeric catalyst 14aa (0.017 mmol) and N-diphenylmethylene glycine tert-butyl ester (12: 0.050 g, 0.170 mmol) were added into a mixed solvent of toluene (0.7 mL) and chloroform (0.3 mL). 50 wt% aqueous KOH solution (0.25 mL) was added to the above mixture. Benzyl bromide (0.035 g, 0.203 mmol) was then added dropwise at 0 °C to the mixture. The reaction mixture was stirred vigorously at 0 °C for several hours. Saturated sodium chloride solution (2 mL) and ethyl acetate (2 mL) were then added, and the mixture was subsequently filtered to recover 14aa, which was washed several times with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic extracts were washed with brine and dried over MgSO4. Evaporation of the solvents and purification of the residual oil by column chromatography on silica-gel (ether/hexane = 1:10 as eluent) gave (S)-tert-butyl N-(diphenylmethylene)phenylalaninate 16. The enantiomeric excess was determined by HPLC analysis [Daicel CHIRALCEL OD-H, hexane/2-propanol = 100:1, flow rate = 0.3 mL/min, retention times: (R)-enantiomer = 27.6 min, (S)-enantiomer = 47.9 min]. The absolute configuration was determined by comparison of the HPLC retention time with the authentic sample independently synthesized by the reported procedure. Acknowledgements

4.5.2. Thioether linked dimeric catalyst 7b Off white solid, yield 95%; mp 164–166 °C; [a]25 85.8 (c 1.0, D = DMSO); 1H NMR (400 MHz, DMSO-d6): d 1.26 (s, 6H), 1.39–1.55 (m, 4H), 1.70–1.80 (m, 4H), 2.3–2.43 (t, J = 6 Hz, 2H), 2.55–2.68 (m, 1H), 3.01–3.13 (m, 2H), 3.41–3.50 (m, 1H), 3.94 (s, 1H), 5.64 (d, J = 3 Hz, 1H), 7.38–7.42 (m, 1H), 7.57 (t, J = 3 Hz, 1H), 7.63–7.67 (m, 1H), 7.95–7.97 (m, 1H), 8.08 (d, J = 6 Hz, 1H), 8.82 (d, J = 3.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d 20.59, 23.82, 24.54, 31.98, 32.61, 41.16, 50.61, 61.28, 63.02, 64.21, 67.49, 120.30, 122.50, 124.05, 126.35, 127.76, 128.75, 130.08, 133.71, 135.34, 149.44; IR (KBr): m 1508 (C@N), 763 (C–S); Anal. Calcd for C60H68Br2N4O2S2: C 65.44, H 6.22, N 5.09. Found: C 65.46, H 6.35, N 4.98.

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