Synthesis of cinchona alkaloid sulfonamide polymers as sustainable catalysts for the enantioselective desymmetrization of cyclic anhydrides

Abstract

The Mizoroki–Heck polymerization of cinchona-based sulfonamide dimers and aromatic diiodides was investigated in the presence of a palladium catalyst, to obtain chiral polymers in high yields. An iodobenzenesulfonamide derivative of a cinchona alkaloid was also polymerized via self-polycondensation under the same reaction conditions. The catalytic activities of these chiral polymers were examined by using them as catalysts in the enantioselective desymmetrization of cyclic anhydrides.

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Introduction

Cinchona alkaloids are extracted from the bark of Cinchona ledgeriana, which is an important medicinal plant of tropical and sub-tropical regions.¹ In addition to their medicinal use in as antimalarial and antiarrhythmic compounds, cinchona alkaloids have also been employed as chiral organocatalysts in asymmetric synthesis.² Various efficient asymmetric catalysts have been designed based on cinchona alkaloids, an important class of which are their sulfonamide derivatives. Cinchona alkaloids have various functionalities, including a quinuclidine group, a secondary alcohol, a quinoline ring, and a vinylic unit. The secondary alcohol can be easily converted into an amine, which may be further modified to incorporate a sulfonamide group. The acidic NH of a sulfonamide can act as a H-bond donor, whereas the tertiary nitrogen of quinuclidine in cinchona alkaloids may act as both a H-bond acceptor and a base. By incorporating both acidic and basic sites into the cinchona alkaloid sulfonamide derivatives, the combination of acidic and basic sites allows the cinchona alkaloid sulfonamide derivatives to hold substrates in a particular orientation, therefore leading to a chiral environment. Several examples of cinchona-based sulfonamide catalysts have been developed for asymmetric reactions. For example, Chin et al. reported that a sulfonamide derived from quinine showed excellent catalytic activity in the enantioselective desymmetrization of cyclic anhydrides.³ When cinchona-based sulfonamide derivatives are incorporated into polymers, the microenvironment of the catalyst site is precisely modified and controlled by polymerization.

Various kinds of polymer-immobilized cinchona alkaloid catalysts have been synthesized via attachment onto the side chain of synthetic polymers like crosslinked polystyrene.⁴ Silica-supported cinchona alkaloids have also been prepared and used as catalysts in asymmetric reactions.^5–7 Interestingly however, chiral polymers containing a cinchona-based catalyst as the repeating unit have rarely been synthesized. We have developed several syntheses of polymeric cinchona-based quaternary ammonium salts, with polymerization methods involving a Menshutkin reaction,⁸ ether formation,⁹ a Mizoroki–Heck coupling reaction,¹⁰ and an ion exchange reaction.^11,12 In this paper, we present a new synthesis of chiral polymers containing repeating cinchona-based sulfonamides in their main chain structure. The well-established Mizoroki–Heck reaction was chosen for the synthesis of the chiral sulfonamide polymers, which usually provides the coupling product in high yield. The chiral polymers were subsequently investigated as catalysts for the asymmetric desymmetrization of cyclic anhydrides.

Results and discussion

Synthesis of chiral polymers of cinchona sulfonamide

9-Amino derivatives of cinchonidine¹³ and quinine¹⁴ (1C, 1Q) were prepared by Mitsunobu-type azide formation, followed by Staudinger reduction. Sulfonamides 3 were easily formed by the reaction of 1 and sulfonyl chloride 2 (Scheme 1). Sulfonamides 3CI and 3QI possess both aromatic iodide and vinyl groups. Since Mizoroki–Heck (MH) coupling reactions occur between aromatic iodides and olefins, repetitive MH reactions may occur with these sulfonamides to give rise to polymers. Indeed, under MH reaction conditions, both 3CI and 3QI readily react intermolecularly to form chiral polymers P1C and P1Q (Scheme 2). The polymers P1 were only soluble in high polar solvents such as DMF and DMSO. This efficient method of one component, self-polycondensation of a chiral monomer represents the first example of polymer synthesis using cinchona alkaloid-derived sulfonamides. The polymerization results are summarized in Table 1.

Scheme 1 Preparation of cinchona alkaloid monomers 3.

Scheme 2 Synthesis of cinchona alkaloid polymers by Mizoroki–Heck polymerization.

Table 1 Synthesis of chiral sulfonamide polymers P1, P2 using Mizoroki–Heck polymerization^a

Entry	Chiral sulfonamide polymer	Y	R	Ar	Yield %	Mn^b	Mw^b	Mw/Mn^b
a Polymerized in DMF at 100 °C for 24 h.b Determined by SEC (polystyrene standards) using DMF as an eluent at a flow rate of 1.0 mL min^−1 at 40 °C.
1	P1C	H	—	—	99	8500	11 000	1.4
2	P1Q	OMe	—	—	95	5800	9400	1.6
3	P2Caa	H			99	9500	29 000	3.1
4	P2Cba	H			99	3800	4100	1.1
5	P2Cbb	H			97	11 000	18 000	1.7
6	P2Cca	H			99	3100	4400	1.4
7	P2Cda	H			98	6200	21 000	3.5
9	P2Qba	OMe			99	7400	12 000	1.6

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The successful synthesis of chiral polymers P1 by repetitive MH polymerization prompted us to apply the same method to a two-component polycondensation system. Two equivalents of 9-amino cinchona alkaloid 1 were allowed to react with disulfonyl dichloride 4 to afford sulfonamide dimers 5, as shown in Scheme 3. Polycondensation between the dimer 5 and aromatic diiodide 6 under the previously identified MH conditions gave the chiral polymer P2. In the case of the two-component polycondensation system, changing the structure of the disulfonyl dichloride 4 and aromatic diiodide 6 allowed the synthesis of various polymeric structures according to Scheme 4. The results of the two-component polycondensation are summarized in Table 1.

Scheme 3 Preparation of cinchona alkaloid dimers 5.

Scheme 4 Synthesis of cinchona alkaloid polymers P2 by two component polycondensation.

Enantioselective desymmetrization reaction with chiral polymer catalysts derived from cinchona alkaloid sulfonamide

Cinchona alkaloid sulfonamides are efficient catalysts in various asymmetric reactions.^15–25 These asymmetric transformations have been applied to the synthesis of biologically active compounds and chiral building blocks for pharmaceutical targets.^26,27 In order to confirm the catalytic activity of the newly explored chiral polymers P1 and P2, we chose to investigate the enantioselective desymmetrization of a cyclic anhydride. In the presence of the polymeric catalyst, which is insoluble in the organic solvent used, methanol reacted with cyclic anhydride 7 to give the hemiester 8 (Scheme 5). To identify the optimum reaction conditions, the influence of solvent upon the P1C-catalyzed enantioselective desymmetrization of 7 was studied (Table 2).

Scheme 5 Enantioselective desymmetrization of cyclic anhydride 7.

Table 2 Solvent effect in enantioselective desymmetrization of cyclic anhydride 7 with polymeric catalyst P1C^a

Entry	Catalyst	Solvent	Temperature °C	Yield^b %	% ee^c
a Unless otherwise indicated, reactions were carried out with 7 (0.1 mmol), methanol (10 equiv., 1.0 mmol), and the polymeric catalyst (10 mol%).b Isolated yield.c Determined by chiral HPLC (Chiralcel AD-H) after derivatization to 4-bromophenyl ester of 8.
1	P1C	Hexane	25	99	10
2	P1C	CH2Cl2	25	91	49
3	P1C	EtOAc	25	39	51
4	P1C	Et2O	25	93	37
5	P1C	Cyclopentyl methyl ether	25	89	34
6	P1C	MTBE	25	23	20
7	P1C	Dioxane	25	81	79
8	P1C	THF	25	86	94
9	P1C	THF	0	40	94
10	P1C	THF	−20	6	95
11	P1Q	THF	25	97	95
12	3CH	THF	25	99	93
13	3CI	THF	25	99	93

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We found that the choice of solvent had a dramatic effect on both the catalytic activity and enantioselectivity of the desymmetrization of 7. In hexane, the reaction occurred smoothly to give 8 in an almost quantitative yield. However, the ee was only 10% (entry 1). Dichloromethane and ethyl acetate gave higher enantioselectivities under the same reaction conditions (entries 2, 3), whereas ethers led to relatively lower enantioselectivity (entries 4–6). However, interestingly, cyclic ethers such as dioxane and THF showed both high reactivity and increased enantioselectivity (entries 7, 8). In the reaction conducted in THF, the polymeric catalyst P1C showed a slightly higher ee of 94% (entry 8) when compared to the corresponding low-molecular-weight model catalyst 3CH (entry 12). The structurally similar polymer P1Q also showed excellent activity under the same reaction conditions, with an ee of 95% observed in THF (entry 11). The effect of temperature on the reaction with polymeric catalyst P1C was also surveyed (entries 9, 10). Although no significant effect on the enantioselectivity was observed, the reaction rate decreased considerably at lower reaction temperatures.

We then used another chiral polymeric catalysts P2, prepared as previously by a two component MH polymerization from 5 and aromatic diiodides. With THF identified as the best solvent for the asymmetric reaction with the polymeric catalyst P1, the same solvent was used in the asymmetric reaction with P2. As shown in Table 3, the reaction with P2 in THF occurred smoothly at room temperature. We also found that the polymer structure of P2 considerably affected both the catalytic activity and enantioselectivity of the reaction. A disulfonamide linker with a biphenyl structure gave a relatively higher yield and enantioselectivity for 8 (entries 2–4) when compared to naphthalene-based disulfonamides (entries 5, 6). Since the polymeric catalyst forms an insoluble suspension in THF, the catalyst could be easily separated from the reaction mixture by simple filtration. The recovered polymer powder could then be reused in subsequent reactions, without any loss of catalytic activity or enantioselectivity. The polymeric catalyst P2Cba can be reused at least 4 times (entries 2–5).

Table 3 Enantioselective desymmetrization of cyclic anhydride 7 with polymeric catalyst in THF^a

Entry	Catalyst	Temperature °C	Yield^b %	ee^c %
a Unless otherwise indicated, reactions were carried out with 7 (0.1 mmol), methanol (10 equiv., 1.0 mmol), and the polymeric catalyst (10 mol%).b Isolated yield.c Determined by chiral HPLC (Chiralcel AD-H) after derivatization to 4-bromophenyl ester of 8.d The recovered polymer catalyst P2Cba used in entry 2 was used.e The recovered polymer catalyst P2Cba used in entry 3 was used.f The recovered polymer catalyst P2Cba used in entry 4 was used.g The recovered polymer catalyst P2Cbb used in entry 6 was used.
1	P2Caa	25	93	90
2	P2Cba	25	98	91
3^d	P2Cba	25	99	92
4^e	P2Cba	25	99	93
5^f	P2Cba	25	99	95
6	P2Cbb	25	99	93
7^g	P2Cbb	25	99	93
8	P2Cca	25	42	84
9	P2Cda	25	32	65
10	P2Qba	25	99	88
11	5Ca	25	99	96
12	5Cb	25	99	93

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In order to further demonstrate the usefulness of chiral polymeric organocatalysts, P1Q was used in the enantioselective desymmetrization of cyclic anhydrides 9 and 11 (Scheme 6). The reaction occurred smoothly to give the corresponding hemiesters 10 and 12, as summarized in Table 4. In addition to methanol, benzyl alcohol and allyl alcohol were also examined in the desymmetrization reaction of cyclic anhydride 7, and gave rise to the corresponding chiral hemiesters 13 and 14 (entries 4, 5). The results obtained from one of the most efficient catalyst 3QF³ in the same asymmetric reaction were shown in Table 4. In case of the reactions of 7, the catalytic activity of the polymer catalyst was equivalent to that of 3QF (Fig. 1).

Scheme 6 Enantioselective desymmetrization of cyclic anhydrides with polymeric catalyst PQ1.

Table 4 Enantioselective desymmetrization of cyclic anhydride with polymeric catalyst P1Q in THF^a

Entry	Cyclic anhydride	Catalyst	Alcohol	Product	Yield^b %	ee^c %
a Unless otherwise indicated, reactions were carried out with cyclic anhydride (0.1 mmol), alcohol (10 equiv., 1.0 mmol), and the polymeric catalyst (10 mol%).b Isolated yield.c Determined by chiral HPLC (Chiralcel AD-H) after derivatization to 4-bromophenyl ester of hemiester.d See ref. 3.
1	7	P1Q	CH3OH	8	97	95
2^d	7	3QF	CH3OH	8	92	95
3	7	P1Q	PhCH2OH	13	99	71
4	7	P1Q	CH2=CHCH2OH	14	80	95
5	9	P1Q	CH3OH	10	88	73
6^d	9	3QF	CH3OH	10	90	94
7	11	P1Q	CH3OH	12	41	78
8^d	11	3QF	CH3OH	12	95	91

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Fig. 1 Quinine derived sulfonamide 3QF.

Conclusions

In conclusion, chiral polymers containing a cinchona-based sulfonamide structure in their main chain were successfully synthesized by Mizoroki–Heck polymerization. This is the first synthesis of a chiral, polymeric catalyst containing both acidic and basic functionality by means of a repeated MH reaction. The chiral polymers showed catalytic activity in the enantioselective desymmetrization reactions of cyclic anhydrides, with high levels of enantioselectivity observed. The polymeric catalysts were easily separated from the reaction mixture and reused several times without loss of either catalytic activity or enantioselectivity. Since the cinchona-based sulfonamides are known to be excellent catalysts in various asymmetric reactions, the polymers developed in this study will find further application as catalysts in alternative asymmetric transformations. For instance, the use of the chiral polymers in asymmetric Michael-type reactions is now under investigation.

Experimental

General methods

All solvents and reagents were purchased from Sigma-Aldrich, Wako Pure Chemical Industries, Ltd., or Tokyo Chemical Industry (TCI) Co., Ltd. at the highest available purity and were used as received, unless otherwise mentioned. Reactions were monitored by thin-layer chromatography using pre-coated 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 the values were not corrected. NMR spectra were recorded on JEOL JNM-ECS400 spectrometers in CDCl₃ or DMSO-d₆ at room temperature operating at 400 MHz (¹H) and 100 MHz (¹³C{¹H}). Tetramethylsilane (TMS) was used as an internal standard for ¹H NMR, and CDCl₃ for ¹³C NMR. Chemical shifts are reported in ppm using TMS as a reference, and the J values were recorded in hertz. The IR spectra, recorded on a JEOL JIR-7000 FTIR spectrometer, are reported in cm⁻¹. Elemental analyses (carbon, hydrogen, nitrogen) were performed on a Yanaco-CHN coder MT-6 analyzer. HRMS (ESI) spectra were recorded on a microTOF-Q II HRMS/MS instrument (Bruker). High-performance liquid chromatography (HPLC) was performed with a Jasco HPLC system composed of a DG-980-50 three-line degasser, a PU 980 HPLC pump, and a CO-965 column oven equipped with a chiral column (Chiralpak AD-H, Daicel) with hexane/2-propanol as an eluent. A Jasco UV-975 UV detector was used for peak detection. Size-exclusion chromatography (SEC) was performed using a Tosoh instrument with HLC 8020 UV (254 nm) or refractive index detection. DMF was used as the carrier solvent at a flow rate of 1.0 mL min⁻¹ at 40 °C. Two polystyrene gel columns of bead size 10 μm were used. A calibration curve was obtained to determine the number-average molecular weight (M_n) and molecular weight distribution (M_w/M_n) values with polystyrene standards. Optical rotation was recorded using a JASCO DIP-149 digital polarimeter, using a 10 cm thermostated microcell.

Synthesis of sulfonamide 3CH. To a stirred mixture of 1C (0.90 g, 3.1 mmol) in CH₂Cl₂ (5 mL) and NEt₃ (0.31 g, 3.1 mmol), a solution of benzenesulfonyl chloride (0.53 g, 3.0 mmol) in CH₂Cl₂ (5 mL) was slowly added under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 24 h. After the addition of water (5 mL), the mixture was extracted with CH₂Cl₂ (10 mL × 3) and the organic extracts were dried over anhydrous Na₂SO₄. After filtration, the solvent was removed by evaporation and the residue was purified by column chromatography (SiO₂, CH₂Cl₂/MeOH = 9/1, v/v) to afford 3CH (1.04 g, 80% yield). ¹H NMR (400 MHz, CDCl₃) δ_H 8.74 (d, 0.25H, J = 3.97 Hz), 8.64 (d, 0.75H, J = 4.58 Hz), 8.36 (d, 0.25H, J = 8.85 Hz), 8.14 (d, 0.75H, J = 8.24 Hz), 8.08 (d, 0.75H, J = 8.24 Hz), 7.95 (d, 0.25H, J = 8.24 Hz), 7.74 (t, 0.75H, J = 7.93 Hz), 7.65–7.56 (m, 1H), 7.48–7.30 (m, 4H), 7.22 (d, 0.25H, J = 3.97 Hz), 7.11 (t, 1.5H, J = 7.63 Hz), 6.95 (t, 0.5H, J = 7.93 Hz), 5.69–5.54 (m, 1H), 5.10 (d, 0.75H, J = 10.4 Hz), 5.00–4.84 (m, 2H), 4.33 (d, 0.25H, J = 10.7 Hz), 3.37–3.22 (m, 1.25H), 3.05–2.94 (m, 1.5H), 2.85–2.63 (m, 2.25H), 2.33 (br s, 1H), 1.68–1.56 (m, 3H), 1.31–1.27 (m, 1H), 0.93–0.86 (m, 1H). IR (KBr) ν_max 3446, 3197, 3064, 2943, 2866, 1636, 1591, 1568, 1509, 1447, 1324, 1239, 1159, 1092, 1059, 1033, 988, 955, 922, 878, 817, 754 cm⁻¹. HRMS (ESI): m/z calc'd for [C₂₅H₂₈N₃O₂S]⁺: 434.1897, found: 434.1898.

Synthesis of sulfonamide dimers 5Ca. A typical procedure for the synthesis of 5 is described. To a stirred mixture of 1C (0.90 g, 3.1 mmol) in CH₂Cl₂ (5.0 mL) and NEt₃ (0.31 g, 3.1 mmol), a solution of m-benzenedisulfonyl dichloride (0.42 g, 1.5 mmol) in CH₂Cl₂ (5 mL) was slowly added under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 24 h. After the addition of water (5 mL), the mixture was extracted with CH₂Cl₂ (10 mL × 3) and the organic extracts were dried over anhydrous Na₂SO₄. After filtration, the solvent was removed by evaporation and the residue was purified by column chromatography (SiO₂, CH₂Cl₂/MeOH = 9/1, v/v) to afford 5Ca (727 mg, 60% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ_H 8.73 (d, J = 4.27 Hz), 8.70 (d, J = 4.27 Hz), 8.64 (d, J = 4.58 Hz), 8.12–8.04 (m), 7.97 (s), 7.89–7.83 (m), 7.75–7.49 (m), 7.30 (d, 1.3H, J = 4.58 Hz), 7.21–7.19 (m), 7.09 (d, J = 7.93 Hz), 6.94 (d, J = 7.93 Hz), 6.79 (q, J = 16.17, 8.24 Hz), 6.54 (t, J = 7.93 Hz), 6.31 (t, J = 7.63 Hz), 5.67–5.51 (m), 5.03–4.82 (m), 4.32 (d, J = 10.7 Hz), 4.19 (d, J = 10.99 Hz), 3.35–3.07 (m), 2.96–2.45 (m), 2.28 (br s), 1.67–1.39 (m), 1.27–1.17 (m), 0.89–0.74 (m). ¹³C NMR (100 MHz, CDCl₃) δ_C 150.0, 149.3, 148.7, 148.1, 144.0, 143.7, 141.0, 140.6, 140.3, 139.7, 139.1, 130.4, 130.2, 130.1, 130.0, 129.6, 129.5, 129.4, 129.2, 128.7, 127.6, 127.5, 127.3, 126.8, 126.7, 126.3, 126.2, 125.4, 124.1, 123.9, 123.8, 122.1, 120.2, 120.1, 115.2, 115.1, 114.9, 62.7, 61.1, 61.0, 56.6, 55.6, 55.3, 52.5, 52.4, 45.8, 40.3, 39.9, 39.6, 39.1, 27.6, 27.3, 27.2, 26.1, 24.8, 8.7. IR (KBr) ν_max 3609, 3421, 3209, 3073, 2942, 2866, 2604, 2495, 1922, 1716, 1636, 1591, 1569, 1510, 1457, 1413, 1326, 1240, 1175, 1154, 1082, 1059, 1032, 988, 956, 912, 879, 814, 795, 759, 684, 580, 517, 418 cm⁻¹. HRMS (ESI): m/z calc'd for C₄₄H₄₇N₆O₄S₂ ([M − H]⁻) 787.3106, found 787.3106.

Synthesis of cinchona alkaloid polymers by self polycondensation.
Synthesis of P1C. A mixture of sulfonamide 3CI (0.21 g, 0.38 mmol) in the presence of 3 mol% Pd (OAc)₂ (2.5 mg, 11.3 μmol) and Et₃N (38 mg, 0.38 mmol) was stirred in 3 mL anhydrous DMF at 100 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was then added dropwise into ether (40 mL) with stirring. The solid precipitate was filtered, then sequentially washed with diethyl ether, ethyl acetate, CH₃OH, and hexane to afford 176 mg (99% yield) of the product P1C. IR (KBr) ν_max 3435, 3061, 2931, 2866, 1656, 1592, 1568, 1510, 1466, 1386, 1327, 1243, 1160, 1089, 1055, 1003, 928, 876, 815, 763, 729, 698 cm⁻¹. [α]²⁵_D = −134.7 (c 1.0, DMSO). M_n (SEC) = 8.5 × 10³; M_w/M_n = 1.4.
Synthesis of P1Q. A mixture of sulfonamide 3QI (224 mg, 0.38 mmol) in the presence of 3 mol% Pd(OAc)₂ (2.5 mg, 11.3 μmol) and NEt₃ (38 mg, 0.38 mmol) was stirred in 3 mL anhydrous DMF at 100 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was then added dropwise into diethyl ether (40 mL) with stirring. The solid precipitate was filtered, then sequentially washed with ether, ethyl acetate, CH₃OH, and hexane to afford 174 mg (99% yield) of the product P1Q. IR (KBr) ν_max 3435, 3061, 2931, 2866, 1656, 1592, 1568, 1510, 1466, 1386, 1327, 1243, 1160, 1089, 1055, 1003, 928, 876, 815, 763, 729, 698 cm⁻¹. [α]²⁵_D = −154.7 (c 1.0, DMSO). M_n (SEC) = 5.8 × 10³; M_w/M_n = 1.6.

Representative procedure for the synthesis of P2C by two component polycondensation. A typical procedure for the synthesis of P2Caa is described. A mixture of sulfonamide dimer 5Ca (0.30 g, 0.38 mmol) and 4,4′-diiodobenzene (0.13 mg, 0.38 mmol) in the presence of 3 mol% Pd (OAc)₂ (2.6 mg, 0.011 mmol) and NEt₃ (77 mg, 0.76 mmol) was stirred in 3 mL anhydrous DMF at 100 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was then added dropwise into ether (40 mL) with stirring. The solid precipitate was filtered, then sequentially washed with ether, ethyl acetate, CH₃OH, and hexane to afford 313 mg (99% yield) of the product P2Caa. ¹³C NMR (DMSO-d₆, 100 MHz) δ_C 170.4, 149.6, 147.3, 137.8, 137.1, 129.4, 129.0, 128.3, 127.4, 126.3, 125.9, 124.1, 122.7, 119.9, 59.8, 59.4, 51.1, 45.7, 41.4, 26.6, 20.8, 14.1, 11.1, 8.6. IR (KBr) ν_max 3421, 3057, 2939, 2864, 1730, 1654, 1591, 1569, 1510, 1465, 1337, 1242, 1154, 1080, 1058, 1003, 967, 908, 878, 795, 762, 683, 580, 521 cm⁻¹. [α]²⁵_D = −134.7 (c 1.0, DMSO). M_n (SEC) = 9.5 × 10³; M_w/M_n = 3.1.

Representative procedure for asymmetric desymmetrization of prochiral cyclic anhydride with methanol. Methanol (40.5 μL, 1.00 mmol) was added dropwise to a solution of 7 (15.4 mg, 0.10 mmol) and P1C (4.3 mg, 0.01 mmol) in THF (2 mL) at room temperature with stirring, and the mixture was stirred at room temperature for 24 h. The reaction mixture was directly subjected to column chromatography (SiO₂, Et₂O) to give the hemiester product 8 (16 mg, 86%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ_H 3.68 (s, 3H), 2.85 (br s, 2H), 2.10–1.94 (m, 2H), 1.82–1.73 (m, 2H), 1.61–1.38 (m, 4H).

To determine the enantiomeric excess (ee), 8 was converted to the corresponding 4-bromophenyl ester according to a literature procedure.²⁸ To a solution of 8 (18.6 mg, 0.10 mmol) and 4-bromophenol (34.6 mg, 0.200 mmol) in CH₂Cl₂ (2 mL) at 0 °C, N,N′-dicyclohexylcarbodiimide (41.3 mg, 0.20 mmol) and 4-dimethylaminopyridine (DMAP, 6.10 mg, 0.05 mmol) were added. The mixture was allowed to warm to room temperature and stirred overnight. The white solid was filtered off and the solvent was removed in vacuo. The residue was then purified via column chromatography (SiO₂, EtOAc/n-hexane = 1/5, v/v) to afford the 4-bromophenyl ester (28.8 mg, 98% based on 8) as a colourless oil. The ee of the 4-bromophenyl ester was determined to be 94% by chiral HPLC analysis (Chiralpak AD-H column, 2-propanol/n-hexane = 1/9 v/v, 1.0 mL min⁻¹). t_(1S,2R) = 7.8 min, t_(1R,2S) = 8.3 min. ¹H NMR (400 MHz, CDCl₃) δ_H 7.47 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 3.70 (s, 3H), 3.06–2.98 (m, 2H), 2.16–2.03 (m, 2H), 1.96–1.89 (m, 2H), 1.82–1.61 (m, 2H), 1.58–1.41 (m, 2H).

In the same way, other polymers and monomers were also employed as catalysts for the enantioselective desymmetrization reaction. These results are summarized in Table 2.

Acknowledgements

The authors would like to thank Dr Naoki Haraguchi at Toyohashi University of Technology for fruitful discussions. This work was supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (Japan).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra14535c

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