Cinchonidine thiourea catalyzed asymmetric addition of phenols to oxindole derivatives

Abstract

A highly enantioselective Friedel–Crafts reaction of activated phenols with isatin derivatives has been developed employing Cinchona-derived thiourea as an organocatalyst. A variety of biologically important 3-aryl-3-hydroxy-2-oxindoles have been synthesized using phenols in good to excellent yield with good enantioselectivity (up to 92% ee).

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Introduction

The oxindole skeleton bearing a oxygenated chiral tetrasubstituted carbon at C3 constitutes a significant structural motif which occurs in a large family of bioactive natural products and therapeutically useful agents.¹ In particular, 3-aryl-3-hydroxy-2-oxindole is an important structural unit found in many pharmaceutically active compounds (Fig. 1) and is a key intermediate for drug development programmes.² Owing to their biological significance, the asymmetric synthesis of 3-aryl-3-hydroxy-2-oxindoles has become an intensively investigated research area.³ Over the years, a variety of catalytic asymmetric methods,^3a including nucleophilic addition to isatins,^3b,c oxidation of 3-aryl-2-oxindoles,^3d,e and intramolecular arylation reactions,^3f,4a have been developed to tackle the synthetic challenge in constructing an aryl substituted chiral tertiary alcohol carbon centre at 3-position of oxindole. Among the available methods, the catalytic asymmetric arylation of isatins is one of the most efficient synthetic routes.^4–6 The asymmetric arylation of isatins, especially, the addition of an organoboronic reagent to isatins, has been well studied in the presence of chiral metal complexes.^4d–i However, despite various advantages associated with organocatalysis and its explosive growth, the synthesis of this subunit by organocatalyzed reactions is limited to the use of heteroarenes.⁵ Recently, our group^6a,b and Wang^6c et al. reported the Friedel–Crafts-type-addition of 1-naphthols and sesamol to isatins, but a systematic study of organocatalyzed asymmetric C-3 arylation of isatins with other electron-rich arenes, such as phenols is lacking.⁷ In addition, the structure activity correlation shows that the biological activity of 3-aryl-3-hydroxy-2-oxindoles is sensitive to absolute stereochemistry at C-3 and substituent pattern on the aryl group.⁸ Hence, Friedel–Crafts addition of phenols to isatins delivers new chiral derivatives of 3-aryl-3-hydroxy-2-oxindoles, which may possess unexplored medicinal advantage and can also be used as synthetic intermediate for the synthesis of highly potent bioactive molecules. Synthesis of similar oxindole derivatives have been achieved using multistep procedure.^8a The novelty of present work consists of achieving this in a single step under mild conditions.

Fig. 1 Biologically active 3-hydroxy-2-oxindole derivatives.

Our group has been actively involved in the synthesis of new 3-hydroxy-2-oxindoles employing bifunctional organocatalysts.⁹ Herein we report the first organocatalyzed synthesis of 3-aryl-3-hydroxy-2-oxindoles using phenols as arylating agents with isatins. The enantioinduction have been achieved in the Friedel–Crafts reaction of phenols with isatins through synergistic activation by a bifunctional Cinchona–thiourea organocatalyst (Scheme 1).

Scheme 1 Proposed dual activation for the thiourea–tertiary amine catalyzed, asymmetric Friedel–Crafts reaction of phenols with isatins.

Result and discussion

Initially, the catalytic ability of Cinchona alkaloids QD, CN, QN and CD (Fig. 2) was evaluated for the Friedel–Crafts-type-addition of 3,4-dimethoxyphenol 10a with N-benzylisatin 9a in THF and 4 Å molecular sieves at room temperature. The desired product 11a was isolated in good yield, but with poor enantioselectivity (Table 1, entries 1–4). The same reaction was performed using modified Cinchona catalysts (CPD, CPN, BnCPD and BnCPN), the desired adduct was obtained with low level of enantioselectivity (Table 1, entries 5–8). Next, we studied the catalytic capability of 9-thiourea derivatives of Cinchona alkaloids on the same reaction (Table 1, entries 9–16). Among different Cinchona-derived thioureas (3a, 3b, 4a and 4b) (Table 1, entries 9–12), the cinchonidine thiourea 3a provided the Friedel–Crafts adduct 11a in good yield of 86% and good enantiomeric excess of 83% ee (Table 1, entry 9). Therefore, we planned to synthesize different cinchonidine-based thioureas (5–7), and evaluated their catalytic potential on the model reaction (Table 1, entries 13–16). The epiCDT-L-Val (5) afforded the adduct 11a in 68% yield and 40% ee (Table 1, entry 13). Using thioureas 6a and 6b the product 11a was isolated in good yield (80–83%) and good enantioselectivity (73–82% ee) (Table 1, entries 14 and 15). The organocatalyst 7 having thiourea group at the distance of six bonds from tertiary amine functionality, yielded adduct 11a in moderate yield with low enantioselectivity (Table 1, entry 16). The amino acid, L-isoleucine-derived bifunctional thiourea 8 was found to be inferior catalyst for this transformation (Table 1, entry 17). After evaluating the catalytic power of diverse thioureas, the epiCDT (3a) emerged as the best catalyst for this reaction (Table 1, entry 9). Lowering the reaction temperature from room temperature to −18 °C resulted in prolonged reaction time without any enhancement in the enantioselectivity (Table 1, entry 18).

Table 1 Catalyst screening^a

Entry	Catalyst	Time (h)	Yield^b (%)	ee^c^,^d (%)
a Reaction conditions: 0.1 mmol of phenols 10a, 0.1 mmol N-benzylisatin 9a, 4 Å molecular sieves (50 mg) and catalysts (1–8, 10 mol%) in dry THF.b Yield refers to isolated yield after column chromatography.c Enantiomeric excess (ee) determined by chiral HPLC.d The sign in parentheses indicates the sign of the optical rotation.e Reaction was performed at −18 °C.
1	1a	12	76	10 (+)
2	1b	12	80	4 (−)
3	2a	12	77	19 (−)
4	2b	12	82	30 (−)
5	1c	12	76	29 (−)
6	2c	12	80	19 (+)
7	1d	12	82	37 (−)
8	2d	12	77	24 (+)
9	3a	12	86	83 (+)
10	3b	12	80	70 (+)
11	4a	12	77	38 (−)
12	4b	12	82	15 (−)
13	5	110	68	40 (+)
14	6a	12	83	73 (+)
15	6b	12	80	82 (+)
16	7	24	64	35 (+)
17	8	12	77	20 (+)
18^e	3a	24	72	82 (+)

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Fig. 2 Structure of organocatalysts.

Further optimization of the reaction condition was performed by screening of different solvents. Variation of solvents had a pronounced effect on the enantioselectivity of the reaction (Table 2). In chlorinated solvents such as chloroform, dichloromethane and 1,2-dichloroethane, the product 11a was isolated in good yield (78–84%) and low to moderate enantioselectivity (35–62% ee) (Table 2, entries 1–3). Non-polar solvents such as xylene and toluene proved to be inefficient in terms of enantio-induction (Table 2, entries 4 and 5). Polar aprotic solvents such as ethyl acetate provided the Friedel–Crafts adduct 11a in good yield and good enantioselectivity (Table 2, entry 6). Among different etheral solvents, MTBE emerged as the best solvent because it provided 11a in good yield (82%) and highest level of enantioselectivity (88% ee). The use of benzoic acid as an additive in the model reaction leads to decrease in the enantioselectivity (Table 2, entry 10). Thus, the best optimized condition consists of 10 mol% of 3a, 4 Å molecular sieves and MTBE as a solvent at ambient temperature providing Friedel–Crafts adduct 11a in 82% yield and 88% ee.

Table 2 Solvent screening^a

Entry	Solvent	Time (h)	Yield^b (%)	ee^c (%)
a Reaction conditions: 0.1 mmol of phenols 10, 0.1 mmol N-benzylisatin 9a, 4 Å molecular sieves (50 mg), additive (10 mol%) and catalysts 3a (10 mol%) in dry solvent.b Yield refers to isolated yield after column chromatography.c Enantiomeric excess (ee) determined by chiral HPLC.d Reaction was performed using benzoic acid as an additive. MTBE = methyl tert-butyl ether.
1	Chloroform	12	78	35
2	DCM	12	84	46
3	DCE	12	80	62
4	Xylene	12	75	57
5	Toluene	12	74	47
6	Ethyl acetate	12	74	74
7	THF	12	86	83
8	MTBE	12	82	88
9	Dioxane	12	78	77
10^d	MTBE	12	84	70

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After optimizing the conditions, the substrate scope was evaluated by studying the Friedel–Crafts addition of phenols to isatins 9a–9z. 5-Halogen-N-benzylisatins 9b–9d reacted well with 3,4-dimethoxyphenol, yielding 3-aryl-3-hydroxy-2-oxindoles 11b–11d in good yield (81–85%) and good enantioselectivity (86–88% ee) (Table 3, entries 2–4). The N-benzylisatins 9f and 9g substituted with electron donating groups in the aromatic ring provided adducts 11f and 11g with slight decrease in the enantioselectivity (81% ee in each case) (Table 3, entries 6 and 7). 5-Iodo-N-benzylisatin gave Friedel–Crafts adduct 11e in good yield (83%) but with moderate enantioselectivity (60% ee) (Table 3, entry 5). The reaction of N-allylisatin derivatives 9h–9k with 3,4-dimethoxyphenol afforded Friedel–Crafts adducts 11h–11k in good yield (79–84%) and good enantioselectivity (84–92% ee) (Table 3, entries 8–11). 5-Methyl-N-allylisatin 9m gave product 11m in good enantiomeric excess (83% ee) (Table 3, entry 13).

Table 3 Substrate scope^a

Entry	10	9 (R1, R2)	11	Time (h)	Yield^b (%)	ee^c (%)
a Reaction conditions: 0.1 mmol of isatin derivatives 9, 0.1 mmol phenols 10, 4 Å molecular sieves (50 mg) and catalysts 3a (10 mol%) in dry MTBE.b Yield refers to isolated yield after column chromatography.c Enantiomeric excess (ee) determined by chiral HPLC.
1	10a	9a (R1 = Bn, R2 = H)	11a	12	82	88
2	10a	9b (R1 = Bn, R2 = F)	11b	12	82	86
3	10a	9c (R1 = Bn, R2 = Cl)	11c	12	85	88
4	10a	9d (R1 = Bn, R2 = Br)	11d	12	81	87
5	10a	9e (R1 = Bn, R2 = I)	11e	12	83	60
6	10a	9f (R1 = Bn, R2 = Me)	11f	12	79	81
7	10a	9g (R1 = Bn, R2 = OMe)	11g	12	80	81
8	10a	9h (R1 = CH2CHCH2, R2 = F)	11h	12	83	84
9	10a	9i (R1 = CH2CHCH2, R2 = Cl)	11i	12	81	92
10	10a	9j (R1 = CH2CHCH2, R2 = Br)	11j	12	79	84
11	10a	9k (R1 = CH2CHCH2, R2 = I)	11k	12	84	90
12	10a	9l (R1 = CH2CHCHCH3, R2 = Cl)	11l	12	80	75
13	10a	9m (R1 = CH2CHCH2, R2 = Me)	11m	12	82	83
14	10a	9n (R1 = Me, R2 = Cl)	11n	12	83	85
15	10a	9o (R1 = CH2CCH, R2 = H)	11o	12	83	70
16	10b	9b (R1 = Bn, R2 = F)	11p	12	85	77
17	10b	9c (R1 = Bn, R2 = Cl)	11q	12	83	82
18	10b	9d (R1 = Bn R2 = Br)	11r	12	86	84
19	10b	9g (R1 = Bn, R2 = OMe)	11s	12	82	63
20	10b	9i (R1 = CH2CHCH2, R2 = Cl)	11t	12	81	85
21	10b	9u (R1 = CH2CCH, R2 = H)	11u	12	73	59
22	10b	9v (R1 = CH3, R2 = H)	11v	12	79	69
23	10c	9b (R1 = Bn, R2 = F)	11w	12	87	71
24	10c	9i (R1 = CH2CHCH2, R2 = Cl)	11x	12	83	76
25	10c	9u (R1 = CH2CCH, R2 = H)	11y	12	82	68
26	10a	9z (R1 = H, R2 = H)	11z	96	78	80

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The N-methylisatins 9n afforded the Friedel–Crafts adduct 11n in good yield (83%) and good enantioselectivity (85% ee) (Table 3, entry 14). The Friedel–Crafts addition of 3,4-dimethoxyphenol to N-propargylisatins 9o provided the corresponding product 11o in 83% yield and 70% ee (Table 3, entry 15).

Next, we screened different derivatives of phenols (10b and 10c) with isatins. The Friedel–Crafts addition of 3-methoxyphenol (10b) to 5-substituted N-benzylisatins 9b–9d provided the corresponding products 11p–11r in good yield (83–86%) and good enantioselectivity (77–84% ee) (Table 3, entries 16–18).

The reaction of 3-methoxyphenol with N-benzylisatins bearing the electron releasing groups provides the desired adduct in good yield (82%) but with moderate enantioselectivity (63% ee) (Table 3, entry 19). Using N-allylisatin 9t, the Friedel–Crafts adduct 11t was isolated in good yield (81%) and good enantioselectivity (85% ee), whereas N-propargylisatin 9u provided the adduct 11u in good yield (73%) but with moderate enantioselectivity (59% ee) (Table 3, entries 20 and 21). The N-methylisatin afforded the Friedel–Crafts adduct in 79% yield and 69% ee (Table 3, entry 22).

Further, we have studied the Friedel–Crafts reaction of 3,5-dimethoxyphenol (10c) with different derivatives of isatin (9b, 9i and 9u). The reaction proceeds smoothly providing desired Friedel–Crafts adducts (11w–11z) in good yield and good enantioselectivity (Table 3, entries 23–25). The N-unprotected isatin 9z react very slowly with 3,4-dimethoxyphenol providing the adduct 11z in good yield (78%) and good enantioselectivity (80% ee) (Table 3, entry 26).

Further, we have performed the reactions of N-benzylisatin with 2-chlorophenol, 4-chlorophenol, 2-bromophenol, 4-bromophenol, 4-iodophenol under the similar conditions but no product was formed even after 72 h. In addition to this, we have tried 4-bromo-3-methoxyphenol, 3-methoxy-5-methylphenol and 3,5-dimethylphenol but no product formation was observed even after two days.

A gram-scale reaction was performed to demonstrate the practical utility of this process (Scheme 2). The reaction of 3,4-dimethoxyphenol (10) with N-benzylisatin (9) on a 4.5 mmol scale with 10 mol% of the catalyst resulted in the formation of 11 in 81% yield after 18 h with a small loss in enantioselectivity (80%).

Scheme 2 Gram-scale preparation of 3-substituted 3-hydroxyoxindole.

The (R) absolute configuration of adducts was assigned on the basis of single-crystal X-ray diffraction analysis of compound 11a (Fig. 3). A transition state model can be proposed to rationalize the stereochemistry of the product (11). The thiourea moiety of the catalyst activates and orients isatin through double H-bonding, while the phenol is activated by the tertiary amine of the catalyst which undergoes Re face addition to the activated isatin via transition state A resulting in the formation of (R)-11. On the other hand, the transition state B results in unfavourable interaction between isatin aromatic ring and the phenol derivative (Fig. 4).

Fig. 3 ORTEP diagram of the molecule (11a) at 30% probability.

Fig. 4 Proposed transition state.

Conclusions

We have developed an organocatalytic enantioselective Friedel–Crafts reaction of phenols with isatins employing chiral thiourea–tertiary amine as catalyst. Through this methodology, a wide variety of biologically relevant 3-aryl-3-hydroxy-2-oxindolins were synthesized in good yield (upto 86%) and good enantioselectivity (upto 92% ee).

Experimental

All reactions were performed in oven-dried glassware. All solvents and commercially available chemical were used without further purification. The molecular sieves were activated at 200 °C for 2 hours in an oven. The column chromatography was carried out on a column packed with silica gel 60–120 using mixtures of hexane and ethyl acetate as an eluents. ¹H NMR spectra were recorded in CDCl₃ on a BRUKER AVANCE III (500 MHz), JNM-ECS400 (400 MHz), BRUKER AVANCE II (400 MHz) and JEOL (300 MHz) spectrometer. ¹³C NMR spectra were recorded in CDCl₃ on BRUKER AVANCE III (125 MHz), JNM-ECS400 (100 MHz), BRUKER AVANCE II (100 MHz) and JEOL (75 MHz). Chemical shifts (δ) are expressed in ppm downfield from internal TMS. MS were recorded on micrOTOF-Q II 10356 Mass Spectrometer. Optical rotation was determined with AUTOPOL IV polarimeter at 25 °C using sodium D light. Enantiomeric excess was determined by using Shimadzu LC-20AD using Daicel Chiralpak IA, IB and IC column.

General procedure

To a solution of isatin derivatives (0.1 mmol), phenols (0.1 mmol), 4 Å MS (50 mg) in 0.3 mL of MTBE, the catalyst epiCDT (3a, 10 mol%) was added at 25 °C. The reaction mixture was stirred for 12–96 hours and the progress of the reaction was monitored at regular intervals by thin layer chromatography (TLC). After the completion of reaction, the crude reaction mixture was purified by column chromatography on silica gel (mesh 60–120) using hexane–ethyl acetate (1 : 1) as eluent. The enantiomeric excess of the purified Friedel–Crafts adducts 11 were determined using Diacel Chiralpak columns. The racemic standards were prepared using triethylamine (10 mol%) as a catalyst.

(R)-1-Benzyl-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl) indolin-2-one (11a). Brown solid; m.p. = 109–110 °C; 82% yield; [α]^D₂₀ = +7.19 (c 0.25, CHCl₃); 88% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 9.04 min (major) and t_R = 16.6 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 9.23 (s, 1H, OH), 7.20–7.56 (m, 8H, ArH), 6.84 (d, J = 5.0 Hz, 1H, ArH), 6.68 (s, 1H, ArH),6.33 (s, 1H, ArH), 4.93 (dd, J = 65.0 Hz, J = 15.0 Hz, 2H, CH₂), 4.38 (s, 1H, OH), 3.88 (s, 3H, OCH₃), 3.62 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 44.08, 55.94, 56.59, 79.31, 104.1, 110.3, 111.3, 115.6, 123.9, 125.9, 127.2, 127.9, 128.9, 129.3, 130.4, 134.9, 142.4, 142.6, 150.8, 151.3, 179.1. HRMS calcd for C₂₃H₂₁NO₅ [M + Na]⁺ 414.1372; found 414.1384.

(R)-1-Benzyl-5-fluoro-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)indolin-2-one (11b). Brown semi-solid; 82% yield; [α]^D₂₀ = +6.28 (c 0.25, CHCl₃); 86% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 8.09 min (major) and t_R = 15.5 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 9.03 (s, 1H, OH), 7.28–7.34 (m, 8H, ArH), 6.68 (s, 1H, ArH), 6.33 (s, 1H, ArH), 4.84–5.00 (m, 2H, CH₂), 4.45 (s, 1H, OH), 3.88 (s, 3H, OCH₃), 3.65 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 44.23, 56.00, 56.74, 79.10, 104.2, 111.0, 111.3, 126.4, 127.2, 128.1, 129.0, 129.4, 130.3, 134.5, 150.9, 151.1, 178.6. HRMS calcd for C₂₃H₂₀FNO₅ [M + Na]⁺ 432.1231; found 432.1238.

(R)-1-Benzyl-5-chloro-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)indolin-2-one (11c). Semi-solid; yield 85%; [α]^D₂₀ = +8.46 (c 0.25, CHCl₃); 88% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1.0 mL min⁻¹, 254 nm, t_R = 7.19 min (major) and t_R = 9.01 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 8.84 (s, 1H, OH), 7.25–7.51 (m, 8H, ArH), 6.65–6.73 (m, 1H, ArH), 6.31 (s, 1H, ArH), 4.91 (dd, J = 40.8 Hz, J = 15.6 Hz, 2H, CH₂), 4.35 (s, 1H, OH), 3.86 (s, 3H, OCH₃), 3.64 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 45.24, 57.01, 57.75, 80.11, 105.2, 112.1, 112.3, 116.3, 127.4, 128.2, 129.1, 130.1, 130.4, 131.3, 135.5, 141.9, 143.9, 151.9, 152.1, 179.6. HRMS calcd for C₂₃H₂₀ClNO₅ [M + Na]⁺ 426.1143; found 426.1141.

(R)-1-Benzyl-5-bromo-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)indolin-2-one (11d). Brown semi-solid; yield 81%; [α]^D₂₀ = +9.26 (c 0.25, CHCl₃); 87% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 7.74 min (minor) and t_R = 8.50 min (major)]; ¹H NMR (300 MHz, CDCl₃) δ 9.50 (s, 1H, OH), 7.09–7.36 (m, 6H, ArH), 6.66–6.93 (m, 2H, ArH), 6.16 (s, 1H, ArH), 6.15 (s, 1H, ArH), 4.81–5.89 (m, 3H), 3.74 (s, 3H, OCH₃), 3.27 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 44.27, 55.32, 55.81, 78.13, 92.00, 95.65, 103.9, 109.9, 110.0, 112.6, 112.8, 116.2, 116.3, 127.7, 127.9, 128.8, 135.5, 157.2, 159.3, 161.4, 176.5. HRMS calcd for C₂₃H₂₀BrNO₅ [M + H]⁺ 470.0603; found 470.0630.

(R)-1-Benzyl-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)-5-iodoindolin-2-one (11e). Brown semi-solid; yield 83%; [α]^D₂₀ = +11.6 (c 0.25, CHCl₃); 60% ee; HPLC [Chiralpak IC, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 10.9 min (major) and t_R = 14.6 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 9.46 (s, 1H, OH), 7.11–7.37 (m, 6H, ArH), 6.67–6.91 (m, 2H, ArH), 6.17 (d, J = 3.0 Hz, 1H, ArH), 5.89 (d, J = 3.0 Hz, 1H, ArH), 4.90 (dd, J = 30.0 Hz, J = 15.0 Hz, 2H, CH₂), 4.57 (s, 1H, OH), 3.75 (s, 3H, OCH₃), 3.28 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 44.10, 55.96, 56.60, 78.45, 79.31, 104.2, 110.3, 111.4, 115.7, 123.9, 125.9, 127.2, 127.9, 128.9, 129.1, 130.4, 134.8, 142.4, 142.6, 150.9, 151.3, 179.1. HRMS calcd for C₂₃H₂₀INO₅ [M + Na]⁺ 540.0283; found 540.0272.

(R)-1-Benzyl-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)-5-methylindolin-2-one (11f). Brown semi-solid; yield 79%; [α]^D₂₀ = +2.36 (c 0.25, CHCl₃); 81% ee; HPLC [Chiralpak IC, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 7.56 min (major) and t_R = 9.15 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 9.56 (s, 1H, OH), 6.91–7.35 (m, 6H, ArH), 6.65–6.89 (m, 2H, ArH), 5.87–6.14 (m, 2H, ArH), 4.97 (s, 1H, OH), 4.09–4.92 (m, 2H, CH₂), 3.75 (s, 3H, OCH₃), 3.73 (s, 3H, OCH₃), 1.76 (s, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 21.13, 44.09, 55.96, 56.69, 79.44, 104.1, 110.1, 111.6, 115.8, 126.6, 127.2, 127.9, 128.9, 129.1, 130.7, 133.7, 134.9, 139.9, 142.6, 150.9, 151.3, 178.9. HRMS calcd for C₂₄H₂₃NO₅ [M + Na]⁺ 428.1473; found 428.1483.

(R)-1-Benzyl-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)-5-methoxyindolin-2-one (11g). Brown oil; yield 80%; [α]^D₂₀ = +3.29 (c 0.25, CHCl₃); 81% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 11.6 min (major) and t_R = 19.1 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 9.24 (s, 1H, OH), 7.07–7.35 (m, 7H, ArH), 6.65–6.70 (m, 2H, ArH), 6.32 (d, J = 1.8 Hz, 1H, ArH), 4.88 (dd, J = 42.4 Hz, J = 15.3 Hz, 2H, CH₂), 4.37 (s, 1H, OH), 3.85 (s, 3H, OCH₃), 3.59 (s, 3H, OCH₃), 2.34 (s, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 21.32, 44.28, 56.14, 56.88, 79.63, 104.3, 110.2, 111.7, 116.0, 126.8, 127.4, 128.1, 129.1, 130.8, 133.8, 135.1, 140.1, 142.8, 151.1, 151.5, 179.2. HRMS calcd for C₂₄H₂₃NO₆ [M + Na]⁺ 444.1423; found 428.1439.

(R)-1-Allyl-5-fluoro-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)indolin-2-one (11h). Brown oil, yield 83%; [α]^D₂₀ = +12.3 (c 0.25, CHCl₃); 84% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 6.07 min (major) and t_R = 8.36 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 9.48 (s, 1H, OH), 6.85–7.41 (m, 4H, ArH), 6.18 (d, J = 2.4 Hz, 1H, ArH), 5.89–5.95 (m, 2H), 5.28–5.40 (m, 2H, CH₂), 4.25–4.54 (m, 2H, CH₂), 3.75 (s, 3H, OCH₃), 3.49 (s, 3H, OCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 42.64, 55.99, 56.72, 78.76, 86.29, 104.1, 111.1, 112.1, 115.2, 118.3, 130.2, 131.4, 134.0, 139.1, 142.1, 142.8, 150.8, 150.9, 177.9. HRMS calcd for C₁₉H₁₈FNO₅ [M + Na]⁺ 382.1066; found 382.4695.

(R)-1-Allyl-5-chloro-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)indolin-2-one (11i). Brown semi-solid; yield 81%; [α]^D₂₀ = +11.5 (c 0.25, CHCl₃); 92% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 8.84 min (major) and t_R = 11.8 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H, OH), 7.26–7.52 (m, 2H, ArH), 6.84 (d, J = 9.0 Hz, 1H, ArH), 6.63 (d, J = 6.0 Hz, 1H, ArH), 6.33 (d, J = 6.0 Hz, 1H, ArH), 5.79–5.85 (m, 1H, CH), 5.19–5.77 (m, 2H, CH₂), 4.28–4.44 (m, 2H, CH₂), 3.87 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 42.72, 55.97, 56.80, 78.97, 104.1, 111.1, 111.2, 115.2, 118.3, 126.3, 129.3, 130.2, 130.3, 130.8, 140.9, 142.8, 150.9, 151.1, 178.3. C₁₉H₁₈ClNO₅ [M + Na]⁺ 398.0767; found 398.0829.

(R)-1-Allyl-5-bromo-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)indolin-2-one (11j). Semi-solid; yield 79%; [α]^D₂₀ = +12.8 (c 0.25, CHCl3); 84% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 10.2 min (major) and t_R = 13.6 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 9.35 (s, 1H, OH), 7.23–7.36 (m, 3H, ArH), 6.17–6.79 (m, 2H, ArH), 5.85–5.94 (m, 2H), 5.28–5.41 (m, 2H, CH₂), 4.22–4.51 (m, 2H, CH₂), 4.11 (s, 1H, OH), 3.76 (s, 3H, OCH₃), 3.49 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 42.69, 55.98, 56.78, 78.90, 104.1, 111.1, 111.6, 115.2, 116.5, 118.3, 129.1, 130.2, 131.2, 133.1, 141.4, 142.8, 150.9, 151.0, 178.1. HRMS calcd for C₁₉H₁₈BrNO₅ [M + Na]⁺ 442.0261; found 442.0320.

(R)-1-Allyl-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)-5-iodoindolin-2-one (11k). Semi-solid; yield 84%; [α]^D₂₀ = +15.6 (c 0.25, CHCl₃); 90% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70/30, 1 mL min⁻¹, 254 nm, t_R = 6.53 min (major) and t_R = 9.83 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 9.56 (s, 1H, OH), 7.11–7.38 (m, 3H, ArH), 6.69–6.71 (m, 2H, ArH), 5.87–5.89 (m, 3H), 4.86–4.98 (m, 2H, CH₂), 3.78 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 42.64, 55.98, 56.73, 78.76, 86.27, 104.1, 111.1, 112.1, 115.2, 118.3, 130.2, 131.4, 134.7, 139.1, 142.1, 142.8, 150.8, 151.0, 177.9. HRMS calcd for C₁₉H₁₈INO₅ [M + Na]⁺ 490.0127; found 490.0121.

(R)-1-((E)-But-2-enyl)-5-chloro-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)indolin-2-one (11l). Light brown oil; yield 80%; [α]^D₂₀ = +5.69 (c 0.25, CHCl₃); 75% ee; HPLC [Chiralpak IC, hexane–i-PrOH, 70/30, 1 mL min⁻¹, 254 nm, t_R = 7.76 min (major) and t_R = 10.0 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 8.94 (s, 1H, OH), 7.28–7.52 (m, 2H, ArH), 6.87 (d, J = 10.0 Hz, 1H, ArH), 6.63 (s, 1H, ArH), 6.33 (s, 1H, ArH), 5.37–5.75 (m, 2H, CH₂), 4.49 (s, 1H, OH), 4.19–4.28 (m, 2H, CH₂), 3.86 (s, 3H, OCH₃), 3.68 (s, 3H, OCH₃), 1.69 (s, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 17.65, 42.23, 55.95, 56.80, 79.00, 104.1, 111.1, 115.2, 122.8, 123.0, 126.3, 129.2, 130.2, 130.3, 131.0, 141.0, 142.7, 151.0, 178.1. HRMS calcd for C₂₀H₂₀ClNO₅ [M + Na]⁺ 412.0922; found 412.0934.

(R)-1-Allyl-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)-5-methylindolin-2-one (11m). Brown semi-solid; yield 82%; [α]^D₂₀ = +14.8 (c 0.25, CHCl₃); 83% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70/30, 1 mL min⁻¹, 254 nm, t_R = 6.08 min (major) and t_R = 7.01 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 9.40 (s, 1H, OH), 6.43–7.44 (m, 5H, ArH), 5.85–5.96 (m, 1H, CH), 5.27–5.33 (m, 2H, CH₂), 4.32–4.50 (m, 3H), 3.94 (s, 3H, OCH₃), 3.72 (s, 3H, OCH₃), 2.47 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 21.16, 42.63, 55.94, 56.73, 79.32, 104.1, 109.9, 111.6, 115.8, 117.9, 126.6, 129.1, 130.6, 133.6, 139.9, 142.6, 150.8, 151.3, 178.7.

(R)-5-Chloro-3-hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)-1-methylindolin-2-one (11n). Brown semi-solid; yield 83%; [α]^D₂₀ = +7.32 (c 0.25, CHCl3); 85% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 7.57 min (minor) and t_R = 8.08 min (major)]; ¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H, OH), 7.26–7.48 (s, 2H, ArH), 6.79–6.86 (s, 1H, ArH), 6.58 (s, 1H, ArH), 6.31 (s, 1H, ArH), 4.67 (s, 1H, OH), 3.83 (s, 3H, OCH₃), 3.65 (s, 3H, OCH₃), 1.67 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 29.84, 56.13, 56.88, 78.23, 104.5, 110.5, 111.4, 112.4, 113.9, 125.6, 126.6, 130.6, 151.2, 178.4. HRMS calcd for C₁₇H₁₆ClNO₅ [M + Na]⁺ 372.0609; found 372.0644.

(R)-3-Hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)-1-(prop-2-ynyl)indolin-2-one (11o). Brown oil; yield 83%; [α]^D₂₀ = +18.3 (c 0.25, CHCl₃); 70% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 7.39 min (major) and t_R = 10.4 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 8.84 (s, 1H, OH), 7.10–7.49 (m, 3H, ArH), 6.55 (s, 1H, ArH), 6.28 (s, 1H, ArH), 4.69 (s, 1H, OH), 4.46 (dd, J = 42.6 Hz, J = 17.7 Hz, 2H, CH₂), 3.79 (s, 3H, OCH₃), 3.59 (s, 3H, OCH₃), 2.26 (s, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ 29.64, 36.72, 56.03, 56.71, 73.14, 79.23, 103.8, 106.1, 110.2, 111.5, 124.2, 129.4, 130.2, 130.5, 142.6, 150.8, 151.2, 162.8, 177.9. HRMS calcd for C₁₉H₁₇NO₅ [M + Na]⁺ 362.0999; found 362.1049.

(R)-1-Benzyl-5-fluoro-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)indolin-2-one (11p). Brown semi-solid; yield 85%; [α]^D₂₀ = +3.11 (c 0.25, CHCl₃); 77% ee; HPLC [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 11.2 min (major) and t_R = 14.6 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 9.13 (s, 1H, OH), 7.24–7.62 (m, 7H, ArH), 6.61–6.75 (m, 3H, ArH), 6.38–6.41 (m, 1H, ArH), 4.89 (dd, J = 50.0 Hz, J = 20.0 Hz, 2H, CH₂), 4.43 (s, 1H, OH), 3.79 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 44.18, 55.38, 79.08, 104.8, 106.8, 111.7, 116.6, 127.1, 128.1, 128.2, 129.0, 129.2, 133.0, 134.4, 141.4, 157.6, 161.8, 178.6. HRMS calcd for C₂₂H₁₈FNO₄ [M + Na]⁺ 402.1112; found 402.1149.

(R)-1-Benzyl-5-chloro-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)indolin-2-one (11q). Brown oil; yield 83%; [α]^D₂₀ = +0.79 (c 0.25, CHCl₃); 82% ee; [Chiralpak IA, hexane–i-PrOH, 80 : 20, 1 mL min⁻¹, 254 nm, t_R = 17.5 min (major) and t_R = 25.9 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 9.34 (s, 1H, OH), 7.00–7.33 (m, 8H, ArH), 6.70–6.99 (m, 2H, ArH), 6.34–6.40 (m, 1H, ArH), 4.90 (dd, J = 55.0 Hz, J = 15.0 Hz, 2H, CH₂), 4.48 (s, 1H, OH), 3.78 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 44.24, 55.37, 79.33, 104.9, 106.8, 110.9, 111.0, 114.1, 114.2, 116.5, 116.7, 116.8, 127.1, 128.0, 128.1, 129.0, 130.9, 131.0, 134.5, 138.2, 157.7, 158.8, 160.7, 161.8, 178.9. HRMS calcd for C₂₂H₁₈ClNO₄ [M + Na]⁺ 418.0822; found 418.0836.

(R)-1-Benzyl-5-bromo-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)indolin-2-one (11r). Semi-solid; yield 86%; [α]^D₂₀ = +2.39 (c 0.25, CHCl₃); 84% ee; [Chiralpak IC, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 7.39 min (major) and t_R = 8.75 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 7.24–7.48 (m, 7H, ArH), 6.62–6.76 (m, 3H, ArH), 6.38–6.41 (m, 1H, ArH), 4.90 (dd, J = 45.0 Hz, J = 15.0 Hz, 2H, CH₂), 3.79 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 44.14, 55.36, 79.03, 104.5, 104.6, 106.6, 106.7, 110.2, 111.6, 116.5, 116.6, 127.1, 127.2, 128.0, 129.0, 131.8, 132.9, 134.4, 141.3, 157.5, 157.9, 161.7, 178.5. HRMS calcd for C₂₂H₁₈BrNO₄ [M + Na]⁺ 462.0311; found 462.0298.

(R)-1-Benzyl-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-5-methoxyindolin-2-one (11s). Brown oil; yield 82%; [α]^D₂₀ = +5.69 (c 0.25, CHCl₃); 63% ee; [Chiralpak IC, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 7.51 min (minor) and t_R = 8.09 min (major)]; ¹H NMR (500 MHz, CDCl₃) δ 9.71 (s, 1H, OH), 7.25–7.34 (m, 6H, ArH), 7.13 (d, J = 5.0 Hz, 1H, ArH), 6.37–6.82 (m, 4H, ArH), 4.90 (dd, J = 35.0 Hz, J = 15.0 Hz, 2H, CH₂), 3.80 (s, 6H, 2 × OCH₃), ¹³C NMR (125 MHz, CDCl₃) δ 44.18, 55.37, 55.87, 79.68, 105.1, 106.8, 110.8, 113.0, 115.0, 117.4, 127.1, 127.9, 128.6, 128.9, 130.2, 134.8, 135.5, 156.7, 158.1, 161.7, 179.1. HRMS calcd for C₂₃H₂₁NO₅ [M + Na]⁺ 414.1312; found 414.1340.

(R)-1-Allyl-5-chloro-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)indolin-2-one (11t). Brown oil; yield 81%; [α]^D₂₀ = +11.9 (c 0.25, CHCl₃); 85% ee; [Chiralpak IC, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 7.58 min (major) and t_R = 9.58 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 7.28–7.49 (m, 2H, ArH), 6.85 (d, J = 10.0 Hz, 2H, ArH), 6.72 (d, J = 10.0 Hz, 1H, ArH), 6.61 (d, J = 5.0 Hz, 1H, ArH), 6.39 (s, 1H, OH), 5.79–5.83 (m, 1H, CH), 5.21–5.27 (m, 2H, CH₂), 4.25–4.42 (m, 2H, CH₂), 3.78 (s, 3H, OCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 42.73, 55.38, 79.08, 104.9, 106.8, 111.1, 116.7, 118.4, 126.5, 128.1, 129.3, 130.2, 130.3, 130.9, 140.8, 157.7, 161.8, 178.4. HRMS calcd for C₁₈H₁₆ClNO₄ [M + Na]⁺ 368.0660; found 368.0715.

(R)-3-Hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1-(prop-2-ynyl)indolin-2-one (11u). Brownish semisolid; yield 73%; [α]^D₂₀= +13.6 (c 0.25, CHCl₃); 59% ee; [Chiralpak IC, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 10.8 min (major) and t_R = 14.3 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 9.18 (s, 1H, OH), 7.11–7.49 (m, 4H, ArH), 6.28–6.67 (m, 3H, ArH), 4.47 (dd, J = 30.9 Hz, J = 17.7 Hz, 2H, CH₂), 3.74 (s, 3H, OCH₃), 2.26 (s, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ 29.83, 55.50, 77.48, 104.8, 106.7, 107.5, 109.6, 110.3, 116.8, 124.3, 126.2, 128.9, 130.5, 141.4, 157.9, 161.8, 178.0. HRMS calcd for C₁₈H₁₅NO₄ [M + Na]⁺ 332.0893; found 332.0869.

(R)-3-Hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1-methylindolin-2-one (11v). Viscous oil; yield 79%; [α]^D₂₀ = +2.89 (c 0.25, CHCl₃); 69% ee; [Chiralpak IC, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 14.8 min (major) and t_R = 22.8 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 9.70 (s, 1H, OH), 7.24–7.53 (m, 3H, ArH), 6.94 (d, J = 10.0 Hz, 1H, ArH), 6.65 (d, J = 5.0 Hz, 1H, ArH), 6.33–6.35 (m, 1H, ArH), 4.05 (s, 1H, OH), 3.79 (s, 3H, OCH₃), 3.25 (s, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 29.69, 55.36, 79.06, 105.1, 106.7, 109.2, 123.9, 126.2, 128.6, 130.4, 158.2, 161.8, 179.2. HRMS calcd for C₁₆H₁₅NO₄ [M + Na]⁺ 308.0893; found 308.0930.

(R)-1-Benzyl-5-fluoro-3-hydroxy-3-(2-hydroxy-4,6-dimethoxyphenyl)indolin-2-one (11w). Semi-solid; yield 87%; [α]^D₂₀ = +0.49 (c 0.25, CHCl₃); 71% ee; [Chiralpak IA, hexane–i-PrOH, 90 : 10, 1 mL min⁻¹, 254 nm, t_R = 17.0 min (major) and t_R = 28.1 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 9.55 (s, 1H, OH), 7.09–7.38 (m, 5H, ArH), 6.66–6.92 (m, 3H, ArH), 6.14 (d, J = 2.1 Hz, 1H, ArH), 5.88 (d, J = 2.1 Hz, 1H, ArH), 4.88 (dd, J = 36.9 Hz, J = 15.6 Hz, 2H, CH₂), 3.74 (s, 3H, OCH₃), 3.26 (s, 3H, OCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 44.34, 55.36, 55.85, 78.92, 103.9, 110.0, 110.1, 112.5, 112.7, 127.5, 127.7, 127.9, 128.4, 128.9, 129.3, 135.5, 138.5, 157.3, 159.4, 160.7, 161.3, 176.9. HRMS calcd for C₂₃H₂₀FNO₅ [M + Na]⁺ 432.1231; found 432.1244.

(R)-1-Allyl-5-chloro-3-hydroxy-3-(2-hydroxy-4,6-dimethoxyphenyl)indolin-2-one (11x). Brown semi-solid; yield 83%; [α]^D₂₀ = +8.76 (c 0.25, CHCl₃); 76% ee; [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 9.67 min (major) and t_R = 10.5 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 9.38 (s, 1H, OH), 7.28–7.38 (m, 3H, ArH), 6.81 (d, J = 5.0 Hz, 1H, ArH), 6.21 (d, J = 5.0 Hz, 1H, ArH), 5.87–5.94 (m, 1H), 5.32–5.39 (m, 2H, CH₂), 4.27–4.50 (m, 2H, CH₂), 4.21 (s, 1H, OH), 3.67 (s, 3H, OCH₃), 3.51 (s, 3H, OCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 42.36, 56.08, 56.22, 78.94, 104.1, 110.9, 111.2, 111.3, 123.1, 126.4, 129.3, 130.3, 130.4, 131.1, 141.0, 141.1, 151.0, 151.1, 178.3. HRMS calcd for C₁₉H₁₈ClNO₅ [M + Na]⁺ 398.0766; found 398.0813.

(R)-3-Hydroxy-3-(2-hydroxy-4,6-dimethoxyphenyl)-1-(prop-2-ynyl)indolin-2-one (11y). Brown semi-solid; yield 82%; [α]^D₂₀ = +5.19 (c 0.25, CHCl₃); 68% ee; [Chiralpak IC, hexane–i-PrOH, 80 : 20, 1 mL min⁻¹, 254 nm, t_R = 26.5 min (major) and t_R = 43.9 min (minor)]; ¹H NMR (500 MHz, CDCl₃) δ 9.44 (s, 1H, OH), 7.07–7.41 (m, 4H, ArH), 6.19 (d, J = 5.0 Hz, 1H, ArH), 5.93 (d, J = 5.0 Hz, 1H, ArH), 4.30–4.87 (m, 2H, CH₂), 3.90 (s, 1H, OH), 3.56 (s, 3H, OCH₃), 2.33 (s, 1H, CH); ¹³C NMR (125 MHz, CDCl₃) δ 29.40, 55.30, 55.89, 77.27, 78.18, 91.79, 95.41, 104.4, 109.3, 123.5, 124.6, 129.9, 130.1, 141.5, 157.2, 159.1, 161.3, 175.6. HRMS calcd for C₁₉H₁₇NO₅ [M + Na]⁺ 362.0999; found 362.1055.

(R)-3-Hydroxy-3-(2-hydroxy-4,5-dimethoxyphenyl)indolin-2-one (11z). Brown semi-solid; yield 78%; [α]^D₂₀ = +10.2 (c 0.25, MeOH); 80% ee; [Chiralpak IA, hexane–i-PrOH, 70 : 30, 1 mL min⁻¹, 254 nm, t_R = 6.88 min (major) and t_R = 9.64 min (minor)]; ¹H NMR (300 MHz, CDCl₃) δ 8.91 (s, 1H, NH), 8.26 (s, 1H, OH), 7.09–7.58 (m, 2H, ArH), 6.54–6.88 (m, 3H, ArH), 6.28 (d, J = 6.1 Hz, 1H, ArH), 4.67 (s, 1H, OH), 3.89 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 56.10, 56.22, 78.92, 104.3, 110.0, 111.3, 111.4, 115.3, 126.5, 129.3, 130.3, 130.4, 130.9, 141.2, 151.1, 151.2, 178.4. HRMS calcd for C₁₆H₁₅NO₅ [M + Na]⁺ 324.0847; found 324.0869.

Acknowledgements

We are thankful to CSIR and UGC for RA fellowship and JRF(NET) to AK and JK, respectively. Our research work was supported by the research project (SR/S1/OC-35/2011) sanctioned to SSC by the DST. Financial support from the Department of Science and Technology (DST), India under FIST program and UGC, India, under CAS-I is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1022904. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra09805f

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