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Stereodivergent Synthesis of 3-Aminooxindole Derivatives Containing Vicinal Tetrasubstituted Stereocenters via Mannich Reaction Koilpitchai Sivamuthuraman, and Venkitasamy Kesavan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01020 • Publication Date (Web): 02 Jul 2018 Downloaded from http://pubs.acs.org on July 4, 2018

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The Journal of Organic Chemistry

Stereodivergent Synthesis of 3-Aminooxindole Derivatives Containing Vicinal Tetrasubstituted Stereocenters via Mannich Reaction Koilpitchai Sivamuthuraman, and Venkitasamy Kesavan* Chemical Biology Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai-600036, India. E-mail: [email protected]; Fax: +91-44-22574102; Tel: +91-44-2257-4124.

Abstract:

A highly enantioselective stereodivergent synthesis of 3-aminooxindole

derivatives was accomplished via asymmetric Mannich reaction between 2-substituted benzofuran-3-one and isatin-derived ketimines. Both anti and syn-selective chiral 3,3disubstituted amino oxindoles bearing two adjacent tetrasubstituted stereogenic centers with high yield and excellent enantioselectivities were obtained using readily available cinchona-alkaloid

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derived organocatalysts. The control experiment revealed that oxygen atom present in the benzofuran ring played an important role in switching diastereodivergence. The obtained Mannich product was further transformed into biologically important 2, 3-dihydrobenzofuran derivative having three contiguous stereocenters with no loss of enantioselectivity.

Introduction Seminal contributions are being made over the past 30 years in asymmetric catalysis to control diastereo- and enantioselectivity of the reaction.1 Identification of suitable catalyst/additive, for a transformation involving the formation of multiple stereocenters, is a formidable task which will enable the full control of both absolute and relative configuration. A reaction is considered to be stereodivergent2 if high selectivity achieved for all the possible stereoisomers. However, very often it is indeed very difficult to achieve this feat. Thus identification of catalyst/s and reaction/s condition which would result in the formation of all possible stereoisomers or diastereomers is an emerging field of research in asymmetric catalysis.3 Hence few notable researchers have engaged in the development of catalytic system(s) or engineering or identification of catalysts to generate every possible stereoisomers in an asymmetric reaction.4 3-amino oxindole skeleton bearing adjacent tetrasubstituted stereogenic centers is of great importance due to its wide biological activity (Figure 1 A-C).5 Similarly 2, 2-disubstituted benzofuran-3(2H)-ones and related frameworks are characteristic of a quaternary stereogenic center at C2 position present in a number of natural products and bioactive molecules (Figure 1 D-F).6-8 The combination of biologically important oxindole and benzofuran-3-one scaffolds will result in hybrid molecules. Due the importance of hybrid molecules9 (incorporation of two drug pharmacophores in a single molecule) in polypharmacology, we wish to synthesize hybrid molecules bearing oxindole and benzofuran-3-one in an enantioselective manner. Isatin derived


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ketimines in combination with various nucleophiles led to the syntheses of structurally diverse 3amino oxindoles.10-11 These protocols invariably yield inherently preferred diastereomers. However, due to the varying biological activity of diastereomers,

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it is pertinent to synthesize

complementary diastereomers also. Till date, there are only two reports in the literature for the diastereodivergent synthesis of 3-aminooxindole derivatives. In 2012, Guo et al13 reported Mannich reaction where solvent played a crucial role in the addition of hydroxyacetone with isatin derived ketimines to synthesize 3-amino oxindoles. It was observed that anti-adduct was preferred in ether; whereas syn-selective addition occurred in toluene (Scheme 1a).

Figure 1: Selected example of biologically active 3-amino oxindole and benzofuran-3-one. In 2017, Shao et al14 reported chiral amine catalysed asymmetric Mannich reaction with isatin derived ketimine and aldehyde. While a primary amine catalyst yielded anti-addition product, syn-addition product was catalysed by a secondary amine (Scheme 1b). These reports indicate that diastereodivergent or stereodivergent synthesis of molecules having multiple stereocenters is not trivial and is a formidable task. To the best of our knowledge, Mannich reaction between isatin derived ketimine and 2-substituted benzofuran-3-one to synthesize structurally diverse


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oxindole derivatives is yet to be reported. For the first time in the literature, we identified organocatalyst(s) and reaction conditions for stereodivergent (synthesis of all the possible stereoisomers) synthesis of vicinal tetrasubstituted stereocenter bearing benzofuran-3-one and oxindole scaffolds (Scheme 1c).

Scheme 1: Diastereodivergent methods for the synthesis of 3-Substituted-3-amino oxindoles

Results and discussion Optimization of syn-selective Mannich reaction Our efforts were dedicated to identify the suitable catalyst for Mannich reaction between 2-substituted benzofuran-3 (2H)-one 1 and Isatin derived ketimine 2 with 10 mol % of catalyst in dichloromethane at room temperature. The observed results were summarized in Table 1. To begin with, commonly used cinchona alkaloid derived bifunctional thiourea organocatalysts C1-


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C4 were employed. Although moderate diastereoselectivity (Table 1, entries 1-4) was observed, the enantioselectivity of syn addition product was found to be excellent. Encouraged by these results, various organocatalysts were utilized to improve the diastereoselectivity. To our disappointment, except cinchonine and quinine derived thioureas, other organocatalysts fail to improve diastereoselectivity (Table 1, entries 5-14). Since enantioselectivity of syn addition product was very good with catalyst C1, it was chosen for further optimization studies. When 4nitrobenzoic acid was used an additive we observed reversal of diastereoselectivity but with lower enantioselectivity (Table 1, entry 15). Table 1. Screening studies for syn-selective Mannich reaction of 1a and 2a.a


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Entry

Catalyst

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

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C1

Yieldb (%) 96 90 90 90 81 78 89 86 80 81 78 74 86 81 80

dr c (%) (syn/anti) 75:25 70:30 75:25 71:29 49:51 47:53 78:22 79:21 64:36 70:30 46:54 46:54 48:52 57:43 32:68

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ee d (%) (syn/antiK) 92 92 e 92 84 e 4 12 84 e 90 18 e 84 e 21 4 48 6 34

a

The reactions were carried out with 1 (0.13 mmol), 2 (0.14 mmol), catalyst (0.013 mmol) in 0.5 ml of CH2Cl2 at 25 °C. b Isolated yield. c, d Determined by chiral HPLC. e signifies the opposite enantiomer. f Additive 4-Nitro Benzoic Acid used. kMinor diastereomer was not separable by Chiral HPLC

Next, the effect of reaction medium has been tested to improve diastereoselectivity (results summarized in Table 2), during solvent screening dichloromethane was found to be most suitable solvent. Neither lowering nor increasing the catalyst loading had no effect in diastereoselectivity (Table 2, entries 10 & 11). To further improve the diastereoselectivity, the reaction was carried out at lower temperature at 0 °C (Table 2, entry 12) which led to a slight improvement in diastereoselectivity. Further lowering reaction temperature to -23 °C using catalyst C1 in dichloromethane, the syn addition product (Table 2, entry 13) was isolated with good diastereoselectivity (80:20 dr) in excellent enantioselectivity (96% ee). Under the identical conditions, catalyst C2 yielded same adduct with opposite configuration with good


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diastereoselectivity (85:15) in excellent enantioselectivity (Table 2, entry 14). Thus, we accomplished the synthesis of both enantiomers of syn-adduct 3 using readily available quinine and cinchonine derived organocatalysts. Table 2. Screening of solvents

Entry

Solvent

1 1 2 3 4 5 6 7 8 9 10f 11g 12h 13i 14j

CH2Cl2 CHCl3 DCE MTBE Diethyl ether Di isopropyl ether Dioxane Toluene CF3-Toluene Acetonitrile CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

Time (h) Yield (%) 3 96 3 90 3 86 6 82 6 88 6 80 5 75 8 93 6 90 3 78 3 87 3 90 3 96 6 96 6 95

dr c (%) (syn/ anti) 80:20 78:28 75:25 62:38 60:40 60:40 63:37 62:38 62:38 72:28 71:29 70:30 78:22 80:20 85:15

ee d (%) (syn / antie) 96 90 92 92 92 92 96 96 94 88 90 90 94 96 96k

a

The reactions were carried out with 1 (0.13 mmol), 2 (0.14 mmol), and catalyst C1(0.013 mmol) in 0.5 ml of solvent at 25 °C. b Isolated yield. c,d Determined by chiral HPLC.e Minor diastereomer was not separable by Chiral HPLC. f Catalyst (0.0065 mmol) used.g Catalyst (0.026 mmol) used.h Reaction performed at 0 °C. i Reaction performed at -23 °C for 6h. j catalyst C2(0.013 mmol) used. k signifies the opposite enantiomer.


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Optimization of anti-selective Mannich reaction We began our optimization studies for anti-selective Mannich reaction of 5-chloroisatin derived ketimines 2c with 2-substituted benzofuran-3-one 1 in dichloromethane at room temperature. Initially, natural cinchona bases (C15-C18) were investigated for their ability to synthesize our target molecule. However, syn-diastereomer 3 was only obtained as a major product in excellent yield, with poor diastereo and enantioselectivity (Table 3, entries 1-4). Table 3. Optimization Studies of anti-Selective Mannich Reaction of 1a and 2c.a


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Entry

Catalyst

1 2 3 4 5 6 7 8 9 10 11 12 13f 14f

C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 C25 C26 C25 C26

Yieldb (%) 90 85 95 91 92 88 90 93 92 87 96 85 96 90

dr c (%) (syn/anti) 64:36 64:36 64:36 72:28 61:39 59:41 23:77 17:83 19:81 64:36 21:79 32:68 17:83 35:65

ee d (%) (syn/anti) 10/40 rac/16e 10/rac 4/33 46/5 43/37 rac/12 rac/10 6/10 2/25 84/95 80/50e 90/96 88/74e

a

The reaction was carried out with 1 (0.13 mmol), 2c (0.14 mmol), catalyst (0.013 mmol) in 0.5 ml of CH2Cl2 at 25 °C. b Isolated yield. c, d Determined by chiral HPLC. e signifies the opposite enantiomer. f at -23 °C

Protection of 9-hydroxyl group of catalyst C18 with benzyl group (C19) and 1-methylnapthyl group neither reversed the diastereoselectivity nor improved the enantioselectivity (Table 3, entries 5 & 6). Interestingly, when the Mannich reaction was catalyzed by cinchona alkaloid derivatives C21 and C22 which consist of 6’-hydroxyquinoline ring, anti-selective diastereomer 4a was obtained as the main product in excellent yield with moderate diastereoselectivity and poor enantioselectivity (Table 3, entries 7 & 8). Intrigued by the role of 6’-hydroxy containing catalyst in reversing the diastereoselectivity, other similar catalysts C23-C26, were examined for their ability to enhance the enantioselectivity. To our delight β-ICD, catalyst C25, efficiently catalyzed the formation of anti-product 4b with very good enantioselectivity and good diastereoselectivity (21: 79 dr) (Table 3, entry 11). To obtain the opposite enantiomer of antiproduct 4b, the reaction was performed with α-ICN, catalyst C26. The expected anti-adduct was isolated with fair diastereoselectivity and moderate enantioselectivity (Table 3, entry 12). In case of β-ICD, lowering the reaction temperature improved both diastereo and enantioselectivity


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(Table 3, entry 13). Although diastereoselectivity did not fare better while lowering the reaction temperature, enantioselectivity considerably improved for ent-4b (Table 3, entry 14). These results suggest that anti-selective addition product 4b could well be synthesized by the employment of readily available β- ICD (10 mol%) in dichloromethane at -23 °C in very good diastereoselectivity and excellent enantioselectivity. α-ICN was employed to synthesize ent-4b. Having identified catalysts capable of forming all the diastereomers of the given transformation substrate scope was studied further.

Substrate scope for syn-selective Mannich reaction The effects of substitution on both nucleophile and electrophile were investigated for the synthesis of syn-selective product 3 and its enantiomer ent-3 (scheme 2) under optimized reaction condition (Table 2, entry 13 & 14). First, the effect of substitutions in the aromatic ring of the N-methyl protected isatin ketimines was studied. Different halogen and electron-donating (OMe) or electron-withdrawing (OCF3) group substituted at the 5th position of the isatin-derived ketimine were tolerated in the Mannich reaction. The corresponding products (3a–3g) were obtained with very good yields (88-96%) with moderate to good diastereoselectivity (68:32 to 83:17 dr) and excellent enantioselectivity (up to 97/97% ee). Moreover, fluoro substituent at 7th position oxindole ring afforded the corresponding product (3h) with very good yield and stereoselectivity. Having established substitutions on oxindole ring, do not influence stereoselectivity, next we probed effect of substitutions on the benzofuran-3-one. It is evident that (Scheme 2), increasing the size of halogen on the 5th position of benzofuran-3-one ring led to the decrease in diastereo- and enantioselectivity (3i–3k). To be more specific, substitution of iodo at the 5th position drastically reduced the enantioselectivity, may be due to increase the steric hindrance in the transition state. However, in the presence of electron releasing substituent (OMe) enantioselectivity (3l) remained unaffected.


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Scheme 2. Substrate scope for syn-selective Mannich reaction of 1 and 2.a, b

a

Reaction conditions: The reactions were carried out with 1 (0.26mmol), 2 (0.31 mmol), catalyst C1 (0.026 mmol) in 0.5ml of CH2Cl2 at -23 °C. Isolated yield after column chromatography. Diastereoselectivity and enantioselectivity was determined by HPLC using chiral stationary phase. Note: dr values for compound 3i, 3j, 3k, 3n were ascertained by 1H NMR of crude reaction mixture. Compound 3v major and minor diastereomers were separable in silica gel column chromatography. b Reaction conditions: The reactions were carried out with 1 (0.13mmol), 2 (0.16 mmol), catalyst C2 (0.013 mmol) in 0.5 ml of CH2Cl2 at - 23 °C.


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Gratifyingly, having ethyl ester substitution on benzofura-3-one derivatives (3m) did not lower the enantioselectivity, however diastereoselectivity remained almost the same. Similar effects were observed for product 3n and 3o. The influence of N1-substitution of isatin ketimines on stereoselectivity and yield was investigated. It is evident that various N1-substitution like ethyl, benzyl, allyl, methyl acetate, ethyl acetate, t-butyl acetate are well tolerated, expected products (3p-3u) were isolated with more than 85% yield and excellent enantioselectivity (up to 98/99% ee) and moderate to good diastereoselectivity (65:35 to 83:17 dr). In the case of product 3v, the minor diastereomer was isolated and absolute configuration was unambiguously determined by X-ray crystallographic analysis. Under identical condition, the enantiomers of compounds 3 were synthesized using catalyst C2 as depicted in scheme 2 with good diastereo and enantioselectivities.

Substrate scope for anti-selective Mannich reaction Under the optimized reaction condition (Table 3, entry 13 & 14) the study of substrate scope was examined for the synthesis of anti-selective Mannich products 4 and its enantiomers (Scheme 3). To our delight, anti-selective products (4a to 4g) were obtained in excellent yield (up to 98%) and enantioselectivity (up to 99% ee) with better diastereoselectivity (up to 14:86 dr) when various substituted N-methyl isatin derived ketimines underwent Mannich reaction with methyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate(1). Identical to the observation of drastic reduction in enantioselectivity for syn-selective product with increase in size of halogen substitution on nucleophile was observed in case of anti-selective product also (4h to 4j). Similarly ethyl ester substituted nucleophile and N-substituted ketimine such as N-CH2COOMe yielded the respective product (4k to 4m) with identical stereoselectivities. We are happy to note that, the enantiomers of anti-selective product 4 were also obtained using C26 with moderate diastereoselectivities.


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Scheme 3. Substrate scope for anti-selective Mannich reaction of 1 and 2.a, b

a

Reaction conditions: The reactions were carried out with 1 (0.26mmol), 2 (0.31 mmol), catalyst C25 (0.026 mmol) in 0.5 ml of CH2Cl2 at - 23 °C. Isolated yield after column chromatography. Diastereoselectivity and enantioselectivity was determined by HPLC using chiral stationary phase. b Reaction conditions: The reactions were carried out with 1 (0.13mmol), 2 (0.16 mmol), catalyst C26 (0.013 mmol) in 0.5 ml of CH2Cl2 at - 23 °C.

Plausible transition state for syn-selective Mannich product The X-ray crystallographic analysis of compound 3i led to the identification of absolute configuration as (8R, 11R)15 and by analogy absolute configuration of other products were assigned accordingly. Based on the stereochemical outcome of the reaction, the plausible transition-state model11b for major syn- selective Mannich product is proposed herewith (Figure 2). Thiourea moiety of catalyst C1 interacts with isatin ketimines (2) via hydrogen bonding. The chiral tertiary-amine part of catalyst interacts with nucleophile (1) and thus preorients the


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substrate. The transition state formed by dual activation facilitates Re-face attack of nucleophile to the ketimines leading to desired syn-selective product (3) with (8R, 11R) configuration.

Figure 2. Plausible transition state for syn-selective Mannich product.

Plausible transition state for anti-selective Mannich product The X-ray crystallographic analysis revealed that absolute configuration of compound 3v (minor diastereomer) as (8S, 11R).16

Figure 3. Plausible transition state for anti-selective Mannich product.

We proposed the transition state model (figure 3) based on the on the work of Li et al.,

17

to

rationalize the stereochemical outcome of asymmetric Mannich reaction between 1 and 2c in the presence of β-ICD. Dual activation of electrophile and nucleophile can happen via hydrogen


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bonding with 6-hydroxy group in quinoline ring of catalyst C25. Nucleophile also gets activated by hydrogen bonding through chiral tertiary-amine part of the catalyst. This orientation led to the Si-face attack of nucleophile resulting in anti-selective product 4b with (8S, 11R) configuration.

Control experiment The switch in diastereomer takes place by using either acid additive or the 6’-hydroxyl group of the catalyst but which alone not enough to induce the switch in diastereomer and the presence of oxygen atom in benzofuranone also plays a vital role in switching diastereoselectivity which was explained by control experiment. To prove the role oxygen atom present in the benzofuran3-one to switch diastereomer , we synthesized a substrate which lacks oxygen atom such as ethyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate(5) which reacted smoothly with isatin ketamine (2a) to yield syn-selective product (6) as major product in the presence of catalyst C1 or C26 and also catalyst C1 with acid additive (Scheme 4). This observation suggests that not only catalyst or additive but also the presence of oxygen atom in the nucleophile is also played a crucial role in switching diastereoselectivity.

Scheme 4. Control experiment with ethyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate


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Gram scale synthesis The practical utility of our syn-selective Mannich addition strategy was demonstrated by performing reaction in 1g scale. We are delighted to observe that, under optimized condition the corresponding product 3c was obtained without any loss of yield (92%) and stereoselectivity (72:28 dr, 96/98 %ee) (Scheme 5).

Scheme 5.Gram scale reaction for syn-selective Mannich reaction

Derivatization of the Mannich adduct Natural products such as avicenol A, smyrindiol, vaginidiol and vaginol (Figure 4)18 contains 2.3-dihydrobenzofuran moiety.

Figure 4. Important 2, 3-dihydro3-hydroxy-2-hydroxyalkyl benzofurans in natural products To obtain similar pharmaceutically active moiety, the Mannich adduct 3c was reduced using sub-stoichiometric sodiumborohydride (0.5 equiv.) to yield compound 7 with no loss of stereoselectivities (Scheme 6). Reduction using 2 equiv. of sodiumborohydride leads to the formation of product 8 having primary hydroxyl at the quaternary centre. Thus we have established synthetic versatility of compound 3c in synthesizing structurally diverse the compounds containing three contiguous stereocenters with excellent enantioselectivity. The


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absolute configuration of the three chiral centres in compound 8 was determined as (8R, 10S, and 11R) on the basis of X-ray crystallographic analysis (see in supporting information)

Scheme 6: synthesis of 2, 3-dihydro3-hydroxy-2-hydroxyalkyl benzofuran

Conclusions In summary, we have described the first stereodivergent synthesis of 3-aminooxindole bearing vicinal tetra substituted sterocentre through operationally simple Mannich reaction of 2substituted benzofuran-3-one with isatin-derived N-Boc-ketimines using readily available chichona alkaloid derived organocatalysts. This new methodology provides an opportunity to access all possible diastereomers of 3-amino oxindoles derivatives. The both enantiomers of synselective 3-substituted-3-aminooxindole (up to 97% yield, 99% ee, dr = 87:13) were obtained using quinine and cinchonine derived organocatalysts whereas, anti-selective 3-substituted-3aminooxindole (up to 96% yield, 98% ee, dr = 13:87) can be accessed using either β-ICD or αICN. The reaction displayed a wide range of substrate scope for different N-Boc-istain ketimines and 2- substituted benzofuran-3-ones. The yield and enantioselectivity was not diminished even when the reaction was performed in a gram scale synthesis.The present study on the asymmetric Mannich reaction with isatin-derived ketimines, provide a new class of biologically important amino oxindole derivatives having benzofuran-3-one for the first time in the literature.


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Experimental Section General remarks All reactions were carried out in a flame dried flask. Solvents used for reactions and column chromatography were commercial grade and distilled prior to use. THF, toluene and dioxane were dried over sodium/benzophenone, whereas dichloromethane (DCM) and dichloroethane (DCE) were dried over CaH2. Solvents (hexane, ethyl acetate) TLC was performed on pre-coated Merck silica gel aluminium plates with 60F254 indicator, visualised by irradiation with UV light. Column chromatography was performed using silica gel Merck 100-200 and 230-400 mesh. 1HNMR and 13C NMR were recorded on 400 MHz, 500 MHz and 100 and 125 MHz using CDCl3, DMSO-d6 as solvent and multiplicity indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), dt (doublet of triplet), ddd (doublet of doublet of doublet) qd (quartet of doublet). Coupling constants J are reported in Hz. Chemical shift are represent in δ. High resolution mass spectra were obtained by ESI using orbitrap elite mass spectrometer, IR spectra were recorded on a FT/IR-420 spectrometer and are reported in terms of frequency of absorption (cm-1). Melting points were measured in open capillaries and are uncorrected. Optical rotations are reported as follows: [α] D rt (c in g per 100 mL, solvent). The 2substituted benzofuran-3-(2H)-ones19 isatin derived ketimines20 and catalysts21 were synthesized from the literature procedure.

Representative experimental procedure for the synthesis of syn-selective 3Substituted 3-Amino-2-oxindoles To a 30 min stirred solution of Isatin derived ketimines (1.2 equiv) and catalyst C1 or C2 (0.1 equiv) in dry CH2Cl2 (0.5ml) was added methyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate (1 equiv) at -23 ᴼC. The reaction mixture was stirred at -23 °C till the consumption of methyl 3-


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oxo-2, 3-dihydrobenzofuran-2-carboxylate, which was monitored by TLC. The crude mixture was purified by flash column chromatography over silica gel (85:15 to 70:30 hexane/EtOAc) to furnish 3a-3v.

Analytical data for syn-selective 3-Substituted 3-Amino-2-oxindoles. Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3a) Compound 3a: Yellow foamy solid, actual mass 114 mg, yield 96%. 1H NMR (500MHz, CDCl3) δ = 7.68 - 7.60 (m, 2 H), 7.35 (dt, J = 1.3, 7.7 Hz, 1 H), 7.19 – 7.00 (m, 6 H), 6.86 - 6.83 (m, 1 H), 3.93 (s, 1 H), 3.85 (s, 3 H), 3.29 (s, 1 H), 3.13 (s, 3 H), 1.28 (s, 13 H). 13C NMR (125MHz ,CDCl3) δ = 192.3, 191.5, 172.5, 171.6, 171.5, 171.3, 170.9, 164.3, 162.1, 153.3, 144.9, 139.2, 139.0, 138.6, 135.9, 130.7, 130.3, 129.8, 125.9, 125.3, 124.9, 124.4, 123.4, 123.3, 123.2, 123.1, 122.9, 122.8, 122.0, 120.5, 119.9, 119.1, 117.4, 113.5, 113.0, 112.9, 108.6, 107.98, 86.8, 80.5, 66.3, 65.1, 54.0, 53.8, 28.1, 26.7, 26.4.Visible peaks of minor diastereoisomer present in 1H and 13

C NMR. IR (ν, cm-1): 3407, 2976, 1750, 1714, 1608, 1479, 1360, 1325, 1296, 1255, 1164,

1098, 971, 861, 759. HRMS (ESI) m/z: [M+Na]+ Calcd for C24H24N2O7Na 475.1476; Found 475.1476. [α]D26 +90.20 (c 0.5, CHCl3).HPLC conditions: dr 80:20 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min, λ= 254 nm, retention time: 41.21 min (major) and 26.69 min (minor).

Methyl (S)-2-((S)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3a) Compound ent-3a: Yellow foamy solid, actual mass 56 mg, yield 95%.1H NMR (500MHz, CDCl3) corresponding to 3a.13C NMR (125MHz, CDCl3) corresponding to 3a. [α]D 26 -85.60 (c 0.5, CHCl3). HPLC conditions: dr 84:16 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 24.54 min (major) and 39.41 min (minor).

Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-fluoro-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3b) Compound 3b: Yellow foamy solid, actual mass 110 mg, yield 90%.1H NMR (500MHz, CDCl3) δ = 7.69 - 7.64(m, 1 H), 7.63 (ddd, J = 1.4, 7.3, 8.4 Hz, 1 H), 7.61 (t, J = 7.6 Hz, 2 H), 7.17 -


19


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7.03 (m, 2 H), 6.96 (dd, J = 2.5, 7.9 Hz, 1 H), 6.86 - 6.83 (m, 1 H), 6.78 (dd, J = 4.1, 8.5 Hz, 1 H), 3.92 (s, 1 H), 3.86 (s, 3 H), 3.28 (s, 1 H), 3.12 (s, 3 H), 1.32 (s, 12 H).13C NMR (125MHz ,CDCl3) δ = 192.0, 191.3, 172.3, 171.6, 171.4, 170.9, 164.2, 160.1(d, J = 266.9 Hz), 159.6, 157.6, 153.3, 140.9, 139.3, 138.7, 127.4, 125.0(d, J = 178.5 Hz),, 124.6, 123.5, 120.4, 119.7, 116.5(d, J = 23.6 Hz),116.1, 115.9, 113.0, 112.8, 111.8(d, J = 25.8 Hz), 111.3, 111.1, 109.1(d, J = 7.7 Hz),108.5, 86.5, 86.1, 80.7, 66.3, 65.1, 53.9, 53.8, 28.1, 26.9, 26.6.Visible peaks of minor diastereoisomer present in 1H and

13

C NMR.IR(ν, cm-1) :3407, 2978, 1718, 1613, 1496, 1386,

1324, 1269, 1196, 1164, 1046, 973, 905, 877, 761, 691. HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23FN2O7Na 493.1382; Found 493.1398. [α]D26 +70.60 (c 0.5, CHCl3). HPLC conditions: dr 82:18 Major diastereomer (94% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:05, flow rate = 0.50 mL/min,λ= 254 nm, retention time: 65.14 min (major) and 36.36 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:05, flow rate = 0.50 mL/min,λ= 254 nm, retention time: 60.49 min (major) and 82.25 min (minor).

Methyl

(S)-2-((S)-3-((tert-butoxycarbonyl)

amino)-5-fluoro-1-methyl-2-

oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3b) Compound ent-3b: Yellow foamy solid, actual mass 56 mg, yield 92%.1H NMR (500MHz, CDCl3) corresponding to 3b.13C NMR (125MHz, CDCl3) corresponding to 3b. [α]D26 -68.50 (c 0.5, CHCl3). HPLC conditions: dr 80:20 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 30.69 min (major) and 60.94 min (minor). Minor diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 78.21 min (major) and 56.12 min (minor).

Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-chloro-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3c) Compound 3c: Yellow solid, actual mass 116 mg, yield 92%. mp: 155-160 °C. 1H NMR (500MHz, CDCl3) δ = 7.69 (dd, J = 0.9, 7.9 Hz, 1 H), 7.64 (ddd, J = 1.4, 7.2, 8.4 Hz, 1 H), 7.33 (dd, J = 2.0, 8.4 Hz, 1 H), 7.18 - 7.07 (m, 5 H), 6.86 - 6.82 (m, 1 H), 6.78 (d, J = 8.2 Hz, 1 H), 3.93 (s, 1 H), 3.87 (s, 3 H), 3.28 (s, 1 H), 3.12 (s, 3 H), 1.33 (s, 13 H).13C NMR (125MHz ,CDCl3) δ = 191.9, 191.2, 172.1, 171.5, 171.2, 170.9, 164.2, 153.3, 143.5, 139.3, 138.7, 130.1, 129.7, 128.2, 127.5, 125.0, 124.6, 124.0, 123.6, 123.6, 123.4, 120.4, 119.8, 112.9, 112.8, 109.5,


20

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108.9, 86.4, 86.0, 80.8, 66.2, 64.9, 54.1, 53.9, 28.1, 26.9, 26.6.Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm-1): 3405, 2978, 1721, 1610, 1491, 1432, 1392, 1162, 1098, 969, 817, 760, 736, 687, 543. HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23ClN2O7 Na 509. 1086; Found 509. 1101. [α]D26 +66.40 (c 0.5, CHCl3).HPLC conditions: dr 69:31 Major diastereomer (95% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 15.52 min (major) and 10.40 min (minor). Minor diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 12.89 min (major) and 26.64 min (minor).

Methyl


amino)-5-chloro-1-methyl-2-

oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3c) Compound ent-3c: Yellow foamy solid, actual mass 60 mg, yield 95%.1H NMR (500MHz, CDCl3) corresponding to 3c.13C NMR (125MHz, CDCl3) corresponding to 3c. [α]D26 -65.30 (c 0.5, CHCl3).HPLC conditions: dr 74:26 Major diastereomer (92% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 9.15 min (major) and 14.14 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 24.69 min (major) and 11.54 min (minor).

Methyl (R)-2-((R)-5-bromo-3-((tert-butoxycarbonyl) amino)-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3d) Compound 3d: Yellow solid, actual mass 124 mg, yield 90%. mp: 175-180 °C.1H NMR (500MHz, CDCl3) δ = 7.66 - 7.63(m, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 7.52 - 7.45 (m, 2 H), 7.28 7.22 (m, 2 H), 7.16 - 7.05 (m, 4 H), 6.82 (d, J = 8.5 Hz, 1 H), 6.72 (d, J = 8.2 Hz, 1 H), 6.61 (d, J = 8.2 Hz, 1 H), 3.91 (s, 1 H), 3.85 (s, 3 H), 3.26 (s, 1 H), 3.09 (s, 3 H), 1.31 (s, 15 H).13C NMR (125MHz ,CDCl3) δ = 191.9, 191.2, 172.0, 171.5, 171.1, 170.8, 169.8, 164.2, 163.5, 153.3, 144.0, 139.3, 138.7, 133.0, 132.6, 127.8, 126.7, 126.2, 125.0, 124.6, 123.6, 123.6, 122.8, 120.4, 119.8, 86.4, 86.0, 80.8, 69.5, 66.1, 64.8, 54.1, 53.9, 53.8, 28.1, 26.9, 26.5.Visible peaks of minor diastereoisomer present in 1H and

13

C NMR.IR(ν, cm-1) : 3404, 2977, 1721, 1608, 1483, 1362,

1257, 1163, 1096, 968, 883, 817, 735, 601. HRMS (ESI) m/z: [M+H]+ Calcd for C24H24BrN2O7 531.0761; Found 531.0781. [α]D26 +88.40 (c 0.5, CHCl3).HPLC conditions: dr 69:31 Major


21


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diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 15:08 min (major) and 10.65 min (minor). Minor diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 12.78 min (major) and 30.25 min (minor).

Methyl (S)-2-((S)-5-bromo-3-((tert-butoxycarbonyl) amino)-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3d) Compound ent-3d: white solid, actual mass 62 mg, yield 90%.1H NMR (500MHz, CDCl3) corresponding to 3d.13C NMR (125MHz, CDCl3) corresponding to 3d. [α]D26 -78.50 (c 0.5, CHCl3).HPLC conditions: dr 69:31 Major diastereomer (94% ee) Chiralpak AD-H, hexane/isoPrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 9.8 min (major) and 14.19 min (minor). Minor diastereomer (84% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 29.08 min (major) and 12.22 min (minor).

Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-iodo-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3e) Compound 3e: Yellow solid, actual mass 132 mg, yield 88%. mp:140-145 °C.1H NMR (500MHz, CDCl3) δ = 7.69 - 7.62 (m, 3 H), 7.54- 7.51 (m, 1 H), 7.47 (s, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 7.18 - 7.07 (m, 3 H), 6.83 (d, J = 8.5 Hz, 1 H), 6.64 (d, J = 8.2 Hz, 1 H), 6.53 (d, J = 8.2 Hz, 1 H), 3.93 (s, 2 H), 3.88 (s, 3 H), 3.27 (s, 2 H), 3.10 (s, 3 H), 1.33 (s, 14 H).13C NMR (125MHz ,CDCl3) δ = 191.9, 191.1, 171.8, 171.5, 170.9, 170.8, 164.2, 153.3, 144.6, 139.3, 138.9, 138.7, 138.5, 132.2, 131.7, 125.0, 124.5, 123.6, 120.4, 119.9, 112.9, 112.8, 110.6, 109.9, 86.4, 86.0, 85.1, 83.9, 80.8, 66.0, 64.7, 54.0, 53.8,28.1, 26.8, 26.5.Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR(ν, cm-1) : 3404, 2977, 1717, 1606, 1481, 1391, 1326, 1162, 1093, 968, 814, 759, 735, 598, 531.HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23IN2O7 Na 601.0442; Found 601.0463. [α]D26 +122.60 (c 0.5, CHCl3).HPLC conditions: dr 68:32 Major diastereomer (94% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 16.16 min (major) and 12.20 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 14.32 min (major) and 33.63 min (minor).


22

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Methyl (S)-2-((S)-3-((tert-butoxycarbonyl) amino)-5-iodo-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3e) Compound ent-3e: Yellow foamy solid, actual mass 64 mg, yield 85%.1H NMR (500MHz, CDCl3) corresponding to 3e.13C NMR (125MHz, CDCl3) corresponding to 3e. [α]D26 -112.30 (c 0.5, CHCl3).HPLC conditions: dr 67:33 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 11.29 min (major) and 15.31 min (minor). Minor diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 32.74 min (major) and 13.30 min (minor).

Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-methoxy-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3f) Compound 3f: Yellow foamy solid, actual mass 115 mg, yield 92%.1H NMR (500MH, CDCl3) δ = 7.61 - 7.47 (m, 2 H), 7.15 (t, J = 7.3 Hz, 2 H), 7.09 - 7.06 (m, 1 H), 6.88 - 6.83 (m, 1 H), 6.81 (d, J = 2.5 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 6.66 (s, 1 H), 3.93 (s, 1 H), 3.86 (s, 3 H), 3.74 (s, 3 H), 3.48 (s, 1 H), 3.27 (s, 1 H), 3.11 (s, 3 H), 1.30 (s, 13 H).13C NMR (125MHz ,CDCl3) δ = 192.3, 191.4, 172.2, 171.7, 171.2, 170.9, 164.3, 156.1, 155.4, 153.3, 139.1, 138.5, 138.4, 125.0, 124.3, 123.5, 123.3, 120.5, 120.0, 115.2, 114.5, 113.1, 112.8, 110.9, 109.9, 108.9, 108.5, 86.8, 86.3, 80.5, 66.5, 65.4, 55.9, 55.8, 54.0, 53.8, 28.1, 26.8, 26.5.Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm-1) : 3407, 2976, 2837, 1750, 1718, 1609, 1497, 1366, 1258, 1164, 1045, 971, 906, 880, 762, 587. HRMS (ESI) m/z: [M+Na]+ Calcd for C25H26N2O8 Na 505.1581; Found 505.1592. [α]D26 +66.40 (c 0.5, CHCl3).HPLC conditions: dr 78:22 Major diastereomer (97% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 109.97 min (major) and 76.40 min (minor). Minor diastereomer (97% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 70.73 min (major) and 193.26 min (minor).

Methyl


amino)-5-methoxy-1-methyl-2-

oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3f) Compound ent-3f: White foam solid, actual mass 57 mg, yield 90%.1H NMR (500MHz, CDCl3) corresponding to 3f.13C NMR (125MHz, CDCl3) corresponding to 3f. [α]D26 -60.80 (c 0.5,


23


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CHCl3).HPLC conditions: dr 82:18 Major diastereomer (96% ee) Chiralpak AD-H, hexane/isoPrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 77.97 min (major) and 112.48 min (minor). Minor diastereomer (94% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 191.46 min (major) and 70.25 min (minor).

Methyl

(R)-2-((R)-3-((tert-butoxycarbonyl)

(trifluoromethoxy)

amino)-1-methyl-2-oxo-5-

indolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-

carboxylate(3g) Compound 3g: Yellow solid, actual mass 132 mg, yield 95%. mp: 100-105 °C.1H NMR (500MHz, CDCl3) δ = 7.62 - 7.48(m, 2 H), 7.22 - 7.20 (m, 1 H), 7.18 - 7.15 (m, 2 H), 7.12 - 7.00 (m, 1 H), 6.84 - 6.74 (m, 1 H), 3.94 (s, 1 H), 3.85 (s, 3 H), 3.31 (s, 1 H), 3.16 (s, 3 H), 1.32 (s, 12 H).13C NMR (125MHz ,CDCl3) δ = 191.1, 172.4, 171.5, 171.4, 170.9, 164.2, 144.7, 144.0, 143.6, 139.3, 138.8, 125.0, 124.7, 123.6, 123.5, 123.4, 123.2, 121.5, 120.4, 119.6, 119.4, 117.6, 117.1, 112.9, 112.8, 109.0, 108.4, 86.5, 80.8, 66.0, 54.1, 53.8, 28.1, 26.9, 26.6.Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm-1): 3406, 2978, 1721, 1613, 1496, 1469, 1384, 1324, 1252, 1163, 1091, 1016, 971, 884, 759, 622, 549. HRMS (ESI) m/z: [M+Na]+ Calcd for C25H23F3N2O8Na 559.1299; Found 559.1315. [α]D26 +53.60 (c 0.5, CHCl3).HPLC conditions: dr 83:17 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 37.15 min (major) and 26.73 min (minor).HPLC conditions: Minor diastereomer (93% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 40.37 min (major) and 111.11 min (minor).

Methyl(S)-2-((S)-3-((tert-butoxycarbonyl)amino)-1-methyl-2-oxo-5(trifluoromethoxy)indolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2carboxylate(ent-3g) Compound ent-3g: Yellow solid, actual mass 65 mg, yield 92%.1H NMR (500MHz, CDCl3) corresponding to 3g.13C NMR (125MHz, CDCl3) corresponding to 3g. [α]D26 -49.20 (c 0.5, CHCl3).HPLC conditions: dr 79:21 Major diastereomer (ee 98%) Chiralpak AD-H, hexane/isoPrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 18.79 min (major) and 28.15


24

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min (minor). Minor diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 94.05 min (major) and 29.38 min (minor).

Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-7-fluoro-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3h) Compound 3h: White solid, actual mass 110 mg, yield 90%. mp:115-120 °C .1H NMR (500MHz, CDCl3) δ = 7.64(d, J = 7.9 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.18 (t, J = 7.4 Hz, 2 H), 7.13 - 7.06 (m, 2 H), 7.00 - 6.91 (m, 2 H), 6.89 - 6.58 (m, 1 H), 3.93 (s, 1 H), 3.86 (s, 3 H), 3.51 (s, 1 H), 3.33 (s, 3 H), 1.32 (s, 12 H).13C NMR (125MHz ,CDCl3) δ = 192.1, 191.2, 172.3, 171.6, 171.4, 170.9, 164.1, 153.3, 148.8(d, J = 241.2 Hz), 146.4, 139.1, 138.7, 131.7, 131.6, 128.9, 125.0, 124.4(d, J = 178.8 Hz),123.4, 123.3(d, J = 2.6 Hz),122.4, 120.5, 119.8, 119.1, 118.7, 118.4(d, J = 19.36 Hz),118.0, 117.9, 113.1, 112.9, 86.6, 86.2, 80.7, 66.3, 54.0, 53.8, 29.3, 29.0, 28.1.Visible peaks of minor diastereoisomer present in 1H and 13C NMR.IR(ν, cm-1) : 3407, 2978, 1721, 1629, 1610, 1481, 1368, 1325, 1240, 1164, 1098, 1021, 970, 759, 697. HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23FN2O7Na 493.1382; Found 493.1373. [α]D26 + 134.40 (c 0.5, CHCl3).HPLC conditions: dr 76:24 Major diastereomer (92% ee) Chiralpak AD-H, hexane/isoPrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 59.29 min (major) and 32.27 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 64.44 min (major) and 73.60 min (minor).

Methyl (S)-2-((S)-3-((tert-butoxycarbonyl) amino)-7-fluoro-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3h) Compound ent-3h: Yellow foamy solid, actual mass 56 mg, yield 92%.1H NMR (500MHz, CDCl3) corresponding to 3h.13C NMR (125MHz, CDCl3) corresponding to 3h. [α]D26 - 127.70 (c 0.5, CHCl3).HPLC conditions: dr 81:19 Major diastereomer (92% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 27.46 min (major) and 55.46 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 68.56 min (major) and 60.88 min (minor).


25


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Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3yl)-5-chloro-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3i) Compound 3i: Yellow solid, actual mass 112 mg, yield 89%.mp:185-190 °C .1H NMR (500MHz, CDCl3) δ = 7.66 - 7.59 (m, 1 H), 7.55 (dd, J = 1.9, 8.8 Hz, 1 H), 7.42 - 7.35 (m, 1 H), 7.17 (d, J = 7.6 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.86 - 6.82 (m, 1 H), 6.78 (dd, J = 8.4, 14.0 Hz, 1 H), 6.72 - 6.69 (m, 1 H), 3.93 (s, 1 H), 3.86 (s, 3 H), 3.29 (s, 1 H), 3.14 (s, 3 H), 1.27 (s, 14 H).13C NMR (125MHz ,CDCl3) δ = 191.1, 190.3, 172.3, 171.4, 169.9, 169.1, 163.9, 153.2, 144.9, 138.9, 138.4, 130.0, 129.1, 128.9, 124.3, 123.7, 123.3, 123.0, 122.8, 122.2, 121.8, 121.0, 114.3, 114.2, 108.6, 108.1, 87.7, 87.3, 80.6, 66.4, 65.0, 54.1, 53.9, 28.1, 26.8, 26.5.Visible peaks of minor diastereoisomer present in 1H and

13

C NMR.IR(ν, cm-1) : 3409, 3059, 2978, 1754,

1719, 1610, 1494, 1370, 1256, 1164, 1017, 910, 884, 826, 755, 735, 519. HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23ClN2O7Na

509.1086;

Found 509.1101. [α]D28 +59.20 (c 0.5,

CHCl3).HPLC conditions: dr 70:30 Major diastereomer (96% ee) Chiralpak AD-H, hexane/isoPrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 16.22 min (major) and 11.44 min (minor). Minor diastereomer (90% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 12.29 min (major) and 15.95 min (minor).

Methyl

(R)-5-bromo-2-((R)-3-((tert-butoxycarbonyl)

amino)-1-methyl-2-

oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3j) Compound 3j: Yellow solid, actual mass 108 mg, yield 78%. mp:165-170 °C .1H NMR (500MHz, CDCl3) δ = 7.83 - 7.75 (m, 1 H), 7.72 - 7.67 (m, 1 H), 7.54 (dd, J = 1.9, 8.8 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.18 - 7.15 (m, 2 H), 7.05 - 7.00 (m, 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 6.86 - 6.82 (m, 1 H), 6.77 - 6.70 (m, 1 H), 3.93 (s, 1 H), 3.86 (s, 3 H), 3.29 (s, 1H), 3.14 (s, 3 H), 1.27 (s, 15 H). 13C NMR (125MHz ,CDCl3) δ = 190.9, 190.1, 172.3, 171.4, 170.3, 169.6, 163.9, 153.2, 144.9, 141.5, 141.1, 130.4, 130.0, 127.4, 126.8, 125.7, 123.3, 123.0, 122.8, 122.3, 122.2, 121.6, 116.2, 115.9, 114.7, 114.6, 108.6, 108.1, 87.6, 87.1, 80.6, 66.3, 65.0, 54.1, 53.9, 28.1, 26.8, 26.5.Visible peaks of minor diastereoisomer present in 1H and

13

C NMR. IR(ν, cm-1) :

3408, 2977, 1722, 1608, 1496, 1496, 1387, 1266, 1116, 1109, 1101, 973, 826, 754, 651. HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23BrN2O7 Na 553.0581; Found 553.0601. [α]D28 +64.40 (c 0.5, CHCl3).HPLC conditions: dr 60:40 Major diastereomer (88% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 16.28 min (major)


26

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and 11.79 min (minor). Minor diastereomer (80% ee)

Chiralpak AD-H, hexane/iso-PrOH =

90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 12.93 min (major) and 16.11 min (minor).

Methyl (R)-5-iodo-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3k) Compound 3k: Yellow solid, actual mass 105 mg, yield 70%. 1H NMR (500MHz, CDCl3) δ = 7.93 - 7.82 (m, 1 H), 7.69 (dd, J = 1.9, 8.8 Hz, 1 H), 7.35 - 7.13 (m, 3 H), 7.02 (t, J = 7.4 Hz, 1 H), 6.88 - 6.80 (m, 2 H), 6.75 - 6.69 (m, 2 H), 6.63 (d, J = 8.8 Hz, 1 H), 3.91 (s, 3 H), 3.85 (m, 1 H), 3.27 (m, 3 H), 3.12 (s, 1 H), 1.26 (s, 15 H).13C NMR (125MHz ,CDCl3) δ = 191.2, 172.3, 171.0, 147.1, 146.7, 144.8, 133.5, 133.0, 130.4, 130.0, 123.3, 123.0, 122.8, 122.2, 122.2, 115.1, 115.0, 109.9, 108.1, 85.5, 80.6, 65.0, 54.2, 53.9, 53.8, 28.2, 28.1, 26.8, 26.5.Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm-1): 3402, 2978, 1722, 1608, 1492, 1342, 1261, 1128, 1100, 970, 885, 738, 678. HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23IN2O7Na 601.0442; Found 601.0434.HPLC conditions: dr 60:40 Major diastereomer (24% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 16.40 min (major) and 12.87 min (minor). Minor diastereomer (rac) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 13.99 min (major) and 16.90 min (minor).

Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3yl)-5-methoxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3l) Compound 3l: Foamy solid, actual mass 106 mg, yield 85%. 1H NMR (500MHz, CDCl3) δ = 7.35 (t, J = 7.7 Hz, 1 H), 7.23 - 7.13 (m, 3 H), 7.09 - 6.98 (m, 4 H), 6.85 (d, J = 7.9 Hz, 1 H), 6.76 - 6.66(m, 1 H), 3.92 (s, 1 H), 3.85 (s, 3 H), 3.79 (s, 4 H), 3.29 (s, 1 H), 3.13 (s, 3 H), 1.27 (s, 13 H).13C NMR (125MHz ,CDCl3) δ = 192.4, 191.6, 172.5, 171.5, 167.2, 166.3, 164.4, 155.9, 155.8, 153.3, 144.9, 130.2, 129.8, 129.0, 128.5, 123.3, 122.8, 122.7, 122.0, 120.7, 119.9, 113.9, 113.7, 108.5, 107.9, 104.6, 103.8, 87.5, 87.1, 80.4, 66.3, 65.1, 55.9, 55.8, 53.9, 53.7, 28.1, 26.7, 26.4.Visible peaks of minor diastereoisomer present in 1H and

13

C NMR.IR(ν, cm-1) : 3407,

2976, 1718, 1611, 1486, 1369, 1275, 1162, 1090, 973, 831, 759, 699, 608, 533. HRMS (ESI) m/z: [M+Na]+ Calcd for C25H26N2O8Na 505.1581; Found 505.1595. [α]D26 +100.00 (c 0.5,


27


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CHCl3). HPLC conditions: dr 77:23 Major diastereomer (96% ee) Chiralpak AD-H, hexane/isoPrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 38.08 min (major) and 33.00 min (minor).

Methyl (S)-2-((S)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3yl)-5-methoxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3l) Compound ent-3l: White foamy solid, actual mass 57 mg, yield 90%.1H NMR (500MHz, CDCl3) corresponding to 3l.13C NMR (125MHz, CDCl3) corresponding to 3l. [α]D26 - 95.80 (c 0.5, CHCl3).HPLC conditions: dr 79:21 Major diastereomer (92% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 29.25 min (major) and 33.84 min (minor).

Ethyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3-yl)3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3m) Compound 3m: Yellow solid, actual mass 110 mg, yield 90%. mp:125-130 °C .1H NMR (500MHz, CDCl3) δ = 7.69 - 7.59 (m, 2 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.22 (d, J = 7.3 Hz, 1 H), 7.16 - 7.13 (m, 1 H), 7.09 - 7.07 (m, 1 H), 7.05 – 7.00 (m, 1 H), 6.86 - 6.75 (m, 2 H), 4.38 - 4.28 (m, 3 H), 3.30 (s, 1 H), 3.13 (s, 3 H), 1.41 (t, J = 7.1 Hz, 1 H), 1.39 - 1.27 (m, 14 H).13C NMR (125MHz ,CDCl3) δ = 191.6, 172.4, 171.7, 171.6, 171.0, 163.8, 153.3, 144.9, 138.9, 138.4, 130.2, 129.7, 124.9, 124.4, 123.5, 123.3, 123.1, 122.8, 122.7, 121.9, 120.6, 119.9, 113.0, 112.9, 108.5, 86.7, 80.4, 66.3, 65.0, 63.6, 63.4, 28.1, 26.4, 14.0,13.9.Visible peaks of minor diastereoisomer present in 1H and

13

C NMR.IR(ν, cm-1) : 3409, 2978, 1718, 1610, 1496, 1370,

1254, 1165, 1089, 932, 885, 756, 695, 612, 538, 513.HRMS (ESI) m/z: [M+Na]+ Calcd for C25H26N2O7 Na 489.1632; Found 489.1646. [α]D26 +89.60 (c 0.5, CHCl3).HPLC conditions: dr 78:22 Major diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 15.65 min (major) and 13.52 min (minor). Minor diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 18.91 min (major) and 22.35 min (minor).

Ethyl (S)-2-((S)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3-yl)3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3m) Compound ent-3m: Yellow foamy solid, actual mass 56 mg, yield 92%.1H NMR (500MHz, CDCl3) corresponding to 3m.13C NMR (125MHz, CDCl3) corresponding to 3m. [α]D26 -82.50 (c


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0.5, CHCl3).HPLC conditions: dr 80:20 Major diastereomer (88% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 12.48 min (major) and 14.78 min (minor). Minor diastereomer (94% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 21.00 min (major) and 18.07 min (minor).

Ethyl (R)-5-bromo-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3n) Compound 3n: Yellow solid, actual mass 122 mg, yield 85%. mp:120-125 °C .1H NMR (500MHz, CDCl3) δ = 7.79 - 7.69 (m, 1 H), 7.67 (d, J = 8.8 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.16 (t, J = 7.6 Hz, 2 H), 7.05 - 6.98 (m, 2 H), 6.87 - 6.82 (m, 1 H), 6.77 - 6.71 (m, 1 H), 4.44 - 4.28 (m, 3 H), 3.29 (s, 2 H), 3.13 (s, 3 H), 1.40 (t, J = 7.1 Hz, 2 H), 1.38 - 1.15 (m, 16 H).13C NMR (125MHz ,CDCl3) δ = 191.2, 190.2, 172.2, 171.5, 170.4, 169.6, 153.2, 144.9, 141.5, 141.0, 130.4, 130.0, 127.4, 126.8, 123.5, 122.9, 122.8, 122.3, 122.2, 121.6, 116.1, 115.8, 114.7, 114.6, 108.6, 108.1, 87.5, 87.2, 80.5, 66.4, 65.0, 63.9, 63.7, 28.1, 26.8, 26.5,13.9.Visible peaks of minor diastereoisomer present in 1H and

13

C

NMR.IR(ν, cm-1) : 3401, 2979, 1725, 1609, 1496, 1368, 1260, 1170, 1091, 1014, 827, 755, 698, 650. HRMS (ESI) m/z: [M+Na]+ Calcd for C25H25BrN2O7Na 567.0737; Found 567.0755. [α]D28 +42.40 (c 0.5, CHCl3).HPLC conditions: dr 65:35 Major diastereomer (90% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 13.16 min (major) and 11.29 min (minor). Minor diastereomer (96% ee)

Chiralpak AD-H, hexane/iso-PrOH =

90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 11.06 min (major) and 14.69 min (minor).

Ethyl (S)-5-bromo-2-((S)-3-((tert-butoxycarbonyl) amino)-1-methyl-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3n) Compound

ent-3n: White solid, actual mass 60 mg, yield 85%.1H NMR (500MHz, CDCl3)

corresponding to 3n.13C NMR (125MHz, CDCl3) corresponding to 3n.HPLC conditions: dr 60:40 Major diastereomer (88% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 10.45 min (major) and 12.13 min (minor). Minor diastereomer (84% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 13.09 min (major) and 10.17 min (minor).


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Ethyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3-yl)6-methyl-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3o) Compound 3o: Foamy solid, actual mass 98 mg, yield 90%.1H NMR (500MHz, CDCl3) δ = 7.54 - 7.49 (m, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.11 - 6.98 (m, 1 H), 6.94 6.92 (m, 1 H), 6.85 - 6.82 (m, 3 H), 6.74 - 6.60 (m, 1 H), 4.35 - 4.25 (m, 3 H), 3.27 (s, 1 H), 3.12 (s, 3 H), 2.40 (s, 3 H), 2.28 (s, 1 H), 1.38 (t, J = 7.1 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 13H).13C NMR (125MHz ,CDCl3) δ = 191.9, 190.9, 172.5, 172.3, 171.90, 171.6, 171.5, 164.0, 153.3, 151.5, 150.9, 144.9, 130.1, 129.7, 125.0, 124.8, 124.4, 123.9, 123.4, 122.9, 122.7, 121.9, 118.2, 117.5, 113.6, 112.9, 108.5, 107.9, 86.9, 80.3, 66.2, 63.5, 63.4, 28.1, 26.4, 22.6, 22.6, 14.1,14.0.Visible peaks of minor diastereoisomer present in 1H and

13

C NMR.IR(ν, cm-1) : 3407, 3057, 2978,

1719, 1614, 1470, 1369, 1258, 1164, 1119, 1092, 939, 860, 733, 607, 535. HRMS (ESI) m/z: [M+Na]+ Calcd for C26H28N2O7Na 503.1789; Found 503.1805. [α]D29 +36.90 (c 3.0, CHCl3).HPLC conditions: dr 81:19 Major diastereomer (96% ee)Chiralpak AD-H, hexane/isoPrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 18.04 min (major) and 12.70 min (minor). Minor diastereomer (99% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 28.55 min (major) and 20.29 min (minor).

Ethyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-ethyl-2-oxoindolin-3-yl)-6methyl-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3p) Compound 3p: Foamy solid, actual mass 103 mg, yield 92%.1H NMR (500MHz, CDCl3) δ = 7.59 (d, J = 7.9 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 2 H), 7.05 (t, J = 7.4 Hz, 1 H), 6.97 (d, J = 7.9 Hz, 1 H), 6.87 - 6.59 (m, 2 H), 4.37 - 4.29 (m, 2 H), 3.87 (dd, J = 7.1, 14.0 Hz, 1 H), 3.45 (s, 1 H), 2.42 (s, 3 H), 2.31 (s, 1 H), 1.41 - 1.27 (m, 15 H), 1.18 (t, J = 7.1 Hz, 4 H).13C NMR (125MHz ,CDCl3) δ = 191.0, 172.3, 172.1, 171.5, 171.2, 163.9, 153.3, 151.3, 150.7, 144.0, 143.9, 130.1, 129.6, 124.9, 124.7, 124.5, 123.9, 123.6, 123.1, 122.6, 121.6, 118.3, 117.6, 112.9, 108.5, 108.0, 87.0, 86.8, 80.2, 66.3, 65.0, 63.4, 63.3, 35.2, 34.9, 28.1, 22.6, 22.5, 14.0, 12.7.Visible peaks of minor diastereoisomer present in 1H and 13C NMR.IR(ν, cm-1) : 3407, 2979, 2934, 1719, 1614, 1492, 1466, 1329, 1253, 1165, 1094, 938, 858, 754, 612. HRMS (ESI) m/z: [M+Na]+ Calcd for C27H30N2O7Na 517.1945; Found 517.1957. [α]D26 +123.20 (c 0.5, CHCl3).HPLC conditions: dr 79:21 Major diastereomer (98% ee) Chiralpak AD-H, hexane/isoPrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 12.25 min (major) and 9.96 min (minor).


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Ethyl (R)-2-((R)-1-benzyl-3-((tert-butoxycarbonyl) amino)-2-oxoindolin-3-yl)6-methyl-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3q) Compound 3q: White solid, actual mass 120 mg, yield 95%.mp:185-190 °C .1H NMR (500MHz, CDCl3) δ = 7.56 (d, J = 7.9 Hz, 1 H), 7.49 (dd, J = 7.7, 19.7 Hz, 1 H), 7.39 - 7.30 (m, 1 H), 7.29 7.24 (m, 8 H), 7.05 - 6.96 (m, 1 H), 6.94 - 6.85 (m, 1 H), 6.77 (dd, J = 7.9, 13.9 Hz, 1 H), 6.74 (d, J = 7.9 Hz, 1 H), 6.70 (s, 1 H), 6.61 - 6.50 (m, 1 H), 5.06 (d, J = 15.4 Hz, 1 H), 4.43 - 4.29 (m, 3 H), 2.39 (s, 3 H), 2.28 (s, 1 H), 1.42 - 1.39 (m, 3 H), 1.33 - 1.28 (m, 12 H).13C NMR (125MHz ,CDCl3) δ = 191.8, 191.1, 172.7, 172.2, 172.0, 171.9, 171.4, 164.0, 163.2, 153.4, 151.5, 151.4, 150.6, 144.4, 143.9, 135.8, 130.1, 129.6, 128.5, 128.5, 127.6, 127.6, 127.4, 125.0, 124.8, 124.5, 124.0, 123.5, 122.9, 122.9, 121.9, 118.2, 117.6, 113.4, 112.8, 109.5, 109.0, 86.9, 86.7, 80.3, 66.3, 65.2, 63.5, 63.4, 44.3, 44.3, 28.2, 22.7, 22.6, 14.0.Visible peaks of minor diastereoisomer present in 1H and 13C NMR.IR(ν, cm-1) : 3408, 3061, 2979, 2934, 1717, 1614, 1491, 1366, 1254, 1118, 1098, 939, 858, 817, 735, 699. HRMS (ESI) m/z: [M+Na]+ Calcd for C32H32N2O7 Na 579.2120; Found 579.2122. [α]D29 +98.40 (c 0.5, CHCl3).HPLC conditions: dr 77:23 Major diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 24.10 min (major) and 12.50 min (minor). Minor diastereomer (94% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 20.28 min (major) and 14.14 min (minor).

Ethyl (R)-2-((R)-1-allyl-3-((tert-butoxycarbonyl) amino)-2-oxoindolin-3-yl)-6methyl-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3r) Compound 3r: Yellow foamy solid, actual mass 103 mg, yield 90%.1H NMR (500MHz, CDCl3) δ = 7.58 (d, J = 7.9 Hz, 1 H), 7.33 - 7.28 (m, 1 H), 7.23 (d, J = 7.3 Hz, 1 H), 7.05 (t, J = 7.6 Hz, 1 H), 6.96 (d, J = 7.9 Hz, 1 H), 6.86 - 6.58 (m, 3 H), 5.77 - 5.75 (m, 1 H), 5.35 (d, J = 17.3 Hz, 1 H), 5.21 (d, J = 10.4 Hz, 1 H), 4.38 (d, J = 15.4 Hz, 1 H), 4.35 - 4.27 (m, 3 H), 2.41 (s, 3 H), 2.31 (s, 1 H), 1.38 (t, J = 7.1 Hz, 2 H), 1.36 - 1.27 (m, 13 H).13C NMR (125MHz ,CDCl3) δ = 191.0, 172.3, 172.2, 171.5, 171.4, 163.9, 153.3, 151.4, 150.7, 144.2, 144.0, 131.4, 131.2, 130.0, 129.5, 125.0, 124.8, 124.5, 124.0, 123.5, 122.9, 122.7, 121.8, 118.3, 117.6, 117.4, 117.2, 113.1, 112.9, 109.4, 108.8, 86.9, 86.7, 80.3, 66.3, 65.0, 63.4, 63.4, 42.7, 42.7, 28.1, 22.6, 22.5, 14.0.Visible peaks of minor diastereoisomer present in 1H and 13C NMR.IR(ν, cm-1) :3408, 2979, 2931, 1716, 1613, 1492, 1386, 1252, 1164, 1098, 935, 858, 817, 752, 611, 533. HRMS (ESI) m/z: [M+Na]+ Calcd for C28H30N2O7Na 529.1945; Found 529.1960. [α]D26 +140.00 (c 0.5, CHCl3).HPLC


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conditions: dr 75:25 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 44.32 min (major) and 36.92 min (minor). Minor diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 48.43 min (major) and 57.76 min (minor).

Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-(2-methoxy-2-oxoethyl)2-oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (3s) Compound 3s: Yellow solid, actual mass 113 mg, yield 85%.1H NMR (500MHz, CDCl3) δ = 7.62 - 7.58 (m, 1 H), 7.49 (t, J = 7.4 Hz, 2 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.30 - 7.27 (m, 1 H), 7.16 (d, J = 7.3 Hz, 1 H), 7.12 - 7.06 (m, 1 H), 7.02 (t, J = 7.4 Hz, 2 H), 6.95-6.67 (m, 2H), 6.57 (d, J = 7.9 Hz, 1 H), 4.62 (d, J = 17.7 Hz, 1 H), 3.95 (d, J = 15.8 Hz, 1 H), 3.82 (s, 1 H), 3.77 (s, 1 H), 3.76 (s, 3 H), 3.68 (s, 3 H), 1.22 (m, 11 H).13C NMR (125MHz ,CDCl3) δ = 191.7, 172.4, 171.9, 171.5, 171.2, 167.5, 164.3, 153.2, 143.6, 143.5, 139.1, 138.3, 132.0, 132.0, 130.2, 129.7, 128.5, 128.4, 125.9, 124.4, 124.2, 123.4, 123.3, 123.3, 123.1, 122.2, 120.3, 119.6, 114.1, 113.2, 108.5, 108.2, 86.4, 80.4, 66.3, 53.9, 53.7, 52.4, 52.3, 41.5, 28.0.Visible peaks of minor diastereoisomer present in 1H and 13C NMR.IR(ν, cm-1) : 3408, 2978, 1714, 1609, 1494, 1469, 1363, 1259, 1164, 1015, 976, 875, 755, 697, 579, 537. HRMS (ESI) m/z: [M+Na]+ Calcd for C26H26N2O9 Na 533.1531; Found 533.1550. [α]D26 +156.00 (c 0.5, CHCl3).HPLC conditions: dr 84:16 Major diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 14.72 min (major) and 11.55 min (minor). Minor diastereomer (99% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time:

16.92 min (major) and 19.02 min (minor).

Methyl (S)-2-(S)-3-((tert-butoxycarbonyl) amino)-1-(2-methoxy-2-oxoethyl)-2oxoindolin-3-yl)-3-oxo-2, 3-dihydrobenzofuran-2-carboxylate (ent-3s) Compound

ent-3s: White solid, actual mass 60 mg, yield 90%.1H NMR (500MHz, CDCl3)

corresponding to 3s.13C NMR (125MHz, CDCl3) corresponding to 3s.HPLC conditions: dr 87:13 Major diastereomer (98% ee)

Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0

mL/min,λ= 254 nm, retention time: 15.23 min (major) and 19.90 min (minor). Minor diastereomer (99% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 25.67 min (major) and 22.90 min (minor).


32

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Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-(2-ethoxy-2-oxoethyl)-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3t) Compound 3t: Yellow solid, actual mass 123 mg, yield 90%.mp:205-210 °C .1H NMR (500MHz ,CDCl3) δ = 7.71 (d, J = 7.9 Hz, 1 H), 7.63 - 7.58 (m, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 1 H), 7.21 (d, J = 8.5 Hz, 1 H), 7.14 (t, J = 7.4 Hz, 1 H), 7.09 (t, J = 7.6 Hz, 1 H), 6.75 (d, J = 7.9 Hz, 1 H), 4.70 (d, J = 17.7 Hz, 1 H), 4.22 (q, J = 6.9 Hz, 2 H), 4.01 (d, J = 19.5 Hz, 1 H), 3.92 (s, 1 H), 3.84 (s, 3 H), 1.39 - 1.34 (m, 2 H), 1.29 (t, J = 6.9 Hz, 12 H).13C NMR (125MHz ,CDCl3) δ = 191.8, 172.5, 172.0, 171.6, 171.3, 167.0, 164.4, 153.3, 143.8, 139.0, 138.3, 130.2, 129.7, 124.5, 124.3, 123.5, 123.3, 123.2, 123.2, 123.0, 122.2, 120.4, 119.8, 114.2, 113.3, 86.5, 86.2, 80.5, 66.4, 61.6, 61.5, 53.9, 53.7, 41.8,41.7, 28.1, 14.2.Visible peaks of minor diastereoisomer present in 1H and

13

C NMR.IR(ν, cm-1) :3408, 3058, 2980, 1717, 1610, 1496,

1366, 1260, 1164, 1045, 970, 872, 755, 698, 612.HRMS (ESI) m/z: [M+Na]+ Calcd for C27H28N2O9 Na 547.1687; Found 547.1702. [α]D26 +152.20 (c 0.5, CHCl3).HPLC conditions: dr 83:17 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 85.46 min (major) and 71.40 min (minor).

Ethyl(R)-2-((R)-1-(2-(tert-butoxy)-2-oxoethyl)-3-((tert-utoxycarbonyl) amino)2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3u) Compound 3u: Yellow foamy solid, actual mass 117 mg, yield 85%.1H NMR (500MHz ,CDCl3) δ = 7.69 (d, J = 7.9 Hz, 1 H), 7.55 (t, J = 7.7 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.33 - 7.27 (m, 2 H), 7.22 (d, J = 8.5 Hz, 1 H), 7.12 - 7.03 (m, 3 H), 6.73 (d, J = 7.9 Hz, 1 H), 4.58 (d, J = 17.7 Hz, 1 H), 4.35 - 4.31 (m, 3 H), 4.27 – 4.23 (m, 1 H), 1.54 (s, 2 H), 1.47 (s, 10 H), 1.40 - 1.36 (m, 2 H), 1.30 - 1.24 (m, 13 H).13C NMR (125MHz ,CDCl3) δ = 192.7, 192.1, 172.3, 172.0, 171.5, 171.4, 166.1, 164.0, 153.2, 143.9, 143.9, 139.0, 138.0, 130.2, 129.6, 124.4, 124.2, 123.7, 123.1, 123.0, 123.0, 122.0, 120.4, 119.9, 114.5, 113.3, 108.5, 108.3, 86.5, 86.3, 82.4, 82.3, 80.3, 66.5, 65.0, 63.5, 63.3, 43.0, 42.1, 28.1, 28.0, 13.9.Visible peaks of minor diastereoisomer present in 1H and

13

C NMR.IR(ν, cm-1) :3411, 3058, 2978, 2932, 1717, 1610, 1496, 1325, 1255, 1096, 931,

883, 734, 698, 879. HRMS (ESI) m/z: [M+Na]+ Calcd for C30H34N2O9Na 589.2157; Found 589.2178. [α]D26 +163.20 (c 0.5, CHCl3).HPLC conditions: dr 83:17 Major diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 7.93 min (major) and 9.38 min (minor).


33


Ethyl(S)-2-((S)-1-(2-(tert-butoxy)-2-oxoethyl)-3-((tert-butoxycarbonyl) amino)-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate 3u) Compound

Page 34 of 52

(ent-

ent-3u: Yellow foamy solid, actual mass 61 mg, yield 88%.1H NMR (500MHz,

CDCl3) corresponding to 3u.13C NMR (125MHz, CDCl3) corresponding to 3u.HPLC conditions: dr 86:14 Major diastereomer (99% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 8.31 min (major) and 7.02 min (minor).

Methyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-chloro-1-methyl-2oxoindolin-3-yl)-5-chloro-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(3v major) Compound 3v: Foamy solid, actual mass 108 mg, yield 53%. 1H NMR (500MHz, CDCl3) δ = 7.65 – 7.58 (m, 1 H), 7.57 (dd, J = 1.9, 8.8 Hz, 1 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.18 (s, 1 H), 7.04 (d, J = 8.8 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 3.88 (s, 3 H), 3.12 (s, 3 H), 1.32 (s, 9 H). 13C NMR (125MHz ,CDCl3) δ = 190.1, 171.1, 169.1, 163.8, 153.2, 143.5, 138.5, 130.2, 129.4, 128.4, 127.32, 124.4, 124.0, 121.6, 114.1, 109.6, 87.3, 80.9, 66.3, 54.0, 28.1, 26.6.IR(ν, cm-1) :3411, 2977, 2928, 1723, 1608, 1490, 1462, 1391, 1258, 1164, 1098, 975, 887, 736, 693, 604. HRMS (ESI) m/z: [M+Na]+ Calcd for C24H22N2O7Cl2Na 543.0696; Found 543.0714. [α]D26 +180.60 (c 0.5, CHCl3).HPLC conditions: dr 60:40 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 11.69 min (major) and 8.73 min (minor).

Methyl (R)-2-((S)-3-((tert-butoxycarbonyl) amino)-5-chloro-1-methyl-2oxoindolin-3-yl)-5-chloro-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(3v minor) Compound 3v: White solid, actual mass 77 mg, yield 38%. mp:178-183 °C.1H NMR (500MHz, CDCl3) δ = 7.64 - 7.62 (m, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 6.83 (d, J = 8.5 Hz, 2 H), 6.69 (d, J = 8.2 Hz, 1 H), 3.92 (s, 3 H), 3.27 (s, 3 H), 1.32 (s, 10 H). 13C NMR (125MHz, CDCl3) δ = 190.8, 171.9, 169.8, 163.1, 153.2, 143.5, 139.2, 130.2, 129.9, 129.3, 127.6, 123.8, 123.4, 120.9, 114.3, 109.1, 87.1, 80.9, 64.8, 54.2, 28.1, 26.9.IR(ν, cm-1) : 3411, 2977, 2928, 1723, 1608, 1490, 1462, 1391, 1258, 1164, 1098, 975, 887, 736, 693, 604.HRMS (ESI) m/z: [M+Na]+ Calcd for C24H22N2O7Cl2Na 543.0696; Found 543.0714. [α]D28 -118.40 (c


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0.5, CHCl3). Minor diastereomer (97% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 10.48 min (major) and 21.85 min (minor).

General procedure for synthesis compound 7 To stirred solution of 3-Substituted 3-Amino-2-oxindole 3c in methanol at 0 °C, then portion wise NaBH4 (0.5 equiv) was added to the reaction mixture stirred for 30min, after completion of the reaction quenched by aqueous ammonium chloride solution followed by extracted in dichloromethane and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography over silica gel (80:20 hexane/EtOAc) to furnish 7.

Methyl (2S, 3R)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-chloro-1-methyl-2oxoindolin-3-yl)-3-hydroxy-2,3-dihydrobenzofuran-2-carboxylate(7 Major) Compound 7 (major) : White solid, actual mass 106 mg, yield 51%. 1H NMR (500MHz, CDCl3) δ = 7.39 (dd, J = 0.9, 7.9 Hz, 1 H), 7.35(dd, J = 1.4, 7.2, 8.4 Hz, 1 H), 7.21 (ddd, J = 2.0, 8.4 Hz, 1 H), 7.06 (d, 1 H), 7.01 (ddd, 2 J = 2.0, 8.4 Hz,1H ),6.81 (d ,J = 2.0, 8.4 Hz, 1 H), 6.71(d, J = 8.2 Hz, 2 H), 6.40(d, J = 8.2 Hz, 1 H), 5.65 (d, J = 8.2 Hz, 1 H , 3.85 (s, 3 H), 3.11 (s, 3 H), 1.29 (s., 11 H).13C NMR(125MHz ,CDCl3) δ = 175.2, 171.0, 156.4, 153.3, 142.7, 131.2, 130.5, 129.9, 129.1, 128.8, 128.7, 126.1, 125.6, 125.4, 123.3, 122.7, 111.2, 110.0, 109.6, 109.2, 94.5, 90.4, 80.9, 80.2, 66.4, 53.2, 28.1, 26.8.Visible peaks of minor diastereoisomer present in 1H and

13

C

NMR. IR(ν, cm-1) : 3605, 3405, 2978, 1721, 1610, 1491, 1432, 1392, 1162, 1098, 969, 817, 760, 736, 687, 543. HRMS (ESI) m/z: [M+Na]+ Calcd for C24H25ClN2O7Na 511.1242; Found 511.1233.HPLC conditions: dr 60:40 Major diastereomer (94% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min, λ= 254 nm, retention time: 25.74 min (major) and 8.24 min (minor).

Methyl (2R, 3R)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-chloro-1-methyl-2oxoindolin-3-yl)-3-hydroxy-2, 3-dihydrobenzofuran-2-carboxylate (7 Minor) Compound 7 (minor) : White solid, actual mass 65 mg, yield 31%. 1H NMR (500MHz, CDCl3) δ = 7.66 (s,1H) 7.45 (d, J = 8.4 Hz, 1 H), 7.41 (t, J = 2.0, 8.4 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1 H),7.16 (d, J = 8.2 Hz, 1 H), 7.09 (t, J = 8.2 Hz, 1 H),6.78 (d, J = 8.2 Hz, 1 H), 6.28 (s,1H), 5.90 (s,1H), 5.57 (s,1H), 3.34 (s, 3 H), 3.23 (s, 3 H), 1.29 (s, 9 H).13C NMR (125MHz ,CDCl3) δ =


35


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175.13, 169.2,158.9, 153.3, 142.1, 131.2, 129.9, 128.7, 126.1, 125.9, 125.6, 122.7, 111.2,109.2, 94.5, 80.7, 64.5, 52.9, 28.1, 26.9.IR(ν, cm-1) :3605, 3405, 2978, 1721, 1610, 1491, 1432, 1392, 1162, 1098, 969, 817, 760, 736, 687, 543.HRMS (ESI) m/z: [M+Na]+ Calcd for C24H25ClN2O7Na 511.1242; Found 511.1233. Minor diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 12.22 min (major) and 16.4 min (minor).

General procedure for synthesis compound 8. To stirred solution of 3-Substituted 3-Amino-2-oxindole 3c in methanol at 0 °C, then portion wise NaBH4( 2 equiv) was added to the reaction mixture stirred for 1h, after completion of the reaction quenched by aqueous ammonium chloride solution followed by extracted in dichloromethane and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography over silica gel (60:40 hexane/EtOAc) to furnish 8.

Tert-butyl ((R)-5-chloro-3-((2S, 3R)-3-hydroxy-2-(hydroxymethyl)-2,3dihydrobenzofuran-2-yl)-1-methyl-2-oxoindolin-3-yl)carbamate(8) Compound 8: White solid, actual mass 174 mg, yield 71%. 1H NMR (500MHz, DMSO-d6) δ = 7.54 (s,1H), 7.39 (d, J = 8.4 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.14 (t, J = 2.0, 8.4 Hz, 1 H), 6.95 (t, J = 8.2 Hz, 1 H), 6.80 (s,1H), 6.78 (d, J = 8.2 Hz, 1 H), 6.57 (d, J = 8.2 Hz, 1 H), 5.67 (s,1H), 4.9 (b.s.,1H), 4.10 (d, J = 8.2 Hz, 1 H), 3.69 (s, 1 H), 3.57(d, J = 8.2 Hz, 1 H), 3.07 (s, 3 H), 1.25 (s, 9 H).13C NMR (125MHz , DMSO-d6) δ = 176.7, 158.5,156.8, 153.5, 142.9, 130.4, 129.7, 128.3 , 127.4, 126.4, 125.6, 121.7, 110.5, 109.5, 92.9, 89.3, 80.3 ,67.62 , 63.95, 28.07, 26.84. IR(ν, cm-1) :3605, 3594 , 3405, 2973, 1608, 1489, 1429, 1396, 1159, 1092, 960, 813, 766, 730, 682, 541.HRMS (ESI) m/z: [M+H]+ Calcd for C23H26ClN2O6 461.1474; Found 461.1463.HPLC conditions: dr 85:15 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 44.00 min (major) and 9.90 min (minor). Minor diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 16.62 min (major) and 20.96 min (minor).


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Representative experimental procedure for the synthesis of anti-selective 3substituted 3-Amino-2-oxindoles To a 30 min stirred solution of Isatin derived ketimines (1.2 equiv) and catalyst C25 or C26 (0.1 equiv) in dry CH2Cl2 (0.5 ml) was added methyl 3-oxo-2,3-dihydrobenzofuran-2carboxylate(1equiv) at -23 ᴼC. The reaction mixture was stirred at -23 ᴼC till the consumption of methyl 3-oxo-2, 3-dihydrobenzofuran-2-carboxylate, which was monitored by TLC. The crude mixture was purified by flash column chromatography over silica gel (85:15 to 70:30 hexane/EtOAc) to furnish 4a-4m.

Analytical data for anti-selective 3-Substituted 3-Amino-2-oxindoles. Methyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-fluoro-1-methyl-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4a) Compound 4a: White foamy solid, actual mass 109 mg, yield 89%.1H NMR (400MHz, CDCl3): δ =

7.66 (d, J=7.7 Hz, 1 H), 7.53 - 7.48 (m, 1 H), 7.11 - 7.07 (m, 1 H), 6.86 - 6.80 (m, 2 H), 6.67 (dd, J=8.5, 4.0 Hz, 1 H), 6.61 (d, J=6.0 Hz, 1 H), 3.92 (s, 3 H), 3.28 (s, 3 H), 1.32 (s, 11 H).13C NMR (100MHz, ,CDCl3): δ = 192.0, 172.3, 171.5, 159.8, 157.4, 140.9, 139.3, 138.7, 125.0, 124.6, 123.5, 119.7, 116.1, 115.9, 113.0, 112.9, 111.3, 111.1, 108.5, 86.1, 80.7, 65.0, 54.1, 28.1, 26.9 . [α]D27 -119.80 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23FN2O7Na 493.1382; Found 493.1392. HPLC conditions: dr 18:82 Major diastereomer (99% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:05, flow rate = 0.50 mL/min,λ= 254 nm, retention time: 64.71 min (major) and 94.96 min (minor).

Methyl

(R)-2-((S)-3-((tert-butoxycarbonyl)

amino)-5-fluoro-1-methyl-2-

oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(ent-4a) Compound ent-4a: Yellow foamy solid, actual mass 50 mg, yield 82%.1H NMR (400MHz, CDCl3) corresponding to 4a.13C NMR (100MHz, CDCl3) corresponding to 4a. [α]D27 +89.80 (c 0.5, CHCl3).HPLC conditions: dr 35:65 Major diastereomer (92/80 %ee) Chiralpak AD-H, hexane/iso-PrOH = 95:05, flow rate = 0.50 mL/min,λ= 254 nm, retention time: 84.86 min (major) and 59.71 min (minor).


37


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Methyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-chloro-1-methyl-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4b) Compound 4b: White solid, actual mass 121 mg, yield 96%.1H NMR (400MHz, CDCl3): δ = 7.69 -

7.67 (m, 1 H), 7.51 (ddd, J=8.5, 7.2, 1.3 Hz, 1 H), 7.12 - 7.07 (m, 2 H), 6.84 - 6.80 (m, 2 H), 6.67 (d, J=8.3 Hz, 1 H), 3.92 (s, 3 H), 3.27 (s, 3 H), 1.32 . (s, 11 H).13C NMR (100MHz, ,CDCl3): δ = 191.9, 172.1, 171.5, 144.3, 143.5, 139.3, 138.7, 130.1, 129.7, 127.4, 125.0, 124.6, 123.6, 123.4, 119.7, 112.9, 112.8, 108.9, 86.0, 80.8, 64.9, 54.1, 28.1, 26.9 . [α]D27 -75.80 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23ClN2O7Na 509.1086; Found 509.1083. HPLC conditions: dr 18:82 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 12.45 min (major) and 27.08 min (minor).

Methyl (R)-2-((S)-3-((tert-butoxycarbonyl) amino)-5-chloro-1-methyl-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(ent-4b) Compound ent-4b: Yellow foamy solid, actual mass 56 mg, yield 89%.1H NMR (400MHz, CDCl3) corresponding to 4b.13C NMR (100MHz, CDCl3) corresponding to 4b. [α]D27 +45.80 (c 0.5, CHCl3).HPLC conditions: dr 35:65 Major diastereomer (88/74 %ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 23.82 min (major) and 11.37 min (minor).

Methyl (S)-2-((R)-5-bromo-3-((tert-butoxycarbonyl) amino)-1-methyl-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4c) Compound 4c: Yellow solid, actual mass 135 mg, yield 98%.1H NMR (400MHz, CDCl3): δ = 7.69

(dd, J=7.8, 0.8 Hz, 1 H), 7.51 (ddd, J=8.5, 7.2, 1.5 Hz, 1 H), 7.23 (dd, J=8.3, 1.8 Hz, 2 H), 7.13 7.09 (m, 1 H), 6.93 - 6.84 (m, 1 H), 6.82 (d, J=8.4 Hz, 1 H), 6.62 (d, J=8.3 Hz, 1 H), 3.92 (s, 3 H), 3.27 (s, 3 H), 1.32 (s, 11 H).13C NMR (100MHz, ,CDCl3): δ = 191.9, 172.0, 171.5, 143.9, 139.4, 138.8, 133.0, 132.6, 126.1, 125.0, 124.6, 123.7, 123.6, 119.8, 114.5, 112.9, 112.8, 109.4, 86.0, 80.8, 64.8, 54.1, 28.1, 26.9 . [α]D27 -48.20 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+H]+ Calcd for C24H24BrN2O7 531.0761; Found 531.0781. HPLC conditions: dr 17:83 Major diastereomer (98% ee)

Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 0.5 mL/min,λ= 254 nm,

retention time: 12.37 min (major) and 29.61 min (minor).


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Methyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-iodo-1-methyl-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4d) Compound 4d: Yellow foamy solid, actual mass 126 mg, yield 84%.1H NMR (400MHz, CDCl3): δ

= 7.70 (d, J=7.7 Hz, 1 H), 7.53 - 7.49 (m, 1 H), 7.41 (d, J=7.9 Hz, 1 H), 7.14 - 7.07 (m, 1 H), 7.06 (s, 1 H), 6.82 (d, J=8.4 Hz, 1 H), 6.52 (d, J=8.2 Hz, 1 H), 3.92 (s, 3 H), 3.26 (s, 3 H), 1.32 (s, 11 H).13C NMR (100MHz, ,CDCl3): δ = 191.9, 171.8, 171.5, 144.6, 139.4, 138.8, 138.5, 132.1, 131.7, 125.0, 124.5, 123.7, 119.8, 112.9, 85.9, 83.9, 80.8, 64.7, 54.1, 28.1, 26.8 . [α]D27 22.80 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23IN2O7Na 601.0442; Found 601.0453. HPLC conditions: dr 14:86 Major diastereomer (98% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 13.74 min (major) and 31.55 min (minor).

Methyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-5-methoxy-1-methyl-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4e) Compound 4e: White foamy solid, actual mass 122 mg, yield 97%.1H NMR (400MHz, CDCl3): δ =

7.65 (dd, J=7.8, 0.8 Hz, 1 H), 7.50 - 7.46 (m, 1 H), 7.09 - 7.05 (m, 1 H), 6.84 (d, J=8.4 Hz, 1 H), 6.65 (d, J=1.2 Hz, 2 H), 6.44 (s, 1 H), 3.92 (s, 3 H), 3.47 (s, 3 H), 3.26 (s, 3 H), 1.30 (s, 10 H).13C NMR (100MHz, ,CDCl3): δ = 192.3, 172.2, 171.6, 155.4, 139.1, 138.6, 138.4, 125.0, 124.3, 123.5, 123.3, 119.9, 115.2, 113.1, 109.8, 108.5, 86.3, 80.5, 65.4, 55.8, 54.1, 28.1, 26.9 . [α]D27 -95.20 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C25H26N2O8Na 505.1581; Found 505.1578. HPLC conditions: dr 15:85 Major diastereomer (96% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 79.20 min (major) and 216.14 min (minor).

Methyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxo-5(trifluoromethoxy)indolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4f) Compound 4f: White foamy solid, actual mass 132 mg, yield 94%.1H NMR (400MHz, CDCl3): δ =

7.66 (d, J=7.2 Hz, 1 H), 7.51 - 7.47 (m, 1 H), 7.11 - 7.06 (m, 2 H), 7.00 (d, J=7.8 Hz, 1 H), 6.83 (d, J=8.4 Hz, 1 H), 6.74 (d, J=8.3 Hz, 2 H), 3.92 (s, 3 H), 3.30 (s, 3 H), 1.32 (s, 11 H).13C NMR (100MHz, ,CDCl3): δ = 191.9, 172.4, 171.5, 144.0, 143.7, 139.3, 138.8, 125.0, 124.7, 123.7, 123.6, 123.5, 123.2, 119.6, 117.6, 117.1, 112.8, 108.4, 85.8, 80.8, 66.0, 54.1, 28.1, 27.0 . [α]D28 -


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89.60 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C25H23F3N2O8Na 559.1299; Found 559.1309. HPLC conditions: dr 24:76 Major diastereomer (97% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 41.60 min (major) and 115.91 min (minor).

Methyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-7-fluoro-1-methyl-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4g) Compound 4g: Yellow foamy solid, actual mass 119 mg, yield 97%.1H NMR (400MHz, CDCl3): δ

= 7.63 (dd, J=7.8, 0.9 Hz, 1 H), 7.50 (ddd, J=8.5, 7.2, 1.5 Hz, 1 H), 7.07 (t, J=7.5 Hz, 1 H), 6.89 (d, J=8.4 Hz, 1 H), 6.84 (dd, J=11.0, 8.7 Hz, 1 H), 6.63 - 6.61 (m, 1 H), 6.59 - 6.54 (m, 1 H), 3.92 (s, 3 H), 3.50 (d, J=2.6 Hz, 3 H), 1.33(s, 11 H). 13C NMR (100MHz, CDCl3): d = 192.1, 172.3, 171.6, 148.6, 146.2, 139.1, 138.7, 125.0, 124.5, 123.6, 123.4, 122.5, 122.4, 119.8, 118.7, 118.1, 117.9, 113.1, 112.9, 86.2, 80.7, 65.0, 54.1, 29.4, 28.1. [α]D28 -105.00 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23FN2O7Na 493.1382; Found 493.1373. HPLC conditions: dr 25:75 Major diastereomer (95% ee) Chiralpak AD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 65.61 min (major) and 75.10 min (minor).

Methyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3yl)-5-chloro-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4h) Compound 4h: Yellow foamy solid, actual mass 102 mg, yield 81%.1H NMR (400MHz, CDCl3): δ

= 7.59 (d, J=2.3 Hz, 1 H), 7.40 (dd, J=8.8, 2.3 Hz, 1 H), 7.15 (t, J=7.6 Hz, 2 H), 6.82 - 6.77 (m, 2 H), 6.76 - 6.71 (m, 2 H), 6.71 - 6.68 (m, 1 H), 3.92 (s, 3 H), 3.28 (s, 3 H), 1.26 (s, 11 H). 13C NMR (100MHz, CDCl3): d = 191.2, 172.3, 169.9, 144.8, 138.9, 138.4, 130.4, 130.0, 128.9, 124.3, 123.7, 122.7, 122.2, 121.0, 114.3, 108.1, 80.6, 65.0, 54.2, 28.1, 26.8. [α]D28 -164.60 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23ClN2O7Na 509.1086; Found 509.1096.

HPLC conditions: dr 15:75 Major diastereomer (94% ee) Chiralpak AD-H,

hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 11.89 min (major) and 15.21 min (minor).


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Methyl (R)-2-((S)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3yl)-5-chloro-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-4h) Compound ent-4h: Yellow foamy solid, actual mass 50 mg, yield 79%.1H NMR (400MHz, CDCl3) corresponding to 4h.13C NMR (100MHz, CDCl3) corresponding to 4h. [α]D28 +9.10 (c 0.5, CHCl3).HPLC conditions: dr 40:60 Major diastereomer (84/80 %ee)

Chiralpak AD-H,

hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 16.45 min (major) and 12.49 min (minor).

Methyl (S)-5-bromo-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4i) Compound 4i: Yellow foamy solid, actual mass 100 mg, yield 73%.1H NMR (400MHz, CDCl3): δ

= 7.75 (d, J=2.1 Hz, 1 H), 7.53 (dd, J=8.8, 2.2 Hz, 1 H), 7.17 - 7.13 (m, 2 H), 6.83 - 6.68 (m, 3 H), 3.92 (s, 3 H), 3.28 (s, 3 H), 1.27 (s, 11 H).13C NMR (100MHz, ,CDCl3): δ = 190.9, 172.3, 170.3, 144.8, 144.3, 141.6, 141.1, 130.0, 127.4, 126.8, 122.7, 122.2, 121.5, 115.9, 114.7, 108.1, 87.1, 80.6, 65.0, 54.2, 28.1, 26.8 . [α]D28 -198.00 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23BrN2O7Na 553.0581; Found 553.0577. HPLC conditions: dr 14:86 Major diastereomer (92% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 11.35 min (major) and 14.97 min (minor).

Methyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3yl)-5-iodo-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4j) Compound 4j: Yellow foamy solid, actual mass 101 mg, yield 63%.1H NMR (400MHz, CDCl3): δ

= 7.94 (d, J=1.6 Hz, 1 H), 7.69 (dd, J=8.7, 1.8 Hz, 1 H), 7.15 (t, J=7.2 Hz, 2 H), 6.82 (d, J=7.6 Hz, 1 H), 6.76 - 6.69 (m, 2 H), 6.63 (d, J=8.7 Hz, 1 H), 3.91 (s, 3 H), 3.28 (s, 3 H), 1.26 (s, 12 H).13C NMR (100MHz, ,CDCl3): δ = 190.6, 172.3, 170.9, 147.1, 146.7, 144.8, 133.0, 130.4, 130.0, 122.7, 122.3, 122.1, 115.1, 108.1, 86.7, 85.5, 80.6, 65.0, 54.2, 28.1, 26.8 . [α]D28 -12.60 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C24H23IN2O7Na 601.0442; Found 601.0434. HPLC conditions: dr 16:84 Major diastereomer (10% ee) Chiralpak AD-H, hexane/isoPrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 14.94 min (major) and 18.89 min (minor).


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Ethyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3-yl)3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4k) Compound 4k: White foamy solid, actual mass 118 mg, yield 97%.1H NMR (400MHz, CDCl3): δ =

7.64 - 7.62 (m, 1 H), 7.47 - 7.43 (m, 1 H), 7.13 - 7.08 (m, 1 H), 7.06 - 7.02 (m, 1 H), 6.82 - 6.80 (m, 2 H), 6.73 (d, J=7.8 Hz, 1 H), 6.62 (t, J=7.5 Hz, 1 H), 4.46 - 4.26 (m, 2 H), 3.28 (s, 3 H), 1.40 (t, J=7.2 Hz, 4 H), 1.30 - 1.25 (m, 11 H).13C NMR (100MHz, ,CDCl3): δ = 192.6, 172.4, 171.7, 144.8, 139.0, 138.5, 130.2, 129.8, 124.9, 124.4, 123.4, 123.1, 122.8, 121.9, 119.9, 113.0, 107.9, 80.4, 65.0, 63.7, 28.1, 26.8, 14.0. [α]D28 -112.20 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C25H26N2O7 Na 489.1632; Found 489.1646. HPLC conditions: dr 22:78 Major diastereomer (95% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 18.81 min (major) and 21.98 min (minor).

Ethyl (R)-2-((S)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3-yl)3-oxo-2,3-dihydrobenzofuran-2-carboxylate(ent-4k) Compound ent-4k: White foamy solid, actual mass 48 mg, yield 86%.1H NMR (400MHz, CDCl3)

corresponding to 4k.13C NMR (100MHz, CDCl3) corresponding to 4k. [α]D28 -88.60 (c 0.5, CHCl3). HPLC conditions: dr 41:59 Major diastereomer (84/80% ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 22.32 min (major) and 19.42 min (minor).

Ethyl (S)-5-bromo-2-((R)-3-((tert-butoxycarbonyl)amino)-1-methyl-2oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4l) Compound 4l: Yellow foamy solid, actual mass 112 mg, yield 79%.1H NMR (400MHz, CDCl3): δ

= 7.74 (d, J=2.1 Hz, 1 H), 7.52 (dd, J=8.8, 2.2 Hz, 1 H), 7.17 - 7.13 (m, 1 H), 6.81 (d, J=7.3 Hz, 1 H), 6.76 - 6.68 (m, 3 H), 4.46 - 4.33 (m, 2 H), 3.28 (s, 3 H), 1.39 (t, J=7.2 Hz, 4 H), 1.30 - 1.25 (m, 10 H).13C NMR (100MHz, ,CDCl3): δ = 191.2, 172.2, 170.4, 144.8, 141.5, 141.0, 130.4, 130.0, 127.4, 126.8, 123.4, 122.7, 122.2, 121.6, 115.8, 114.7, 108.1, 87.2, 80.5, 64.9, 63.9, 28.1, 26.8, 14.0. [α]D28 -181.40 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C25H25BrN2O7Na 567.0737; Found 567.0749. HPLC conditions: dr 13:87 Major diastereomer (99% ee)

Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm,

retention time: 11.09 min (major) and 14.96 min (minor).


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Methyl (S)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-(2-methoxy-2-oxoethyl)2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(4m) Compound 4m: Yellow foamy solid, actual mass 126 mg, yield 96%.1H NMR (400MHz, CDCl3): δ

= 7.61 (d, J=7.8 Hz, 1 H), 7.48 - 7.44 (m, 1 H), 7.09 - 7.00 (m, 2 H), 6.92 - 6.86 (m, 2 H), 6.67 6.60 (m, 2 H), 4.92 (d, J=17.6 Hz, 1 H), 4.19 (d, J=15.9 Hz, 1 H), 3.90 (s, 3 H), 3.84 (s, 3 H), 1.29 (s, 11 H).13C NMR (100MHz, ,CDCl3): δ = 192.3, 172.5, 172.0, 167.7, 153.3, 143.5, 139.1, 138.3, 133.0, 130.3, 129.8, 128.6, 128.4, 124.3, 123.2, 123.1, 122.3, 119.7, 114.1, 113.3, 108.2, 86.2, 80.5, 65.0, 54.0, 52.5, 41.6, 28.1. [α]D28 -172.40 (c 0.5, CHCl3). HRMS (ESI) m/z: [M+Na]+ Calcd for C26H26N2O9 Na 533.1531; Found 533.1550. HPLC conditions: dr 20:80 Major diastereomer (99% ee)

Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0

mL/min,λ= 254 nm, retention time: 25.99 min (major) and 30.42 min (minor).

Methyl (R)-2-((S)-3-((tert-butoxycarbonyl) amino)-1-(2-methoxy-2-oxoethyl)2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate(ent-4m) Compound ent-4m: Yellow foamy solid, actual mass 60 mg, yield 91%.1H NMR (400MHz, CDCl3)

corresponding to 4m.13C NMR (100MHz, CDCl3) corresponding to 4m. [α]D28 +113.60 (c 0.5, CHCl3).HPLC conditions: dr 40:60 Major diastereomer (88/80 %ee) Chiralpak AD-H, hexane/iso-PrOH = 90:10, flow rate = 1.0 mL/min,λ= 254 nm, retention time: 32.02 min (major) and 22.86 min (minor).

Control Experiment Ethyl (R)-2-((R)-3-((tert-butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3-yl)1-oxo-2,3-dihydro-1H-indene-2-carboxylate(6) (Catalyst C1) Compound 6: Yellow liquid, actual mass 57 mg, yield 95%. 1H NMR (CDCl3, 500MHz): d = 7.72- 7.70 (m, 1 H), 7.56 (t, J=7.5 Hz, 1 H), 7.36 - 7.29 (m, 4 H), 7.23 (s, 1 H), 6.97 (s, 1 H), 6.81 (d, J=7.6 Hz, 1 H), 4.28- 4.21(m, J=34 Hz, 2 H), 3.53 (d, J=18.2 Hz, 1 H), 3.22 (s, 1 H), 3.21 (s, 1 H), 3.15 (s, 3 H), 1.38-1.20 (m, 17H).

13

C NMR (CDCl3, 125MHz): δ = 198.0, 173.6,

173.3, 153.8, 151.1, 144.5, 135.9, 135.5, 135.5, 129.7, 129.5, 128.0, 127.8, 126.0, 125.7, 124.7, 124.5, 124.1, 122.8, 108.3, 80.0, 62.7, 36.6, 28.1, 26.5, 24.7, 13.9 .Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm-1): 3409, 2978, 1750, 1721, 1610, 1496,


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1370, 1254, 1165, 1089, 932, 885, 756, 695, 612, 538, 513.HRMS (ESI) m/z: [M+H]+ Calcd for C26H29N2O6 465.2020; Found 465.2025. [α]D26 +30.73 (c 1.5, CHCl3).HPLC conditions: dr 82:18 Major diastereomer (98% ee) Chiralpak OD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 34.20 min (major) and 30.12 min (minor). Minor diastereomer (99% ee) Chiralpak OD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 25.24 min (major) and 42.30 min (minor). (Catalyst C25) Compound 6: Yellow liquid, actual mass 56mg, yield 93%.HPLC conditions: dr 65:35 Major diastereomer (98% ee) Chiralpak OD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 36.01 min (major) and 31.06 min (minor). Minor diastereomer (99% ee) Chiralpak OD-H, hexane/iso-PrOH = 95:5, flow rate = 0.5 mL/min,λ= 254 nm, retention time: 26.04 min (major) and 42.04 min (minor).

Analytical data for Isatin derived ketimines The analytical data for known isatin derived ketimines (2a-k) were matched with reported values in the literature.20a-b The analytical data for other isatin derived ketimines (2l-n) as follows.

Methyl (E)-2-(3-((tert-butoxycarbonyl)imino)-2-oxoindolin-1-yl)acetate (2l) Compound 2l (400mg from 1g batch), yellow solid. mp:155-160 °C. 1H NMR (400MHz, CDCl3) δ = 7.79 - 7.61 (m, 1 H), 7.51 - 7.44 (m, 1 H), 7.13 (s, 1 H), 6.74 (d, J = 7.6 Hz, 1 H), 4.47 (s, 2 H), 3.77 (s, 3 H), 1.62 (s, 9 H). 13C NMR (100MHz, CDCl3) δ = 167.3, 146.8, 135.4, 124.6, 123.9, 109.4, 83.7, 52.8, 41.1, 28.0. HRMS (ESI) m/z: [M+Na]+ Calcd for C16H18N2O5 Na 341.1108; Found 341.1107.

Ethyl (E)-2-(3-((tert-butoxycarbonyl)imino)-2-oxoindolin-1-yl)acetate (2m) Compound 2m (500mg from 1g batch), yellow solid. mp:142-145 °C. 1H NMR (400MHz, CDCl3) δ = 7.68 (s, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.12 (s, 1 H), 6.74 (d, J = 7.7 Hz, 1 H), 4.45 (s, 2 H), 4.23 (q, J = 7.1 Hz, 2 H), 1.62 (s, 10 H), 1.27 (t, J = 7.0 Hz, 3 H). 13C NMR (100MHz, CDCl3) δ = 166.8, 146.9, 135.3, 124.6, 123.8, 109.4, 83.6, 62.1, 41.3, 28.0, 14.1. HRMS (ESI) m/z: [M+Na]+ Calcd for C17H20N2O5 Na 355.1264; Found 355.1262.


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Tert-butyl (2n)

(E)-2-(3-((tert-butoxycarbonyl)imino)-2-oxoindolin-1-yl)acetate

Compound 2n (700mg from 1g batch), yellow solid. mp:138-142 °C 1H NMR (400MHz, CDCl3) δ = 7.67 (s, 1 H), 7.48 (t, J = 7.7 Hz, 1 H), 7.11 (s, 1 H), 6.72 (d, J = 7.7 Hz, 1 H), 4.36 (s, 2 H), 1.62 (s, 10 H), 1.45 (s, 9 H). 13C NMR (100MHz, CDCl3) δ = 165.8, 147.1, 135.3, 124.5, 123.7, 109.5, 83.3, 42.1, 28.0, 27.91. HRMS (ESI) m/z: [M+Na]+ Calcd for C19H24N2O5 Na 383.1577; Found 383.1578.

AUTHOR INFORMATION Corresponding Author *E mail: [email protected]

ACKNOWLEDGMENT We acknowledge Board of Research in Nuclear Sciences, Mumbai, INDIA (35/14/01/2015BRNS/10464) for financial support. K.S.M.R thanks Council of Scientific & Industrial Research (CSIR) for fellowship. We thank Dr. Sudha Devi for crystallographic analysis SAIF-IIT Madras and SAIF-IIT Madras for spectral analysis (NMR and IR). We thank department of Biotechnology IIT Madras for LCMS. We thank Prof. Anju chadha for AUTOPOL IV Polarimeter.

ASSOCIATED CONTENT Supporting Information Copies of 1H and

13

C NMR spectra, CD Spectra and Crystallographic data. The Supporting

Information is available free of charge on the ACS Publications website. http://pubs.acs.org. Supporting Information (PDF) Crystallographic data for compound 3i (CIF) Crystallographic data for compound 3v (Minor diastereomer) (CIF) Crystallographic data for compound 8 (CIF)


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REFERENCES 1. a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.; Editors, Comprehensive Asymmetric Catalysis I-III, Volume 1. Springer: 1999; p 487 pp. b) Cossy, J. R.; Editor, Comprehensive

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Volume

1:

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Significance-Pharmacology,

Pharmaceutical, Agrochemical. Elsevier B.V.: 2012; p 245 pp. 2. a) Oliveira, M. T.; Luparia, M.; Audisio, D.; Maulide, N., Dual Catalysis Becomes Diastereodivergent. Angew. Chem., Int. Ed. 2013, 52 (50), 13149-13152. b) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M., Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes. Science 2013, 340 (6136), 1065-8. 3. a) Bihani, M.; Zhao, J. C. G., Advances in Asymmetric Diastereodivergent Catalysis. Adv. Synth. Catal. 2017, 359 (4), 534-575.b) Zhan, G.; Du, W.; Chen, Y.-C., Switchable divergent asymmetric synthesis via organocatalysis. Chem. Soc. Rev. 2017, 46 (6), 1675-1692. c) Lin, L.; Feng, X., Catalytic Strategies for Diastereodivergent Synthesis. Chem. - Eur. J. 2017, 23 (27), 6464-6482. d) Krautwald, S.; Carreira, E. M., Stereodivergence in Asymmetric Catalysis. J. Am. Chem. Soc. 2017, 139 (16), 56275639. 4. a) Ping, X.-N.; Wei, P.-S.; Zhu, X.-Q.; Xie, J.-W., Catalyst-Controlled Switch in Diastereoselectivities: Enantioselective Construction of Functionalized 3,4-Dihydro2H-thiopyrano[2,3-b]quinolines with Three Contiguous Stereocenters. J. Org. Chem. 2017, 82 (4), 2205-2210. b) Uraguchi, D.; Yoshioka, K.; Ooi, T.; Ooi, T., Complete diastereodivergence in asymmetric 1,6-addition reactions enabled by minimal


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modification of a chiral catalyst. Nat Commun 2017, 8, 14793. and references cited therein. 5. a) Periyasami, G.; Raghunathan, R.; Surendiran, G.; Mathivanan, N., Synthesis of novel spiropyrrolizidines as potent antimicrobial agents for human and plant pathogens. Bioorg. Med. Chem. Lett. 2008, 18 (7), 2342-2345. b) Girgis, A. S., Regioselective synthesis of dispiro[1H-indene-2,3'-pyrrolidine-2',3''-[3H]indole]-1,2''(1''H)-diones of potential antitumor properties. Eur. J. Med. Chem. 2009, 44 (1), 91-100.c) Ali, M. A.; Ismail, R.; Choon, T. S.; Yoon, Y. K.; Wei, A. C.; Pandian, S.; Kumar, R. S.; Osman, H.; Manogaran, E., Substituted spiro[2.3']oxindolespiro[3.2'']-5,6-dimethoxy-indane1''-one-pyrrolidine analogue as inhibitors of acetylcholinesterase. Bioorg. Med. Chem. Lett. 2010, 20 (23), 7064-7066. 6. a) Miyoshi, E.; Shizuri, Y.; Yamamura, S., Isolation and structures of diomuscinone and diomuscipulone from Dionaea muscipula. Phytochemistry 1984, 23 (10), 23852387. b) Hu, K.; Kobayashi, H.; Dong, A.; Iwasaki, S.; Yao, X., Antifungal, Antimitotic and Anti-HIV-1 Agents from the Roots of Wikstroemia indica. Planta Med 2000, 66 (06), 564-567.c) Ho, Y. S.; Duh, J. S.; Jeng, J. H.; Wang, Y. J.; Liang, Y. C.; Lin, C. H.; Tseng, C. J.; Yu, C. F.; Chen, R. J.; Lin, J. K., Griseofulvin potentiates antitumorigenesis effects of nocodazole through induction of apoptosis and G2/M cell cycle arrest in human colorectal cancer cells. Int J Cancer 2001, 91 (3), 393-401.d) Rathinasamy, K.; Jindal, B.; Asthana, J.; Singh, P.; Balaji, P. V.; Panda, D., Griseofulvin stabilizes microtubule dynamics, activates p53 and inhibits the proliferation of MCF-7 cells synergistically with vinblastine. BMC Cancer 2010, 10,


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bearing a tetra-substituted stereocenter. Tetrahedron: Asymmetry 2013, 24 (7), 343356. b) Kaur, J.; Chimni, S. S.; Mahajan, S.; Kumar, A., Stereoselective synthesis of 3amino-2-oxindoles from isatin imines: new scaffolds for bioactivity evaluation. RSC Adv. 2015, 5 (65), 52481-52496. 11. Selected examples on vicinal tetrasubstituted 3-substituted-3-amino oxinolde: a) Amr, F. I.; Vila, C.; Blay, G.; Munoz, M. C.; Pedro, J. R., Organocatalytic Enantioselective Alkylation of Pyrazol-3-ones with Isatin-Derived Ketimines: Stereocontrolled Construction of Vicinal Tetrasubstituted Stereocenters. Adv. Synth. Catal. 2016, 358 (10), 1583-1588. b) Nakamura, S.; Yamaji, R.; Iwanaga, M., Enantioselective construction of imidazolines having vicinal tetra-substituted stereocenters by direct Mannich reaction of α-substituted α-isocyanoacetates with ketimines. Chem. Commun. (Cambridge, U. K.) 2016, 52 (47), 7462-7465. c) Ricko, S.; Meden, A.; Ciber, L.; Stefane, B.; Pozgan, F.; Svete, J.; Groselj, U., Construction of Vicinal Tetrasubstituted Stereogenic Centers via a Mannich-Type Organocatalyzed Addition of ∆2-Pyrrolin-4ones to Isatin Imines. Adv. Synth. Catal. 2018, 360 (6), 1072-1076 and references cited therein. 12. a) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H., Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products. Nat Chem 2010, 2 (9), 73540. b) Yeung, B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang, S. H.; Leong, S. Y.; Tan, J.; Wong, J.; Keller-Maerki, S.; Fischli, C.; Goh, A.; Schmitt, E. K.; Krastel, P.; Francotte, E.; Kuhen, K.; Plouffe, D.; Henson, K.; Wagner, T.; Winzeler, E. A.; Petersen, F.; Brun, R.; Dartois, V.; Diagana, T. T.; Keller, T. H., Spirotetrahydro


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beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria. J Med Chem 2010, 53 (14), 5155-64. 13. Guo, Q.-X.; Liu, Y.-W.; Li, X.-C.; Zhong, L.-Z.; Peng, Y.-G., Enantioselective and Solvent-Controlled Diastereoselective Mannich Reaction of Isatin Imines with Hydroxyacetone: Synthesis of 3-Substituted 3-Aminooxindoles. J. Org. Chem. 2012, 77 (7), 3589-3594. 14. Dai, J.; Xiong, D.; Yuan, T.; Liu, J.; Chen, T.; Shao, Z., Chiral Primary Amine Catalysis for Asymmetric Mannich Reactions of Aldehydes with Ketimines: Stereoselectivity and Reactivity. Angew. Chem., Int. Ed. 2017, 56 (41), 12697-12701. 15. The structure of 3i is also shown in supporting information CCDC 1530657 contains the supplementary crystallographic date for 3i.These data can be obtained free of charge

from

the

Cambridge

crystallographic

data

centre

via

www.ccdc.cam.ac.uk/data_request/cif 16. The structure of 3v (minor diastereomer) is shown in table 2 in the supporting information. CCDC 1530662 contains the supplementary crystallographic data for 3v. 17. a) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L., Stereocontrolled creation of adjacent quaternary and tertiary stereocenters by a catalytic conjugate addition. Angew. Chem., Int. Ed. 2005, 44 (1), 105-108. b) Chauhan, P.; Chimni, S. S., Aromatic hydroxyl group-a hydrogen bonding activator in bifunctional asymmetric organocatalysis. RSC Adv. 2012, 2 (3), 737-758.


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18. a) Alami, I.; Clerivet, A.; Naji, M.; Van Munster, M.; Macheix, J. J., Elicitation of Platanus × acerifolia cell-suspension cultures induces the synthesis of xanthoarnol, a dihydrofuranocoumarin phytoalexin. Phytochemistry 1999, 51 (6), 733-736.b) Zou, Y.; Lobera,

M.;

Snider,

B.

hydroxylalkylbenzofurans

from

B.,

Synthesis

Epoxy

of

Aldehydes.

2,3-Dihydro-3-hydroxy-2One-Step

Syntheses

of

Brosimacutin G, Vaginidiol, Vaginol, Smyrindiol, Xanthoarnol, and Avicenol A. Biomimetic Syntheses of Angelicin and Psoralen. J. Org. Chem. 2005, 70 (5), 17611770. c) Enders, D.; Fronert, J.; Bisschops, T.; Boeck, F., Asymmetric total synthesis of smyrindiol employing an organocatalytic aldol key step. Beilstein J. Org. Chem. 2012, 8, 1112-1117, No. 123. 19. Zhao, L.; Huang, G.; Guo, B.; Xu, L.; Chen, J.; Cao, W.; Zhao, G.; Wu, X., Diastereoand enantioselective propargylation of benzofuranones catalyzed by pybox-copper complex. Org Lett 2014, 16 (21), 5584-7. 20. a)Yan, W.; Wang, D.; Feng, J.; Li, P.; Zhao, D.; Wang, R., Synthesis of Nalkoxycarbonyl ketimines derived from isatins and their application in enantioselective synthesis of 3-aminooxindoles. Org Lett 2012, 14 (10), 2512-5. b) Hara, N.; Nakamura, S.; Sano, M.; Tamura, R.; Funahashi, Y.; Shibata, N., Enantioselective Synthesis of AG-041R

by

using

N-Heteroarenesulfonyl

Cinchona

Alkaloid

Amides

as

Organocatalysts. Chem. - Eur. J. 2012, 18 (30), 9276-9280, S9276/1-S9276/82. 21. a) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T., Highly enantioselective conjugate addition of nitromethane to chalcones using bifunctional cinchona organocatalysts. Org. Lett. 2005, 7 (10), 1967-1969. b) Malerich, J. P.; Hagihara, K.; Rawal, V. H.,


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Chiral Squaramide Derivatives are Excellent Hydrogen Bond Donor Catalysts. J. Am. Chem. Soc. 2008, 130 (44), 14416-14417. c) Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H., Enantioselective α-Amination of 1,3-Dicarbonyl Compounds Using Squaramide Derivatives as Hydrogen Bonding Catalysts. Org. Lett. 2010, 12 (9), 20282031. d) Waldmann, H.; Khedkar, V.; Dueckert, H.; Schuermann, M.; Oppel, I. M.; Kumar, K., Asymmetric synthesis of natural product inspired tricyclic benzopyrones by an organocatalyzed annulation reaction. Angew. Chem., Int. Ed. 2008, 47 (36), 68696872. e) Xu, X.-H.; Kusuda, A.; Tokunaga, E.; Shibata, N., Catalyst-free and catalytic Friedel-Crafts alkylations of indoles in Solkane 365mfc, an environmentally benign alternative solvent. Green Chem. 2011, 13 (1), 46-50. f) Nakamoto, Y.; Urabe, F.; Takahashi, K.; Ishihara, J.; Hatakeyama, S., α-Isocupreine, an Enantiocomplementary Catalyst of β-Isocupreidine. Chem. - Eur. J. 2013, 19 (38), 12653-12656.


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Stereodivergent Synthesis of 3-Aminooxindole ... - ACS Publications

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