Synthesis method of chiral C2 spiro indoline compound

Abstract

The invention provides a method and application of a chiral C2 spiroindoline skeleton-containing compound, and belongs to the technical field of chemical synthesis.The method comprises the steps that dialdehyde and o-aminobenzaldehyde serve as raw materials, a one-pot two-step method is used, the dialdehyde is catalyzed under the catalysis of an N-heterocyclic carbene catalyst, oxidation is conducted through an oxidizing agent DQ, and the chiral C2 spiroindoline skeleton-containing compound is obtained. The preparation method comprises the following steps: reacting furanone as a raw material with o-aminobenzaldehyde to obtain a furanone-containing skeleton compound with central chirality, and adding alkali to obtain a C2 spiroindoline-containing skeleton compound. The method adopts the N-heterocyclic carbene catalyst to realize the synthesis of the C2 spiroline skeleton compound under mild conditions, is simple to operate, low in cost, green, pollution-free and suitable for industrial production, and solves the problems of uncleanness and harsh reaction conditions caused by the use of a metal catalyst in the existing method for synthesizing the chiral C2 spiroline skeleton compound.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to a method for green and efficient synthesis of C2-spiroindoline compounds. Background Art

[0002] C2-spiroindoline compounds widely exist in alkaloids and natural products. According to literature research, C2-spiroindoline compounds are intermediates of many synthetic drugs and have potential pharmaceutical activities. For example, Brevanamide A has certain biological activities against pests such as Spodoptera litura and Helicoverpa assulta, and may have potential application value in the control of agricultural pests. In addition, spiro(2H-indole-2,1'(5'H)-pyrrolizine)-7'-acetic acid, a compound related to mitragynine, its biological activity can act as an opioid receptor and analgesic effect. Therefore, effective methods for synthesizing functional molecules containing C2-spiroindoline compounds have received extensive attention.

[0003] Currently, there are few literature reports on the synthesis of C2-spiroindoline compounds. However, it is an important part of many synthetic drugs and has potential pharmaceutical activities. It is an important field in the chemical field and has broad application prospects in the preparation of complex functional molecules. Common synthetic methods include metal-catalyzed tandem reactions and dearomatization reactions. However, these methods have their advantages and inherent limitations. For example, (1) factors such as impurities, moisture, and oxygen in the reaction system may cause a decrease or even inactivation of the catalyst activity, requiring strict control of the reaction conditions and increasing the difficulty of reaction operation; (2) common transition metal catalysts such as palladium and rhodium are expensive and cause serious environmental pollution, increasing the synthesis cost and being unfavorable for large-scale industrial production; (3) there are certain requirements for the structure and functional groups of the substrates, and many substrates with special structures or functional groups cannot participate in the reaction, or have low reaction activity and poor yields.

[0004] Through literature research, it is found that using N-heterocyclic carbene as a catalyst for the synthesis of C2-spiroindoline compounds can achieve the benefits of an efficient and inexpensive synthesis process: (1) Under mild conditions, it is possible to avoid using expensive and toxic metal catalysts, reducing environmental pollution and conforming to the development concept of green chemistry; (2) N-heterocyclic carbene has strong electron-donating ability, can form stable intermediates with substrates, and can effectively reduce the reaction activation energy and accelerate the construction of the C2-spiroindole structure. (3) Without harsh conditions, the reaction operation is simple, reducing the risk and improving the operability and safety of the reaction. Summary of the Invention

[0005] To solve the problems of harsh reaction conditions and metal catalyst contamination existing in the existing methods for synthesizing chiral C2-spiroindolines, the present invention provides a method for green and efficient synthesis of chiral C2-spiroindoline compounds. This method uses dialdehyde and o-sulfonylaminobenzaldehyde as raw materials and employs an N-heterocyclic carbene catalyst to achieve the synthesis of C2-spiroindoline compounds under mild conditions. This method is simple to operate, low in cost, green and pollution-free, suitable for industrial production, and solves the problems of harsh unclean reaction conditions caused by the use of metal catalysts in the existing methods for synthesizing chiral C2-spiroindolines.

[0006] The present invention is achieved through the following technical solutions:

[0007] The present invention provides a method for green and efficient synthesis of C2-spiroindoline compounds, and the method includes:

[0008] Using dialdehyde and o-sulfonylaminobenzaldehyde as raw materials and using an N-heterocyclic carbene catalyst for catalysis to obtain chiral C2-spiroindoline compounds.

[0009] Further, the general structural formulas of the dialdehyde, the o-sulfonylaminobenzaldehyde, the N-heterocyclic carbene catalyst, the oxidant, and the C2-spiroindoline compounds are respectively shown in Formulas 1 to 5:

[0010]

[0011] Among them, the carbon atom marked with * is a chiral carbon atom;

[0012] R 1 is a halogen atom, a phenyl group, a substituted phenyl group, a naphthyl group, or an isopropyl group;

[0013] R 2 is a halogen atom, a methyl group, or a methoxy group;

[0014] In the present invention, for the chiral C2-spiroindoline compound, it is characterized in that in R 1 , the substituted phenyl group is a fluorophenyl group, a chlorophenyl group, a tolyl group, or a methoxyphenyl group.

[0015] Preferably, for the chiral C2-spiroindoline compound, it is characterized in that in R 2 , the halogen atom is fluorine or chlorine.

[0016] Further, the method specifically includes:

[0017] Dispersing the dialdehyde, the o-sulfonylaminobenzaldehyde, the oxidant, the N-heterocyclic carbene catalyst, and the base in an organic solvent together to obtain a mixed solution;

[0018] The mixed solution is subjected to a one-pot two-step method (the mixed solution reacts at 35 °C for 5 h, and then alkali is added and the reaction is carried out at 0 °C for 6 h) to obtain the C2 spiroindoline compound.

[0019] Furthermore, the dialdehyde, the o-sulfamoylbenzaldehyde, the oxidant, the N-heterocyclic carbene catalyst and the alkali are jointly dispersed in an organic solvent to obtain a mixed solution, specifically including:

[0020] The dialdehyde, the o-sulfamoylbenzaldehyde, the oxidant, the N-heterocyclic carbene catalyst and the alkali are jointly dispersed in an organic solvent to obtain a mixed solution;

[0021] Among them, the organic solvent includes any one of tetrahydrofuran, dichloromethane, ethyl acetate and acetonitrile;

[0022] The molar ratio of the o-sulfamoylbenzaldehyde to the dialdehyde is 1:1.4.

[0023] Furthermore, the mixed solution is subjected to a one-pot two-step method (the mixed solution reacts at 35 °C for 5 h, and then alkali is added and the reaction is carried out at 0 °C for 6 h) to obtain the C2 spiroindoline compound. Specifically including:

[0024] Using DIPEA (N,N-diisopropylethylamine) or Na2CO3 or NaOAc or Cs2CO3, the mixed solution reacts at 35 °C for 5 h, and then alkali is added and the reaction is carried out at 0 °C for 6 h to obtain the C2 spiroindoline compound.

[0025] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0026] 1. The method for green and efficient synthesis of chiral C2 spiroindoline compounds in the present invention uses a dialdehyde and o-sulfamoylbenzaldehyde as raw materials, DQ as a catalyst, and an N-heterocyclic carbene catalyst to realize the synthesis of C2 spiroindoline compounds under mild conditions. This method is simple to operate, low in cost, green and pollution-free, suitable for industrial production, and solves the problems of uncleanliness and harsh reaction conditions caused by the use of metal catalysts in the existing methods for synthesizing C2 spiroindoline.

[0027] 2. The method for green and efficient chiral C2 spiro compounds in the present invention uses an N-heterocyclic carbene as a catalyst to catalyze the Breslow intermediate formed by the dialdehyde, DQ as an oxidant for oxidation, and then reacts with the raw material o-sulfamoylbenzaldehyde to generate a central chiral furanone compound. Then alkali is added and the reaction is carried out at 0 °C for 6 h to obtain the C2 spiroindoline compound. This method has good generality, with excellent yields of 90% and enantioselectivity of 96:4 er. When the mass of o-aminobenzaldehyde is scaled up to 1 g, the yield reaches 83% using a low-loading catalyst (1 mol%).

[0028] 3. The method for green and efficient synthesis of C2 spiroindoline compounds in the present invention realizes the synthesis of chiral compound C2 spiroindoline compounds by designing a route, optimizing conditions, conducting generality research and then scaling up the synthesis reaction. In the experiment, a low-loading N-heterocyclic carbene catalyst (1 mol%) is used, achieving a yield of up to 90% for the target product and an enantioselectivity of 96:4 er. When scaled up to 1 g under the same reaction conditions, a yield of 83% and an enantioselectivity of 96:4 er are obtained. It has the potential for industrial production. Moreover, the synthesis process of the present invention does not involve high temperature, high pressure, or the use of toxic and harmful substances, greatly reducing the production cost and ensuring the safety and cleanliness of the reaction process. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0030] Figure 1 It is the synthetic route diagram of compound 4a;

[0031] Figure 2 It is the scaled-up reaction diagram of compound 4a;

[0032] Figure 3 It is the high-performance liquid chromatography diagram of compound 4a;

[0033] Figure 4 It is the high-performance liquid chromatography diagram of compound 4a;

[0034] Figure 5 It is the scaled-up high-performance liquid chromatography diagram of compound 4a;

[0035] Figure 6 It is the scaled-up high-performance liquid chromatography diagram of compound 4a; Figure 7 It is the structural formula diagram of the compound synthesized in the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0036] The following will specifically describe the present invention in combination with the detailed implementation manners and embodiments, and the advantages and various effects of the present invention will be more clearly presented therefrom. Those skilled in the art should understand that these detailed implementation manners and embodiments are used to illustrate the present invention, rather than limiting the present invention.

[0037] Throughout the specification, unless otherwise specifically stated, the terms used herein shall be understood to have the meanings as commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention pertains. In case of any contradiction, the present specification shall prevail.

[0038] Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment, etc. used in the present invention can be obtained through market purchase or can be prepared by existing methods.

[0039] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods.

[0040] The method for a green and efficient C2 spiroindoline compound of the present invention will be described in detail below in combination with examples and experimental data.

[0041] Unless otherwise stated, chemicals are all purchased from commercial products and do not require further purification. Thin layer chromatography (TLC) uses (HSGF 254) silica gel plates. Silica gel column chromatography uses Qingdao Marine silica gel (200 - 300 mesh). TLC color development is carried out using UV light (254 nm). 1H NMR spectra are characterized using a Bruker 400 nuclear magnetic resonance instrument, 1 1H NMR is at 400 MHz, 13 13C NMR is at 100 MHz, with DMSO as the solvent. The unit of chemical shift is ppm, and the unit of coupling constant is Hz.

[0042] Example 1

[0043] This example provides a method for a green and efficient chiral C2 spiroindoline compound.

[0044] 1. Optimization of reaction conditions

[0045] As Figure 1 shown, using dialdehyde 1a and o-sulfonamidobenzaldehyde 2a as the model reaction substrates to explore the optimal reaction conditions of the process route of the present invention. First, under the condition of using tetrahydrofuran as the solvent, potassium carbonate was used as the base to screen the carbene catalyst. After screening, it was found that the effect of catalyst C was more outstanding than that of other catalysts; then, using C as the catalyst, the base was screened, and it was found that the strong base DIPEA was the best; finally, using DIPEA as the base, the solvent was screened, and it was found that DCM showed the best effect, with a yield reaching 90% and an er of 96:4. The process of optimizing the reaction conditions is shown in Table 1. It can be seen from Table 1 that the optimal reaction conditions are entry 18.

[0046] Table 1 Optimization results of reaction conditions

[0047]

[0048]

[0049] In Table 1: Unless otherwise specified, the reaction conditions were 1a (0.1 mmol), 2a (0.14 mmol), base (0.05 mmol), DQ (0.1 mmol), carbene precursor (0.02 mmol), solvent (2 mL), reaction at 35 °C for 5 h [b] 。 [c] Isolated yield of 4a. The er value was determined by chiral stationary phase high performance liquid chromatography, [d] Add 50 mg MS (molecular sieve), [e] Under N2 protection, add 50 mg MS, [f] React for 6 h, [g] Cesium carbonate (0.05 mmol), [h] N-heterocyclic carbene (0.01 mmol), [i] After the reaction, add cesium carbonate (0.12 mmol) and react at room temperature for 6 h. [j] After the reaction, add cesium carbonate (0.12 mmol) and react at 0 °C for 6 h.

[0050] 2. General experiment

[0051] The preparation implementation method and conditions are as follows:

[0052] To an oven-dried 4 mL vial equipped with a magnetic stir bar, add o-sulfonylaminobenzaldehyde 2a (0.1 mmol), dialdehyde (0.14 mmol), N-heterocyclic carbene catalyst (0.02 mmol), and oxidant (DQ) (0.1 mmol). Evacuate the vial using the Schlenk technique and backfill with N2, then add base (DIPEA) (0.05 mmol) and anhydrous dichloromethane (DCM) (2 mL). Stir the reaction mixture in a 35 °C water bath for 5 h until the starting materials are completely consumed (monitored by TLC), then add Cs2CO3 (0.1 mmol) and react at 0 °C for 6 h. Concentrate the mixture under reduced pressure. Separate by column chromatography, eluent polarity (petroleum ether / ethyl acetate = 3 / 1), to obtain the desired product 4a.

[0053] 3. Scale-up reaction

[0054] As Figure 2As shown, a magnetic stir bar was added to a 200 mL Schlenk flask, and 2a (2.94 mmol, 1.00 g), an N - heterocyclic carbene catalyst (293.95 μmol, 131.33 mg), DQ (3.53 mmol, 1.44 g), DIPEA (1.47 mmol, 266.01 mL), and 1a (4.12 mmol, 659.16 mg) were added in sequence. The mixture was stirred at 35 °C for 8 h under nitrogen protection, and the reaction progress was monitored by TLC. Then Cs2CO3 (3.53 mmol, 1.15 g) was added and the reaction was carried out at 0 °C for 8 h. Work - up: The mixture was concentrated under reduced pressure, and the solvent of the eluent (petroleum ether: ethyl acetate = 3:1) was evaporated to obtain the product 4a (1.25 g, 83%, 99:1 er). The enantioselectivity was detected by liquid chromatography equipped with a chiral column.

[0055] 4. Product Characterization

[0056]

[0057] (2S,3′S)-1′-((2 - Bromophenyl)sulfonyl)-3′-hydroxy-3 - phenyl-5H - spiro[furan - 2,2′-indoline]-5 - one (3a)

[0058] White solid, 90% yield, 45.0 mg, m.p. 125 - 127 °C.

[0059] [α] 25 D =-278.6(c=0.1 in CHCl3)

[0060] 1 1H NMR(400 MHz, DMSO - d6)δ 7.86(dd, J=7.7, 1.4 Hz, 1H), 7.72(m, 3H), 7.53–7.43(m, 6H), 7.38(d, J=7.5 Hz, 1H), 7.33(d, J=8.1 Hz, 1H), 7.25(t, J=7.0 Hz, 1H), 7.13(s, 1H), 6.77(d, J=9.0 Hz, 1H), 5.38(d, J=9.0 Hz, 1H).

[0061] 1313C NMR (101 MHz, DMSO) δ 169.13, 162.44, 140.46, 139.19, 136.47, 135.16, 131.94, 130.47, 129.76, 129.59, 129.11, 129.05, 128.69, 128.41, 128.21, 126.23, 125.01, 119.74, 116.94, 114.56, 101.88, 79.65, 75.73.

[0062] HRMS (ESI, m / z): Mass calcd. For C 23 H 16 BrNO5SNa + [M + Na] + , 519.9825; found 519.9816.

[0063] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 18.9 min, Rt2 (minor) = 23.4 min; 97:3 er.

[0064]

[0065] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3′-hydroxy-3-(m-tolyl)-5H-spiro[furan-2,2'-indoline]-5-one (3b)

[0066] White solid, 87% yield, 44.3 mg, m.p. 108 - 111 °C.

[0067] [α] 25 D = -226.7 (c = 0.1 in CHCl3)

[0068] 1 1H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 7.8, 1.4 Hz, 1H), 7.71 (dd, J = 7.8, 1.8 Hz, 1H), 7.53 (s, 1H), 7.45 (m, 4H), 7.41–7.36 (m, 2H), 7.33–7.24 (m, 3H), 7.09 (s, 1H), 6.73 (d, J = 8.9 Hz, 1H), 5.37 (d, J = 8.9 Hz, 1H), 2.27 (s, 3H).

[0069] 1313C NMR(101MHz,DMSO)δ169.18,162.19,140.62,139.14,138.83,136.33,135.13,132.58,130.38,129.87,129.36,129.14,128.79,128.41,126.12,125.16,124.92,119.82,117.10,114.67,102.11,79.64,75.72,21.39.

[0070] HRMS(ESI,m / z):Mass calcd.For C 24 H 18 BrNO5SNa + [M+Na] + ,533.9981;found533.99755.

[0071] HPLC analysis(ChiralcelOD-H;25℃,IPA / Hexane=30 / 70,0.8mL / min,254nm),Rt1(major)=16.5min,Rt2(minor)=18.8min;97.5:2.5er.

[0072]

[0073] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3′-hydroxy-3-(3-methoxyphenyl)-5H-spiro[furan-2,2'-indoline]-5-one(3e)

[0074] White solid,94%yield,50.0mg,m.p.94-96℃.

[0075] [α] 25 D =-408.5(c=0.1in CHCl3)

[0076] 1 1H NMR(400MHz,DMSO-d6)δ7.88(dd,J=7.8,1.4Hz,1H),7.71(dd,J=7.8,1.8Hz,1H),7.54–7.44(m,3H),7.37(t,J=8.0Hz,2H),7.33–7.22(m,4H),7.16(s,1H),7.07(dd,J=8.5,2.6Hz,1H),6.77(d,J=9.0Hz,1H),5.35(d,J=9.0Hz,1H),3.70(s,3H).

[0077] 13 C NMR(101MHz, DMSO) δ 169.19, 162.59, 159.86, 140.38, 139.21, 136.48, 135.14, 130.77, 130.56, 130.29, 129.66, 128.94, 128.44, 126.37, 125.03, 120.49, 119.71, 117.59, 117.17, 114.42, 113.62, 101.66, 75.80, 55.66.

[0078] HRMS(ESI, m / z): Mass calcd. For C 24 H 18 BrNO5SNa + [M + Na] + , 549.9930; found 549.9933.

[0079] HPLC analysis(Chiralcel OD - H; 25℃, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1(major) = 21.3 min, Rt2(minor) = 29.1 min; 84:16 er.

[0080] (2S,3'S)-1'-((2 - bromophenyl)sulfonyl)-3'-hydroxy-3-(3 - fluorophenyl)-3'-hydroxy-5H - spiro

[0081] (2S,3′S)-1′-((2 - bromophenyl)sulfonyl)-3′-hydroxy-3-(3 - fluorophenyl)-3′-hydroxy-5H - spiro[furan - 2,2'-indoline]-5 - one(3h)

[0082] White solid, 83% yield, 43.1 mg, m.p. 113 - 115℃.

[0083] [α] 25 D = - 86.9(c = 0.1 in CHCl3)

[0084] 11H NMR (400 MHz, DMSO-d6) δ 7.86 (dd, J = 7.8, 1.5 Hz, 1H), 7.73 (dd, J = 7.8, 1.9 Hz, 1H), 7.60 (d, J = 9.3 Hz, 1H), 7.53–7.45 (m, 5H), 7.42–7.34 (m, 3H), 7.31–7.26 (m, 1H), 7.25 (s, 1H), 6.79 (d, J = 8.9 Hz, 1H), 5.42 (d, J = 8.9 Hz, 1H).

[0085] 13 13C NMR (101 MHz, DMSO) δ 168.81, 162.53 (d, J = 244.5 Hz) 160.82 (d, J = 2.6 Hz),, 140.46, 139.04, 136.45, 135.26, 131.72 (d, J = 8.3 Hz), 131.23 (d, J = 8.2 Hz),, 130.46, 129.87, 129.04, 128.45, 126.21, 125.05, 124.21 (d, J = 2.4 Hz) 119.85, 118.93, 118.70, 115.07 (d, J = 23.2 Hz) 114.66, 101.92, 75.56.

[0086] 19 19F NMR (377 MHz, DMSO) δ -111.46.

[0087] HRMS (ESI, m / z): Mass calcd. For C24H15BrFNO5SNa+ [M+Na]+, 537.9731; found 537.97283.

[0088] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 19.9 min, Rt2 (minor) = 25.9 min; 84:16 er.

[0089] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3-(3-chlorophenyl)-3'-hydroxy-5H-spiro[furan-

[0090] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3-(3-chlorophenyl)-3′-hydroxy-5H-spiro[furan-2,2'-indoline]-5-one (3k)

[0091] White solid, 65% yield, 34.6 mg, m.p. 119 - 121℃.

[0092] [α] 25 D =-86.9 (c=0.1 in CHCl3)

[0093] 1 H NMR (400 MHz, DMSO - d6) δ 7.86 (dd, J=7.8, 1.4 Hz, 1H), 7.78 (t, J=1.9 Hz, 1H), 7.71 (dd, J=7.8, 1.8 Hz, 1H), 7.63–7.59 (m, 1H), 7.56–7.51 (m8 2H), 7.51–7.43 (m, 4H), 7.40 (d, J=2.3 Hz, 1H), 7.28–7.24 (m, 2H), 6.76 (d, J=8.7 Hz, 1H), 5.38 (d, J=8.8 Hz, 1H).

[0094] 13 C NMR (101 MHz, DMSO) δ 168.87, 160.97, 140.47, 139.13, 136.74, 136.51, 135.21, 130.45, 129.99, 129.85, 129.72, 129.09, 128.48, 127.98, 126.18, 125.05, 119.79, 117.80, 114.68, 101.96, 79.66, 75.56.

[0095] HRMS (ESI, m / z): Mass calcd. For C 24 H 15 BrClNO5SNa + [M + Na] + , 553.9435;found 553.9443.

[0096] HPLC analysis (Chiralcel ID;25℃, IPA / Hexane=30 / 70, 0.8 mL / min, 254 nm), Rt1 (major)=21.3 min, Rt2 (minor)=27.5 min;98:2 er.

[0097] (2S,3'S)-1'-((2 - bromophenyl)sulfonyl)-3'-hydroxy - 3-(2 - methoxyphenyl)-5H - spiro[furo

[0098] (2S,3′S)-1′-((2-bromophenyl)sulfonyl)-3′-hydroxy-3-(2-methoxyphenyl)-5H-spiro[furan-2,2'-indolin]-5-one (3d)

[0099] White solid,32%yield,15.6mg,mp97-99℃.

[0100] [α] 25 D =-364.5 (c = 0.1 in CHCl3)

[0101] 1 H NMR (400MHz, DMSO-d6) δ7.83(dd,J=7.6,1.7Hz,1H),7.71(dd,J=7.6,2.1Hz,1H),7.53–7.38(m,6H),7.35(t,J=7.8Hz,1H),7.27– 7.22(m,1H),7.19(d,J=8.5Hz,1H),7.03(s,1H),6.93(t,J=7.8Hz,1H),6.69(d,J=9.2Hz,1H),5.37(d,J=9.2Hz,1H),3.89(s,3H).

[0102] 13 C NMR (101MHz, DMSO) δ169.89,159.67,157.89,140.66,139.23,136.39,135.07,133.40,130.45,129.78,129.10,128 .33,126.27,124.91,120.84,119.80,119.51,117.55,114.57,113.00,102.73,79.64,75.97,56.50,56.21,19.03.

[0103] HRMS(ESI,m / z):Mass calcd.For C 24 H 18 BrNO5SNa + [M+Na] + ,549.9930;found549.9929.

[0104] HPLC analysis (Chiralcel OD-H; 25℃, IPA / Hexane=30 / 70, 0.8mL / min, 254nm), Rt1(major)=18.5min, Rt2(minor)=22.1min; 98:2er.

[0105] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3'-hydroxy-3-(o-tolyl)-5H-spiro[furan-

[0106] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3′-hydroxy-3-(o-tolyl)-5H-spiro[furan-2,2'-indoline]-5-one (3g)

[0107] White solid, 85% yield, 43.6 mg, m.p. 218 - 223 °C.

[0108] [α] 25 D = -283.6 (c = 0.1 in CHCl3)

[0109] 1 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J = 7.9, 1.3 Hz, 1H), 7.66–7.59 (m, 2H), 7.55 (td, J = 7.7, 1.7 Hz, 1H), 7.50–7.44 (m, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.37–7.28 (m, 2H), 7.26–7.13 (m, 3H), 6.82 (d, J = 9.0 Hz, 1H), 6.75 (s, 1H), 5.02 (d, J = 9.0 Hz, 1H), 2.44 (s, 3H).

[0110] 13 13C NMR (101 MHz, DMSO) δ 169.37, 162.52, 140.36, 139.32, 138.60, 136.55, 135.05, 132.13, 130.72, 130.57, 129.36, 129.11, 128.84, 128.33, 127.97, 126.53, 126.41, 124.94, 121.69, 119.53, 114.02, 102.91, 74.54, 21.64.

[0111] HRMS (ESI, m / z): Mass calcd. For C 24 H 18 BrNO5SNa + [M+Na] + , 533.9981; found 533.9980.

[0112] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 17.2 min, Rt2 (minor) = 19.4 min; 80:20 er.

[0113] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3-(2-fluorophenyl)-3'-hydroxy-5H-spiro[furan-

[0114] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3-(2-fluorophenyl)-3′-hydroxy-5H-spiro[furan-2,2'-indoline]-5-one (3j)

[0115] White solid, 94% yield, 48.8 mg, m.p. 107 - 109 °C.

[0116] [α] 25 D = -78.9 (c = 0.1 in CHCl3)

[0117] 1 1H NMR (400 MHz, Chloroform-d) δ 7.78 (dd, J = 7.7, 1.9 Hz, 1H), 7.70 (dd, J = 7.7, 1.6 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.43–7.27 (m, 6H), 7.24–7.18 (m, 1H), 7.14 (m, 1H), 6.54 (s, 1H), 5.41 (d, J = 12.3 Hz, 1H), 2.95–2.76 (m, 1H).

[0118] 13 13C NMR (101 MHz, CDCl3) δ 167.92, 163.96, 161.98 (m, 125.6 Hz), 140.88, 139.40, 135.92, 133.97, 131.05, 130.96, 130.75, 130.54 (d, J = 7.9 Hz), 129.93, 127.52, 127.21, 125.38, 124.90, 123.70 (d, J = 3.1 Hz), 120.60, 118.81 (d, J = 21.3 Hz),, 117.06, 115.34, 115.04, 114.81, 100.89.

[0119] 1919F NMR (377 MHz, CDCl3) δ -110.31.

[0120] HRMS (ESI, m / z): Mass calcd. For C 24 H 15 BrFNO5SNa + [M+Na] + , 537.9731; found 537.97283.

[0121] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 16.2 min, Rt2 (minor) = 19.0 min; 80.5:19.5 er.

[0122] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3'-hydroxy-3-(p-tolyl)-5H-spiro[furan-2,2'-

[0123] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3′-hydroxy-3-(p-tolyl)-5H-spiro[furan-2,2'-indoline]-5-one (3c)

[0124] White solid, 99% yield, 50.8 mg, m.p. 97 - 99 °C.

[0125] [α] 25 D = -531.3 (c = 0.1 in CHCl3)

[0126] 1 1H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J = 7.8, 1.2 Hz, 1H), 7.71 (dd, J = 7.9, 1.7 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.45 - 7.51 (m, 3H), 7.39 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 7.4 Hz, 3H), 7.04 (s, 1H), 6.76 (d, J = 9.0 Hz, 1H), 5.36 (d, J = 9.0 Hz, 1H), 2.32 (s, 3H).

[0127] 1313C NMR (101 MHz, DMSO) δ 169.28, 162.58, 142.25, 140.46, 139.25, 136.46, 135.08, 130.46, 130.17, 129.73, 129.06, 128.40, 128.16, 126.40, 126.23, 124.98, 119.71, 115.77, 114.53, 101.82, 79.65, 75.84, 21.48.

[0128] HRMS (ESI, m / z): Mass calcd. For C 24 H 18 BrNO5SNa + [M + Na] + , 533.9981; found 533.99755.

[0129] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 23.3 min, Rt2 (minor) = 24.9 min; 96:4 er.

[0130] (2S,3'S)-1'-(( (2-Bromophenyl)sulfonyl) -3'-hydroxy-3-(4-methoxyphenyl)-5H- spiro[furan-

[0131] (2S,3′S)-1′-(( (2-Bromophenyl)sulfonyl) -3′-hydroxy-3-(4-methoxyphenyl)-5H- spiro[furan-2,2'-indoline]-5-one (3f)

[0132] White solid, 94% yield, 46.5 mg, m.p. 96 - 98 °C.

[0133] [α] 25 D = -447.4 (c = 0.1 in CHCl3)

[0134] 11H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J = 7.8, 1.4 Hz, 1H), 7.72 (dd, J = 7.8, 1.8 Hz, 1H), 7.67 (d, J = 8.9 Hz, 2H), 7.53–7.43 (m, 3H), 7.39 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.9 Hz, 2H), 6.95 (s, 1H), 6.76 (d, J = 9.1 Hz, 1H), 5.35 (d, J = 9.1 Hz, 1H), 3.79 (s, 3H).

[0135] 13 13C NMR (101 MHz, DMSO) δ 169.44, 162.49, 162.14, 140.48, 139.30, 136.47, 135.09, 130.46, 130.13, 129.77, 129.05, 128.40, 126.27, 124.99, 123.30, 121.62, 119.75, 115.11, 114.54, 114.17, 101.67, 79.65, 76.01, 55.96.

[0136] HRMS (ESI, m / z): Mass calcd. For C 24 H 18 BrNO5SNa + [M + Na] + , 549.9930; found 549.99277

[0137] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 18.1 min, Rt2 (minor) = 21.5 min; 85:5 er.

[0138] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3-(4-fluorophenyl)-3'-hydroxy-5H-spiro[furan-2,2'-

[0139] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3-(4-fluorophenyl)-3′-hydroxy-5H-spiro[furan-2,2′-indoline]-5-one (3i)

[0140] White solid, 95% yield, 48.7 mg, m.p. 106 - 108 °C.

[0141] [α] 25 D = -612.2 (c = 0.1 in CHCl3)

[0142] 1 1H NMR (400 MHz, DMSO-d6) δ 7.83 (dd, J = 7.6, 1.6 Hz, 1H), 7.75 (dd, J = 7.6, 2.2 Hz, 1H), 7.70–7.63 (m, 2H), 7.52–7.39 (m, 6H), 7.24 (dd, J = 10.2, 2.3 Hz, 1H), 7.15 (s, 1H), 7.10 (td, J = 8.8, 2.3 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.36 (d, J = 8.8 Hz, 1H).

[0143] 13 13C NMR (101 MHz, DMSO) δ 168.98, 164.05 (d, J = 251.3 Hz), 161.18, 140.46, 139.13, 136.48, 136.40, 135.20, 130.93, 130.88 (d, J = 8.9 Hz), 129.84, 129.06, 128.44, 126.19, 125.80 (d, J = 3.3 Hz), 125.03, 119.79, 116.99, 115.81 (d, J = 21.8 Hz)., 114.64, 105.96, 101.90, 79.64, 75.62.

[0144] 19 19F NMR (377 MHz, DMSO) δ -107.79.

[0145] HRMS (ESI, m / z): Mass calcd. For C 24 H 15 BrFNO5SNa + [M+Na] + , 537.9731; found 537.97260.

[0146] HPLC analysis (Chiralcel ID; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 34.3 min, Rt2 (minor) = 50.2 min; 94:6 er.

[0147] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3-(4-chlorophenyl)-3'-hydroxy-5H-spiro[furan-2,2'-

[0148] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3-(4-chlorophenyl)-3′-hydroxy-5H-spiro[furan-2,2'-indoline]-5-one (3l)

[0149] White solid, 65% yield, 34.7 mg, m.p. 120 - 122 °C.

[0150] [α] 25 D = -222.7 (c = 0.1 in CHCl3)

[0151] 1 1H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J = 7.9, 1.4 Hz, 1H), 7.75–7.69 (m, 2H), 7.55–7.52 (m, 2H), 7.50–7.43 (m, 3H), 7.41–7.34 (m, 2H), 7.28–7.25 (m, 1H), 7.18 (s, 1H), 6.78 (d, J = 8.9 Hz, 1H), 5.39 (d, J = 8.9 Hz, 1H).

[0152] 13 13C NMR (101 MHz, DMSO) δ 168.87, 160.97, 140.46, 139.12, 136.74, 136.50, 136.45, 135.21, 130.45, 129.99, 129.85, 129.72, 129.08, 128.48, 127.97, 126.18, 125.06, 119.79, 117.79, 114.68, 102.02, 101.96, 75.56.

[0153] HRMS (ESI, m / z): Mass calcd. For C 24 H 15 BrClNO5SNa + [M + Na] + , 562.0294; found 562.02938.

[0154] HPLC analysis (Chiralcel IC; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 30.4 min, Rt2 (minor) = 37.1 min; 97:3 er.

[0155] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3'-hydroxy-3-(4-isopropylphenyl)-5H-spiro[furan-

[0156] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3′-hydroxy-3-(4-isopropylphenyl)-5H-spiro[furan-2,2'-indoline]-5-one (3n)

[0157] White solid, 81% yield, 44.1 mg, m.p. 227 - 233 °C.

[0158] [α] 25 D = -114.8 (c = 0.1 in CHCl3)

[0159] 1 1H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 7.7, 1.4 Hz, 1H), 7.71 (dd, J = 7.7, 1.9 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.50–7.22 (m, 8H), 7.05 (s, 1H), 6.73 (d, J = 9.0 Hz, 1H), 5.36 (d, J = 8.9 Hz, 1H), 2.89 (p, J = 6.9 Hz, 1H), 1.18 (dd, J = 6.9, 1.9 Hz, 7H).

[0160] 13 13C NMR (101 MHz, DMSO) δ 169.31, 162.37, 152.78, 140.52, 139.20, 136.44, 135.15, 130.44, 129.84, 129.06, 128.39, 128.29, 127.57, 126.73, 126.21, 124.97, 119.82, 116.01, 114.58, 101.80, 75.83, 55.37, 33.86, 23.87.

[0161] HRMS (ESI, m / z): Mass calcd. For C 26 H 22 BrNO5SNa +[M+Na] + , 533.9981; found 533.9979.

[0162] HPLC analysis (Chiralcel IB; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 42.3 min, Rt2 (minor) = 53.9 min; 87:13 er

[0163] (2S,3'S)-1'-((2-bromophenyl)sulfonyl)-3'-hydroxy-3-(4-(methylthio)-phenyl)-5H-spiro

[0164] (2S,3′S)-1′-((2-bromophenyl)sulfonyl)-3′-hydroxy-3-(4-(methylthio)-phenyl)-5H-spiro[furan-2,2'-indoline]-5-one (3m)

[0165] White solid, 78% yield, 42.6 mg, m.p. 105 - 107 °C.

[0166] [α] 25 D = -380.5 (c = 0.1 in CHCl3)

[0167] 1 1H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J = 7.8, 1.3 Hz, 1H), 7.70 (dd, J = 7.9, 1.8 Hz, 1H), 7.65–7.59 (m, 2H), 7.42 - 7.52 (mf, 3H), 7.38 (d, J = 7.5 Hz, 1H), 7.34–7.28 (m, 3H), 7.26 (dd, J = 7.4, 0.9 Hz, 1H), 7.05 (s, 1H), 6.76 (d, J = 9.0 Hz, 1H), 5.36 (d, J = 9.0 Hz, 1H), 2.49 (s, 3H).

[0168] 1313C NMR (101 MHz, DMSO) δ 170.76, 169.26, 162.13, 143.99, 140.40, 139.22, 136.47, 135.11, 130.42, 129.74, 129.15, 128.49, 128.43, 126.26, 125.94, 125.13, 124.99, 119.70, 115.47, 114.51, 101.71, 75.73, 62.40, 55.42, 21.09, 14.43.

[0169] HRMS (ESI, m / z): Mass calcd. For C 24 H 18 BrNO5S2Na + [M + Na] + , 565.9702; found 565.9702.

[0170] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 31.4 min, Rt2 (minor) = 35.4 min; 91:9 er.

[0171] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3'-hydroxy-3-(naphthalen-1-yl)-5H-spiro[furan-

[0172] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3′-hydroxy-3-(naphthalen-1-yl)-5H-spiro[furan-2,2'-indoline]-5-one (3o)

[0173] White solid, 98% yield, 50.6 mg, m.p. 113 - 115 °C.

[0174] [α] 25 D = -510.3 (c = 0.1 in CHCl3)

[0175] 11H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.97–7.86 (m, 3H), 7.80–7.75 (m, 2H), 7.68 (dd, J = 7.8, 1.4 Hz, 1H), 7.63–7.58 (m, 1H), 7.57–7.53 (m, 1H), 7.52–7.49 (m, 1H), 7.45–7.42 (m, 2H), 7.37 (td, J = 7.7, 1.4 Hz, 1H), 7.34–7.27 (m, 2H), 7.26 (s, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.55 (dd, J = 8.8, 1.2 Hz, 1H).

[0176] 13 13C NMR (101 MHz, DMSO) δ 169.31, 162.37, 152.78, 140.52, 139.20, 136.44, 135.15, 130.44, 129.84, 129.06, 128.39, 128.29, 127.57, 126.73, 126.21, 124.97, 119.82, 116.01, 114.58, 101.80, 75.83, 55.37, 33.86, 23.87.

[0177] HRMS (ESI, m / z): Mass calcd. For C 27 H 18 BrNO5SNa + [M + Na] + , 569.9981; found 569.9982.

[0178] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 28.6 min, Rt2 (minor) = 32.3 min; 85.5:14.5 er.

[0179] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3'-hydroxy-4'-methyl-3-phenyl-5H-spiro[furan-

[0180] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3′-hydroxy-4′-methyl-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one (3aa)

[0181] White solid, 80% yield, 41.3 mg, m.p. 157 - 159 °C.

[0182] [α] 25 D =-67.9 (c=0.1 in CHCl3)

[0183] 1 1H NMR (400 MHz, DMSO - d6) δ 7.89 (dd, J=7.6, 1.6 Hz, 1H), 7.74 (dd, J=7.6, 1.9 Hz, 1H), 7.72–7.67 (m, 2H), 7.55–7.44 (m, 5H), 7.26 (t, J=7.9 Hz, 1H), 7.09 (s, 1H), 7.07 (s, 1H), 7.01 (d, J=7.6 Hz, 1H), 6.65 (d, J=9.7 Hz, 1H), 5.40 (d, J=9.7 Hz, 1H), 2.38 (s, 3H).

[0184] 13 13C NMR (101 MHz, DMSO) δ 169.31, 163.32, 140.47, 139.36, 138.10, 136.47, 135.05, 131.99, 130.40, 129.70, 129.59, 129.13, 128.39, 128.14, 126.71, 126.19, 119.55, 116.35, 111.80, 101.23, 79.64, 76.01, 55.37, 18.38.

[0185] HRMS (ESI, m / z): Mass calcd. For C 24 H 18 BrNO5SNa + [M + Na] + , 533.9981;found 533.9979.

[0186] HPLC analysis (Chiralcel OD - H;25 °C, IPA / Hexane=30 / 70, 0.8 mL / min, 254 nm), Rt1 (major)=23.5 min, Rt2 (minor)=30.1 min;80:20 er.

[0187] (2S,3'S)-1'-((2 - bromophenyl)sulfonyl)-3'-hydroxy - 6'-methyl - 3 - phenyl - 5H - spiro[furan -

[0188] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3′-hydroxy-6′-methyl-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one (3ab)

[0189] White solid, 96% yield, 49.4 mg, m.p. 105 - 107℃

[0190] [α] 25 D =-494.3 (c=0.1 in CHCl3)

[0191] 1 1H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J=7.4, 1.7 Hz, 1H), 7.72 (d, J=7.2 Hz, 3H), 7.53–7.43 (m, 5H), 7.37 (d, J=7.7 Hz, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.72 (d, J=9.0 Hz, 1H), 5.32 (d, J=9.0 Hz, 1H), 2.30 (s, 3H).

[0192] 13 13C NMR (101 MHz, DMSO) δ 169.21, 162.83, 140.65, 140.35, 139.36, 136.44, 135.10, 131.95, 129.63, 129.13, 128.41, 128.17, 126.20, 126.04, 125.78, 119.66, 116.62, 114.76, 101.96, 79.65, 75.59, 21.92.

[0193] HRMS (ESI, m / z): Mass calcd. For C 24 H 18 BrNO5SNa + [M+Na] + , 533.9981;found 533.9975.

[0194] HPLC analysis (Chiralcel OD-H;25℃, IPA / Hexane=30 / 70, 0.8 mL / min, 254 nm), Rt1 (major)=16.9 min, Rt2 (minor)=25.2 min;88:12 er.

[0195] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-3'-hydroxy-5'-methyl-3-phenyl-5H-spiro[furan-

[0196] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-3′-hydroxy-5′-methyl-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one (3ac)

[0197] White solid, 88% yield, 45.3 mg, m.p. 110 - 112 °C

[0198] [α] 25 D = -172.8 (c = 0.1 in CHCl3)

[0199] 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 (dd, J = 7.7, 1.5 Hz, 1H), 7.70 (m, 3H), 7.53–7.44 (m, 5H), 7.28 (s, 1H), 7.19 (s, 2H), 7.10 (s, 1H), 6.72 (d, J = 9.0 Hz, 1H), 5.33 (d, J = 9.0 Hz, 1H), 2.33 (s, 3H).

[0200] 13 13C NMR (101 MHz, DMSO) δ 169.19, 162.54, 139.32, 138.21, 136.42, 135.06, 134.33, 131.94, 130.90, 129.70, 129.59, 129.12, 129.04, 128.38, 128.18, 126.58, 119.70, 116.77, 114.28, 101.94, 79.64, 75.75, 55.37, 20.87.

[0201] 19 19F NMR (377 MHz, DMSO) δ -118.62.

[0202] HRMS (ESI, m / z): Mass calcd. For C 24 H 18 BrNO5SNa + [M+Na] + , 533.9981; found 533.9974.

[0203] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 16.6 min, Rt2 (minor) = 21.7 min; 92:8 er.

[0204] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-5'-chloro-3'-hydroxy-3-phenyl-5H-spiro[furan-

[0205] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-5′-chloro-3′-hydroxy-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one (3ad).

[0206] White solid, 59% yield, 30.7 mg, m.p. 107 - 109 °C

[0207] [α] 25 D = -393.5 (c = 0.1 in CHCl3)

[0208] 1 1H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 7.5, 1.6 Hz, 1H), 7.74–7.67 (m, 3H), 7.52–7.40 (m, 8H), 7.16 (s, 1H), 6.87 (d, J = 9.0 Hz, 1H), 5.42 (d, J = 9.0 Hz, 1H).

[0209] 13 13C NMR (101 MHz, DMSO) δ 168.92, 161.75, 139.58, 138.91, 136.48, 135.38, 131.98, 131.51, 130.29, 130.03, 129.56, 129.03, 128.97, 128.89, 128.77, 128.56, 128.24, 126.08, 119.93, 117.37, 116.35, 102.14, 75.24.

[0210] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 19.6 min, Rt2 (minor) = 23.4 min; 97:3 er.

[0211] (2S,3'S)-1'-((2-bromophenyl)sulfonyl)-7'-fluoro-3'-hydroxy-3-phenyl-5H-spiro[furan-

[0212] (2S,3′S)-1′-((2-bromophenyl)sulfonyl)-7′-fluoro-3′-hydroxy-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one (3ae)

[0213] White solid, 48% yield, 24.8 mg, m.p. 109 - 111 °C

[0214] [α] 25 D =-164.8 (c=0.1 in CHCl3)

[0215] 1 1H NMR (400 MHz, DMSO) δ 7.93–7.84 (m, 4H), 7.58–7.50 (m, 5H), 7.36–7.22 (m, 3H), 7.14 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 5.50 (d, J=8.8 Hz, 1H).

[0216] 1 1H NMR (400 MHz, DMSO-d6) δ 168.95, 161.83, 159.62 (d, J=241.5 Hz),, 139.04, 136.72 (d, J=1.9 Hz), 136.46, 135.26, 131.94, 131.48 (d, J=8.2 Hz), 129.95, 129.55, 128.95, 128.49, 128.23, 119.87, 117.04 (d, J=23.8 Hz), 116.92, 116.12, 116.03, 113.43, 113.19, 102.34, 79.64, 75.28, 55.37.

[0217] 19 19F NMR (377 MHz, DMSO) δ -118.62.

[0218] HRMS (ESI, m / z): Mass calcd. For C 23 H 15 BrFNO5SNa + [M+Na] + , 537.9731;found 537.97253.

[0219] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 31.5 min, Rt2 (minor) = 39.6 min; 85:15 er.

[0220] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-5'-fluoro-3'-hydroxy-3-phenyl-5H-spiro[furan-

[0221] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-5′-fluoro-3′-hydroxy-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one (3af)

[0222] White solid, 49% yield, 25.3 mg, m.p. 141 - 143 °C

[0223] [α] 25 D = -223.7 (c = 0.1 in CHCl3)

[0224] 1 1H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 7.6, 1.6 Hz, 1H), 7.71 (m, 3H), 7.50–7.37 (m, 6H), 7.31–7.22 (m, 2H), 7.14 (s, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.39 (d, J = 8.8 Hz, 1H).

[0225] 13 13C NMR (101 MHz, DMSO) δ 168.96, 161.83, 159.61 (d, J = 241.6 Hz), 139.03, 136.72 (d, J = 1.5 Hz), 136.47, 135.28, 131.95, 131.48 (d, J = 8.0 Hz), 129.94, 129.56, 128.95, 128.74, 128.51, 128.23, 119.86, 117.27, 117.05 (d, J = 23.7 Hz), 117.05 (d, J = 23.7 Hz), 113.44, 113.19, 102.34, 75.28.

[0226] HRMS (ESI, m / z): Mass calcd. For C 23 H 15 BrClNO5SNa + [M+Na]+ ,537.9731; found 537.9719.

[0227] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 20.7 min, Rt2 (minor) = 26.3 min; 83:17 er.

[0228] (2S,3'S)-1'-((2-bromophenyl)sulfonyl)-6'-fluoro-3'-hydroxy-3-phenyl-5H-spiro[furan-

[0229] (2S,3′S)-1′-((2-bromophenyl)sulfonyl)-6′-fluoro-3′-hydroxy-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one (3ag)

[0230] White solid, 95% yield, 49.2 mg, m.p. 90 - 94 °C

[0231] 1 1H NMR (400 MHz, DMSO-d6) δ 7.83 (dd, J = 7.5, 1.6 Hz, 1H), 7.75 (dd, J = 7.5, 2.2 Hz, 1H), 7.69–7.64 (m, 2H), 7.52–7.39 (m, 6H), 7.24 (dd, J = 10.2, 2.3 Hz, 1H), 7.15 (s, 1H), 7.10 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.36 (d, J = 8.8 Hz, 1H).

[0232] 13 13C NMR (101 MHz, DMSO) δ 168.92, 163.20 (d, J = 243.6 Hz), 161.62, 142.03 (d, J = 12.3 Hz), 138.73, 136.47, 135.50, 131.96, 130.29, 129.52, 129.08, 128.86, 128.72, 128.59, 128.16, 127.69 (d, J = 10.0 Hz), 125.12 (d, J = 2.7 Hz), 120.13, 117.49, 111.72 (d, J = 22.6 Hz), 102.90 (d, J = 29.8 Hz), 102.39, 75.05.

[0233] 19 19F NMR (377 MHz, DMSO) δ -110.30.

[0234] HRMS(ESI, m / z): Mass calcd. For C 23 H 15 BrFNO5SNa + [M + Na] + , 537.9363; found 537.9361.

[0235] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 18.6 min, Rt2 (minor) = 26.9 min; 92.5:7.5 er.

[0236] (2S,3'S)-1'-((2-bromophenyl)sulfonyl)-4'-fluoro-3'-hydroxy-3-phenyl-5H-spiro[furan-2,2'-

[0237] (2S,3′S)-1′-((2-bromophenyl)sulfonyl)-4′-fluoro-3′-hydroxy-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one

[0238] White solid, 97% yield, 50.0 mg, m.p. 135 - 146 °C

[0239] [α] 25 D = -340.6 (c = 0.1 in CHCl3)

[0240] 1 1H NMR (400 MHz, DMSO-d6) δ 7.88 (dd, J = 7.6, 1.6 Hz, 1H), 7.76 (dd, J = 7.6, 1.9 Hz, 1H), 7.70–7.67 (m, 2H), 7.54–7.44 (m, 6H), 7.17 (d, J = 8.2 Hz, 1H), 7.13 (s, 1H), 7.10–7.04 (m, 1H), 6.91 (d, J = 9.3 Hz, 1H), 5.51 (d, J = 9.3 Hz, 1H).

[0241] 1313C NMR (101 MHz, DMSO) δ 169.02, 162.58, 160.34 (d, J = 250.0 Hz), 142.70 (d, J = 7.8 Hz), 139.00, 136.53, 135.34, 132.91 (d, J = 8.4 Hz), 132.09, 129.71, 129.17, 128.84, 128.71, 128.56, 128.14, 119.67, 116.88, 115.39 (d, J = 20.1 Hz), 112.26 (d, J = 19.6 Hz), 110.81 (d, J = 3.3 Hz), 105.91, 101.57, 78.93, 74.18.

[0242] 19 19F NMR (377 MHz, DMSO) δ -117.39.

[0243] HRMS (ESI, m / z): Mass calcd. For C 23 H 15 BrFNO5SNa + [M+Na] + , 537.9363; found 537.9358.

[0244] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 19.2 min, Rt2 (minor) = 34.2 min; 83:17 er.

[0245] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-6'-chloro-3'-hydroxy-3-phenyl-5H-spiro[furan-

[0246] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-6′-chloro-3′-hydroxy-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one (4aj)

[0247] White solid, 97% yield, 53.4 mg, m.p. 122 - 124 °C

[0248] [α] 25 D = -398.5 (c = 0.1 in CHCl3)

[0249] 11H NMR (400 MHz, DMSO-d6) δ 7.84 (dd, J = 7.3, 1.8 Hz, 1H), 7.74 (dd, J = 7.3, 2.3 Hz, 1H), 7.70–7.64 (m, 2H), 7.51–7.40 (m, 7H), 7.33 (dd, J = 8.0, 1.9 Hz, 1H), 7.16 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.37 (d, J = 8.8 Hz, 1H).

[0250] 13 13C NMR (101 MHz, DMSO) δ 168.84, 161.59, 141.87, 138.68, 136.51, 135.55, 134.42, 131.96, 130.21, 129.54, 129.03, 128.82, 128.76, 128.64, 128.31, 128.19, 127.69, 124.96, 120.05, 117.51, 114.60, 102.20, 75.11.

[0251] HRMS (ESI, m / z): Mass calcd. For C 23 H 15 BrClNO5SNa + [M + Na] + , 531.9615; found 531.9614.

[0252] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 19.1 min, Rt2 (minor) = 29.1 min; 99:1 er.

[0253] (2S,3'S)-1'-((2-Bromophenyl)sulfonyl)-4'-chloro-3'-hydroxy-3-phenyl-5H-spiro[furan-2,2'-

[0254] (2S,3′S)-1′-((2-Bromophenyl)sulfonyl)-4′-chloro-3′-hydroxy-3-phenyl-5H-spiro[furan-2,2'-indoline]-5-one (4aj)

[0255] White solid, 83% yield, 44.5 mg, m.p. 97 - 104 °C

[0256] [α] 25 D= -281.6 (c = 0.1 in CHCl3)

[0257] 1 1H NMR (400 MHz, DMSO-d6) δ 7.88 - 7.90 f (m, 1H), 7.82–7.77 (m, 1H), 7.66 - 7.69 (m 2H), 7.54–7.52 (m, 1H), 7.51 (d, J = 1.7 Hz, 1H), 7.49–7.39 (m, 4H), 7.33–7.27 (m, 2H), 7.14 (s, 1H), 6.88 (d, J = 9.4 Hz, 1H), 5.39 (d, J = 9.4 Hz, 1H).

[0258] 13 13C NMR (101 MHz, DMSO) δ 169.06, 162.94, 142.46, 139.07, 136.54, 135.33, 132.59, 132.39, 132.12, 129.78, 129.29, 128.87, 128.63, 128.08, 125.82, 125.68, 119.62, 116.79, 113.32, 105.20, 101.13, 80.41, 75.46.

[0259] HRMS (ESI, m / z): Mass calcd. For C 23 H 15 BrClNO5SNa + [M+Na] + , 553.9435; found 553.9436.

[0260] HPLC analysis (Chiralcel OD-H; 25 °C, IPA / Hexane = 30 / 70, 0.8 mL / min, 254 nm), Rt1 (major) = 19.3 min, Rt2 (minor) = 29.3 min; 99:1 er.

[0261] In this application, through route design, condition optimization, generality research, and scale-up synthesis reactions, in the experiments, using N-heterocyclic carbene as a catalyst, a mild, efficient, and green method was achieved for the synthesis of chiral C2 spiroindoline compounds, with the yield of the target product reaching as high as 90% and 96:4 er. Moreover, under the same conditions, when the reaction was scaled up to 1 g, the yield could also reach 83% and the enantioselectivity reached 99:1. And in the reduction method of the present invention, high temperature, high pressure, and the use of toxic and harmful substances are not involved, greatly reducing the production cost and ensuring the safety and cleanliness of the reaction process.

[0262] Finally, it should also be noted that the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, such that a process, method, article or apparatus comprising a series of elements not only includes those elements but also includes other elements not expressly listed, or elements inherent to such process, method, article or apparatus.

[0263] Although the preferred embodiments of the present invention have been described, additional changes and modifications can be made by those skilled in the art once they learn of the basic inventive concept. Therefore, the appended claims are intended to be construed to include the preferred embodiments as well as all changes and modifications falling within the scope of the present invention.

[0264] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A method for preparing C2 spirocyclic indoline compounds, characterized in that: The method comprises: C2 spirocyclic indoline compounds were obtained using dialdehyde and o-sulfonylaminobenzaldehyde as raw materials, nitrogen heterocyclic carbene as catalyst and DQ as oxidant.

2. A green and efficient method for synthesizing C2 spirocyclic indoline compounds according to claim 1, characterized in that: The general structural formulas of the dialdehyde, the o-aminobenzaldehyde, the nitrogen heterocyclic carbene catalyst, the oxidant DQ and the C2 spirocyclic indoline compound are shown in Formulas 1 to 5, respectively: Among them, the carbon atoms marked with * are chiral carbon atoms; R 1 is a halogen atom, a phenyl group, a substituted phenyl group, a naphthyl group, or an isopropyl group; R 2 It is a halogen atom, a methyl group, or a methoxy group.

3. A chiral C2 spirocyclic indoline compound according to claim 1, characterized in that: R 1 wherein the substituted phenyl group is a fluorophenyl group, a chlorophenyl group, a tolyl group or a methoxyphenyl group.

4. A chiral C2 spirocyclic indoline compound according to claim 1, characterized in that: R 2 In the above, the halogen atom is fluorine or chlorine.

5. A green and efficient method for synthesizing C2 spirocyclic indoline compounds according to claim 1, characterized in that: The method specifically comprises: Dispersing the dialdehyde, the o-sulfonylaminobenzaldehyde, the oxidant, the nitrogen heterocyclic carbene catalyst and a base in an organic solvent to obtain a mixed solution; The mixed solution was subjected to a one-pot two-step method (the mixed solution was reacted at 35° C. for 5 h, and then a base was added and reacted at 0° C. for 6 h) to obtain the C2 spiroindoline compound.

6. A green and efficient method for synthesizing C2 spirocyclic indoline compounds according to claim 3, characterized in that: The dialdehyde, the o-sulfonylaminobenzaldehyde, the oxidant, the nitrogen heterocyclic carbene catalyst and the base are dispersed together in an organic solvent to obtain a mixed solution, which specifically comprises: Dispersing the dialdehyde, the o-sulfonylaminobenzaldehyde, the oxidant, the nitrogen heterocyclic carbene catalyst and a base in an organic solvent to obtain a mixed solution; Wherein, the organic solvent includes any one of tetrahydrofuran, dichloromethane, ethyl acetate, acetonitrile and toluene; The molar ratio of the o-sulfonylaminobenzaldehyde to the dialdehyde is 1:1.

4.

7. A green and efficient method for synthesizing C2 spirocyclic indoline compounds according to claim 3, characterized in that: The mixed solution was subjected to a one-pot two-step method (the mixed solution was reacted at 35° C. for 5 h, and then a base was added and reacted at 0° C. for 6 h) to obtain the C2 spiroindoline compound.

8. A green and efficient method for synthesizing C2 spirocyclic indoline compounds according to claim 7, characterized in that: The mixed solution is reacted with DIPEA or NaOAc or Cs2CO3 or Na2CO3 at 35°C for 5 hours, and then a base is added and reacted at 0°C for 6 hours to obtain the C2 spirocyclic indoline compound.

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