Chiral spiro compound as well as preparation method and application thereof

Abstract

The invention provides a chiral spiro compound as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis. Spiroolefin, alkyl iodide, cobalt salt, a chiral ligand, an organic solvent, a reducing agent and an alkaline substance are mixed and subjected to a hydrogen alkylation reaction, and the chiral spiro compound is obtained. The invention discloses a cobalt-catalyzed three-dimensional divergent asymmetric synthesis method, efficient preparation of a 1, 3-nonadjacent three-dimensional center spiro-containing compound is realized through ligand regulation and control, and the product has excellent biological activity. The method has the advantages of wide substrate compatibility and high selectivity, and provides a new way for drug development.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a chiral spiro compound, a preparation method thereof, and an application thereof. Background Art

[0002] In the field of natural and pharmacologically active compounds, chiral spiro compounds with multiple stereocenters are a unique and important class of structures, exhibiting a wide range of biological activities (such as anti-tumor and anti-inflammatory properties) and pharmacological effects (including the treatment of hypertension and nephrotic syndrome). It is worth noting that introducing a spiro skeleton into drug candidate molecules can improve their pharmacokinetic properties, such as potency, selectivity, protein binding affinity, and metabolic stability. Due to the unique interaction between the molecule and the chiral environment formed by biological macromolecules, different stereoisomers have significantly different effects on human physiological activities. However, the diastereodivergent asymmetric synthesis strategy for such skeletons with 1,3-non-adjacent stereocenters remains a great challenge, and the main problems faced include:

[0003] 1. Difficult stereochemical control: The rigid spiro skeleton leads to a highly restricted spatial environment of the substrate, making it difficult to achieve diastereo- and enantioselective control;

[0004] 2. Limitations of existing methods: Related technologies mostly rely on cyclization or cycloaddition reactions, which are only applicable to the construction of contiguous stereocenters, and have a narrow substrate scope and insufficient selectivity;

[0005] 3. Undeveloped catalytic system: The metal hydride-catalyzed hydroalkylation reaction has not been successfully used for the diastereodivergent synthesis of non-adjacent stereocenters. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to provide a chiral spiro compound, a preparation method thereof, and an application thereof. The preparation method of the present invention realizes the efficient stereodivergent synthesis of spiro compounds containing 1,3-non-adjacent stereocenters.

[0007] To achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0008] The present invention provides a preparation method of a chiral spiro compound, comprising the following steps:

[0009] Mixing a spiro olefin, an alkyl iodide, a cobalt salt, a chiral ligand, an organic solvent, a reducing agent, and a basic substance to carry out a hydroalkylation reaction to obtain the chiral spiro compound;

[0010] When the chiral ligand is a first ligand, the chiral spiro compound is a cis product, and the first ligand has the structure shown in formula a:

[0011]

[0012] In formula a, R is -H, -Me, -Et or -tBuC6H4;

[0013] When the chiral ligand is the second ligand, the chiral spiro compound is a trans product, and the second ligand has the structure shown in formula b:

[0014]

[0015] In formula b, R is -Me, R' is -tBu or R is -iPr, R' is -tBu or R is -tBu, R' is -tBu or R is -Me, R' is -phenyl;

[0016] When the chiral ligand is the third ligand, the chiral spiro compound is an enantiomeric cis product, and the third ligand is the enantiomer of the first ligand;

[0017] When the chiral ligand is the fourth ligand, the chiral spiro compound is an enantiomeric trans product, and the fourth ligand is the enantiomer of the second ligand.

[0018] Preferably, the spiroalkene includes one of indolinone, benzofuranone, 3-isochromanone, pyrrolidone, piperidone and their derivatives.

[0019] Preferably, the spiroalkene has the structure shown in any one of formulas 1, 6-29:

[0020]

[0021] Preferably, the alkyl iodide is methyl iodide, ethyl iodide, propyl iodide, probenecid-derived iodoalkane or has the structure shown in any one of formulas I-X, and the probenecid-derived iodoalkane has the structure shown in formula A:

[0022]

[0023] Preferably, the molar equivalent ratio of the spiroalkene to the alkyl iodide is 1:1.2-4.

[0024] Preferably, the cobalt salt includes one or more of cobalt halide, cobalt(II) bromide dimethoxyethane adduct and cobalt tetrafluoroborate; the molar amount of the cobalt salt is 5-40% of the molar amount of the spiroalkene.

[0025] Preferably, the organic solvent includes methyl tert-butyl ether and / or dimethoxyethane; the reducing agent includes dimethoxymethylsilane; the basic substance includes potassium phosphate hydrate.

[0026] Preferably, the temperature of the hydroalkylation reaction is -20-25°C and the time is 48-96 h.

[0027] The present invention also provides a chiral spiro compound, including a cis product, a trans product, an enantiomeric cis product and an enantiomeric trans product;

[0028] The cis product has the structure shown in Formula M:

[0029]

[0030] In Formula M, X is C, O or NR, R is methyl, ethyl, tert-butyl, benzyl, aryl, substituted aryl or tert-butoxycarbonyl; alkyl is alkyl or substituted alkyl; n is 0 or 1; the dotted line represents fused to an aromatic ring, a substituted aromatic ring, a heteroaromatic ring, a substituted heteroaromatic ring or no fusion;

[0031] The trans product has the structure shown in Formula N:

[0032]

[0033] In Formula N, X is C, O or NR, R is methyl, ethyl, butyl, benzyl, aryl, substituted aryl or tert-butoxycarbonyl; alkyl is alkyl or substituted alkyl; n is 0 or 1; the dotted line represents fused to an aromatic ring, a substituted aromatic ring, a heteroaromatic ring, a substituted heteroaromatic ring or no fusion;

[0034] The enantiomeric cis product has the structure shown in Formula P:

[0035]

[0036] In Formula P, X is C, O or NR, R is methyl, ethyl, butyl, benzyl, aryl, substituted aryl or tert-butoxycarbonyl; alkyl is alkyl or substituted alkyl; n is 0 or 1; the dotted line represents fused to an aromatic ring, a substituted aromatic ring, a heteroaromatic ring, a substituted heteroaromatic ring or no fusion;

[0037] The enantiomeric trans product has the structure shown in Formula Q:

[0038]

[0039] In Formula Q, X is C, O or NR, R is methyl, ethyl, butyl, benzyl, aryl, substituted aryl or tert-butoxycarbonyl; alkyl is alkyl or substituted alkyl; n is 0 or 1; the dotted line represents fused to an aromatic ring, a substituted aromatic ring, a heteroaromatic ring, a substituted heteroaromatic ring or no fusion.

[0040] The present invention also provides the use of the chiral spiro compound according to the above technical solution in the preparation of anti-inflammatory drugs.

[0041] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0042] The present invention discloses a cobalt-catalyzed stereodivergent asymmetric synthesis method, which is a cobalt-catalyzed ligand-regulated C(sp 3 )-C(sp 3 ) coupling reaction. Through ligand regulation, the efficient preparation of spiro compounds containing 1,3-non-adjacent stereocenters is achieved, and the products have excellent biological activities. This method has a wide substrate compatibility and high selectivity, providing a new approach for drug development.

[0043] The present invention also provides a chiral spiro compound prepared by the preparation method described in the above technical solution, which has excellent biological activities. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 is the expression level of inflammatory factor IL-6 in the LPS-induced BV2 cell model inhibited by the compound;

[0045] Figure 2 is the expression level of inflammatory factor TNF-α in the LPS-induced BV2 cell model inhibited by the compound;

[0046] Figure 3 is the expression level of inflammatory factor IL-1β in the LPS-induced BV2 cell model inhibited by the compound. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0047] The present invention provides a preparation method of a chiral spiro compound, comprising the following steps:

[0048] Mix a spiroolefin, an alkyl iodide, a cobalt salt, a chiral ligand, an organic solvent, a reducing agent, and a basic substance to carry out a hydroalkylation reaction to obtain the chiral spiro compound;

[0049] When the chiral ligand is a first ligand, the chiral spiro compound is a cis product, and the first ligand has the structure shown in Formula a;

[0050] When the chiral ligand is a second ligand, the chiral spiro compound is a trans product, and the second ligand has the structure shown in Formula b;

[0051] When the chiral ligand is a third ligand, the chiral spiro compound is an enantiomeric cis product, and the third ligand is an enantiomer of the first ligand;

[0052] When the chiral ligand is a fourth ligand, the chiral spiro compound is an enantiomeric trans product, and the fourth ligand is an enantiomer of the second ligand.

[0053] In the present invention, unless otherwise specified, the raw materials used are commercially available products in the art or products obtained by conventional methods in the art.

[0054] In the present invention, the spiroolefin preferably includes indolinone, benzofuranone, 3-isochromanone, pyrrolidone, piperidone and their derivatives, and more preferably has the structure shown in any one of Formulas 1, 6 to 29.

[0055] In the present invention, the alkyl iodide is preferably methyl iodide, ethyl iodide, n-propyl iodide or has the structure shown in any one of Formulas I to X.

[0056] In the present invention, the molar equivalent ratio of the spiroolefin to the alkyl iodide is preferably 1:1.2 to 4, and more preferably 1:2.

[0057] In the present invention, the cobalt salt preferably includes one or more of cobalt halide, cobalt(II) bromide dimethoxyethane adduct and cobalt tetrafluoroborate. The cobalt halide more preferably includes one or more of cobalt chloride, cobalt bromide and cobalt iodide. The cobalt tetrafluoroborate is preferably used in the form of cobalt tetrafluoroborate hydrate. The molar amount of the cobalt salt is preferably 4 to 40% of the molar amount of the spiroolefin, more preferably 10 to 18%, and further preferably 12 to 15%. The molar amount of the chiral ligand is preferably 6 to 60% of the molar amount of the spiroolefin, more preferably 12 to 18%.

[0058] In the present invention, the organic solvent preferably includes methyl tert-butyl ether and / or dimethoxyethane; the reducing agent preferably includes dimethoxymethylsilane; the basic substance preferably includes potassium phosphate hydrate.

[0059] In the present invention, the molar equivalent ratio of the spiroolefin to the reducing agent is preferably 1:2 to 6, and more preferably 1:3 to 5.

[0060] In the present invention, the molar equivalent ratio of the spiroolefin to the basic substance is preferably 1:2 to 6, and more preferably 1:2.5 to 5.

[0061] In the present invention, the first ligand preferably has the structure shown in Formula L1:

[0062] (i.e., (S,S,R,R)L1).

[0063] In the present invention, the second ligand preferably has the structure shown in Formula L2:

[0064] (i.e., (S,S)L2).

[0065] In the present invention, the third ligand is preferably (R,R,S,S,)L1.

[0066] In the present invention, the fourth ligand is (R,R)L2.

[0067] In the present invention, the temperature of the hydroalkylation reaction is preferably -20 to 25 °C, more preferably 0 °C, and the time is preferably 48 to 96 h.

[0068] In the present invention, the hydroalkylation reaction is preferably carried out under stirring conditions, and the stirring speed is preferably 650 revolutions per minute.

[0069] After the hydroalkylation reaction is completed, in the present invention, the resulting reaction mixture is preferably diluted with saturated ammonium chloride aqueous solution and ethyl acetate, the obtained aqueous phase is extracted with ethyl acetate, the organic phases are combined, concentrated under reduced pressure, and the obtained crude mixture is purified by silica gel column chromatography using petroleum ether / ethyl acetate (volume ratio, 10:1) as the eluent to obtain the chiral spiro compound.

[0070] The present invention realizes diastereodivergent synthesis (dr up to >20:1, ee>99%) by switching the chirality of the first ligand and the second ligand.

[0071] In the present invention, for the preparation of the cis product, dr>20:1, ee>99%; for the preparation of the trans product, dr>20:1, ee 90:10 to 99:1; for the preparation of stereodivergent isomers (including enantiomeric cis products and enantiomeric trans products), dr>10:1.

[0072] The present invention is applicable to a variety of spiroalkenes (such as indolinones, 3-isochromanone derivatives) and alkyl iodides (including drug molecule derivatives such as ibuprofen and naproxen); and has the potential for scale-up: high yield (55%) and stereoselectivity (dr>20:1) are still maintained at a scale of 5.0 mmol.

[0073] The present invention also provides a chiral spiro compound, including a cis product, a trans product, an enantiomeric cis product, and an enantiomeric trans product.

[0074] In the present invention, the alkyl in alkyl of the cis product, trans product, enantiomeric cis product, and enantiomeric trans product preferably includes methyl, ethyl, or propyl, and the substituted alkyl preferably includes phenethyl, 3-phenylpropyl, 3-(4-methoxyphenyl)propyl, 3-(4-bromophenyl)propyl, 3-methoxypropyl, 4-(benzyloxy)butyl, 4-ethyl butyrate, 4-(4-methoxyphenoxy)butyl, 3-phenoxypropyl, 3-(tert-butyldimethylsilyloxy)propyl, propyl thiophene-2-carboxylate, propyl furan-2-carboxylate, 3-(benzoyloxy)propyl, or propyl p-[(dipropylamino)sulfonyl]benzoate.

[0075] In the present invention, the chiral spiro compound preferably has a structure represented by the formula trans-3af, cis-3ab, cis-3f, cis-3y, cis-3i', trans-3ax, cis-3ao, cis-3j, trans-3az, ent-cis-3ar, trans-3ah, cis-3o, trans-3an, cis-3s, trans-3v, trans-3ao, trans-3ah', trans-3pp, cis-3al, cis-3e, cis-3v, trans-3at, cis-3a, cis-3b, cis-3c, cis-3d, cis-3g, cis-3h, cis-3i, trans-3a, trans-3c, trans-3ai, trans-3aj, trans-3ak, trans-3d, trans-3u or trans-3ar. The specific structure can be seen in the examples and will not be elaborated here.

[0076] The present invention also provides the use of the chiral spiro compound as described in the above technical solution in the preparation of anti-inflammatory drugs.

[0077] Next, the technical solution of the present invention will be clearly and completely described in conjunction with the examples in the present invention. Obviously, the described examples are only a part of the examples of the present invention, rather than all the examples. All other examples obtained by those of ordinary skill in the art based on the examples in the present invention without making creative efforts belong to the scope of protection of the present invention.

[0078] Example 1

[0079] (1R,3R)-1'-benzyl-3-(3-methoxypropyl)spiro[cyclopentane-1,3'-indoline]-2'-one

[0080]

[0081] Under a nitrogen atmosphere, a magnetic stir bar was added to an oven-dried Teflon screw-cap test tube using glovebox technique. Subsequently, cobalt chloride (0.015 mmol, 15 mol%) and the first ligand L1 (0.018 mmol, 18 mol%) were added. Then anhydrous methyl tert-butyl ether was added and stirred at room temperature for 15 min. Subsequently, potassium phosphate (hydrate) (0.20 mmol, 2 equiv), spiroolefin 1 (0.10 mmol, 1 equiv), 1-iodo-3-methoxypropane (0.12 mmol, 1.2 equiv), and dimethoxymethylsilane (0.20 mmol, 2 equiv) were added in sequence. Subsequently, the test tube was sealed with airtight insulating tape, taken out of the glovebox, and stirred at 0 °C at a speed of 650 rpm for 48 h. After the reaction was completed, the reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography on silica gel using petroleum ether / ethyl acetate (volume ratio, 10:1) as the eluent to obtain 22.6 mg of the target cis product with a yield of 65%.

[0082] 1 H NMR (600 MHz, CDCl3) δ 7.33 - 7.28 (m, 2H), 7.28 - 7.22 (m, 3H), 7.20 (dd, J = 7.4, 1.3 Hz, 1H), 7.10 (td, J = 7.7, 1.3 Hz, 1H), 7.00 (td, J = 7.5, 1.0 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 4.89 (d, J = 3.0 Hz, 2H), 3.41 (td, J = 6.5, 1.3 Hz, 2H), 3.34 (s, 3H), 2.50 (m, J = 10.4, 7.1 Hz, 1H), 2.35 (dd, J = 13.1, 7.5 Hz, 1H), 2.28 - 2.18 (m, 2H), 1.99 - 1.93 (m, 1H), 1.72 - 1.48 (m, 6H).

[0083] 13 C NMR (151 MHz, CDCl3) δ 182.4, 142.0, 136.7, 136.2, 128.7, 127.5, 127.2, 127.2, 122.6, 122.2, 108.6, 77.2, 77.0, 76.8, 72.9, 58.5, 53.5, 45.0, 43.6, 40.7, 38.1, 33.8, 32.0, 28.7.

[0084] HRMS (ESI) m / z: [M+H] + Calcd for C 23 H 28 NO2+ 350.2115; Found 350.2117.

[0085] HPLC: >99:1 as determined by analytical HPLC, Daicel Column, 25 °C, Hexane:i - PrOH = 90:10, 1.0 mL / min, 254 nm, t minor = 17.9 min, t major = 23.6 min.

[0086] [α]D 20 = -133.5 (c = 0.60, CHCl3).

[0087] Example 2

[0088] (1R,3S)-5'-Chloro-3-methyl-1'-phenylspiro[cyclopentane-1,3'-indolin]-2'-one

[0089]

[0090] The preparation method is the same as that of Example 1, except that 1-iodo-3-methoxypropane is replaced with iodomethane and spiroolefin 1 is replaced with spiroolefin 7.

[0091] 1 H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 8.0 Hz, 2H), 7.61 - 7.49 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 7.5 Hz, 2H), 7.09 - 6.95 (m, 2H), 6.54 (d, J = 3.0 Hz, 1H), 5.83 (q, J = 7.0 Hz, 1H), 1.93 (d, J = 7.0 Hz, 3H), 1.30 (s, 12H).

[0092] 13 C NMR (126 MHz, CDCl3) δ 147.4, 137.0, 135.7 (2C), 129.8, 126.1, 125.8, 121.9, 121.3, 120.0, 111.0, 102.0, 84.4, 55.5, 25.1, 21.8.

[0093] HRMS (ESI) m / z: [M + H] + Calcd for C 19 H 19 ClNO + 312.1150; Found 312.1155.

[0094] HPLC: >99:1, determined by analytical HPLC, Daicel IC column, 25 °C, Hexane:i - PrOH = 95:5, 1.0 mL / min, 254 nm, t minor = 10.2 min, t major = 14.5 min.

[0095] [α]D 20 = - 81.1 (c = 1.08, CHCl3).

[0096] Example 3

[0097] (1R,3S)-3 - ethyl - 1'-phenylspiro[cyclopentane - 1,3'-indoline]-2'-one

[0098]

[0099] The preparation method is the same as that of Example 1, except that 1 - iodo - 3 - methoxypropane is replaced by iodoethane, and spiroolefin 1 is replaced by spiroolefin 13.

[0100] 1 H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.26 - 7.15 (m, 2H), 7.11 (d, J = 6.5 Hz, 2H), 7.01 (t, J = 8.5 Hz, 2H), 6.49 (d, J = 3.5 Hz, 1H), 5.60 (q, J = 7.0 Hz, 1H), 3.79 (s, 3H), 1.83 (d, J = 7.0 Hz, 3H).

[0101] 13 C NMR (126 MHz, CDCl3) δ 166.8, 143.2, 136.0, 130.6, 130.4, 128.9, 128.8, 128.7, 127.1, 124.6, 121.6, 121.0, 119.6, 109.9, 101.8, 54.6, 52.1, 21.6.

[0102] HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 22 NO + 292.1696; Found 292.1695.

[0103] HPLC: >99:1 as determined by analytical HPLC, Daicel IC column, 25 °C, Hexane:i-PrOH = 95:5, 1.0 mL / min, 254 nm, t minor = 14.1 min, t major = 20.3 min.

[0104] [α]D 20 = -221.4 (c = 0.80, CHCl3).

[0105] Example 4

[0106] (1R,3S)-1'-Benzyl-3-propylspiro[cyclopentane-1,3'-indolin]-2'-one

[0107]

[0108] The preparation method is the same as that of Example 1, except that 1-iodo-3-methoxypropane is replaced with iodopropane.

[0109] 1 H NMR (500 MHz, CDCl3) δ 7.35 - 7.18 (m, 6H), 7.11 (td, J = 7.7, 1.3 Hz, 1H), 7.05 - 6.96 (m, 1H), 6.69 (d, J = 7.6 Hz, 1H), 4.90 (d, J = 1.8 Hz, 2H), 2.37 (m, J = 10.1, 8.7, 5.2 Hz, 1H), 2.29 (m, J = 13.0, 8.8, 4.1 Hz, 1H), 2.13 (m, J = 12.1, 7.4, 3.8 Hz, 1H), 1.99 (dd, J = 12.7, 7.1 Hz, 1H), 1.93 - 1.82 (m, 2H), 1.73 (dt, J = 12.4, 9.1 Hz, 1H), 1.50 (m, J = 14.6, 11.0, 6.1 Hz, 2H), 1.43 - 1.32 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[0110] 13 C NMR (126 MHz, CDCl3) δ 182.0, 141.8, 137.3, 136.1, 128.7, 127.4, 127.2, 127.2, 122.5, 122.4, 108.7, 77.3, 77.0, 76.7, 53.9, 44.9, 43.7, 41.3, 37.8, 37.7, 33.0, 21.9, 14.3.

[0111] HRMS(ESI) m / z: [M+H] + Calcd for C 22 H 26 NO2 + 320.2009; Found 320.2010.

[0112] HPLC: >99:1 er determined by analytical HPLC, Daicel ID column, 25 °C, Hexane:i-PrOH = 95:5, 1.0 mL / min, 254 nm, t minor = 9.8 min, t major = 11.7 min.

[0113] [α]D 20 = -58 (c = 1.24, CHCl3).

[0114] Example 5

[0115] (1R,3R)-1'-Benzyl-3-(3-phenoxypropyl)spiro[cyclopentane-1,3'-indoline]-2'-one

[0116]

[0117] The preparation method was the same as that of Example 1, except that 1-iodo-3-methoxypropane was replaced by (3-iodopropoxy)benzene, and 20.8 mg of the cis target product was obtained with a yield of 50%.

[0118] 1 H NMR (500 MHz, CDCl3) δ 7.34 - 7.18 (m, 8H), 7.12 (td, J = 7.7, 1.2 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.96 - 6.87 (m, 3H), 6.69 (d, J = 7.7 Hz, 1H), 4.91 (s, 2H), 3.99 (t, J = 6.4 Hz, 2H), 2.41 (m, J = 11.8, 8.3, 7.7 Hz, 1H), 2.31 (m, J = 12.9, 8.7, 4.1 Hz, 1H), 2.17 (m, J = 11.9, 9.4, 5.6 Hz, 1H), 2.04 (dd, J = 12.7, 7.1 Hz, 1H), 1.96 - 1.81 (m, 4H), 1.82 - 1.63 (m, 3H).

[0119] 1313C NMR(126MHz,CDCl3)δ181.9,159.0,141.8,137.0,136.1,129.4,128.7,127.5,127.3,127.2,127.2,122.6,122.4,120.5,114.5,108.8,77.3,77.0,76.7,67.8,53.9,44.8,43.7,41.2,37.8,33.0,31.8,28.5.

[0120] HRMS(ESI)m / z:[M+H] + Calcd for C 28 H 30 NO2 + 412.2171;Found412.2173.

[0121] HPLC:>99:1 er determined by analytical HPLC,Daicel IDcolumn,25℃,Hexane:i-PrOH=80:20,1.0mL / min,254nm,t minor =11.7min,t major =14.5min.

[0122] [α]D 20 =-164.0(c=0.56,CHCl3).

[0123] Example 6

[0124] (1R,3S)-1'-Benzyl-3-(4-(4-methoxyphenoxy)butyl)spiro[cyclopentane-1,3'-indoline]-2'-one

[0125]

[0126] The preparation method was the same as that of Example 1, except that 1-iodo-3-methoxypropane was replaced by 1-(3-iodopropoxy)-4-methoxybenzene, and 23.7 mg of the cis target product was obtained in a yield of 52%.

[0127] 11H NMR (500 MHz, CDCl3) δ 7.35 - 7.18 (m, 6H), 7.11 (m, J = 7.7, 1.3 Hz, 1H), 7.00 (m, J = 7.5, 1.1 Hz, 1H), 6.83 (d, J = 1.2 Hz, 4H), 6.71 - 6.65 (m, 1H), 4.94 - 4.84 (m, 2H), 3.92 (t, J = 6.5 Hz, 2H), 3.76 (s, 3H), 2.42 - 2.33 (m, 1H), 2.29 (m, J = 13.0, 8.7, 4.2 Hz, 1H), 2.19 - 2.11 (m, 1H), 2.01 (dd, J = 12.7, 7.1 Hz, 1H), 1.93 - 1.84 (m, 2H), 1.83 - 1.72 (m, 3H), 1.63 - 1.49 (m, 4H).

[0128] 13 13C NMR (126 MHz, CDCl3) δ 182.0, 153.6, 153.2, 141.8, 137.1, 136.1, 128.7, 127.5, 127.2, 127.2, 127.1, 122.5, 122.4, 115.4, 114.6, 108.7, 77.3, 77.0, 76.7, 68.5, 55.7, 53.9, 44.8, 43.7, 41.4, 37.8, 35.2, 33.0, 29.5, 25.3.

[0129] HRMS (ESI) m / z: [M + H] + Calcd for C 30 H 34 NO3 + 456.2533; Found 456.2530.

[0130] HPLC: >99:1 er determined by analytical HPLC, Daicel IG column, 25 °C, Hexane:i - PrOH = 80:20, 1.0 mL / min, 254 nm, t minor = 23.7 min, t major = 43.6 min.

[0131] [α]D 20 = -95.0 (c = 1.00, CHCl3).

[0132] Example 7

[0133] (1R,3S)-1'-Benzyl-3-(3-phenylpropyl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0134]

[0135] The preparation method is the same as that of Example 1, except that 1-iodo-3-methoxypropane is replaced by 3-iodopropylbenzene.

[0136] 1 H NMR(500MHz,CDCl3)δ7.38 - 7.14(m,11H),7.14 - 7.04(m,1H),6.99(t,J=7.4Hz,1H),6.68(d,J=7.7Hz,1H),4.89(d,J=2.4Hz,2H),2.64(t,J=7.6Hz,2H),2.36(m,J=10.1,7.1Hz,1H),2.28(m,J=13.0,8.8,4.2Hz,1H),2.13(m,J=8.2,3.5Hz,1H),1.99(dd,J=12.6,7.0Hz,1H),1.93 - 1.81(m,2H),1.78 - 1.62(m,3H),1.62 - 1.47(m,2H).

[0137] 13 C NMR(126MHz,CDCl3)δ181.9,142.6,141.8,137.1,136.1,128.7,128.4,128.3,128.2,127.4,127.2,127.1,125.6,122.5,122.4,122.3,108.7,108.7,77.3,77.0,76.7,53.9,44.8,43.7,43.6,41.4,38.5,37.8,36.2,35.1,33.0,30.7,26.7.

[0138] HRMS(ESI)m / z:[M+H] + Calcd for C 28 H 30 NO + 396.2322;Found 396.2320.

[0139] HPLC:>99:1 er determined by analytical HPLC,Daicel AD-Hcolumn,25℃,Hexane:i-PrOH=95:5,1.0mL / min,254nm,t minor= 11.1 min, t major = 18.6 min.

[0140] [α]D 20 = -124 (c = 0.60, CHCl3).

[0141] Example 8

[0142] (1R,3S)-1'-Benzyl-3-(3-(4-methoxyphenyl)propyl)spiro[cyclopentane-1,3'-indoline]-2'-one

[0143]

[0144] The preparation method is the same as that of Example 1, except that 1-iodo-3-methoxypropane is replaced by 1-(3-iodopropyl)-4-methoxybenzene.

[0145] 1 H NMR (500 MHz, CDCl3) δ 7.32 - 7.28 (m, 2H), 7.27 - 7.23 (m, 3H), 7.21 (dd, J = 7.4, 1.3 Hz, 1H), 7.11 (td, J = 7.8, 1.3 Hz, 3H), 6.99 (td, J = 7.5, 1.0 Hz, 1H), 6.85 - 6.80 (m, 2H), 6.68 (d, J = 7.5 Hz, 1H), 4.90 (d, J = 2.3 Hz, 2H), 3.78 (s, 3H), 2.58 (t, J = 7.5 Hz, 2H), 2.36 (m, J = 10.0, 8.6, 5.4 Hz, 1H), 2.28 (m, J = 13.0, 8.8, 4.1 Hz, 1H), 2.17 - 2.08 (m, 1H), 1.99 (dd, J = 12.7, 7.0 Hz, 1H), 1.92 - 1.82 (m, 2H), 1.73 (m, J = 12.4, 9.1 Hz, 1H), 1.68 - 1.62 (m, 2H), 1.59 - 1.49 (m, 2H).

[0146] 13 C NMR (126 MHz, CDCl3) δ 181.9, 157.6, 141.8, 137.2, 136.1, 134.7, 129.2, 129.2, 128.7, 127.4, 127.2, 127.2, 127.1, 122.5, 122.4, 113.7, 108.7, 77.3, 77.0, 76.7, 55.2, 53.9, 44.9, 43.7, 41.4, 37.8, 35.2, 35.0, 33.0, 30.9.

[0147] HRMS(ESI) m / z: [M+H] + Calcd for C 29 H 32 NO2 + 426.2428; Found 426.2430.

[0148] HPLC: >99:1 er determined by analytical HPLC, Daicel ID column, 25 °C, Hexane:i-PrOH = 95:5, 1.0 mL / min, 254 nm, t minor = 17.7 min, t major = 27.6 min.

[0149] [α]D 20 = -134.5 (c = 0.60, CHCl3).

[0150] (1R,3R)-1'-Benzyl-3-(3-((tert-butyldimethylsilyl)oxy)propyl)spiro[cyclopentane-1,3'-indoline]-2'-one

[0151] Example 9

[0152] (1R,3R)-1'-Benzyl-3-(3-((tert-butyldimethylsilyl)oxy)propyl)spiro[cyclopentane-1,3'-indoline]-2'-one

[0153]

[0154] The preparation method was the same as that of Example 1, except that 1-iodo-3-methoxypropane was replaced by tert-butyl(3-iodopropyl)dimethylsilane, and 38.7 mg of the cis target product was obtained in a yield of 86%.

[0155] 11H NMR (600 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.28 - 7.22 (m, 4H), 7.12 (td, J = 7.7, 1.3 Hz, 1H), 7.01 (td, J = 7.5, 1.0 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 4.91 (d, J = 3.7 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 2.36 (m, J = 16.9, 9.8, 8.4, 5.0 Hz, 1H), 2.30 (m, J = 13.0, 8.9, 4.1 Hz, 1H), 2.18 - 2.11 (m, 1H), 2.00 (dd, J = 12.7, 7.0 Hz, 1H), 1.92 - 1.85 (m, 2H), 1.73 (m, J = 12.5, 9.1 Hz, 1H), 1.61 - 1.58 (m, 2H), 1.58 - 1.50 (m, 2H), 0.90 (s, 9H), 0.06 (s, 6H).

[0156] 13 13C NMR (151 MHz, CDCl3) δ 182.0, 141.8, 137.2, 136.1, 128.7, 127.5, 127.2, 127.2, 122.5, 122.4, 108.7, 77.2, 77.0, 76.8, 63.4, 53.9, 45.0, 43.7, 41.4, 37.8, 33.1, 32.1, 31.6, 26.0, 18.4, -5.3.

[0157] HRMS (ESI) m / z: [M + H] + Calcd for C 28 H 40 NO2Si + 450.2823; Found 450.2823.

[0158] [α]D 20 = -8.0 (c = 0.60, CH2Cl2).

[0159] Example 10

[0160]

[0161] The preparation method is obtained by treating cis-3i with tetrabutylammonium fluoride (TBAF).

[0162] 11H NMR (500 MHz, CDCl3) δ 7.29 - 7.11 (m, 6H), 7.05 (m, J = 7.7, 1.2 Hz, 1H), 6.93 (m, J = 7.5, 1.1 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 4.83 (s, 2H), 3.61 (t, J = 6.2 Hz, 2H), 2.30 (m, J = 10.0, 7.0 Hz, 1H), 2.22 (m, J = 12.9, 8.7, 4.3 Hz, 1H), 2.12 - 2.04 (m, 1H), 1.95 (dd, J = 12.8, 7.1 Hz, 1H), 1.87 - 1.77 (m, 2H), 1.69 (m, J = 12.5, 8.9 Hz, 1H), 1.62 - 1.55 (m, 3H), 1.52 (m, J = 12.5, 5.6, 3.5 Hz, 2H).

[0163] 13 13C NMR (126 MHz, CDCl3) δ 182.0, 141.8, 137.1, 136.1, 128.7, 127.5, 127.3, 127.2, 122.6, 122.4, 108.8, 77.3, 77.0, 76.7, 63.1, 53.9, 44.7, 43.7, 41.2, 37.8, 33.1, 31.9, 31.4.

[0164] HPLC: >99:1 er determined by analytical HPLC, Daicel ID column, 25 °C, Hexane:i - PrOH = 80:20, 1.0 mL / min, 254 nm, t minor = 14.4 min, t major = 19.1 min.

[0165] [α]D 20 = -1.5 (c = 0.84, CH2Cl2).

[0166] Example 11

[0167]

[0168] The preparation method was the same as that of Example 1, except that 1 - iodo - 3 - methoxypropane was replaced with ethyl 4 - iodobutyrate, and 24.1 mg of the cis - target product was obtained with a yield of 62%.

[0169] 11H NMR (500 MHz, CDCl3) δ 7.34 - 7.17 (m, 6H), 7.11 (m, J = 7.7, 1.3 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 4.90 (d, J = 2.5 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.42 - 2.25 (m, 4H), 2.19 - 2.10 (m, 1H), 2.01 (dd, J = 12.8, 7.1 Hz, 1H), 1.93 - 1.83 (m, 2H), 1.80 - 1.65 (m, 3H), 1.56 (qt, J = 9.7, 6.7 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0170] 13 13C NMR (126 MHz, CDCl3) δ 181.9, 173.6, 141.8, 137.0, 136.1, 128.7, 127.4, 127.3, 127.1, 122.5, 122.3, 108.7, 77.3, 77.0, 76.7, 60.2, 53.8, 44.7, 43.7, 41.2, 37.7, 34.9, 34.5, 32.9, 24.2, 14.2.

[0171] HRMS (ESI) m / z: [M + H] + Calcd for C 25 H 30 NO3 + 392.2220; Found 392.2223.

[0172] HPLC: >99:1 er determined by analytical HPLC, Daicel IC column, 25 °C, Hexane:i - PrOH = 96:4, 1.0 mL / min, 254 nm, t minor = 58.1 min, t major = 52.4 min.

[0173] [α]D 20 = -55.0 (c = 1.00, CHCl3).

[0174] Example 12

[0175]

[0176] The preparation method was the same as that of Example 1, except that 1-iodo-3-methoxypropane was replaced by iodoethane and spiroolefin 1 was replaced by spiroolefin 17, and 21.9 mg of the cis target product was obtained with a yield of 93%.

[0177] 1 H NMR(500MHz,CDCl3)δ7.28-7.21(m,2H),7.04(td,J=7.5,1.1Hz,1H),6.81(dd,J=8.0,1.0Hz,1H),3.20(s,3H),2.30-2.18(m,2H),2.12(m,J=12.2,7.5,4.5,1.2Hz,1H),1.97-1.87(m,1H),1.85-1.76(m,2H),1.68(m,J=12.5,8.9Hz,1H),1.51(m,J=13.5,6.7Hz,2H),0.95(t,J=7.4Hz,3H).

[0178] 13 C NMR(126MHz,CDCl3)δ181.8,142.7,137.3,127.3,122.4,122.3,107.6,77.3,77.0,76.7,54.0,44.5,43.2,37.4,32.6,28.3,26.2,13.1.

[0179] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 20 NO + 230.1539;Found 230.1541.

[0180] HPLC:98:2er determined by analytical HPLC,Daicel IGcolumn,25℃,Hexane:i-PrOH=98:2,0.6mL / min,250nm,t minor =12.8min,t major =14.1min.

[0181] [α]D 20 =-392.5(c=0.44,CHCl3).

[0182] Example 13

[0183]

[0184] The preparation method was the same as that of Example 1, except that 1-iodo-3-methoxypropane was replaced with iodomethane and spiroolefin 1 was replaced with spiroolefin 18, and 17.2 mg of the cis target product was obtained with a yield of 75%.

[0185] 1 H NMR(500MHz,CDCl3)δ7.23(td,J=7.6,1.2Hz,2H),7.03(td,J=7.5,1.0Hz,1H),6.86-6.79(m,1H),3.76(q,J=7.2Hz,2H),2.44(m,J=13.5,10.3,6.7Hz,1H),2.23(m,J=13.0,8.7,4.1Hz,1H),2.09(m,J=11.3,7.3,4.1,1.3Hz,1H),1.91(m,J=12.6,7.0,1.3Hz,1H),1.86-1.76(m,2H),1.67(m,J=12.5,9.9,8.9Hz,1H),1.26(t,J=7.2Hz,3H),1.16(d,J=6.5Hz,3H).

[0186] 13 C NMR(126MHz,CDCl3)δ181.5,141.8,137.7,127.2,122.5,122.2,107.8,77.3,77.0,76.7,54.2,46.6,38.0,36.0,35.1,34.6,19.7,12.7.

[0187] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 20 NO + 230.1539;Found230.1541.

[0188] HPLC:98:2er determined by analytical HPLC,Daicel IGcolumn,25℃,Hexane:i-PrOH=98:2,0.6mL / min,250nm,t minor =11.3min,t major =12.2min.

[0189] [α]D 20 =-227.5(c=0.44,CHCl3).

[0190] Example 14

[0191]

[0192] The preparation method was the same as that of Example 1, except that spiroolefin 1 was replaced by spiroolefin 7, and 30.9 mg of the cis target product was obtained with a yield of 84%.

[0193] 1 H NMR(500MHz,CDCl3)δ7.51(dd,J=8.7,7.0Hz,2H),7.42-7.37(m,3H),7.26(s,1H),7.14(dd,J=8.4,2.1Hz,1H),6.75(d,J=8.4Hz,1H),3.41(t,J=6.3Hz,2H),3.35(s,3H),2.36(m,J=17.2,9.1,4.0Hz,2H),2.21-2.12(m,1H),2.08(dd,J=12.8,7.1Hz,1H),1.93(m,J=13.1,9.1,7.1Hz,2H),1.76(dt,J=12.6,9.2Hz,1H),1.67(m,J=14.7,12.7,6.8Hz,2H),1.58(m,J=10.5,7.5,5.2Hz,2H).

[0194] 13 C NMR(126MHz,CDCl3)δ180.7,141.1,138.5,134.4,129.6,128.2,128.0,127.1,126.3,123.1,110.0,77.3,77.0,76.7,72.9,58.6,54.1,45.0,41.4,38.2,32.9,31.8,28.8.

[0195] HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 25 ClNO2 + 370.1568;Found 370.1570.

[0196] HPLC:>99:1 er determined by analytical HPLC,Daicel ICcolumn,25℃,Hexane:i-PrOH=95:5,1.0mL / min,254nm,t minor =26.0min,t major =33.6min.

[0197] [α]D20 = -162.0 (c = 0.56, CHCl3).

[0198] Example 15

[0199]

[0200] The preparation method was the same as that of Example 1, except that 1-iodo-3-methoxypropane was replaced with iodomethane and spiroolefin 1 was replaced with spiroolefin 7, to obtain 27.8 mg of the cis target product with a yield of 89%.

[0201] 1 H NMR (500 MHz, CDCl3) δ 7.56 - 7.50 (m, 2H), 7.44 - 7.37 (m, 3H), 7.20 (d, J = 7.9 Hz, 1H), 7.04 (dd, J = 8.0, 1.9 Hz, 1H), 6.80 (d, J = 1.9 Hz, 1H), 2.47 (m, J = 10.3, 6.8 Hz, 1H), 2.36 (m, J = 13.0, 8.8, 4.1 Hz, 1H), 2.12 (m, J = 12.6, 7.3, 4.1, 1.3 Hz, 1H), 2.03 (m, J = 12.8, 7.1, 1.3 Hz, 1H), 1.96 - 1.87 (m, 2H), 1.72 (m, J = 12.5, 9.1 Hz, 1H), 1.18 (d, J = 6.5 Hz, 3H).

[0202] 13 C NMR (126 MHz, CDCl3) δ 181.2, 143.8, 135.5, 134.3, 133.0, 129.6, 128.1, 126.5, 123.6, 122.8, 109.6, 77.3, 77.0, 76.7, 54.1, 47.0, 38.6, 36.1, 35.0, 19.6.

[0203] HRMS (ESI) m / z: [M+H] + Calcd for C 19 H 19 ClNO + 312.1150; Found 312.1153.

[0204] HPLC: >99:1 er determined by analytical HPLC, Daicel IC column, 25 °C, Hexane:i-PrOH = 97:3, 1.0 mL / min, 254 nm, t minor = 5.7 min, t major= 6.5 min.

[0205] [α]D 20 = -88.0 (c = 0.64, CHCl3).

[0206] Example 16

[0207]

[0208] The preparation method was the same as that of Example 1, except that 1-iodo-3-methoxypropane was replaced with iodomethane and spiroalkene 1 was replaced with spiroalkene 11, and 18.2 mg of the cis target product was obtained with a yield of 63%.

[0209] 1 H NMR (500 MHz, CDCl3) δ 7.55 - 7.48 (m, 2H), 7.40 (m, J = 15.0, 6.9, 1.4 Hz, 3H), 7.18 (d, J = 7.5 Hz, 1H), 6.89 (dd, J = 7.4, 1.4 Hz, 1H), 6.64 (d, J = 1.5 Hz, 1H), 2.48 (m, J = 10.2, 6.7 Hz, 1H), 2.35 (m, J = 13.0, 8.9, 4.2 Hz, 1H), 2.30 (s, 3H), 2.12 (m, J = 16.0, 7.3, 4.7, 1.3 Hz, 1H), 2.06 - 2.00 (m, 1H), 1.96 - 1.86 (m, 2H), 1.70 (m, J = 12.4, 9.1 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H).

[0210] 13 C NMR (126 MHz, CDCl3) δ 181.7, 142.6, 137.3, 134.9, 134.3, 129.4, 127.7, 126.6, 123.4, 122.4, 109.8, 77.3, 77.0, 76.7, 54.2, 47.1, 38.6, 36.0, 35.1, 21.6, 19.7.

[0211] HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 22 NO + 292.1696; Found 292.1697.

[0212] HPLC: >99:1 er determined by analytical HPLC, Daicel IC column, 25 °C, Hexane:i-PrOH = 99:1, 1.0 mL / min, 254 nm, t minor = 35.4 min, t major = 56.9 min.

[0213] [α]D 20 = -3.8 (c = 0.44, CH2Cl2).

[0214] Example 17

[0215]

[0216] The preparation method was the same as that of Example 1, except that 1-iodo-3-methoxypropane was replaced with iodopropane and spiroolefin 1 was replaced with spiroolefin 17, to obtain 20.0 mg of the cis target product with a yield of 81%.

[0217] 1 H NMR (500 MHz, CDCl3) δ 7.28 - 7.20 (m, 2H), 7.04 (td, J = 7.5, 1.0 Hz, 1H), 6.81 (dd, J = 8.1, 1.1 Hz, 1H), 3.20 (s, 3H), 2.38 - 2.29 (m, 1H), 2.22 (m, J = 13.1, 8.9, 4.4 Hz, 1H), 2.15 - 2.05 (m, 1H), 1.92 (dd, J = 12.7, 7.0 Hz, 1H), 1.85 - 1.76 (m, 2H), 1.68 (m, J = 12.5, 9.0 Hz, 2H), 1.53 - 1.41 (m, 2H), 1.40 - 1.30 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0218] 13 C NMR (126 MHz, CDCl3) δ 181.8, 142.8, 137.3, 127.3, 122.5, 122.3, 107.7, 77.3, 77.0, 76.7, 54.0, 44.8, 41.1, 37.7, 37.5, 32.9, 26.3, 21.9, 14.3.

[0219] HRMS (ESI) m / z: [M+H] + Calcd for C 16 H 22 NO + 244.1696; Found 244.1695.

[0220] HPLC: >99:1 as determined by analytical HPLC, Daicel AZ-3 column, 25 °C, Hexane:i-PrOH = 99:1, 1.0 mL / min, 254 nm, t minor = 14.7 min, t major = 16.8 min.

[0221] [α]D 20 = -1.8 (c = 0.25, CH2Cl2).

[0222] Example 18

[0223]

[0224] The preparation method was the same as that of Example 1, except that 1-iodo-3-methoxypropane was replaced by ethyl 4-iodobutyrate, and spiroolefin 1 was replaced by spiroolefin 13, to obtain 23.4 mg of the cis target product with a yield of 62%.

[0225] 1 H NMR (500 MHz, CDCl3) δ 7.46 - 7.41 (m, 2H), 7.36 - 7.29 (m, 3H), 7.22 (dd, J = 7.5, 1.3 Hz, 1H), 7.09 (td, J = 7.7, 1.3 Hz, 1H), 7.01 (td, J = 7.5, 1.1 Hz, 1H), 6.75 (dd, J = 7.9, 1.1 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 2.38 - 2.23 (m, 4H), 2.14 - 2.05 (m, 1H), 2.02 (dd, J = 12.8, 7.1 Hz, 1H), 1.91 - 1.82 (m, 2H), 1.71 - 1.58 (m, 3H), 1.48 (m, J = 13.9, 12.3, 7.3, 3.9 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H).

[0226] 13 C NMR (126 MHz, CDCl3) δ 181.2, 173.6, 142.6, 136.8, 134.8, 129.4, 127.7, 127.2, 126.5, 123.0, 122.6, 109.0, 77.3, 77.0, 76.7, 60.2, 54.0, 45.0, 41.2, 38.2, 34.9, 34.5, 32.9, 24.2, 14.2.

[0227] HRMS (ESI) m / z: [M+H] +Calcd for C 24 H 28 NO3 + 378.2064; Found 378.2065.

[0228] HPLC:>99:1 er determined by analytical HPLC,Daicel ICcolumn,25℃,Hexane:i-PrOH=80:20,1.0mL / min,254nm,t minor =20.8min,t major =27.5min.

[0229] [α]D 20 =-0.7(c=1.04,CH2Cl2).

[0230] Example 19

[0231] (1R,3S)-1'-Benzyl-3-(3-methoxypropyl)spiro[cyclopentane-1,3'-indoline]-2'-one

[0232]

[0233] Under a nitrogen atmosphere, a magnetic stir bar was added to an oven-dried Teflon screw-cap tube using glovebox techniques. Subsequently, cobalt chloride (0.015 mmol, 15 mol%) and the second ligand (0.018 mol, 18 mol%) were added. Then anhydrous methyl tert-butyl ether was added and stirred at room temperature for 15 min. Then potassium phosphate (hydrate) (0.20 mmol, 2 equiv), spiroolefin 1 (0.10 mmol, 1 equiv), 1-iodo-3-methoxypropane (0.12 mmol, 1.2 equiv), and dimethoxymethylsilane (0.20 mmol, 2 equiv) were added in sequence. Subsequently, the tube was sealed with airtight insulating tape, removed from the glovebox, and stirred at 0 °C at 650 rpm for 48 h. After completion of the reaction, the reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The crude mixture was purified by flash column chromatography on silica gel using petroleum ether / ethyl acetate (volume ratio, 10:1) as the eluent to give 30.4 mg of the target trans product in 87% yield.

[0234] 11H NMR (600 MHz, CDCl3) δ 7.32 - 7.28 (m, 2H), 7.28 - 7.22 (m, 3H), 7.20 (dd, J = 7.4, 1.3 Hz, 1H), 7.10 (td, J = 7.7, 1.3 Hz, 1H), 7.00 (td, J = 7.5, 1.0 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 4.89 (d, J = 3.0 Hz, 2H), 3.41 (td, J = 6.5, 1.3 Hz, 2H), 3.34 (s, 3H), 2.50 (m, J = 10.2, 6.9 Hz, 1H), 2.35 (dd, J = 13.1, 7.5 Hz, 1H), 2.26 - 2.18 (m, 2H), 1.98 - 1.93 (m, 1H), 1.70 - 1.62 (m, 2H), 1.62 - 1.56 (m, 2H), 1.55 - 1.49 (m, 2H).

[0235] 13 13C NMR (151 MHz, CDCl3) δ 182.4, 142.0, 136.7, 136.2, 128.7, 127.5, 127.2, 127.2, 122.6, 122.2, 108.6, 77.2, 77.0, 76.8, 72.9, 58.5, 53.5, 45.0, 43.6, 40.7, 38.1, 33.8, 32.0, 28.7.

[0236] HRMS (ESI) m / z: [M + H] + Calcd for C 23 H 28 NO2 + 350.2115; Found 350.2112.

[0237] HPLC: 90:10er determined by analytical HPLC, Daicel ID column, 25 °C, Hexane:i - PrOH = 90:10, 1.0 mL / min, 254 nm, t minor = 16.3 min, t major = 20.8 min.

[0238] [α]D 20 = -2.6 (c = 0.34, CH2Cl2).

[0239] Example 20

[0240] (1R,3S)-3-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6'-chloro-1'-methylspiro[cyclopentane-1,3'-indolin]-2'-one

[0241]

[0242] The preparation method was the same as that of Example 19, except that 1-iodo-3-methoxypropane was replaced by tert-butyl(3-iodopropyl)dimethylsilane, and spiroolefin 1 was replaced by spiroolefin 20, to obtain 24.5 mg of the trans target product with a yield of 60%.

[0243] 1 H NMR(500MHz,CDCl3)δ7.05(d,J=7.9Hz,1H),6.96(dd,J=7.9,1.9Hz,1H),6.74(d,J=1.8Hz,1H),3.57(t,J=6.3Hz,2H),3.12(s,3H),2.42-2.32(m,1H),2.24-2.18(m,1H),2.10(m,J=32.6,13.0,9.8,6.8Hz,2H),1.81(m,J=13.0,7.9,2.6Hz,1H),1.53-1.36(m,6H),0.84(s,9H).

[0244] 13 C NMR(126MHz,CDCl3)δ182.2,144.2,135.2,133.1,123.1,122.3,108.4,77.3,77.2,77.0,76.7,63.3,53.3,44.8,40.6,38.0,33.9,32.0,31.7,26.3,26.0,18.4,-5.3.

[0245] HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 35 ClNO2Si + 408.2120;Found408.2125.

[0246] [α]D 20 =-0.3(c=0.68,CH2Cl2).

[0247] Example 21

[0248] (1R,3R)-3-Ethyl-1'-phenylspiro[cyclopentane-1,3'-indolin]-2'-one

[0249]

[0250] The preparation method was the same as that of Example 19, except that 1-iodo-3-methoxypropane was replaced with iodoethane, and spiroolefin 1 was replaced with spiroolefin 13.

[0251] 1 H NMR(600MHz,CDCl3)δ7.53 - 7.48(m,2H),7.46 - 7.40(m,2H),7.38(td,J=7.3,1.3Hz,1H),7.28(dd,J=7.4,1.3Hz,1H),7.16(td,J=7.7,1.3Hz,1H),7.08(td,J=7.5,1.1Hz,1H),6.81(dd,J=7.8,1.0Hz,1H),2.47 - 2.37(m,2H),2.31 - 2.19(m,2H),2.02(m,J=12.2,8.2,2.7Hz,1H),1.65 - 1.56(m,2H),1.51(m,J=13.4,10.5,6.6Hz,2H),0.97(t,J=7.4Hz,3H).

[0252] 13 C NMR(151MHz,CDCl3)δ181.8,142.8,136.8,134.8,129.4,127.7,127.2,126.5,123.0,122.5,109.0,77.2,77.0,76.8,53.7,45.2,42.6,38.4,33.6,28.4,13.1.

[0253] HRMS(ESI)m / z:[M + H] + Calcd for C 20 H 22 NO + 292.1696; Found 292.1699.

[0254] HPLC:88:12er determined by analytical HPLC,Daicel ICcolumn,25℃,Hexane:i - PrOH=95:5,1.0mL / min,254nm,t minor =14.5min,t major =16.2min.

[0255] [α]D 20 = - 110.0(c=0.92,CHCl3).

[0256] Example 22

[0257] (1R,3S)-1'-Methyl-3-(3-phenoxypropyl)spiro[cyclopentane-1,3'-indoline]-2'-one

[0258]

[0259] The preparation method is the same as that of Example 19, except that 1-iodo-3-methoxypropane is replaced by iodoethane and spiroolefin 1 is replaced by spiroolefin 17.

[0260] 1 H NMR(600MHz,CDCl3)δ7.27(dd,J=8.7,7.2Hz,3H),7.22(m,J=11.1,7.5,1.2Hz,2H),7.06(td,J=7.5,1.0Hz,1H),6.96 - 6.88(m,3H),6.80(d,J=7.8Hz,1H),3.98(td,J=6.4,1.5Hz,2H),3.19(s,3H),2.50(m,J=10.2,7.1Hz,1H),2.31(m,J=13.2,7.6,1.1Hz,1H),2.26 - 2.19(m,1H),2.16(m,J=13.0,10.2,7.4Hz,1H),1.92(m,J=12.9,8.0,2.8Hz,1H),1.89 - 1.80(m,2H),1.67 - 1.59(m,3H),1.54(dd,J=13.3,10.2Hz,1H).

[0261] 13 C NMR(151MHz,CDCl3)δ182.3,159.0,143.0,136.8,129.4,127.4,122.6,122.1,120.5,114.5,107.7,77.2,77.0,76.8,67.9,53.5,44.8,40.6,37.9,33.9,31.9,28.5,26.2.

[0262] HRMS(ESI)m / z:[M + H] + Calcd for C 22 H 26 NO2 + 336.1958; Found 336.1960.

[0263] HPLC:90:10er determined by analytical HPLC,Daicel OD-3 column, 25 °C, Hexane:i-PrOH = 95:5, 0.8 mL / min, 254 nm, t minor = 26.9 min, t major = 15.2 min.

[0264] [α]D 20 = -3.6 (c = 0.28, CH2Cl2).

[0265] Example 23

[0266] Ethyl 4-((1R,3R)-1'-methyl-2'-oxospiro[cyclopentane-1,3'-indoline]-3-yl)butanoate

[0267]

[0268] The preparation method was the same as that of Example 19, except that 1-iodo-3-methoxypropane was replaced with ethyl 4-iodobutyrate, and spiroolefin 1 was replaced with spiroolefin 17.

[0269] 1 H NMR (600 MHz, CDCl3) δ 7.24 (td, J = 7.7, 1.2 Hz, 1H), 7.21 - 7.18 (m, 1H), 7.05 (td, J = 7.5, 1.0 Hz, 1H), 6.80 (dt, J = 7.7, 0.8 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.19 (s, 3H), 2.44 (tq, J = 10.3, 7.2 Hz, 1H), 2.33 (t, J = 7.4 Hz, 2H), 2.28 (m, J = 13.2, 7.6, 1.2 Hz, 1H), 2.23 - 2.10 (m, 2H), 1.90 (m, J = 13.0, 8.0, 2.7 Hz, 1H), 1.74 - 1.63 (m, 2H), 1.60 - 1.53 (m, 1H), 1.53 - 1.46 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H).

[0270] 13 C NMR (151 MHz, CDCl3) δ 182.2, 173.6, 142.9, 136.8, 127.3, 122.6, 122.1, 107.6, 77.2, 77.0, 76.8, 60.2, 53.5, 44.7, 40.5, 37.9, 35.0, 34.5, 33.8, 26.2, 24.0, 14.2.

[0271] HRMS (ESI) m / z: [M+H] + Calcd for C 19H 26 NO3 + 316.1907; Found 316.1912.

[0272] HPLC: 90:10er determined by analytical HPLC, Daicel OD-H column, 25 °C, Hexane:i-PrOH = 98:2, 1.0 mL / min, 254 nm, t minor = 15.7 min, t major = 11.6 min.

[0273] [α]D 20 = -3.9 (c = 0.31, CH2Cl2).

[0274] Example 24

[0275] 3-((1R,3S)-1'-Methyl-2'-oxospiro[cyclopentane-1,3'-indoline]-3-yl)propyl furan-2-carboxylate

[0276]

[0277] The preparation method is the same as that of Example 19, except that 3-iodopropyl furan-2-carboxylate and spiroolefin 17 are used.

[0278] 1 H NMR (500 MHz, CDCl3) δ 7.58 (dd, J = 1.8, 0.9 Hz, 1H), 7.24 (td, J = 7.7, 1.3 Hz, 2H), 7.23 - 7.16 (m, 2H), 7.05 (td, J = 7.5, 1.0 Hz, 1H), 6.82 - 6.78 (m, 1H), 6.51 (dd, J = 3.5, 1.7 Hz, 1H), 4.33 (t, J = 6.7 Hz, 2H), 3.19 (s, 3H), 2.54 - 2.44 (m, 1H), 2.30 (m, J = 13.3, 7.6, 1.2 Hz, 1H), 2.25 - 2.19 (m, 1H), 2.15 (m, J = 13.0, 10.0, 7.3 Hz, 1H), 1.91 (m, J = 13.0, 8.0, 2.6 Hz, 1H), 1.82 (m, J = 15.7, 13.7, 7.6, 4.6 Hz, 2H), 1.61 - 1.49 (m, 4H).

[0279] 1313C NMR (126 MHz, CDCl3) δ 182.2, 158.8, 146.2, 144.8, 143.0, 136.7, 127.4, 122.6, 122.1, 117.8, 111.8, 107.7, 77.3, 77.2, 77.0, 76.7, 65.1, 53.5, 44.7, 40.5, 37.8, 33.8, 31.8, 27.9, 26.2.

[0280] HRMS (ESI) m / z: [M+H] + Calcd for C 21 H 24 NO4 + 354.1700; Found 354.1703.

[0281] HPLC: 90:10er determined by analytical HPLC, Daicel AZ-3 column, 25 °C, Hexane:i-PrOH = 90:10, 1.0 mL / min, 254 nm, t minor = 48.7 min, t major = 43.9 min.

[0282] [α]D 20 = -1.2 (c = 0.48, CH2Cl2).

[0283] Example 25

[0284] (1R,3R)-1'-Benzyl-3-propylspiro[cyclopentane-1,3'-indoline]-2'-one

[0285]

[0286] The preparation method is the same as that of Example 19, except that iodopropane is used.

[0287] 11H NMR (500 MHz, CDCl3) δ 7.34 - 7.18 (m, 6H), 7.11 (td, J = 7.7, 1.3 Hz, 1H), 7.01 (td, J = 7.5, 1.1 Hz, 1H), 6.67 (dd, J = 7.8, 0.9 Hz, 1H), 4.89 (d, J = 2.6 Hz, 2H), 2.48 (m, J = 10.4, 6.7, 3.3 Hz, 1H), 2.34 (m, J = 13.2, 7.7, 1.1 Hz, 1H), 2.26 - 2.16 (m, 2H), 1.99 - 1.91 (m, 1H), 1.62 - 1.49 (m, 2H), 1.49 - 1.33 (m, 4H), 0.94 (t, J = 7.1 Hz, 3H).

[0288] 13 13C NMR (126 MHz, CDCl3) δ 182.5, 142.0, 137.0, 136.2, 128.7, 127.5, 127.2, 127.2, 122.6, 122.2, 108.6, 77.3, 77.0, 76.7, 53.5, 45.1, 43.6, 40.7, 38.1, 37.9, 33.9, 21.8, 14.4.

[0289] HRMS (ESI) m / z: [M + H] + Calcd for C 22 H 26 NO + 320.2009; Found 320.2012.

[0290] HPLC: 90:10er determined by analytical HPLC, Daicel IG column, 25 °C, Hexane:i - PrOH = 97:3, 1.0 mL / min, 254 nm, t minor = 18.5 min, t major = 23.2 min.

[0291] [α]D 20 = -0.7 (c = 0.36, CH2Cl2).

[0292] Example 26

[0293] (1R,3S)-3-(3 - Methoxypropyl)-4'-methyl-1'-phenylspiro[cyclopentane - 1,3'-indolin]-2'-one

[0294]

[0295] The preparation method was the same as that of Example 19, except that spiroolefin 6 was used.

[0296] 1 H NMR(600MHz,CDCl3)δ7.50(m,J=8.2,2.3Hz,2H),7.41-7.36(m,3H),7.06(t,J=7.8Hz,1H),6.87(d,J=7.7Hz,1H),6.64(d,J=7.8Hz,1H),3.40(td,J=6.5,2.5Hz,2H),3.34(d,J=4.2Hz,3H),2.65-2.55(m,1H),2.42(s,3H),2.35-2.20(m,3H),2.14(m,J=13.0,6.4,1.4Hz,1H),1.85(dd,J=13.0,11.9Hz,1H),1.70-1.61(m,3H),1.55-1.49(m,2H).

[0297] 13 C NMR(151MHz,CDCl3)δ182.4,143.5,134.8,133.7,132.0,129.4,127.8,127.2,126.8,125.5,106.9,77.2,77.0,76.8,73.0,58.5,53.8,43.2,40.7,33.9,33.9,31.5,28.8,18.3.

[0298] HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 28 NO2 + 350.2115;Found 350.2114.

[0299] HPLC:91:9er determined by analytical HPLC,Daicel IF-3column,25℃,Hexane:i-PrOH=95:5,1.0mL / min,254nm,t minor =20.6min,t major =27.7min.

[0300] [α]D 20 =-1.8(c=0.52,CH2Cl2).

[0301] Example 27

[0302] (1R,3S)-5'-Chloro-3-(3-methoxypropyl)-1'-phenylspiro[cyclopentane-1,3'-indolin]-2'-one

[0303]

[0304] The preparation method was the same as that of Example 19, except that 1-iodo-3-methoxypropane and spiroolefin 7 were used to obtain 18.6 mg of the trans target product with a yield of 50%.

[0305] 1 H NMR(500MHz,CDCl3)δ7.53 - 7.50(m,2H),7.42 - 7.37(m,3H),7.23(d,J = 2.1Hz,1H),7.13(dd,J = 8.4,2.1Hz,1H),6.74(d,J = 8.4Hz,1H),3.41(t,J = 6.4Hz,2H),3.35(s,3H),2.54 - 2.39(m,2H),2.32 - 2.20(m,2H),2.05 - 2.00(m,1H),1.70 - 1.63(m,2H),1.62(d,J = 1.6Hz,1H),1.59(d,J = 2.9Hz,1H),1.57 - 1.51(m,2H).

[0306] 13 C NMR(126MHz,CDCl3)δ181.2,141.3,138.3,134.4,129.6,128.3,128.0,127.1,126.4,123.0,110.0,77.3,77.0,76.7,72.8,58.6,53.8,45.4,40.7,38.4,33.9,31.9,28.8.

[0307] HRMS(ESI)m / z:[M + H] + Calcd for C 22 H 25 ClNO2 + 370.1568; Found 370.1573.

[0308] HPLC:91:9er determined by analytical HPLC,Daicel IC column,25℃,Hexane:i - PrOH = 95:5,1.0mL / min,254nm,t minor =26.9min,t major =22.8min.

[0309] [α]D 20 = -0.3 (c = 0.28, CH2Cl2).

[0310] Example 28

[0311]

[0312] The preparation method is obtained by treating trans-3ah with tetrabutylammonium fluoride.

[0313] 1 H NMR (500 MHz, CDCl3) δ 7.10 (d, J = 7.8 Hz, 1H), 7.01 (dd, J = 7.9, 1.9 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 3.67 (t, J = 6.4 Hz, 2H), 3.17 (s, 3H), 2.43 (m, J = 10.3, 7.1 Hz, 1H), 2.26 (m, J = 13.2, 7.5, 1.2 Hz, 1H), 2.23 - 2.08 (m, 2H), 1.87 (m, J = 13.0, 8.0, 2.5 Hz, 1H), 1.66 - 1.58 (m, 2H), 1.56 - 1.50 (m, 2H), 1.49 - 1.43 (m, 1H), 1.40 (s, 1H).

[0314] 13 C NMR (126 MHz, CDCl3) δ 182.2, 144.1, 135.1, 133.1, 123.0, 122.3, 108.4, 77.3, 77.2, 77.0, 76.7, 63.0, 53.2, 44.8, 40.6, 37.9, 33.9, 31.8, 31.6, 26.3.

[0315] HRMS (ESI) m / z: [M + H] + Calcd for C 16 H 21 ClNO2 + 294.1255; Found 294.1256.

[0316] HPLC: 92:8er determined by analytical HPLC, Daicel IC column, 25 °C, Hexane:i-PrOH = 85:15, 1.0 mL / min, 220 nm, tminor = 20.7 min, tmajor = 16.7 min.

[0317] [α]D 20 = -0.4 (c = 0.66, CH2Cl2).

[0318] Example 29

[0319]

[0320] The preparation method was the same as that of Example 19, except that methyl iodide and spiroolefin 26 were used, and 19.1 mg of the trans target product was obtained with a yield of 85%.

[0321] 1 H NMR(500MHz,CDCl3)δ7.68 - 7.63(m,2H),7.36(m,J = 10.9,5.7,2.1Hz,2H),7.14 - 7.10(m,1H),3.75 - 3.70(m,2H),2.38 - 2.22(m,2H),2.14 - 1.97(m,4H),1.74 - 1.68(m,1H),1.31 - 1.22(m,1H),1.17(dd,J = 12.4,8.0Hz,1H),1.04(d,J = 6.4Hz,3H).

[0322] 13 C NMR(126MHz,CDCl3)δ179.4,139.9,128.7,124.0,119.4,119.4,77.3,77.0,76.7,52.3,45.7,45.2,36.6,35.0,34.8,34.6,20.5.

[0323] HRMS(ESI)m / z:[M + H] + Calcd for C 15 H 20 NO + 230.1539; Found 230.1543.

[0324] HPLC:92:8er determined by analytical HPLC,Daicel IGcolumn,25℃,Hexane:i - PrOH = 97:3,1.0mL / min,254nm,t minor = 32.8min,t major = 37.5min.

[0325] [α]D 20 =-492.0(c = 0.64,CHCl3).

[0326] Example 30

[0327]

[0328] The preparation method was the same as that of Example 19, except that spiroolefin 9 was used, and 27.8 mg of the trans target product was obtained with a yield of 76%.

[0329] 1 H NMR(500MHz,CDCl3)δ7.50(t,J=7.9Hz,2H),7.45 - 7.39(m,2H),7.39 - 7.33(m,1H),6.87(d,J=2.6Hz,1H),6.75(d,J=8.6Hz,1H),6.68(dd,J=8.6,2.6Hz,1H),3.81(s,3H),3.41(t,J=6.4Hz,2H),3.34(s,3H),2.46(m,J=28.5,11.9,7.3Hz,2H),2.32 - 2.18(m,2H),2.04 - 1.98(m,1H),1.69 - 1.48(m,6H).

[0330] 13 C NMR(126MHz,CDCl3)δ181.4,156.4,138.0,136.2,134.9,129.4,127.5,126.2,111.2,109.9,109.3,77.3,77.0,76.7,72.9,58.5,55.8,54.0,45.5,40.6,38.4,33.9,32.0,28.7.

[0331] HRMS(ESI)m / z:[M + H] + Calcd for C 23 H 28 NO3 + 366.2064;Found 366.2067.

[0332] HPLC:87:13er determined by analytical HPLC,Daicel IGcolumn,25℃,Hexane:i - PrOH=90:10,1.0mL / min,254nm,t minor =25.0min,t major =32.9min.

[0333] [α]D 20 = - 32.0(c=1.16,CHCl3).

[0334] Example 31

[0335]

[0336] The preparation method was the same as that of Example 19, except that spiroolefin 16 was used, and 19.2 mg of the trans target product was obtained with a yield of 67%.

[0337] 1 H NMR (500 MHz, CDCl3) δ 7.04 (dd, J = 7.0, 1.8 Hz, 1H), 6.99 - 6.90 (m, 2H), 3.47 (s, 3H), 3.39 (td, J = 6.5, 1.2 Hz, 2H), 3.34 (s, 3H), 2.57 (s, 3H), 2.44 (m, J = 10.4, 7.1 Hz, 1H), 2.25 (m, J = 13.1, 7.4, 1.2 Hz, 1H), 2.21 - 2.08 (m, 2H), 1.87 (m, J = 12.9, 7.9, 2.3 Hz, 1H), 1.68 - 1.58 (m, 2H), 1.58 - 1.43 (m, 4H).

[0338] 13 C NMR (126 MHz, CDCl3) δ 183.1, 140.6, 137.5, 131.0, 122.5, 120.1, 119.2, 77.3, 77.0, 76.7, 72.9, 58.5, 52.9, 45.4, 40.7, 38.3, 33.9, 31.9, 29.5, 28.7, 19.0.

[0339] HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 26 NO2 + 288.1958; Found 288.1954.

[0340] HPLC: 90:10er determined by analytical HPLC, Daicel OJ - 3 column, 25 °C, Hexane:i - PrOH = 98:2, 1.0 mL / min, 254 nm, t minor = 7.9 min, t major = 11.8 min.

[0341] [α]D 20 = -1.1 (c = 0.48, CH2Cl2).

[0342] Example 32

[0343]

[0344] The preparation method was the same as that of Example 19, except that spiroolefin 11 was used, and 21.5 mg of the trans target product was obtained with a yield of 61%.

[0345] 1 H NMR (500 MHz, CDCl3) δ 7.55 - 7.48 (m, 2H), 7.43 - 7.36 (m, 3H), 7.15 (d, J = 7.6 Hz, 1H), 6.90 (dt, J = 7.5, 1.2 Hz, 1H), 6.63 (d, J = 1.5 Hz, 1H), 3.41 (td, J = 6.4, 1.0 Hz, 2H), 3.34 (s, 3H), 2.53 - 2.37 (m, 2H), 2.24 (m, J = 12.5, 6.2, 2.4 Hz, 2H), 2.03 - 1.97 (m, 1H), 1.69 - 1.61 (m, 3H), 1.61 - 1.58 (m, 1H), 1.57 - 1.50 (m, 2H).

[0346] 13 C NMR (126 MHz, CDCl3) δ 182.0, 142.8, 137.4, 134.8, 133.6, 129.4, 127.7, 126.6, 123.5, 122.3, 109.8, 77.3, 77.0, 76.7, 72.9, 58.5, 53.4, 45.4, 40.6, 38.4, 33.8, 32.0, 28.7, 21.6.

[0347] HRMS (ESI) m / z: [M + H] + Calcd for C 23 H 28 NO2 + 350.2115; Found 350.2111.

[0348] HPLC: 90:10er determined by analytical HPLC, Daicel IG column, 25 °C, Hexane:i - PrOH = 95:5, 1.0 mL / min, 254 nm, t minor = 21.8 min, t major = 25.9 min.

[0349] [α]D 20 = -1.3 (c = 0.68, CH2Cl2).

[0350] Example 33

[0351]

[0352] The preparation method was the same as that of Example 19, except that iodopropane and spiroolefin 17 were used, and 18.5 mg of the trans target product was obtained with a yield of 76%.

[0353] 1 H NMR (500 MHz, CDCl3) δ 7.28 - 7.20 (m, 1H), 7.23 - 7.18 (m, 1H), 7.05 (td, J = 7.5, 1.0 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 3.19 (s, 3H), 2.44 (m, J = 10.1, 6.8 Hz, 1H), 2.27 (dd, J = 13.2, 7.6 Hz, 1H), 2.23 - 2.07 (m, 2H), 1.93 - 1.80 (m, 1H), 1.60 - 1.28 (m, 5H), 1.37 (s, 1H), 0.93 (t, J = 7.1 Hz, 3H).

[0354] 13 C NMR (126 MHz, CDCl3) δ 182.4, 142.9, 137.1, 127.3, 122.5, 122.1, 107.6, 77.3, 77.0, 76.7, 53.5, 44.8, 40.6, 38.0, 37.9, 34.0, 26.2, 21.8, 14.4.

[0355] HRMS (ESI) m / z: [M + H] + Calcd for C 16 H 22 NO + 244.1696; Found 244.1698.

[0356] HPLC: 91:9er determined by analytical HPLC, Daicel AZ - 3 column, 25 °C, Hexane:i - PrOH = 99:1, 1.0 mL / min, 254 nm, t minor = 13.8 min, t major = 15.9 min.

[0357] [α]D 20 = -2.8 (c = 0.32, CH2Cl2).

[0358] Example 34

[0359]

[0360] The preparation method was the same as that of Example 19, except that iodopropane and spiroolefin 13 were used, and 19.6 mg of the trans target product was obtained with a yield of 74%.

[0361] 1 H NMR(500MHz,CDCl3)δ7.54 - 7.47(m,2H),7.44 - 7.35(m,3H),7.28(dd,J=7.3,1.4Hz,1H),7.16(td,J=7.7,1.4Hz,1H),7.08(td,J=7.5,1.1Hz,1H),6.81(dd,J=7.8,1.1Hz,1H),2.54 - 2.37(m,2H),2.32 - 2.16(m,2H),2.02(m,J=12.1,7.9,2.4Hz,1H),1.64 - 1.54(m,2H),1.52 - 1.32(m,4H),0.94(t,J=7.1Hz,3H).

[0362] 13 C NMR(126MHz,CDCl3)δ181.8,142.7,136.8,134.7,129.4,127.7,127.2,126.5,123.0,122.5,108.9,77.3,77.0,76.7,53.7,45.5,40.6,38.4,37.9,34.0,21.8,14.4.

[0363] HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 24 NO + 306.1852;Found 306.1855.

[0364] HPLC:90:10er determined by analytical HPLC,Daicel IDcolumn,25℃,Hexane:i-PrOH=95:5,1.0mL / min,254nm,t minor =9.2min,t major =10.0min.

[0365] [α]D 20 =-1.7(c=0.12,CH2Cl2).

[0366] Example 35

[0367]

[0368] The preparation method was the same as that of Example 19, except that propylsulfinyl iodinated alkane and spiroolefin 17 were used, and 21.5 mg of the trans target product was obtained with a yield of 41%.

[0369] 1 H NMR(500MHz,CDCl3)δ8.19 - 8.11(m,2H),7.92 - 7.84(m,2H),7.27 - 7.17(m,2H),7.05(td,J=7.5,1.0Hz,1H),6.81(d,J=7.7Hz,1H),4.38(t,J=6.6Hz,2H),3.20(s,3H),3.14 - 3.04(m,4H),2.52(m,J=10.4,7.2Hz,1H),2.31(dd,J=13.1,7.4Hz,1H),2.27 - 2.12(m,2H),1.97 - 1.79(m,3H),1.65 - 1.49(m,8H),0.87(t,J=7.4Hz,6H).

[0370] 13 C NMR(126MHz,CDCl3)δ182.2,165.3,144.1,142.9,136.6,133.7,130.2,127.4,127.0,122.6,122.1,107.7,77.3,77.2,77.0,76.7,65.8,53.4,49.9,44.8,40.5,37.8,33.8,31.8,27.9,26.2,21.9,11.1.

[0371] HRMS(ESI)m / z:[M + H] + Calcd for C 29 H 39 N2O5S + 527.2574;Found 527.2578.

[0372] HPLC:90:10er determined by analytical HPLC,Daicel IA - 3column,25℃,Hexane:i - PrOH=90:10,1.0mL / min,254nm,t minor =32.7min,t major =23.8min.

[0373] [α]D 20 = - 106.7(c=0.67,CHCl3).

[0374] Example 36

[0375]

[0376] The preparation method was the same as that of Example 19, except that ethyl 4-iodobutyrate and spiroolefin 21 were used, and 24.5 mg of the trans target product was obtained with a yield of 68%.

[0377] 1 H NMR(600MHz,CDCl3)δ8.10(dd,J=5.2,1.7Hz,1H),7.33(dd,J=7.2,1.7Hz,1H),6.86(dd,J=7.3,5.2Hz,1H),4.12(m,J=7.2,3.7Hz,2H),2.43-2.34(m,1H),2.33-2.25(m,3H),2.20-2.09(m,2H),1.85-1.79(m,1H),1.76(d,J=3.9Hz,9H),1.72-1.59(m,3H),1.51-1.42(m,3H),1.24(td,J=7.1,2.0Hz,3H).

[0378] 13 C NMR(151MHz,CDCl3)δ182.7,173.6,158.1,145.3,131.4,128.7,117.4,77.2,77.0,76.8,60.2,58.2,52.9,44.8,40.7,38.1,34.9,34.4,33.9,28.8,24.0,14.2.

[0379] HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 31 N2O3 + 359.2329;Found 359.2325.

[0380] HPLC:91:9er determined by analytical HPLC,Daicel IDcolumn,25℃,Hexane:i-PrOH=99:1,1.0mL / min,254nm,t minor =16.3min,t major =21.8min.

[0381] [α]D 20 =-0.6(c=0.64,CH2Cl2).

[0382] Example 37

[0383]

[0384] The preparation method was the same as that of Example 1, except that the ligand was changed to its enantiomer, and ethyl 4-iodobutyrate and spiroolefin 21 were used as reaction substrates to obtain 19.7 mg of the enantiomeric cis target product with a yield of 55%.

[0385] 1 H NMR(500MHz,CDCl3)δ8.12(dd,J=5.2,1.7Hz,1H),7.36(dd,J=7.3,1.7Hz,1H),6.87(dd,J=7.3,5.2Hz,1H),4.13(q,J=7.2Hz,2H),2.32(t,J=7.5Hz,2H),2.29 - 2.17(m,2H),2.12 - 2.03(m,1H),1.90(dd,J=12.7,7.2Hz,1H),1.77(m,10H),1.72 - 1.63(m,3H),1.51(m,J=9.5,7.6,4.9Hz,2H),1.26(m,J=7.1Hz,4H).

[0386] 13 C NMR(151MHz,CDCl3)δ182.1,173.7,157.9,145.3,131.6,128.8,117.3,77.3,77.0,76.7,60.3,58.3,53.4,44.7,41.2,37.6,34.8,34.5,32.9,28.8,24.1,14.2.

[0387] HRMS(ESI)m / z:[M + H] + Calcd for C 21 H 31 N2O3 + 359.2329;Found 359.2334.

[0388] HPLC:>99:1 er determined by analytical HPLC,Daicel IDcolumn,25℃,Hexane:i-PrOH=99:1,1.0mL / min,254nm,t minor =25.8min,t major =17.4min.

[0389] [α]D 20= +22.5 (c = 0.12, CH2Cl2).

[0390] Anti-inflammatory activity test

[0391] Mouse microglial cells, namely BV2 cell line, were purchased from the Cell Bank of the Chinese Academy of Sciences, catalog number: GNM45.

[0392] After BV2 cells are stimulated by lipopolysaccharide (LPS), the gene expression levels of pro-inflammatory factors in the cells increase significantly, prompting the cells to secrete a large amount of inflammatory factors, such as TNF-α, IL-6, and IL-1β, etc. These inflammatory factors play important roles in the process of neuroinflammation. Especially TNF-α and IL-6, they can activate the downstream inflammatory cascade reaction, thereby exacerbating the inflammatory state of the nervous system.

[0393] BV2 cell culture

[0394] The gas phase composition of the culture is: 95 vol% air, 5 vol% carbon dioxide; temperature 37 °C; humidity 70% - 80%. The components of the complete medium are: 88 wt% DMEM high-glucose medium, 10 wt% fetal bovine serum, 1 wt% L-glutamine, 1 wt% penicillin-streptomycin.

[0395] During resuscitation, the cryopreservation tube containing 1 mL of cell suspension is thawed in a 37 °C water bath, shaken well and then transferred to a centrifuge tube containing 4 mL of complete medium, centrifuged at 800 rpm for 3 min, the supernatant is discarded, and 2 mL of medium is added and gently blown to make a uniform suspension. 1 mL of the cell suspension is transferred to a T25 culture flask, 5 mL of complete medium is added and cultured routinely in an incubator.

[0396] When the cell density reaches 80%, subculture is carried out. Discard the culture supernatant, wash with 1 mL of PBS, add 1 mL of digestive solution to the culture flask, digest in a 37 °C incubator for 1 min, observe the digestion situation. If most of the cells become round and detached, quickly add 2 mL of complete medium to terminate the digestion. Transfer the cells to a centrifuge tube, centrifuge at 800 rpm for 3 min, discard the supernatant, add 1 mL of culture medium and blow to make a uniform suspension. Finally, transfer the cell suspension to a T25 flask and supplement with complete medium to 5 mL, and shake crosswise.

[0397] Experiment on the inhibition of LPS-induced BV2 cell model by the compound

[0398] First, the normally cultured BV2 cells are transferred from a T25 cell culture flask to a 15 mL centrifuge tube through steps such as digestion, centrifugation, and resuspension of the cells. Then, take a part of the cells, dilute them ten times for counting, and at 3.2×10 per well 4Cells were seeded into 6-well plates at a cell density of

[0399] qPCR was used to detect the expression levels of inflammatory factors

[0400] (1) RNA extraction from BV2 cells

[0401] After removing the supernatant of BV2 cell culture medium, 500 μL of PBS was added to each well for washing. Then, 500 μL of Buffer RL was added for cell digestion and lysis. The lysed samples were transferred to FastPure gDNA-FilterColumnsⅢ and centrifuged at 12,000 rpm for 30 s. Subsequently, FastPure gDNA-Filter ColumnsⅢ were discarded and the filtrate was collected. 250 μL of absolute ethanol was added to the filtrate and mixed well. The mixture was completely transferred to FastPure RNA ColumnsⅢ and centrifuged at 12,000 rpm for 30 s, and the filtrate was discarded.

[0402] Next, 700 μL of Buffer RW1 was added to FastPure RNA ColumnsⅢ and centrifuged at 12,000 rpm for 30 s, and the filtrate was discarded. Subsequently, 700 μL of Buffer RW2 (pre-added with absolute ethanol) was added and centrifuged and the filtrate was discarded in the same manner. Then, 500 μL of Buffer RW2 (pre-added with absolute ethanol) was added and centrifuged at 12,000 rpm for 2 min, and the filtrate was discarded. Finally, FastPure RNA ColumnsⅢ were placed back into the collection tube and centrifuged at 12,000 rpm for 1 min to prevent ethanol contamination.

[0403] The adsorption column was carefully transferred to a new 1.5 mL centrifuge tube, and 50 μL of RNase-free MQ H2O was added dropwise in the center of the adsorption column and allowed to stand at room temperature for 3 min, and then centrifuged at 12,000 rpm for 1 min to elute the RNA. The extracted total RNA can be directly used for reverse transcription and qPCR, or stored at -80 °C.

[0404] (2) Reverse transcription

[0405] To remove genomic DNA, add 1 μg of template RNA and 4 μL of 4×gDNA Wiper Mix to an RNase-free centrifuge tube, and make up to 16 μL with RNase-free MQ H2O. Mix well and centrifuge briefly. Incubate the mixture at 42 °C for 2 min. Then add 4 μL of 5×HiScript III qRT SuperMix to make the reaction system reach 20 μL. Mix well and centrifuge briefly.

[0406] Perform reverse transcription reaction at 37 °C for 15 min, then raise the temperature to 85 °C and hold for 5 s. The resulting 20 μL cDNA product can be immediately used for qPCR reaction or stored at 4 °C for a short time to avoid repeated freezing and thawing.

[0407] (3) Real-time fluorescence quantitative polymerase chain reaction (qPCR)

[0408] Reaction solution preparation: 10 μL of 2×Taq Pro Universal SYBR qPCR Master Mix, 0.4 μL of Primer 1 (5 μM), 0.4 μL of Primer 2 (5 μM), 2 μL of Template DNA / cDNA, add water to 20 μL.

[0409] Reaction program setting: Stage 1, pre-denaturation, Rep: 1, 95 °C, 30 s; Stage 2, cycling reaction, Rep: 40, 95 °C, 10 s, 60 °C, 30 s; Stage 3, melting curve, using the instrument default melting curve acquisition program.

[0410] Data processing: First, record the fluorescence signal intensity (Ct value) of each reaction in the Roche qPCR instrument. Subtract the Ct value of the target gene from that of the internal reference gene to calculate the ΔCt value (ΔCt = Ct target gene - Ct internal reference gene), and then calculate the ΔΔCt value (ΔΔCt = ΔCt - ΔCt control group). Then, calculate the relative expression level of the target gene using the 2^(-ΔΔCt) method.

[0411] The primers used and their sequences are shown in Table 4.

[0412] Table 4 qPCR primer sequences

[0413]

[0414] In the present invention, the forward primer sequence of IL-1β is shown as SEQ ID NO.1, the reverse primer sequence of IL-1β is shown as SEQ ID NO.2, the forward primer sequence of IL-6 is shown as SEQ ID NO.3, the reverse primer sequence of IL-6 is shown as SEQ ID NO.4, the forward primer sequence of TNF-α is shown as SEQ ID NO.5, and the reverse primer sequence of TNF-α is shown as SEQ ID NO.6.

[0415] Inhibitory effect of the compound on the mRNA level of the inflammatory factor IL-6 in BV2 cells

[0416] A blank control group, an LPS-induced model group, and an LPS and drug combination treatment group were designed. After 24 hours of treatment, the cells were collected and RNA was extracted. After reverse transcription, qPCR was used to detect the expression levels of pro-inflammatory genes. Figure 1 To investigate the inhibitory effect of the compound on the expression level of the inflammatory factor IL-6 in the LPS-induced BV2 cell model, Table 1 shows the inhibition rate of the compound on IL-6. The results showed that LPS stimulation significantly up-regulated the expression of IL-6 in BV2 cells. Most of the compounds had an obvious inhibitory effect on IL-6, with an inhibition rate greater than 30%. Only cis-3e, cis-3v, and trans-3at had an inhibition rate less than 30%.

[0417] Table 1 Inhibition rate of the compound on IL-6

[0418] Name Inhibition rate against IL-6 (%) Name Inhibition rate against IL-6 (%) trans-3af 95.56 cis-3o 55.66 cis-3ab 92.19 trans-3an 54.25 cis-3f 88.35 cis-3s 49.99 cis-3y 86.32 trans-3v 49.03 cis-3i' 86.22 trans-3ao 43.64 trans-3ax 84.17 trans-3ah' 35.37 cis-3ao 83.43 trans-3pp 35.08 cis-3j 82.71 cis-3al 30.90 trans-3az 65.78 cis-3e 26.02 ent-cis-3ar 60.41 cis-3v -3.63 trans-3ah 60.10 trans-3at -39.96

[0419] Inhibitory effect of the compound on the mRNA level of the inflammatory factor TNF-α in BV2 cells

[0420] A blank control group, an LPS-induced model group, and an LPS and drug combination treatment group were designed. After 24 hours of treatment, the cells were collected and RNA was extracted. After reverse transcription, qPCR was used to detect the expression levels of pro-inflammatory genes. Figure 2 To investigate the inhibitory effect of the compound on the expression level of the inflammatory factor TNF-α in the LPS-induced BV2 cell model, Table 2 shows the inhibition rate of the compound on TNF-α. The results showed that LPS stimulation significantly up-regulated the expression of TNF-α in BV2 cells. 15 compounds had an inhibitory effect on TNF-α. Among them, those with an inhibitory effect greater than 30% were: cis-3o, trans-3ah’, cis-3s, trans-3ao, cis-3j.

[0421] Table 2 Inhibition rate of the compound on TNF-α

[0422]

[0423]

[0424] Inhibitory effect of the compound on the mRNA level of inflammatory factor IL-1β in BV2 cells

[0425] A blank control group, an LPS-induced model group, and an LPS-drug combination treatment group were designed. After 24 h of treatment, the cells were collected and RNA was extracted. After reverse transcription, qPCR was used to detect the expression levels of pro-inflammatory genes. Figure 3 The compound inhibited the expression level of the inflammatory factor IL-1β in the LPS-induced BV2 cell model. Table 3 shows the inhibition rates of the compound on IL-1β. The results showed that LPS stimulation significantly up-regulated the expression of IL-1β in BV2 cells. Most of the compounds had no obvious inhibitory effect on IL-1β, and some even promoted the expression of IL-1β. Only trans-3ah and trans-3ah’ had inhibition rates greater than 30%.

[0426] Table 3 Inhibition rates of the compound on IL-1β

[0427]

[0428] In summary, except for cis-3e, cis-3v, and trans-3at, there were 20 compounds with an inhibition rate of IL-6 greater than 30%; 15 compounds had an inhibitory effect on TNF-α, and those with an inhibition rate greater than 30% were: cis-3o, trans-3ah’, cis-3s, trans-3ao, cis-3j; most of the compounds had no obvious inhibitory effect on IL-1β, and only trans-3ah and trans-3ah’ had inhibition rates greater than 30%. Therefore, the compound with inhibition rates of IL-6, TNF-α, and IL-1β all greater than 30% was: trans-3ah’.

[0429] The above is only the preferred embodiment of the present invention, and it does not impose any form of limitation on the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing a chiral spiro compound, characterized in that, It includes the following steps: Mix a spiroolefin, an alkyl iodide, a cobalt salt, a chiral ligand, an organic solvent, a reducing agent, and a basic substance to conduct a hydroalkylation reaction to obtain the chiral spiro compound; When the chiral ligand is a first ligand, the chiral spiro compound is a cis product, and the first ligand has the structure shown in Formula a: In Formula a, R is -H, -Me, -Et, or -tBuC6H4; When the chiral ligand is a second ligand, the chiral spiro compound is a trans product, and the second ligand has the structure shown in Formula b: In Formula b, R is -Me, R' is -tBu, or R is -iPr, R' is -tBu, or R is -tBu, R' is -tBu, or R is -Me, R' is -phenyl; When the chiral ligand is a third ligand, the chiral spiro compound is an enantiomeric cis product, and the third ligand is the enantiomer of the first ligand; When the chiral ligand is a fourth ligand, the chiral spiro compound is an enantiomeric trans product, and the fourth ligand is the enantiomer of the second ligand.

2. The preparation method according to claim 1, wherein The spiroolefin includes one of the derived spiroolefins of indolinone, benzofuranone, 3-isochromanone, pyrrolidone, and piperidone.

3. The preparation method according to claim 1 or 2, characterized in that, The spiroolefin has the structure shown in any one of Formulas 1, 6 to 29:

4. The preparation method according to claim 1, characterized in that The alkyl iodide is methyl iodide, ethyl iodide, propyl iodide, probenecid-derived iodoalkane, or has the structure shown in any one of Formulas I to X. The probenecid-derived iodoalkane has the structure shown in Formula A:

5. The preparation method according to claim 1, wherein The molar equivalent ratio of the spiroolefin to the alkyl iodide is 1:1.2 to 4.

6. The preparation method according to claim 1, characterized in that, The cobalt salt includes one or more of cobalt halide, cobalt(II) bromide ethylene glycol dimethyl ether adduct, and cobalt tetrafluoroborate; the molar amount of the cobalt salt is 5 to 40% of the molar amount of the spiroolefin.

7. The preparation method according to claim 1, wherein, The organic solvent includes methyl tert-butyl ether and / or ethylene glycol dimethyl ether; the reducing agent includes dimethoxymethylsilane; the basic substance includes potassium phosphate hydrate.

8. The preparation method according to claim 1, characterized in that, The temperature of the hydroalkylation reaction is -20 to 25 °C, and the time is 48 to 96 h.

9. A chiral spiro compound, characterized in that, It includes a cis product, a trans product, an enantiomeric cis product, and an enantiomeric trans product; The cis product has the structure shown in Formula M: In Formula M, X is C, O, or NR, R is methyl, ethyl, butyl, benzyl, aryl, substituted aryl, or tert-butoxycarbonyl; alkyl is alkyl or substituted alkyl; n is 0 or 1; the dashed line represents fused to an aromatic ring, fused to a substituted aromatic ring, fused to a heteroaromatic ring, fused to a substituted heteroaromatic ring, or not fused to a ring; The trans product has the structure shown in Formula N: In Formula N, X is C, O, or NR, R is methyl, ethyl, butyl, benzyl, aryl, substituted aryl, or tert-butoxycarbonyl; alkyl is alkyl or substituted alkyl; n is 0 or 1; the dashed line represents fused to an aromatic ring, fused to a substituted aromatic ring, fused to a heteroaromatic ring, fused to a substituted heteroaromatic ring, or not fused to a ring; The enantiomeric cis product has the structure shown in Formula P: In formula P, X is C, O or NR, R is methyl, ethyl, butyl, benzyl, aryl, substituted aryl or tert-butoxycarbonyl; alkyl is alkyl or substituted alkyl; n is 0 or 1; the dotted line represents fused to an aromatic ring, a substituted aromatic ring, a heteroaromatic ring, a substituted heteroaromatic ring or no fusion. The enantiomeric trans product has the structure shown in formula Q: In formula Q, X is C, O or NR, R is methyl, ethyl, butyl, benzyl, aryl, substituted aryl or tert-butoxycarbonyl; alkyl is alkyl or substituted alkyl; n is 0 or 1; the dotted line represents fused to an aromatic ring, a substituted aromatic ring, a heteroaromatic ring, a substituted heteroaromatic ring or no fusion.

10. Use of the chiral spiro compound according to claim 9 in the preparation of anti-inflammatory drugs.

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