Chiral azaspirocyclic compound, preparation method and application thereof

Abstract

The application discloses a kind of chiral nitrogen a spiro compound and its preparation method and application, specifically related to a kind of chiral nitrogen a spiro compound and its synthesis method, wherein the preparation method includes with metal chiral cobalt (III) complex anion as catalyst, with amine, aromatic aldehyde, alkyne acid and isocyanide as starting material asymmetric Ugi four-component reaction, obtain chiral alpha-amido propargyl amide;The species is deformed under the action of metal (such as Au (I), Ag (I), Sc (III) and the like), and controllable intramolecular Michael addition reaction, finally obtain chiral nitrogen a spiro derivative and nitrogen a spiro fused ring compound with multiple stereogenic centers, the optical purity of obtained compound can be up to 98%ee.The chiral nitrogen a spiro compound and nitrogen a spiro fused ring compound prepared by the application have potential use as a kind of bioactive molecular skeleton, and preliminary antibacterial biological activity test results show that it has certain antibacterial activity to plant pathogenic fungi.

Description

TECHNICAL FIELD

[0001] The present application relates to chiral azaspiro compounds, in particular, to a chiral azaspiro compound and a preparation method and application thereof. BACKGROUND

[0002] Azaspiro-containing polycyclic skeleton molecules are widely present in alkaloids such as leadiformine, (+)-plicamine, perophoramidine, and these compounds exhibit excellent biological activities, such as anticholinergic, immunosuppressive, antitumor, anticancer, and analgesic properties (Nat. Prod. Rep. 2016, 33, 1318-1343; Molecules, 2020, 25, 5621; Nat. Prod. Rep. 2013, 30, 849-868; Chem. Eur. J. 2015, 21, 16318-16343). In 1954, Le Men et al. first isolated Tabersonine (hydrastinine, azaspiro compound) from plants of the family of Oleaceae. Shortly thereafter, this alkaloid was isolated from several other natural products, indicating that azaspiro-containing polycyclic skeleton molecules are widely present in natural products. Many literatures have reported the biological activities of various azaspiro compounds, for example: the literature J. Am. Chem. Soc. 2002, 124, 4628-4641 reported that the azaspiro-containing alkaloid Vinblastine (Vinblastine) and Vincristine (Vincristine) have strong anticancer activity, and these compounds are currently used to treat various types of tumors (acute leukemia, malignant lymphoma, germ cell tumors, small cell lung cancer). At the same time, Vincristine is also very effective when used in combination with other anticancer drugs for the treatment of pediatric leukemia, with a success rate of more than 90%; the literature (Life Sciences, 2002, 7, 2521-2529) reported that Galanthamine, an azaspiro alkaloid with pharmacological activity, is an effective acetylcholinesterase inhibitor and is used to treat Alzheimer's disease.

[0003] Chiral azaspirocyclic skeleton compounds have broad application prospects in medicinal chemistry and agriculture. However, since the bioactive component in drug molecules is often an enantiomer of the racemic mixture, the synthesized chiral azaspirocyclic alkaloids reported in the literature suffer from drawbacks such as long synthesis routes, poor atom economy, and low efficiency in generating chiral structures (Angew. Chem. Int. Ed. 2002, 41, 2194–2197; Angew. Chem. 2020, 132, 21396–21401). Therefore, it is essential to develop a simple, stereoselective, and structurally diverse synthetic method to obtain chiral azaspirocyclic skeletons.

[0004] Multicomponent reactions (MCRs) are considered fundamental methods for synthesizing molecules with complex biological activities, characterized by atom economy, versatility, and high efficiency. Among MCRs, the Ugi / post-Ugi reaction is an effective method for synthesizing racemic azirospirocyclic framework molecules. However, constructing chiral azirospirocyclic framework molecules via the Ugi reaction remains a significant challenge. Therefore, the synthesis of novel chiral azirospirocyclic compounds and the development of efficient asymmetric catalytic synthesis methods are essential for discovering potential bioactive drug lead compounds. Summary of the Invention

[0005] The purpose of this invention is to provide a chiral azaspirocyclic compound, its preparation method, and its application, so as to fill the gap in the prior art and meet the needs of related fields.

[0006] To achieve the above objectives, the present invention provides a chiral azaspirocyclic compound, wherein the general structural formula of the chiral azaspirocyclic compound is:

[0007]

[0008] Among them, R 1 For hydrogen, C 1-6 Straight-chain or branched alkyl groups, C 6-14 One of the aryl or substituted aryl groups;

[0009] The substituted aryl group is C. 1-6 alkyl-substituted aryl, C 1-3 One of the following: alkyl-substituted aryl, nitro-substituted aryl, cyano-substituted aryl, or haloaryl;

[0010] R 2 For hydrogen, C 1-6 Straight-chain or branched alkyl groups, halogens, C 1-3 One of the oxoalkyl groups;

[0011] R 3 For hydrogen, C1-10 linear or branched alkyl, C 3-6 one of the cycloalkyl groups.

[0012] In a preferred embodiment of the present application, the alkyl group is one of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl, i-heptyl, n-octyl or i-octyl.

[0013] In a preferred embodiment of the present application, the cycloalkyl group is one of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0014] In a preferred embodiment of the present application, the halogen is one of fluorine, chlorine, bromine or iodine.

[0015] The present application also provides a preparation method of the chiral azaspiro compound, which comprises:

[0016] 1) mixing an amine, an aldehyde, a metal-centered chiral cobalt(III) complex anion, ethylbenzene and acetone to obtain a first mixed solvent;

[0017] 2) sequentially adding an alkyne acid, an isonitrile and NaHCO3 to quench to obtain a second mixed solvent;

[0018] 3) distilling the second mixed solvent under reduced pressure, and separating and purifying the obtained mixture to obtain an Ugi product;

[0019] 4) mixing the Ugi product, TFA and CHCl3, and then adding Au(PPh3)Cl and AgTFA to obtain a third mixed solvent;

[0020] 5) distilling the third mixed solvent under reduced pressure, and separating and purifying the obtained mixture to obtain the chiral azaspiro compound;

[0021]

[0022] The preparation method (Method I) of the above chiral azaspiro compound is an asymmetric Ugi four-component reaction of aromatic aldehyde, amine, isonitrile and propargyl carboxylic acid catalyzed by a metal-centered chiral cobalt(III) complex anion sodium salt, and a series of chiral α-amido propargyl amide compounds are efficiently obtained. The species can be realized by a "one-pot multi-step" post-Ugi reaction, including acid-promoted deprotection reaction and gold-catalyzed cyclization reaction to efficiently construct azaspiro skeleton compounds.

[0023] In a preferred embodiment of the present application, in step (4), the Ugi product, TFA, CHCl3 are mixed, then Au(PPh3)Cl and AgTFA are added to obtain a third mixed solvent, then stirred at 68-72℃ for 20-24h, after cooling to room temperature, Sc(OTf)3 is added;

[0024]

[0025] The above method (Method two) is an asymmetric Ugi four-component reaction of aromatic aldehyde, amine, isonitrile and propargyl carboxylic acid catalyzed by a metal center chiral cobalt (III) complex anion sodium salt, which can efficiently obtain a series of chiral α-amido propargyl amide compounds. The species can be efficiently constructed through a "one-pot multi-step" post-Ugi reaction, including The acid-promoted deprotection reaction, gold-catalyzed de-aromatization reaction and Sc(III)-catalyzed Michael addition reaction present an efficient construction of azaspiro-fused ring skeleton compounds.

[0026] In a preferred embodiment of the present application, in step (2), the first mixed solvent is stirred at room temperature for 25-35min, then the alkyne acid is added, then stirred at -79℃ to -77℃ for 25-35min, then the isonitrile is added, and then stirred at -79℃ to -77℃ for 70-74h, then quenched with NaHCO3.

[0027] In a preferred embodiment of the present application, in step (4), the Ugi product, TFA, CHCl3 are mixed, then Au(PPh3)Cl and AgTFA are added to obtain a third mixed solvent, then stirred at 68-72℃ for 20-24h, after cooling to room temperature, Sc(OTf)3 is added;

[0028] In a preferred embodiment of the present application, in step (5), the third mixed solvent is stirred at 68-72℃ for 10-14h, then distilled under reduced pressure.

[0029] In a preferred embodiment of the present application, with respect to 0.10mmol of amine, the amount of aldehyde is 0.12mmol, the amount of metal center chiral cobalt (III) complex anion is 0.01mmol, the amount of ethylbenzene is 0.80mL, the amount of acetone is 0.20mL, the amount of alkyne acid is 0.20mmol, the amount of isonitrile is 0.30mmol, the amount of NaHCO3 is 1.0mmol, the amount of Ugi product is 0.05mmol, the amount of TFA is 0.75mmol, the amount of CHCl3 is 1.0mL, the amount of Au(PPh3)Cl is 10mol% or 5mol%, the amount of AgTFA is 10mol% or 5mol%, and the amount of Sc(OTf)3 is 10mol%.

[0030] The application also provides a chiral azaspirocyclic compound for use in a bioactive molecule skeleton.

[0031] In the above method, the metal-centered chiral cobalt(III) complex catalyst can be prepared by the method reported in Angew. Chem. Int. Ed. 2015, 54, 11209; Angew. Chem. Int. Ed. 2017, 56, 11931; ZL201510426983.X. In the above reaction, the enantiomeric excess (ee) of the obtained chiral azaspirocyclic compound can be up to 98%.

[0032] The method for preparing a chiral azaspirocyclic compound according to the application uses a metal-centered chiral cobalt(III) complex catalyst to participate in an asymmetric Ugi four-component reaction of propargylic acid, to obtain an α-amido propargyl amide compound, and in the subsequent post-Ugi reaction conversion, including TFA-promoted deprotection, Au-catalyzed ipso cyclization, and convertible aza-Michael addition reaction, to obtain a series of alkaloid-like azaspirocyclic compounds with multiple consecutive chiral centers with excellent diastereoselectivity while maintaining the enantioselectivity. The operation is simple, the reaction conditions are mild, the raw materials are economical and easy to obtain, and the prepared product has high optical purity (ee value up to 98%). The chiral azaspirocyclic compounds prepared by the method of the application are expected to be widely used in the fields of asymmetric synthesis, and research and development of medicines, pesticides, etc.

[0033] Other features and advantages of the application will be described in detail in the following specific embodiments. BRIEF DESCRIPTION OF DRAWINGS

[0034] The accompanying drawings are included to provide a further understanding of the application, and constitute a part of the specification, and are used together with the following specific embodiments to explain the application, but do not constitute a limitation of the application. In the drawings:

[0035] Figure 1 is a crystal diffraction structure of compound 1a prepared in Example 1;

[0036] Figure 2 is a crystal diffraction structure of compound 1g prepared in Example 7;

[0037] Figure 3 is a crystal diffraction structure of compound 1k prepared in Example 8. DETAILED DESCRIPTION

[0038] The specific embodiments of the present application are described in detail below. It should be appreciated that the detailed description is only for the purpose of explanation and is not intended to limit the present application. In the examples, the yield of the reaction refers to the isolated yield, and the ee refers to the percentage of enantiomeric excess of the reaction.

[0039] The reagents used in the examples, unless otherwise indicated, were purchased from Sigma-Aldrich, Aladdin, Shanghai Generay Pharmaceutical Co., Ltd. The solvents used in the examples, unless otherwise indicated, were purchased from Uptai Co., Ltd. The thin layer chromatography silica gel used in the examples, unless otherwise indicated, was purchased from Qingdao Haoyang Chemical Co., Ltd.

[0040] Example 1 : Synthesis and characterization of compound 1a

[0041]

[0042] Step 1: 4-trifluoromethylaniline 3a (0.10 mmol), 4-formylphenyl tert-butyl carbonate 4a (0.12 mmol), metal-centered chiral cobalt (III) complex anion Λ-(S,S)-7 (0.01 mmol), and a mixed solvent of ethylbenzene (0.8 mL) and acetone (0.2 mL) were added to a 10 mL dry reaction tube at room temperature. After the reaction mixture was stirred at room temperature for 30 minutes, propargyl acid 5a (0.20 mmol) was added. After the reaction system was stirred at -78 °C for 30 minutes, tert-butyl isocyanide 6 (0.30 mmol) was added. After the reaction solution was stirred at -78 °C for 72 hours, NaHCO3 (1.0 mmol) was added to quench it. After the reaction solvent was removed by reduced pressure distillation, the obtained mixture was separated and purified by column chromatography to obtain Ugi four-component product 8a.

[0043] Step 2: To a 10 mL Schlenk tube was added Ugi product 8 (0.05 mmol), TFA (0.75 mmol) and CHCl3(1.0 mL) at room temperature. The mixture was stirred at 70 °C for 2 h and then allowed to cool to room temperature. Subsequently, Au(PPh3)Cl (10 mol%) and AgTFA (10 mol%) were added to the reaction mixture. The reaction mixture was stirred at 70 °C for 22 h. The resulting mixture was concentrated by distillation under reduced pressure and the reaction mixture was diluted with 1.0 mL of dichloromethane, loaded onto a thin layer chromatography silica gel packed in a normal glass column and pressure column chromatographed (column length 15 cm, flow rate 3 drops / sec) using nitrogen gas, eluent petroleum ether: ethyl acetate: dichloromethane = 2:1:1 (v / v), purified directly by flash column chromatography and the chiral azaspirocyclic compound 1a was finally isolated in 94% yield with 92% ee. The absolute configuration was determined to be (R)-type by single crystal X-ray diffraction of the crystal (ee > 99%) obtained by recrystallization at 120 K using Oxford Diffraction’s Gemini S Ultra four-circle single crystal diffractometer and the absolute configurations of compounds 1b-1f, 1o-1t in the following examples were determined by analogy.

[0044] The structure of compound 1a is as follows:

[0045]

[0046] Characterization data of compound 1a:

[0047] (R)-N-(tert-butyl)-4-methylene-3,8-dioxo-2-(4-(trifluoromethyl)phen-yl)-2-azaspiro-[4.5]deca-6,9-diene-1-carboxamid: white solid; m.p.: 252.7-253.3 °C; [a] D 20 = -67.3 (c 0.07 CH3OH); 1 H-NMR (600 MHz, CDC13) δ 7.73 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 6.94-6.85 (m, 2H), 6.46 (d, J = 10.2 Hz, 1H), 6.32 (s, 1H), 6.29-6.22 (m, 2H), 5.43 (s, 1H), 4.48 (s, 1H), 1.31 (s, 9H) ppm; 13C-NMR (151 MHz, CDC13) δ 184.8, 165.4, 165.2, 148.1, 145.9, 140.9, 139.2, 131.3, 128.1 (q, J = 33.1 Hz), 127.9, 126.5 (q, J = 3.8 Hz), 123.9 (q, J = 272.2 Hz), 121.6, 121.1, 66.9, 52.8, 48.1, 28.6 ppm; 19 F-NMR (564 MHz, CDC13) δ -62.5 ppm; HRMS (ESI) calculated for C 22 H 21 F3N2NaO3[M + Na] + : 441.1402, found: 441.1408; Enantiomeric ratio: 96:4, determined by HPLC (Daicel Chiralpak IB, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 5.47 min (major), t R = 6.98 min (minor).

[0048] Example 2: Synthesis and characterization of compound 1b

[0049] The same procedure as in Example 1 was used, wherein: the amine used was 4- cyan aniline. The product 1b was isolated in 98% yield, ee = 94%.

[0050] The structure of compound 1b is as follows:

[0051]

[0052] Characterization data of compound 1b:

[0053] (R)-N-(tert-butyl)-2-(4-cyanophenyl)-4-methylene-3,8-dioxo-2-azasp-iro[4.5]deca-6,9-diene-1-c-arboxamide: white solid; m.p.: 125.6 - 126.3 °C; [a] D 20 = -12.0 (c 0.12 CH3OH); 1H-NMR (600 MHz, CDC13) δ 7.74 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 6.86 (t, J = 10.1 Hz, 2H), 6.47 (d, J = 10.0 Hz, 1H), 6.36 (s, 1H), 6.33 (d, J = 9.9 Hz, 1H), 5.84 (s, 1H), 5.48 (s, 1H), 4.43 (s, 1H), 1.30 (s, 9H) ppm; 13 C-NMR (151 MHz, CDC13) δ 184.4, 165.0, 164.8, 147.4, 145.2, 141.7, 138.8, 133.2, 131.1, 128.3, 122.1, 120.8, 118.2, 109.2, 66.6, 52.8, 47.6, 28.5 ppm; HRMS (ESI) calculated for C 22 H 21 N3NaO3[M+Na] + :398.1481, found:398.1485; Enantiomeric ratio: 97:3, determined by HPLC (Daicel Chiralpak IA, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 5.24 min (major), t R = 6.73 min (minor).

[0054] Example 3: Synthesis and characterization of compound 1c

[0055] The same procedure as in Example 1 was used, wherein: the amine used was 4- bromoaniline. The product 1c was finally isolated in 62% yield, ee = 82%.

[0056] The structure of compound 1c is as follows:

[0057]

[0058] Characterization data of compound 1c:

[0059] (R)-2-(4-bromophenyl)-N-(tert-butyl)-4-methylene-3,8-dioxo-2-azas-piro[4.5]deca-6,9-diene-1-carboxamide: white solid; m.p.: 233.4-234.1 °C; [a] D20 = -97.4 (c 0.13 CH3OH); 1 H-NMR (600 MHz, (CD3)2CO) δ 7.66 (d, J = 8.9 Hz, 2H), 7.62 - 7.51 (m, 3H), 7.12 (dd, J = 10.0, 2.7 Hz, 1H), 6.90 (dd, J = 10.2, 2.7 Hz, 1H), 6.45 (d, J = 10.2 Hz, 1H), 6.22 (d, J = 9.9 Hz, 1H), 6.11 (s, 1H), 5.40 (s, 1H), 4.77 (s, 1H), 1.29 (s, 9H) ppm; 13 C-NMR (151 MHz, (CD3)2CO) δ 185.2, 167.0, 165.8, 149.4, 146.8, 142.2, 139.0, 132.6, 131.7, 127.8, 123.9, 119.5, 118.7, 66.9, 52.5, 48.7, 28.6 ppm; HRMS (ESI) calculated for C 22 H 21 79 BrN2NaO3[M+Na] + : 451.0633, found: 451.0637; HRMS (ESI) calculated for C 22 H 21 81 BrN2NaO3[M+Na] + : 453.0613, found: 453.0623; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak IA, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 5.15 min (major), t R = 7.79 min (minor).

[0060] Example 4: Synthesis and characterization of compound 1d

[0061] The same procedure as in Example 1 was used, wherein: the amine used was 4- chloroaniline. The product 1d was isolated in 92% yield, ee = 82%.

[0062] The structure of compound 1d is as follows:

[0063]

[0064] (R)-N-(tert-butyl)-2-(4-chlorophenyl)-4-methylene-3,8-dioxo-2-azaspiro[4.5]deca-6,9-diene-1-carboxamide: white solid; m.p.: 228.3–229.4 °C; [a] D 20 = -100.9 (c 0.07 CH3OH); 1 H-NMR (600 MHz, (CD3)2CO) δ 7.70 (d, J = 8.8 Hz, 2H), 7.57 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.11 (dd, J = 9.9, 2.7 Hz, 1H), 6.90 (dd, J = 10.1, 2.6 Hz, 1H), 6.44 (d, J = 10.1 Hz, 1H), 6.21 (d, J = 9.8 Hz, 1H), 6.10 (s, 1H), 5.39 (s, 1H), 4.76 (s, 1H), 1.28 (s, 9H) ppm; 13 C-NMR (151 MHz, (CD3)2CO) δ 185.2, 167.0, 165.8, 149.4, 146.9, 142.2, 138.5, 131.7, 131.0, 129.6, 127.9, 123.7, 119.5, 67.0, 52.5, 48.7, 28.6 ppm; HRMS (ESI) calculated for C 21 H 21 35 ClN2NaO3 [M+Na] + : 407.1138, found: 407.1144; HRMS (ESI) calculated for C 21 H 21 37 ClN2NaO3 [M+Na] + : 409.1109, found: 409.1111; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak IA, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 4.92 min (major), t R = 6.88 min (minor).

[0065] Example 5: Synthesis and characterization of compound 1e

[0066] The same procedure as in Example 1 was followed, wherein: the amine used was 3- trifluoromethyl aniline. The product 1e was finally isolated in 92% yield, ee = 76%.

[0067] The structure of compound 1e is as follows:

[0068]

[0069] (R)-N-(tert-butyl)-4-methylene-3,8-dioxo-2-(3-(trifluoromethyl)phen-yl)-2- azaspiro-[4.5]deca-6,9-diene-1-carboxamide: white solid; m.p.: 227.3-228.1 °C; [a] D 20 = -60.7 (c 0.15 CH3OH); 1 H-NMR (600 MHz, CDC13) δ 7.95 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 9.5 Hz, 2H), 6.44 (d, J = 10.8 Hz, 1H), 6.29 (s, 2H), 6.26 (d, J = 9.3 Hz, 1H), 5.41 (s, 1H), 4.46 (s, 1H), 1.31 (s, 9H) ppm; 13 C-NMR (151 MHz, CDC13) δ 184.9, 165.5, 165.3, 148.2, 146.1, 139.2, 138.5, 131.7 (q, J = 32.8 Hz), 131.1, 129.9, 128.0, 125.1, 123.8 (q, J = 272.2 Hz), 122.8 (q, J = 3.7 Hz), 121.3, 117.7 (q, J = 3.9 Hz), 66.9, 52.7, 48.1, 28.5 ppm; 19 F-NMR (564 MHz, CDC13) δ -62.8 ppm; HRMS (ESI) calculated for C 22 H 21 F3N2NaO3 [M + Na] +: 441.1402, found: 441, 1408; Enantiomeric ratio: 88: 12, determined by HPLC (Daicel Chiralpak IA, isopropanol / n-hexane = 10 / 90, flowrate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 9.90 min (major), t R = 11.98 min (minor).

[0070] Example 6: Synthesis and characterization of compound 1f

[0071] The same procedure as in Example 1 was used, wherein: the amine used was 3- cyan aniline. The product If was finally isolated in 86% yield, ee = 84%.

[0072] The structure of compound If is as follows:

[0073]

[0074] (R)-N-(tert-butyl)-2-(3-cyanophenyl)-4-methylene-3,8-dioxo-2-azaspiro[4.5]deca-6,9-diene-1-carboxamide: white solid; m.p.: 119.5-120.3 °C; [a] D 20 = -57.0 (c 0.12 CH3OH); 1 H-NMR (600 MHz, CDC13) δ 7.96 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.56 - 7.49 (m, 2H), 6.91 (dd, J = 7.6, 2.0 Hz, 2H), 6.53 (s, 1H), 6.45 (d, J = 9.8 Hz, 1H), 6.31 (s, 1H), 6.27 (d, J = 10.2 Hz, 1H), 5.44 (s, 1H), 4.52 (s, 1H), 1.32 (s, 9H) ppm; 13 C-NMR (151 MHz, CDC13) δ 185.0, 165.3, 148.2, 146.2, 139.0, 138.9, 131.1, 130.3, 129.4, 127.9, 126.0, 124.4, 121.6, 118.2, 113.2, 66.41, 52.7, 48.0, 28.6 ppm; HRMS (ESI) calculated for C 22 H 21N3NaO3 [M+Na] + : 398.1481, found: 398.1487; Enantiomeric ratio: 92:8, determined by HPLC (Daicel Chiralpak IC, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 22.83 min (major), t R = 15.39 min (minor).

[0075] Example 7: Synthesis and characterization of compound 1g

[0076] The same procedure as in Example 1 was used, wherein: the aldehyde used was tert-butyl 2-bromo-4-formylphenyl carbonate. The product 1g was finally isolated in 62% yield with an ee = 88%. The absolute configuration was determined by single crystal X-ray diffraction of crystals obtained after recrystallization (ee > 99%) of the (1R,5S)-form, which was used as reference for the absolute configuration of the compounds 1h-1i in the following examples.

[0077] The structure of compound 1g is as follows:

[0078]

[0079] (1R,5S)-7-bromo-N-(tert-butyl)-4-methylene-3,8-dioxo-2-(4-(trifle-orometh yl)phenyl)-2-azasp-iro[4.5]deca-6,9-diene-1-carboxamide: white solid; m.p.: 281.9-282.6 °C; [a] D 20 = -48.1 (c 0.14 CH2Cl2); 1 H-NMR (600 MHz, (CD3)2CO) δ 7.91 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.74 (s, 1H), 7.33 (d, J = 2.7 Hz, 1H), 7.27 (dd, J = 9.8, 2.8 Hz, 1H), 6.38 (d, J = 9.8 Hz, 1H), 6.22 (s, 1H), 5.62 (s, 1H), 4.94 (s, 1H), 1.32 (s, 9H) ppm; 13C-NMR (151 MHz, (CD3)2CO) d 178.2, 166.6, 165.6, 149.6, 147.4, 142.9, 140.7, 127.4 (q, J = 32.6 Hz), 127.2, 126.8 (q, J = 3.9 Hz), 126.5, 125.2 (q, J = 270.9 Hz), 121.6, 121.2, 66.1, 52.6, 51.5, 28.6 ppm; 19 F-NMR (564 MHz, (CD3)2CO) d -62.7 ppm; HRMS (ESI) calculated for C 22 H 20 79 BrF3N2NaO3[M+Na] + : 519.0507, found: 519.0509; HRMS (ESI) calculated for C 22 H 20 81 BrF3N2NaO3[M+Na] + : 521.0487, found: 521.0490; Enantiomeric ratio: 94:6, determined by HPLC (Daicel Chiralpak IA, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 4.39 min (major), t R = 5.71 min (minor).

[0080] Example 8: Synthesis and characterization of compound 1k

[0081] The same procedure as in Example 1 was used, wherein: the aldehyde used was 3-chloro-4-formylphenyl tert-butyl carbonate. The product 1k was finally isolated in 98% yield with an ee = 80%. The absolute configuration was determined to be (1R, 5R)-form by single crystal X-ray diffraction of crystals (ee > 99%) obtained after recrystallization (determined at 120 K on a Gemini S Ultra four-circle single crystal diffractometer from Oxford Diffraction), and the absolute configuration of the compounds 1j, 1l-1n in the following examples was determined by analogy.

[0082] The structure of compound 1k is as follows:

[0083]

[0084] (1R,5R)-N-(tert-butyl)-6-chloro-4-methylene-3,8-dioxo-2-(4-(trifluoro- omet hyl)phenyl)-2-azasp-iro[4.5]deca-6,9-diene-1-carboxamid: white solid; m.p.: 118.3-118.8 °C; [a] D 20 = -150.8 (c 0.15 CH3OH); 1 H-NMR (600 MHz, CDC13) δ 7.72 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 10.0 Hz, 1H), 6.57 (d, J = 1.5 Hz, 1H), 6.49 (s, 1H), 6.42 (dd, J = 10.0, 1.5 Hz, 1H), 5.65 (s, 1H), 5.50 (s, 1H), 4.70 (s, 1H), 1.24 (s, 9H) ppm; 13 C-NMR (151 MHz, CDC13) δ 183.3, 164.8, 154.8, 145.8, 140.5, 138.8, 129.7, 128.6, 128.5 (q, J = 33.3 Hz), 126.5 (q, J = 3.4 Hz), 123.9 (q, J = 272.1 Hz), 123.5, 121.6, 67.2, 52.8, 51.4, 28.5 ppm; 19 F-NMR (564 MHz, CDC13) δ -62.5 ppm; HRMS (ESI) calculated for C 22 H 20 35 ClF3N2NaO3 [M + Na] + : 475.1012, found: 475.1009; HRMS (ESI) calculated for C 22 H 20 37 ClF3N2NaO3 [M + Na] + : 477.0983, found: 477.0989; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak IA, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R= 4.17 min (major), t R = 5.81 min (minor).

[0085] Example 9: Synthesis and characterization of compound 1p

[0086] The same procedure as in Example 1 was used, wherein: the isonitrile used was n-butyl isonitrile. The product 1p was isolated in 98% yield, ee = 76%.

[0087]

[0088] (R)-N-butyl-4-methylene-3,8-dioxo-2-(4-(trifluoromethyl)phenyl)-2-azaspiro[4.5]deca-6,9-diene-1-carboxamide: yellow oil; [a] D 20 = -32.8 (c 0.06 CH3OH); 1 H-NMR (600 MHz, CDC13) δ 7.74 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 6.91 (dd, J = 9.9, 2.8 Hz, 1H), 6.81 (dd, J = 10.1, 2.7 Hz, 1H), 6.47 - 6.41 (m, 2H), 6.33 (s, 1H), 6.29 (d, J = 9.9 Hz, 1H), 5.46 (s, 1H), 4.59 (s, 1H), 3.31 - 3.19 (m, 2H), 1.43 - 1.39 (m, 2H), 1.24 - 1.19 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H) ppm; 13 C-NMR (151 MHz, CDC13) δ 184.5, 166.0, 165.0, 147.3, 145.2, 140.6, 139.0, 131.2, 128.1 (q, J = 33.3 Hz), 128.0, 126.5 (q, J = 3.7 Hz), 123.7 (q, J = 271.9 Hz), 121.9, 120.9, 66.8, 47.6, 39.7, 31.2, 19.8, 13.4 ppm; 19 F-NMR (564 MHz, CDC13) δ -62.5 ppm; HRMS (ESI) calculated for C 22 H 21 F3N2NaO3 [M + Na] +: 441.1402, found: 441.1408; Enantiomeric ratio: 88: 12, determined by HPLC (Daicel Chiralpak IA, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 4.69 min (major), t R = 5.34 min (minor).

[0089] Example 10: Synthesis and characterization of compound 1t

[0090] The same procedure as in Example 1 was used, wherein: the isonitrile used was 2- isonitrile-2,4,4-trimethylpentane. The product 1t was isolated in 63% yield and 98% ee.

[0091]

[0092] (R)-4-methylene-3,8-dioxo-2-(4-(trifluoromethyl)phenyl)-N-(2,4,4-trimethyl pentan-2-yl)-2-az-aspiro[4.5]deca-6,9-diene-1-carboxamid: white solid; m.p.: 177.5-178.8 °C; [a] D 20 = -93.3 (c 0.22 CH2Cl2); 1 H-NMR (600 MHz, CDC13) δ 7.73 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 6.92 - 6.87 (m, 2H), 6.47 (d, J = 10.1 Hz, 1H), 6.33 (s, 1H), 6.30 (d, J = 10.0 Hz, 1H), 6.01 (s, 1H), 5.45 (s, 1H), 4.47 (s, 1H), 1.73 (d, J = 14.9 Hz, 1H), 1.43 - 1.40 (m, 4H), 1.33 (s, 3H), 0.85 (s, 9H) ppm; 13C-NMR (151 MHz, CDCI3) δ 184.8, 165.2, 165.1, 148.0, 145.8, 140.8, 139.2, 131.3, 128.6 (q, J = 32.9 Hz), 128.1, 126.5 (q, J = 3.7 Hz), 123.9 (q, J = 272.0 Hz), 121.8, 121.6, 67.4, 57.0, 53.1, 48.1, 31.6, 31.4, 28.4 ppm; 19 F-NMR (564 MHz, CDCI3) δ -62.5 ppm; HRMS (ESI) calculated for C 26 H 29 F3N2NaO3[M + Na] + : 497.2028, found: 497.2024; Enantiomeric ratio: 99:1, determined by HPLC (Daicel Chiralpak IA, isopropanol / n-hexane = 30 / 70, flowrate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 3.95 min (major), t R = 4.66 min (minor).

[0093] Example 11 : Synthesis and characterization of compound 2a

[0094]

[0095] Step 1 : To a 10 mL dry reaction tube was added 4-trifluoromethylaniline 3a (0.10 mmol), tert-butyl 4-formylphenyl carbonate 4a (0.12 mmol), metal-centered chiral cobalt(III) complex anion Λ-(S,S)-7 (0.01 mmol) and a mixed solvent of ethylbenzene (0.8 mL) and acetone (0.2 mL) at room temperature. After the reaction mixture was stirred at room temperature for 30 min, propargyl acid 5a (0.20 mmol) was added. After the reaction system was stirred at -78 °C for 30 min, tert-butyl isocyanide 6 (0.30 mmol) was added. After the reaction solution was stirred at -78 °C for 72 h, NaHC03(1.0 mmol) was added to quench. After the reaction solvent was removed by reduced pressure distillation, the resulting mixture was separated and purified by column chromatography to give Ugi four-component product 8a.

[0096] Step 2: To a 10 mL Schlenk tube was added Ugi product 8a (0.05 mmol), TFA (0.75 mmol) and CHCl3(1.0 mL) at room temperature. The mixture was stirred at 70 °C for 2 h and then allowed to cool to room temperature. Subsequently, Au(PPh3)Cl (10 mol%) and AgTFA (10 mol%) were added to the reaction mixture. The reaction mixture was stirred at 70 °C for 22 h. The resulting mixture was concentrated by distillation under reduced pressure and the reaction mixture was diluted with 1.0 mL of dichloromethane, loaded onto thin layer chromatography silica gel in a normal glass column and pressure column chromatographed (column length 15 cm, flow rate 3 drops / sec) using nitrogen gas, eluent petroleum ether: ethyl acetate: dichloromethane = 2:1:1 (v / v), purified directly by flash column chromatography and finally the chiral azaspirocyclic compound 2a was isolated in 66% yield with 90% ee.

[0097] The structure of compound 2a is as follows:

[0098]

[0099] (3aR,5aR,9aR)-5-(tert-butyl)-1-methylene-3-(4-(trifluoromethyl)ph-enyl)-3,3a,5a,6-tetrahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)-trione: white solid; m.p.: 172.1-172.9 °C; [a] D 20 = +40.7 (c 0.08 CH2Cl2); 1 H-NMR (600 MHz, CDC13) δ 8.15 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 6.65 (d, J = 10.1 Hz, 1H), 6.51 (s, 1H), 6.19 (d, J = 10.0 Hz, 1H), 5.72 (s, 1H), 4.81 (s, 1H), 4.35 (dd, J = 11.9, 5.2 Hz, 1H), 3.18 (dd, J = 15.7, 4.8 Hz, 1H), 2.56 (dd, J = 15.0, 12.7 Hz, 1H), 1.42 (s, 9H) ppm; 13C-NMR (151 MHz, CDC13) δ 194.9, 168.1, 164.3, 145.6, 144.7, 141.5, 128.1, 127.6 (q, J = 33.0 Hz), 126.2 (q, J = 3.7 Hz), 124.1 (q, J = 271.6 Hz), 121.6, 121.2, 66.0, 58.7, 55.9, 46.1, 46.0, 28.0 ppm; 19 F-NMR (564 MHz, CDC13) δ -62.4 ppm; HRMS (ESI) calculated for C 22 H 21 F3N2NaO3[M + Na] + : 441.1402, found: 441.1407; Enantiomeric ratio: 95:5, determined by HPLC (Daicel Chiralpak IB, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 10.61 min (major), t R = 9.35 min (minor).

[0100] Example 12: Synthesis and characterization of compound 2b

[0101] The same procedure as in Example 11 was used, wherein: the amine used was 4- cyanonaniline. The product 2b was finally isolated in 55% yield, ee = 90%.

[0102] The structure of compound 2b is as follows:

[0103]

[0104] 4-((3aR,5aR,9aR)-5-(tert-butyl)-1-methylene-2,4,7-trioxo-1,2,3a,4,5,5a,6,7- octahydro-3H-pyrrolo[2,3-c]indol-3-yl)benzonitrile: white solid; m.p.: 241.1-241.6 °C; [a] D 20 = +67.5 (c 0.09 CH2CI2); 1H-NMR (600 MHz, CDC13) δ 8.15 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 6.65 (d, J = 10.1 Hz, 1H), 6.51 (s, 1H), 6.19 (d, J = 10.0 Hz, 1H), 5.72 (s, 1H), 4.81 (s, 1H), 4.35 (dd, J = 11.9, 5.2 Hz, 1H), 3.18 (dd, J = 15.7, 4.8 Hz, 1H), 2.56 (dd, J = 15.0, 12.7 Hz, 1H), 1.42 (s, 9H) ppm; 13 C-NMR (151 MHz, CDC13) δ 194.8, 168.0, 164.3, 145.4, 144.5, 142.4, 133.0, 128.2, 122.1, 121.2, 118.7, 108.8, 65.8, 58.8, 56.0, 46.0, 45.9, 28.0 ppm; HRMS (ESI) calculated for C 22 H 21 N3NaO3[M+Na] + :398.1481, found:398.1487; Enantiomeric ratio:95:5, determined by HPLC (Daicel Chiralpak IB, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 21.90 min (major), t R = 18.25 min (minor).

[0105] Example 13: Synthesis and characterization of compound 2c

[0106] The same procedure as in Example 11 was used, wherein: the amine used was 4- bromoaniline. The product 2c was isolated in 28% yield and 78% ee.

[0107] The structure of compound 2c is as follows:

[0108]

[0109] (3aR,5aR,9aR)-3-(4-bromophenyl)-5-(tert-butyl)-1-methylene-3,3a,5a,6-tetrahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)-trione: white solid; m.p.: 235.2-236.0 °C; [a] D 20 = +20.3 (c 0.08 CH2Cl2); 1 H-NMR (600 MHz, CDC13) δ 7.88 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 10.1 Hz, 1H), 6.46 (s, 1H), 6.18 (d, J = 10.1 Hz, 1H), 5.67 (s, 1H), 4.70 (s, 1H), 4.32 (dd, J = 11.9, 5.3 Hz, 1H), 3.16 (dd, J = 15.7, 5.1 Hz, 1H), 2.52 (dd, J = 15.5, 12.2 Hz, 1H), 1.41 (s, 9H) ppm; 13 C-NMR (151 MHz, CDC13) δ 195.0, 168.2, 164.1, 145.8, 144.9, 137.6, 132.1, 128.0, 123.3, 121.0, 119.2, 66.3, 58.7, 55.8, 46.2, 46.0, 28.0 ppm; HRMS (ESI) calculated for C 21 H 21 79 BrN2NaO3[M+Na] + : 451.0633, found: 451.0636; HRMS (ESI) calculated for C 21 H 21 81 BrN2NaO3[M+Na] + : 453.0613, found: 453.0618; Enantiomeric ratio: 89: 11, determined by HPLC (Daicel Chiralpak AS, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 17.41 min (major), t R = 13.61 min (minor).

[0110] Example 14: Synthesis and characterization of compound 2d

[0111] The same method as in Example 11 was used, except that the amine used was 4-chloroaniline. The final product was obtained after separation at 2d, with a yield of 41% and an ee of 80%.

[0112] The structure of compound 2d is as follows:

[0113]

[0114] [α] D 20 = +44.4 (c 0.02CH2Cl2); 1 H-NMR (600MHz, CDCl3) δ7.93(d,J=8.8Hz,2H),7.37(d,J=8.8Hz,2H),6.65(d,J=10.1Hz,1H),6.46(s,1H),6.18(d,J=10.1Hz,1H),5 .67(s,1H),4.70(s,1H),4.33(dd,J=11.9,5.3Hz,1H),3.16(dd,J=15.6,5.0Hz,1H),2.52(dd,J=15.4,12.2Hz,1H),1.42(s,9H)ppm; 13 C-NMR (151MHz, CDCl3) δ195.0,168.2,164.1,145.8,144.9,137.0,131.4,129.1,1 28.0,123.1,120.9,66.3,58.7,55.8,46.2,46.0,28.0ppm; HRMS(ESI)calculated for C 21 H 21 35 ClN2NaO3[M+Na] + :407.1138,found:407.1143; HRMS(ESI)calculated for C 21 H 21 37 ClN2NaO3[M+Na] +:409.1109, found: 409.1105; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak AS, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 16.58 min (major), t R = 12.65 min (minor).

[0115] Example 15: Synthesis and characterization of compound 2g

[0116] The same procedure as in Example 11 was used, wherein: the aldehyde used was 3-bromo-4-formylphenyl tert-butyl carbonate. The product 2g was isolated in the end, yield 64%, ee = 80%.

[0117] The structure of compound 2g is as follows:

[0118]

[0119] (3aR,5aR,9aS)-9-bromo-5-(tert-butyl)-1-methylene-3-(4-(trifluor- omethyl)phenyl)-3,3a,5a,6-te-trahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)- trione: white solid; m.p.: 246.0 - 247.4 °C; [a] D 20 = +48.6 (c 0.25 CH2Cl2); 1 H-NMR (600 MHz, CDC13) δ 8.11 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 6.65 (s, 1H), 6.58 (s, 1H), 5.80 (s, 1H), 4.80 (s, 1H), 4.40 (dd, J = 12.0, 5.4 Hz, 1H), 3.18 (dd, J = 15.5, 5.3 Hz, 1H), 2.54 (dd, J = 15.5, 12.1 Hz, 1H), 1.42 (s, 9H) ppm; 13C-NMR (151 MHz, CDC13) δ 191.1, 167.2, 164.2, 147.0, 144.9, 141.3, 132.6, 127.7 (q, J = 32.8 Hz), 126.1 (q, J = 3.7 Hz), 123.9 (q, J = 271.7 Hz), 121.6, 121.3, 66.4, 58.8, 56.0, 50.9, 45.5, 27.8 ppm; 19 F-NMR (564 MHz, CDC13) δ -62.4 ppm; HRMS (ESI) calculated for C 22 H 20 79 BrF3N2NaO3[M + Na] + : 519.0507, found: 519.0510; HRMS (ESI) calculated for C 22 H 20 81 BrF3N2NaO3[M + Na] + : 521.0487, found: 521.0489; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak IB, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 10.98 min (major), t R = 10.24 min (minor).

[0120] Example 16: Synthesis and characterization of compound 2h

[0121] The same method as in Example 11 was used, wherein: the aldehyde used was 3-chloro-4-formylphenyl tert-butyl carbonate. The product 2h was finally isolated in 62% yield with an ee = 82%.

[0122] The structure of compound 2h is as follows:

[0123]

[0124] (3aR,5aR,9aS)-5-(tert-butyl)-9-chloro-1-methylene-3-(4-(trifluorome-thyl)phenyl)-3,3a,5a,6-te-trahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)-trione: white solid; m.p.: 230.7–231.8 °C; [α] D 20 = +66.9 (c 0.17 CH2Cl2); 1 1H-NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 6.58 (s, 1H), 6.40 (s, 1H), 5.82 (s, 1H), 4.86 (s, 1H), 4.39 (dd, J = 12.0, 5.4 Hz, 1H), 3.18 (dd, J = 15.6, 5.3 Hz, 1H), 2.55 (dd, J = 15.4, 12.2 Hz, 1H), 1.42 (s, 9H) ppm; 13 13C-NMR (151 MHz, CDCl3) δ 191.4, 167.4, 164.5, 155.1, 144.0, 141.3, 128.6, 127.8 (q, J = 32.9 Hz), 126.2 (q, J = 3.7 Hz), 124.0 (q, J = 271.8 Hz), 121.7, 121.4, 66.1, 58.9, 56.1, 50.3, 45.5, 27.9 ppm; <sdo194>19F-NMR (564 MHz, CDCl3) δ -62.4 ppm; HRMS (ESI) calculated for C 22 18H 20 <00OO197>18ClF3N2NaO3 [M+Na] + : 475.1012, found: 475.1010; HRMS (ESI) calculated for C 22 18H 20 37 18ClF3N2NaO3 [M+Na] + : 477.0983, found: 477.0988; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak IF, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): tR = 10.52 min (major), t R = 6.58 min (minor).

[0125] Example 17: Synthesis and characterization of compound 2j

[0126] The same procedure as in Example 11 was used, wherein: cyclopentyl isonitrile was used. The product 2j was finally isolated in 76% yield, ee = 79%.

[0127] The structure of compound 2j is as follows:

[0128]

[0129] (3aR,5aR,9aR)-5-cyclopentyl-1-methylene-3-(4-(trifluoromethyl)phenyl)-3,3a,5a,6-tetrahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)-trione: white solid; m.p.: 210.2-211.4 °C; [a] D 20 = +20.2 (c 0.19 CH2Cl2); 1 H-NMR (600 MHz, CDC13) δ 8.08 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 6.63 (d, J = 10.1 Hz, 1H), 6.48 (s, 1H), 6.23 (d, J = 10.1 Hz, 1H), 5.70 (s, 1H), 4.79 (s, 1H), 4.23 (dd, J = 9.6, 5.5 Hz, 1H), 4.04 - 3.96 (m, 1H), 3.07 (dd, J = 15.9, 5.4 Hz, 1H), 2.62 (dd, J = 15.8, 10.0 Hz, 1H), 1.98 - 1.91 (m, 1H), 1.86 - 1.73 (m, 3H), 1.71-1.67 (m, 1H), 1.64 - 1.57 (m, 3H) ppm; 13 C-NMR (151 MHz, CDC13) δ 194.6, 167.7, 164.3, 144.9, 143.8, 141.0, 128.9, 127.8 (q, J = 32.9 Hz), 126.1 (q, J = 3.7 Hz), 124.0 (q, J = 271.9 Hz), 121.9, 121.6, 65.4, 59.3, 55.5, 46.3, 43.0, 30.2, 28.8, 23.9, 23.9 ppm; 19F NMR (564 MHz, CDC13) δ -62.4 ppm; HRMS (ESI) calculated for C 23 H 21 F3N2NaO3[M+Na] + : 453.1402, found: 453.1407; Enantiomeric ratio: 89.5:10.5, determined by HPLC (Daicel Chiralpak IB, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 17.98 min (major), t R = 12.29 min (minor).

[0130] Example 18: Synthesis and characterization of compound 8k

[0131] The same procedure as in Example 11 was used, wherein: cyclohexyl isonitrile was used. The product 2k was isolated in 75% yield and 84% ee.

[0132] The structure of compound 2k is as follows:

[0133]

[0134] (3aR,5aR,9aR)-5-cyclohexyl-1-methylene-3-(4-(trifluoromethyl)p-henyl)-3,3a,5a,6-tetrahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)-trione: white solid; m.p.: 223.0-225.4 °C; [a] D 20 = +17.9 (c 0.20 CH2CI2); 1H-NMR (600 MHz, CDC13) δ 8.07 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 6.63 (d, J = 10.1 Hz, 1H), 6.47 (s, 1H), 6.22 (d, J = 10.1 Hz, 1H), 5.69 (s, 1H), 4.80 (s, 1H), 4.25 (dd, J = 10.0, 5.6 Hz, 1H), 3.73 (t, J = 11.8 Hz, 1H), 3.10 (dd, J = 15.9, 5.4 Hz, 1H), 2.62 (dd, J = 15.8, 10.2 Hz, 1H), 1.88 - 1.76 (m, 3H), 1.72 - 1.64 (m, 2H), 1.58 - 1.51 (m, 1H), 1.47 - 1.41 (m, 1H), 1.32 (dd, J = 27.4, 13.8 Hz, 2H), 1.15 - 1.08 (m, 1H) ppm; 13 C-NMR (151 MHz, CDC13) δ 194.7, 167.5, 164.2, 144.9, 143.9, 141.1, 128.7, 127.8 (q, J = 32.9 Hz), 126.1 (q, J = 3.7 Hz), 124.0 (q, J = 271.7 Hz), 121.9, 121.6, 65.4, 58.1, 53.8, 46.4, 43.8, 31.8, 29.9, 25.8, 25.6, 25.3 ppm; 19 F-NMR (564 MHz, CDC13) δ -62.4 ppm; HRMS (ESI) calculated for C 24 H 23 F3N2NaO3[M+Na] + : 467.1558, found: 467.1555; Enantiomeric ratio: 92:8, determined by HPLC (Daicel Chiralpak IB, isopropanol / n-hexane = 30 / 70, flowrate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 15.94 min (major), t R = 10.49 min (minor).

[0135] Example 19: Synthesis and characterization of compound 2l

[0136] The same procedure as in Example 11 was used, wherein: the isonitrile used was 2- isonitrile-2,4,4-trimethylpentane. The product 21 was isolated in 33% yield with 90% ee.

[0137] The structure of compound 21 is as follows:

[0138]

[0139] (3aR,5aR,9aR)-1-methylene-3-(4-(trifluoromethyl)phenyl)-5-(2,4,4-trimethylpentan-2-yl)-3,3-a,5a,6-tetrahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)-trione: white solid; m.p.: 140.8-141.5 °C; [a] D 20 = +49.3 (c 0.10 CH2Cl2); 1 H-NMR (600 MHz, CDC13) δ 8.13 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 10.1 Hz, 1H), 6.51 (s, 1H), 6.19 (d, J = 10.0 Hz, 1H), 5.72 (s, 1H), 4.80 (s, 1H), 4.38 (dd, J = 11.9, 5.4 Hz, 1H), 3.22 (dd, J = 15.5, 5.3 Hz, 1H), 2.57 (dd, J = 15.4, 12.1 Hz, 1H), 2.52 (d, J = 14.7 Hz, 1H), 1.49 (s, 3H), 1.45 (s, 3H), 1.40 (d, J = 14.8 Hz, 1H), 0.92 (s, 9H); 13 C-NMR (151 MHz, CDC13) δ 195.0, 168.1, 164.3, 145.9, 145.1, 141.5, 127.8, 127.7 (q, J = 32.9 Hz), 126.2 (q, J = 3.8 Hz), 124.1 (q, J = 271.7 Hz), 122.0, 121.3, 66.0, 60.6, 59.2, 50.7, 46.4, 45.7, 31.7, 31.7, 29.0, 26.9 ppm; 19 F-NMR (564 MHz, CDC13) δ -62.4 ppm; HRMS (ESI) calculated for C 26 H 29 F3N2NaO3[M + Na] +:497.2028, found: 497.2033; Enantiomeric ratio: 95:5, determined by HPLC (Daicel Chiralpak ID, isopropanol / n-hexane = 30 / 70, flow rate = 1.0 mL / min, T = 30 °C, λ = 254 nm): t R = 9.91 min (major), t R = 6.54 min (minor).

[0140] Table 1. Synthesis of chiral azaspirocyclic compounds in the present application

[0141]

[0142]

[0143] Table 2. Synthesis of chiral azaspiro-fused cyclic compounds in the present application

[0144]

[0145]

[0146] Table 3. Cytotoxic activity of compounds in the present application

[0147]

[0148]

[0149] a The antibacterial activity of selected products was determined at a concentration of 100 μg / mL, all data being the average of triplicate; b Carbendazim was used as a control agent; c " / " no antibacterial activity.

[0150] The mycelium growth rate method was used to test the in vitro antibacterial test of some chiral nitrogen spiro compounds on three pathogenic fungi (wheat fusarium, green trichoderma and tomato botrytis). Acetone was used as the solvent (solvent amount was 0.02%), and the drug-containing medium with a concentration of 100 μg / mL was prepared. Carbendazim was used as the positive control. The activated strains were punched along the outermost periphery with a punch with an inner diameter of 5 mm, and were picked up with a inoculation needle and moved into a culture dish. The culture dish was placed in a dark environment at 25°C, and was photographed after 72, 96 and 120 hours. The same amount of solvent and drug-free medium were used as blank control group CK (the solvent of the treatment group and the blank group was equivalent), and the cross method was used to measure the results (the diameter of each colony was measured twice, and the accuracy was mm). Each group was operated in parallel for 3 times. As shown in Table 3, chiral nitrogen spiro compounds 1a, 1l, 1o, 2a and 2i all showed certain antifungal activity, wherein 1l showed good antifungal activity against green trichoderma disease, and 2a showed good antifungal activity against wheat fusarium.

[0151] The chiral nitrogen spiro compounds prepared by the present application have potential use as a bioactive molecular skeleton. In addition, the present application has carried out preliminary antibacterial biological activity test on the compounds, and the results show that the compounds have certain antibacterial activity on plant pathogenic fungi.

[0152] The above describes the preferred embodiments of the present application, but the present application is not limited to the specific details in the above embodiments, and various simple modifications can be made to the technical solutions of the present application within the technical concept of the present application, and these simple modifications all belong to the protection scope of the present application.

[0153] In addition, it should be noted that each specific technical feature described in the above specific embodiments can be combined in any appropriate manner without contradiction, and in order to avoid unnecessary repetition, the present application will not further describe various possible combination manners.

[0154] In addition, various different embodiments of the present application can also be combined in any manner, as long as it does not deviate from the idea of the present application, and it should be considered as disclosed by the present application.

Claims

1. A chiral azaspirocyclic compound, characterized in that, The structural general formula of the chiral azaspirocyclic compound is: or ; wherein R is a linear or branched alkyl group, substituted or unsubstituted C 1 aryl group; and 1-6 R is a linear or branched alkyl group, substituted or unsubstituted C 6-14 aryl group; and said substituted aryl is one of an alkyl substituted aryl, a C 1-6 alkoxy substituted aryl, a nitro substituted aryl, a cyano substituted aryl, or a halo substituted aryl; 1-3 alkoxy substituted aryl, a nitro substituted aryl, a cyano substituted aryl, or a halo substituted aryl; R 2 is hydrogen, C 1-6 a straight-chain or branched alkyl group, halogen, C 1-3 alkoxy; R 3 C 1-10 Straight-chain or branched alkyl groups, C 3-6 One of the cycloalkyl groups.

2. The chiral azaspirocyclic compound according to claim 1, wherein, The alkyl is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and isohexyl.

3. The chiral azaspirocyclic compound of claim 1, wherein, The cycloalkyl is one of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

4. The chiral azaspirocyclic compound of claim 1, wherein, The halogen is one of fluorine, chlorine, bromine and iodine.

5. A process for the preparation of a compound of formula 1 according to claim 1, characterized in that The preparation method comprises: 1) mixing the amine of Formula 3, the aldehyde of Formula 4, the chiral cobalt (III) complex anion of Formula 5, ethylbenzene, and acetone to obtain a first mixed solvent; 1) mixing the amine of Formula 3, the aldehyde of Formula 4, the chiral cobalt (III) complex anion of Formula 5, ethylbenzene, and acetone to obtain a first mixed solvent; 2) sequentially adding the alkyne acid shown in chemical formula 5, the isonitrile shown in chemical formula 6 and NaHCO3 to quench, to obtain a second mixed solvent; 3) the second mixed solvent is subjected to reduced pressure distillation, and the obtained mixture is separated and purified to obtain the Ugi product shown in chemical formula 8; 4) the Ugi product shown in chemical formula 8, TFA and CHCl3 are mixed, then Au(PPh3)Cl and AgTFA are added to obtain a third mixed solvent; 5) the third mixed solvent is subjected to reduced pressure distillation, and the obtained mixture is separated and purified to obtain the chiral azaspirocyclic compound shown in chemical formula 1; ； R in the above formulae 1 R 2 R 3 as defined in claim 1.

6. A process for the preparation of a compound of formula 2 as claimed in claim 1, characterized in that, The preparation method comprises: 1) mixing the amine of Formula 3, the aldehyde of Formula 4, the chiral cobalt (III) complex anion of Formula 5, ethylbenzene, and acetone to obtain a first mixed solvent; 1) mixing the amine of Formula 3, the aldehyde of Formula 4, the chiral cobalt (III) complex anion of Formula 5, ethylbenzene, and acetone to obtain a first mixed solvent; 2) sequentially adding the alkyne acid shown in chemical formula 5, the isonitrile shown in chemical formula 6 and NaHCO3 to quench, to obtain a second mixed solvent; 3) the second mixed solvent is subjected to reduced pressure distillation, and the obtained mixture is separated and purified to obtain the Ugi product shown in chemical formula 8; 4) the Ugi product shown in chemical formula 8, TFA and CHCl3 are mixed, then Au(PPh3)Cl and AgTFA are added, and then stirring is performed at 68-72°C for 20-24h, and then Sc(OTf)3 is added after cooling to room temperature; 5) the above mixed solvent is subjected to reduced pressure distillation, and the obtained mixture is separated and purified to obtain the chiral azaspirocyclic compound shown in chemical formula 2; ； R in the above formulae 1 R 2 R 3 as defined in claim 1.

7. The production method according to claim 5 or 6, wherein In step (2), the first mixed solvent is stirred at room temperature for 25-35min, then the alkyne acid is added, then the isonitrile is added after stirring at-79°C~-77°C for 25-35min, and then NaHCO3 is added to quench after stirring at-79°C~-77°C for 70-74h.

8. The production method according to claim 5, wherein In step (4), the Ugi product, TFA and CHCl3 are mixed, then Au(PPh3)Cl and AgTFA are added after stirring at 68-72°C for 1.5-2.5h and restoring to room temperature; In step (5), the third mixed solvent is subjected to reduced pressure distillation after stirring at 68-72°C for 10-14h.

9. The production method according to claim 6, wherein In step (4), the Ugi product, TFA and CHCl3 are mixed, then Au(PPh3)Cl and AgTFA are added after stirring at 68-72°C for 1.5-2.5h and restoring to room temperature; then stirring is performed at 68-72°C for 20-24h, and then Sc(OTf)3 is added after cooling to room temperature; In step (5), the above mixed solvent is subjected to reduced pressure distillation after stirring at 68-72°C for 10-14h.

10. The production method according to claim 5, wherein The amounts used were 0.12 mmol of aldehyde, 0.01 mmol of chiral cobalt(III) complex, 0.80 mL of ethylbenzene, 0.20 mL of acetone, 0.20 mmol of alkynoic acid, 0.30 mmol of isonitrile, 1.0 mmol of NaHC03, 0.05 mmol of Ugi product, 0.75 mmol of TFA, 1.0 mL of CHC13, 10 mol% or 5 mol% of Au(PPh3)CI, and 10 mol% or 5 mol% of AgTFA, relative to 0.10 mmol of amine.

11. The production method according to claim 6, wherein The amounts used were 0.12 mmol of aldehyde, 0.01 mmol of chiral cobalt(III) complex, 0.80 mL of ethylbenzene, 0.20 mL of acetone, 0.20 mmol of alkynoic acid, 0.30 mmol of isonitrile, 1.0 mmol of NaHC03, 0.05 mmol of Ugi product, 0.75 mmol of TFA, 1.0 mL of CHC13, 10 mol% or 5 mol% of Au(PPh3)CI, and 10 mol% or 5 mol% of AgTFA, relative to 0.10 mmol of amine. The amounts used were 0.12 mmol of aldehyde, 0.01 mmol of chiral cobalt(III) complex, 0.80 mL of ethylbenzene, 0.20 mL of acetone, 0.20 mmol of alkynoic acid, 0.30 mmol of isonitrile, 1.0 mmol of NaHC03, 0.05 mmol of Ugi product, 0.75 mmol of TFA, 1.0 mL of CHC13, 10 mol% or 5 mol% of Au(PPh3)CI, and 10 mol% or 5 mol% of AgTFA, relative to 0.10 mmol of amine.

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