A method for synthesizing chiral cyano-containing all-carbon quaternary carbon cyclic compounds

Abstract

This application discloses a method for synthesizing chiral cyano-containing full-carbon quaternary cyclic compounds, characterized by the following steps: mixing a solvent, an oxidant, an alkynyl malononitrile compound, a carboxylic acid compound, a palladium salt, and a chiral dinitrogen ligand; reacting the mixture; drying; and separating to obtain the chiral cyano-containing full-carbon quaternary cyclic compound. This method can achieve a palladium-catalyzed tandem reaction of alkynyl malononitrile with a carboxylic acid involving asymmetric acyl oxidative cyclization / acyl migration, yielding cyano-containing full-carbon quaternary cyclic compounds with optical purity in good yields (enantiomer ratios up to 96.5:3.5). This invention features a broad substrate range, readily available raw materials, simple and practical operation, and mild reaction conditions.

Description

Technical Field

[0001] This application relates to a method for synthesizing chiral, cyano-containing, all-carbon quaternary cyclic compounds, belonging to the field of organic synthesis. Background Technology

[0002] The cyano group is an important pharmacophore, whose biocompatibility and metabolic stability can promote polar interactions, enhance hydrogen bonding, and improve the toxicological properties of molecules. Chiral cyano-containing all-carbon quaternary carbon cyclic compounds are widely found in natural products, drugs, and bioactive molecules (References: (a) Fleming, FF Nat. Prod. Rep. 1999, 16, 597-606.. (b) Fleming, FF; Yao, L.; Ravikumar, PC; Funk, L.; Shook, BCJ Med. Chem. 2010, 53, 7902-7917.). Compounds with this structure can inhibit the oxidation of the carbon atom directly in contact with the cyano group and avoid the release of toxic cyanides. Furthermore, the cyano group, as an important functional group in organic synthesis, can be readily converted into formyl, ketone carbonyl, amino, and carboxyl functional groups. Therefore, developing efficient catalytic enantioselective methods for constructing chiral cyano-containing all-carbon quaternary carbon cyclic compounds is essential.

[0003] Desymmetry is an effective method for constructing quaternary carbon stereocenters. This method avoids the steric hindrance that needs to be overcome when constructing quaternary carbon stereocenters. In recent years, a series of all-carbon quaternary carbon cyclic compounds containing cyano groups have been synthesized through the enantioselective desymmetry cyclization of alkynyl malononitriles catalyzed by transition metals. This strategy can be divided into two categories according to the reaction initiation step: one is the in-situ generated organometallic species inserting into the alkyne moiety of the substrate; the other is the transition metal activating the alkyne moiety of the substrate, followed by nucleophilic addition (i.e., nucleophilic metallization) of the alkyne. Utilizing the elementary reaction of nucleophilic metallation, Professor Wenbo Liu's research group achieved two asymmetric tandem cyclization reactions initiated by intramolecular amine palladiumization and oxypalladiumization by introducing nucleophilic units into alkynyl malononitriles, synthesizing different chiral, cyano-containing, all-carbon quaternary cyclic compounds (References: (c) Hu, X.-D.; Chen, Z.-H.; Zhao, J.; Sun, R.-Z.; Zhang, H.; Qi, X.; Liu, W.-BJAm.Chem.Soc.2021,143,3734-3740.(d) Zhang, H.; Li, W.; Hu, X.-D.; Liu, W.-BJOrg.Chem.2021,86,10799-10811.). This method of pre-introducing nucleophilic units into alkynyl malononitriles limits the substrate range to some extent. Summary of the Invention

[0004] The purpose of this invention is to provide a method for synthesizing cyano-containing all-carbon quaternary carbon cyclic compounds with high optical purity via a palladium-catalyzed tandem reaction of alkynyl malononitrile with carboxylic acid through asymmetric acyl oxidative cyclization / acyl migration.

[0005] According to one aspect of this application, a method for synthesizing chiral, cyano-containing, all-carbon quaternary cyclic compounds is provided, characterized in that...

[0006] Includes the following steps:

[0007] The solvent, oxidant, alkynyl malononitrile compound, carboxylic acid compound, palladium salt and chiral dinitrogen ligand are mixed, reacted, dried and separated to obtain a chiral cyano-containing all-carbon quaternary carbon cyclic compound.

[0008] 2. The method according to claim 1, characterized in that,

[0009] The alkynyl malononitrile compound is selected from at least one of compounds having the structure of Formula I:

[0010]

[0011] The carboxylic acid compound is selected from at least one of compounds having the structure of Formula II:

[0012]

[0013] The palladium salt is selected from at least one of palladium trifluoroacetate, palladium acetate, or palladium acetylacetonate;

[0014] The chiral dinitrogen ligand is selected from (S)-AdPyox, (S)-tBuPyox, (S)-iPrPyox, (S)-BnPyox, (S)-PhPyox, (S,R)-InPyox, (R a ,S,S)-C3-ACBP or (R p At least one of )-COXPY;

[0015] The chiral, cyano-containing, all-carbon quaternary cyclic compound is selected from at least one of compounds having the structure of Formula III:

[0016]

[0017] The solvent is selected from at least one of toluene, ethyl acetate, 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane;

[0018] The oxidant is selected from oxygen and / or benzoquinone.

[0019] The molar ratio of the carboxylic acid compound to the alkynyl malononitrile compound is 3 to 25:1;

[0020] The molar ratio of the oxidant to the alkynyl malononitrile compound is 0.1 to 1:1;

[0021] The molar ratio of the palladium salt to the alkynyl malononitrile compound is 0.1–0.15:1;

[0022] The molar ratio of the chiral dinitrogen ligand to the alkynyl malononitrile compound is 0.11–0.165:1;

[0023] The ratio of the solvent to the alkynyl malononitrile compound is 1 ml: 0.1 mmol to 2 ml: 0.1 mmol.

[0024] The reaction temperature is 60℃~80℃;

[0025] The reaction time is 72–98 hours.

[0026] The drying temperature is 20℃~30℃;

[0027] The drying time is 10 min to 30 min.

[0028] Includes the following steps:

[0029] The palladium salt and chiral dinitrogen ligand were mixed with a solvent and stirred for 120 min. Then, an alkynyl malononitrile compound and a carboxylic acid compound were added, reacted, dried, and separated to obtain the chiral cyano-containing all-carbon quaternary carbon cyclic compound.

[0030] That is, the organic solvent is added in two parts: the first organic solvent is added during the preparation of the catalyst, and the second organic solvent is added during the synthesis of the product. The volume ratio of the first organic solvent to the second organic solvent is 1:1.

[0031] Specifically, it includes the following steps:

[0032] Under nitrogen protection, a palladium precursor and a chiral dinitrogen ligand were added to a sealed tube, followed by the addition of an organic solvent. After stirring at room temperature for 120 minutes, an alkynyl malononitrile compound, a carboxylic acid, an oxidant, and the organic solvent were added under nitrogen. The mixture was stirred at 60°C for 72-98 hours, the solvent was evaporated, and dichloromethane was added to dissolve the residue. A saturated sodium bicarbonate aqueous solution was then added to the mixture, and the mixture was stirred and separated. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Silica gel was added, and the mixture was dried under vacuum. Column chromatography was used to separate the pure chiral cyano-containing all-carbon quaternary carbon cyclic compound.

[0033] The beneficial effects that this application can produce include:

[0034] The method provided in this application enables a palladium-catalyzed tandem reaction of asymmetric acyloxidation cyclization / acyl migration of alkynyl malononitrile with carboxylic acid, yielding optically pure, all-carbon quaternary cyclic compounds containing cyano groups in good yields (enantiomeric ratios up to 96.5:3.5). This invention features a broad substrate range, readily available raw materials, simple and practical operation, and mild reaction conditions. Attached Figure Description

[0035] Figure 1 This is a schematic diagram of the X-ray single crystal structure of compound 3gb. Detailed Implementation

[0036] The present invention is described in detail below through embodiments, but the present invention is not limited to the embodiments described below.

[0037] References for the synthesis of ligand (S)-Ad-Pyox used in the following examples: (a) Poh, J.-S.; Makai, S.; von Keutz, T.; Tran, DN; Battilocchio, C.; Pasau, P.; Ley, S V Angew. Chem. Int. Ed. 2017, 56, 1864-1868. (b) Guo, K.; Han, C.; Xie, X.; Chen, B.; Cao, S.; Yuan, W.; Chen, K.; Liu, F.; Zhu, Y. Chem. Commun. 2022, 58, 13353-13356. (c) Satake, A.; Kadohama, H.; Koshino, H.; Nakata, T. Tetrahedron Lett.1999,40,3597-3600.

[0038] The ligands (R) used in the following examples a Patent No. ZL201410708419.2: A class of axially chiral bipyridine ligands and their synthesis method.

[0039] The ligands (R) used in the following examples p The patent of )-COXPY: A class of planar chiral oxazopyridine ligand compounds based on cycloaryl skeletons and their synthesis methods and applications, patent number: ZL202210468188.7.

[0040] The synthesis of the alkynyl malononitrile compounds used in the following examples is based on the following references: (a) Zeng, G.; Liu, J.; Shao, Y.; Zhang, F.; Chen, Z.; Lv, N.; Chen, J.; Li, R. J. J. G. Chem. 2021, 86, 861-867. (b) Kelley, AM; Frost, JA; Baber, TM; Youngblood, KC; Michishita, E.; Bain, SA; Lykins, TC; Petersen, K. Sterahedron Lett.2022,88,153573.(c)Mills,LR;Graham,JM;Patel,P.;Rousseaux,SALJAm.Chem.Soc.2019,141,19257-19262.(d)Qiu,Y.-F.;Ya ng,F.;Qiu,Z.-H.;Zhong,M.-J.;Wang,L.-J.;Ye,Y.-Y.;Song,B.;Liang,Y.-MJOrg.Chem.2013,78,12018-12028.(e)Wu,W.;Chen,T.;C hen, J.; Han, ann,M.Angew.Chem.Int.Ed.2018,57,15553-15557.(g)Long,J.;Lu,Z.;Li,X.-L.;Xue,P.;Liu,W.-B.Chin.J.Chem.2024,42,873-878.

[0041] Example 1

[0042] Under nitrogen protection, Pd(TFA)2 (0.01 mmol) of trifluoroacetic acid and (S)-tBu-Pyox (0.011 mmol) of chiral dinitrogen ligand were added to a sealed tube, followed by toluene (0.5 mL). After stirring at room temperature for 120 minutes, alkynyl malononitrile compound 1a (0.1 mmol), benzoic acid 2a (0.7 mmol), and toluene (0.5 mL) were added under nitrogen. The mixture was stirred at 60 °C and reacted for 72 hours. The solvent was evaporated, and dichloromethane was added to dissolve the residue. Saturated sodium bicarbonate aqueous solution was then added to the mixture, and the mixture was stirred and separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was then dried under vacuum, and the internal standard trimethoxybenzene (0.1 mmol) was added. The 1H NMR spectrum was measured, and the NMR yield was 55%. The sample was analyzed by high performance liquid chromatography, and the enantiomeric ratio was 92.5:7.5.

[0043] Example 2

[0044] Under nitrogen protection, trifluoroacetic acid Pd(TFA)2 (0.01 mmol) and chiral dinitrogen ligand (S)-tBu-Pyox (0.011 mmol) were added to a Schlenk tube, followed by toluene (0.5 mL). After stirring at room temperature for 120 minutes, alkynyl malononitrile compound 1a (0.1 mmol), benzoic acid 2a (0.7 mmol), and toluene (0.5 mL) were added under nitrogen. The reaction tube was then inserted into an oxygen bulb to collect the reaction mixture. Nitrogen was replaced with oxygen, and the reaction was stirred at 60°C. After 72 hours of reaction, the solvent was evaporated, and dichloromethane was added to dissolve the residue. Then, a saturated sodium bicarbonate aqueous solution was added to the mixture, stirred, and separated. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was then dried under vacuum, and the internal standard trimethoxybenzene (0.1 mmol) was added. The 1H NMR spectrum was measured, and the NMR yield was 59%. The sample was analyzed by high performance liquid chromatography, and the enantiomeric ratio was 92.5:7.5.

[0045] Example 3-20

[0046] Under nitrogen protection, a palladium precursor (0.01 mmol) and a chiral dinitrogen ligand (0.011 mmol) were added to a sealed tube, followed by an organic solvent (0.5 mL). After stirring at room temperature for 120 minutes, an alkynyl malononitrile compound 1a (0.1 mmol), benzoic acid 2a (x mmol), benzoquinone (0.05 mmol), and another organic solvent (0.5 mL) were added under nitrogen. The reaction was carried out at 60 °C with stirring for 72 hours. The solvent was then evaporated, and dichloromethane was added to dissolve the residue. A saturated sodium bicarbonate aqueous solution was then added to the mixture, and the mixture was stirred and separated. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was then dried under vacuum, and the internal standard trimethoxybenzene (0.1 mmol) was added. The NMR yield was obtained by measuring the 1H NMR spectrum, and the enantiomeric ratio was obtained by measuring the enantiomeric ratio by high performance liquid chromatography.

[0047] The types of oxidants, organic solvents, palladium precursors, chiral ligands, and the amount of benzoic acid 2a are detailed in Table 1; er represents the enantiomeric ratio.

[0048]

[0049] Table 1. Conditions and experimental results of Examples 1-20

[0050]

[0051]

[0052]

[0053] Example 21 Palladium-catalyzed asymmetric intermolecular tandem cyclization reaction of alkynyl malononitrile 1a and benzoic acid 2a

[0054] Under nitrogen protection, Pd(TFA)2 (0.02 mmol) of trifluoroacetic acid and the chiral diazaphosphonate ligand (S)-Ad-Pyox (0.022 mmol) were added to a sealed tube, followed by toluene (1.0 mL). After stirring at room temperature for 120 minutes, alkynyl malononitrile compound 1a (0.2 mmol), benzoic acid 2a (1.4 mmol), benzoquinone (0.10 mmol), and toluene (1.0 mL) were added under nitrogen atmosphere, and the mixture was reacted at 60 °C. After stirring and reacting for 72 hours, the solvent was evaporated, and dichloromethane was added to dissolve the residue. Then, a saturated sodium bicarbonate aqueous solution was added to the mixture, stirred, and separated. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Silica gel was added, and the mixture was dried under vacuum. Column chromatography was used to separate the pure chiral cyano-containing all-carbon quaternary carbon cyclic compound 3aa, with a yield of 63%. The sample was analyzed by high performance liquid chromatography, and the enantiomeric ratio was 94.5:5.5.

[0055] Example 22 Palladium-catalyzed asymmetric intermolecular tandem cyclization reaction of alkynyl malononitrile 1b and benzoic acid 2a

[0056] Under nitrogen protection, trifluoroacetic acid Pd(TFA)2 (0.03 mmol) and chiral diazaphosphonate ligand (S)-Ad-Pyox (0.033 mmol) were added to a sealed tube, followed by toluene (1.0 mL). After stirring at room temperature for 120 minutes, alkynyl malononitrile compound 1b (0.2 mmol), benzoic acid 2a (1.4 mmol), and benzoquinone (0.10 mmol) were added under nitrogen. Molecular sieve (50 mg) and toluene (1.0 mL) were stirred at 60 °C and reacted for 98 hours. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate and dichloromethane, and the solvent was evaporated. Dichloromethane was added to dissolve the residue. Saturated sodium bicarbonate aqueous solution was then added to the mixture, stirred, and separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Silica gel was added, and the mixture was dried under vacuum. Column chromatography was used to separate the pure chiral cyano-containing all-carbon quaternary carbon cyclic compound 3ba, with a yield of 66%. The sample was analyzed by high performance liquid chromatography, and the enantiomeric ratio was 90.5:9.5.

[0057] Examples 23-26: Palladium-catalyzed asymmetric intermolecular tandem cyclization reaction of alkynylmalononitrile 1 and benzoic acid 2a

[0058] Under nitrogen protection, trifluoroacetic acid Pd(TFA)2 (0.02 mmol) and chiral diazonium ligand (S)-Ad-Pyox (0.022 mmol) were added to a sealed tube, followed by toluene (1.0 mL). After stirring at room temperature for 120 minutes, alkynyl malononitrile compound 1 (0.2 mmol), benzoic acid 2a (1.4 mmol), benzoquinone (0.10 mmol), and toluene (1.0 mL) were added under nitrogen. The mixture was stirred at 60 °C and reacted for 72 hours. The solvent was evaporated, and dichloromethane was added to dissolve the residue. Saturated sodium bicarbonate aqueous solution was then added to the mixture, and the mixture was stirred and separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Silica gel was added, and the mixture was dried under vacuum. Column chromatography was used to separate the chiral cyano-containing all-carbon quaternary carbon cyclic compounds 3ca, 3da, 3ea, and 3fa. The enantiomeric ratios were obtained by high-performance liquid chromatography.

[0059] Examples 27-31: Palladium-catalyzed asymmetric intermolecular tandem cyclization reaction of alkynylmalononitrile 1 and benzoic acid 2a

[0060] Under nitrogen protection, trifluoroacetic acid Pd(TFA)2 (0.02 mmol) and chiral diazonium ligand (S)-Ad-Pyox (0.022 mmol) were added to a sealed tube, followed by toluene (1.0 mL). After stirring at room temperature for 120 minutes, alkynyl malononitrile compound 1 (0.2 mmol), benzoic acid 2a (5.0 mmol), benzoquinone (0.10 mmol), and toluene (1.0 mL) were added under nitrogen. The mixture was stirred at 60 °C and reacted for 72 hours. The solvent was evaporated, and dichloromethane was added to dissolve the residue. Saturated sodium bicarbonate aqueous solution was then added to the mixture, and the mixture was stirred and separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Silica gel was added, and the mixture was dried under vacuum. Column chromatography was used to separate the pure chiral cyano-containing all-carbon quaternary carbon cyclic compounds 3ga, 3ha, 3ia, 3ja, and 3ka. The enantiomeric ratios were obtained by high-performance liquid chromatography.

[0061] Example 32 Palladium-catalyzed asymmetric intermolecular tandem cyclization reaction of alkynylmalonic acid 1l and benzoic acid 2a

[0062] Under nitrogen protection, trifluoroacetic acid Pd(TFA)2 (0.02 mmol) and chiral diazonium ligand (S)-Ad-Pyox (0.022 mmol) were added to a sealed tube, followed by toluene (1.0 mL). After stirring at room temperature for 120 minutes, alkynyl malononitrile compound 1l (0.2 mmol), benzoic acid 2a (1.4 mmol), benzoquinone (0.10 mmol), and toluene (1.0 mL) were added under nitrogen. The mixture was stirred at 60 °C and reacted for 72 hours. The solvent was evaporated, and dichloromethane was added to dissolve the residue. Saturated sodium bicarbonate aqueous solution was then added to the mixture, and the mixture was stirred and separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Silica gel was added, and the mixture was dried under vacuum. Column chromatography was used to separate the pure chiral cyano-containing all-carbon quaternary carbon cyclic compound 3la in 37% yield. The sample was analyzed by high performance liquid chromatography, and the enantiomeric ratio was 91:9.

[0063] Examples 33-37: Palladium-catalyzed asymmetric intermolecular tandem cyclization reaction of alkynylmalononitrile 1 and benzoic acid 2a

[0064] Under nitrogen protection, trifluoroacetic acid Pd(TFA)2 (0.02 mmol) and chiral diazonium ligand (S)-Ad-Pyox (0.022 mmol) were added to a sealed tube, followed by toluene (1.0 mL). After stirring at room temperature for 120 minutes, alkynyl malononitrile compound 1 (0.2 mmol), benzoic acid 2a (5.0 mmol), benzoquinone (0.10 mmol), and toluene (1.0 mL) were added under nitrogen. The mixture was stirred at 60 °C and reacted for 72 hours. The solvent was evaporated, and dichloromethane was added to dissolve the residue. Saturated sodium bicarbonate aqueous solution was then added to the mixture, and the mixture was stirred and separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Silica gel was added, and the mixture was dried under vacuum. Column chromatography was used to separate the pure chiral cyano-containing all-carbon quaternary carbon cyclic compounds 3ma, 3na, 3oa, 3pa, and 3qa. The enantiomeric ratios were obtained by high-performance liquid chromatography.

[0065] Examples 38-46: Palladium-catalyzed asymmetric intermolecular tandem cyclization reaction of 1 g of alkynyl malononitrile with 2 carboxylic acids

[0066] Under nitrogen protection, Pd(TFA)2 (0.02 mmol) of trifluoroacetic acid and (S)-Ad-Pyox (0.022 mmol) of chiral dinitrogen ligand were added to a sealed tube, followed by toluene (1.0 mL). After stirring at room temperature for 120 minutes, 1 g (0.2 mmol) of an alkynyl malononitrile compound, 5.0 mmol of carboxylic acid 2, and 0.10 mmol of benzoquinone were added under nitrogen. Molecular sieve (50 mg) and toluene (1.0 mL) were stirred at 60 °C and reacted for 72 hours. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate and dichloromethane, and the solvent was evaporated. Dichloromethane was added to dissolve the residue. Saturated sodium bicarbonate aqueous solution was then added to the mixture, stirred, and separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Silica gel was added, and the mixture was dried under vacuum. Column chromatography was used to separate pure chiral cyano-containing all-carbon quaternary carbon cyclic compounds 3gb, 3gc, 3gd, 3ge, 3gf, 3gg, 3gh, 3gi, and 3gj. The corresponding enantiomeric ratios were obtained by high-performance liquid chromatography.

[0067] The chiral, cyano-containing, all-carbon quaternary cyclic compound prepared in the above examples has the following structure:

[0068]

[0069] 3gb single crystal structure of compound Figure 1 As shown; the 3gb crystal of the compound belongs to the orthorhombic crystal system, space group P212121, and cell parameters are... β=90°, Z = 4.

[0070] The characterization data of the compounds in the above embodiments are shown below:

[0071] (-)-N-(5-Benzoyl-3-benzyl-3-cyano-3,6-dihydro-2H-pyran-4-yl)benzamide(3aa):

[0072] 53.6 mg, 63% yield, pale yellow foamy solid, melting range 67-68 °C, new compound, R f = 4.73(d,J=16.5Hz,1H), 4.60(d,J=16.6Hz,1H), 4.14(d,J=11.2Hz,1H), 3.94(d,J=11.3Hz,1H), 3.61(d,J=13.4Hz,1H), 3.29(d,J=13.5Hz,1H). 13 C10 NMR (100MHz, CDCl3) δ 194.5, 165.3, 137.2, 134.3, 133.5, 133.0, 132.8, 132.4, 130.6, 129.1, 128.6, 128.5, 128.4, 128.2, 127.1, 125.3, 118.3, 69.2, 67.4, 42.7, 41.0. HPLC: Chiralpak IC column, 210nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 16.5min and 18.3min (major). HRMS C10 27 H 23 N₂O₃[M+H] + Theoretical value: 423.1703; Actual value: 423.1711.

[0073] (-)-N-(3-Benzyl-3-cyano-5-(2-methylbenzoyl)-3,6-dihydro-2H-pyran-4-yl)benzamide(3ba):

[0074] 57.4 mg, 66% yield, pale yellow foamy solid, melting range 71-72 °C, new compound, R f = 7.41-7.36(m,2H),7.35-7.29(m,2H),7.28-7.21(m,2H),7.20-7.15(m,1H),4.45(d,J=16.1Hz,1H),4.35(d,J=16.1Hz, 1H), 4.06 (d, J = 11.4Hz, 1H), 3.91 (d, J = 13.2Hz, 1H), 3.76 (dd, J = 11.4, 0.8Hz, 1H), 3.22 (d, J = 13.2Hz, 1H), 2.35 (s, 3H). 13 C10 NMR (100MHz, CDCl3) δ 198.7, 165.2, 142.8, 138.1, 135.5, 134.4, 133.2, 132.8, 131.4, 130.9, 130.7, 128.87, 128.85, 128.0, 127.9, 126.4, 125.8, 117.8, 117.3, 68.7, 67.2, 42.1, 39.3, 19.5. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 12.0min and 14.0min (major). HRMS C10 28 H 25 N₂O₃[M+H] + Theoretical value: 437.1860; Actual value: 437.1852.

[0075] (-)-N-(3-Benzyl-3-cyano-5-(3-methylbenzoyl)-3,6-dihydro-2H-pyran-4-yl)benzamide(3ca):

[0076] 55.0 mg, 63% yield, pale yellow foamy solid, melting range 69-70 °C, new compound, R f = 7.28-7.25(m,2H),4.70(d,J=16.5Hz,1H),4.59(d,J=16.5Hz,1H),4.12(d,J=11.3Hz,1 H), 3.92 (d, J = 11.3Hz, 1H), 3.65 (d, J = 13.4Hz, 1H), 3.28 (d, J = 13.4Hz, 1H), 2.33 (s, 3H). 13C10 NMR (100MHz, CDCl3) δ 195.1, 165.3, 138.6, 137.4, 134.39, 134.36, 133.6, 133.1, 132.5, 130.6, 129.1, 128.7, 128.6, 128.3, 128.2, 127.2, 125.5, 124.9, 118.3, 69.2, 67.5, 42.6, 40.8, 21.4. HPLC: Chiralpak IC column, 210nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 16.0min and 17.8min (major). HRMS C10 28 H 25 N₂O₃[M+H] + Theoretical value: 437.1860; Actual value: 437.1868.

[0077] (-)-N-(3-Benzyl-3-cyano-5-(3,5-dimethylbenzoyl)-3,6-dihydro-2H-pyran-4-yl)benzamide(3da):

[0078] 60.4 mg, 67% yield, pale yellow foamy solid, melting range 75-76 °C, new compound, R f = 16.4Hz, 1H), 4.58 (d, J = 16.5Hz, 1H), 4.12 (d, J = 11.3Hz, 1H), 3.91 (d, J = 11.3Hz, 1H), 3.71 (d, J = 13.4Hz, 1H), 3.27 (d, J = 13.4Hz, 1H), 2.31 (s, 6H). 13 C10 NMR (100MHz, CDCl3) δ 195.6, 165.3, 138.3, 137.7, 135.3, 134.5, 134.4, 133.1, 132.4, 130.7, 129.0, 128.6, 128.1, 127.3, 125.8, 124.3, 118.3, 69.3, 67.5, 42.5, 40.6, 21.3. HPLC: Chiralpak IC column, 210nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 14.8min and 16.9min (major). HRMS C10 29 H 27 N₂O₃[M+H] + Theoretical value: 451.2016; Actual value: 451.2022.

[0079] (-)-N-(3-Benzyl-3-cyano-5-(4-methylbenzoyl)-3,6-dihydro-2H-pyran-4-yl)benzamide(3ea):

[0080] 56.8 mg, 65% yield, pale yellow foamy solid, melting range 64-65 °C, new compound, R f = 7.42-7.35(m,4H),7.35-7.28(m,3H),7.18(d,J=8.0Hz,2H),4.71(d,J=16.6Hz,1H),4.59(d,J=16.6Hz,1H), 4.12(d,J=11.2Hz,1H), 3.93(d,J=11.2Hz,1H), 3.61(d,J=13.4Hz,1H), 3.29(d,J=13.5Hz,1H), 2.34(s,3H). 13 C10 NMR (100MHz, CDCl3) δ 194.2, 165.3, 143.9, 134.4, 133.1, 132.9, 132.4, 130.6, 129.3, 129.1, 128.8, 128.6, 128.2, 127.2, 126.1, 118.4, 69.2, 67.5, 42.6, 40.8, 21.8. HPLC: Chiralpak IC column, 210nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 19.5min and 24.5min (major). HRMS C10 28 H 25 N₂O₃[M+H] + Theoretical value: 437.1860; Actual value: 437.1865.

[0081] (-)-N-(3-Benzyl-3-cyano-5-(3-methoxybenzoyl)-3,6-dihydro-2H-pyran-4-yl)benzamide(3fa):

[0082] 59.1 mg, 65% yield, yellow frothy solid, melting range 54-55 °C, new compound, R f = 7.35-7.26(m,5H),7.25-7.20(m,1H),7.03-6.95(m,1H),4.71(d,J=16.5Hz,1H),4.60(d,J=16.5Hz,1H),4 .13(d,J=11.3Hz,1H),3.93(d,J=11.3Hz,1H),3.77(s,3H),3.63(d,J=13.4Hz,1H),3.28(d,J=13.4Hz,1H). 13 C10 NMR (100MHz, CDCl3) δ 194.4, 165.3, 159.8, 138.6, 134.3, 133.9, 133.0, 132.5, 130.6, 129.5, 129.1, 128.6, 128.2, 127.2, 125.4, 120.9, 119.1, 118.3, 112.9, 69.2, 67.4, 55.6, 42.6, 40.9. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 18.5min and 20.7min (major). HRMS C10 28 H 25 N₂O₄[M+H] + Theoretical value: 453.1809; Actual value: 453.1805.

[0083] (-)-N-(3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)benzamide(3ga):

[0084] 55.1 mg, 63% yield, pale yellow foamy solid, melting range 66-67 °C, new compound, R f = 7.11(td,J=8.3,2.4Hz,1H),4.69(d,J=16.5Hz,1H),4.62(d,J=16.6Hz,1H),4.15(d,J =11.2Hz,1H),3.96(d,J=11.2Hz,1H),3.58(d,J=13.5Hz,1H),3.30(d,J=13.5Hz,1H). 13 CNMR (100MHz, CDCl3) δ 192.7 (d, 4 J C-F =2.2Hz), 165.1, 162.5(d, 1 J C-F =246.6Hz), 139.2(d,3 J C-F =6.4Hz),134.3,133.0,132.7,132.5,130.5,130.1(d, 3 J C-F =7.8Hz),129.3,128.6,128.4,127.0,125.3,124.2(d, 4 J C-F =3.0Hz), 119.6(d, 2 J C-F =21.2Hz), 118.2, 115.3 (d, 2 J C-F =22.5Hz),69.4,67.3,42.8,41.5. 19 FNMR (376MHz, CDCl3) δ -111.96. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 12.3min and 13.8min (major). HRMSC 27 H 22 FN2O3[M+H] + Theoretical value: 441.1609; Actual value: 441.1617.

[0085] (-)-N-(3-Benzyl-5-(3-chlorobenzoyl)-3-cyano-3,6-dihydro-2H-pyran-4-yl)benzamide(3ha):

[0086] 50.0 mg, 55% yield, pale yellow foamy solid, melting range 70-71 °C, new compound, R f = 2H),7.47-7.40(m,3H),7.39-7.32(m,2H),7.31-7.21(m,5H),4.74-4.59(m,2H),4.16(d ,J=11.2Hz,1H),3.98(d,J=11.2Hz,1H),3.59(d,J=13.4Hz,1H),3.31(d,J=13.5Hz,1H). 13CNMR (100MHz, CDCl3) δ 192.7, 165.1, 138.9, 134.5, 134.3, 133.2, 132.59, 132.56, 132.5, 130.5, 129.8, 129.4, 128.6, 128.4, 128.3, 127.0, 126.6, 125.1, 118.2, 69.6, 67.3, 42.8, 41.7. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 60 / 40, flow rate = 0.8mL / min, retention times 10.4min and 11.1min (major). HRMS C 27 H 22 ClN2O3[M+H] + Theoretical value 457.1313 35 Cl)and 459.1296( 37 Cl), actual value 457.1320 ( 35 Cl)and 459.1300( 37 Cl).

[0087] (-)-N-(3-Benzyl-5-(3-bromobenzoyl)-3-cyano-3,6-dihydro-2H-pyran-4-yl)benzamide(3ia):

[0088] 50.8 mg, 51% yield, pale yellow foamy solid, melting range 66-67 °C, new compound, R f = 7.37-7.31(m,1H),7.31-7.18(m,5H),4.72-4.56(m,2H),4.16(d,J=11.2Hz, 1H), 3.97 (d, J = 11.2Hz, 1H), 3.58 (d, J = 13.4Hz, 1H), 3.30 (d, J = 13.5Hz, 1H). 13 C10 NMR (100MHz, CDCl3) δ 192.6, 165.1, 139.1, 135.4, 134.2, 133.2, 132.6, 131.1, 130.5, 130.0, 129.4, 128.6, 128.4, 127.0, 125.1, 122.5, 118.1, 69.6, 67.3, 42.8, 41.6. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 80 / 20, flow rate = 0.8mL / min, retention times 20.5min and 22.7min (major). HRMS C1027 H 22 BrN2O3[M+H] + Theoretical value: 501.0808 79 Br)and 503.0792( 81 Br), actual value 501.0809 ( 79 Br)and 503.0792( 81 Br).

[0089] (-)-N-(5-(3-Acetylbenzoyl)-3-benzyl-3-cyano-3,6-dihydro-2H-pyran-4-yl)be nzamide(3ja):

[0090] 52.2 mg, 56% yield, pale yellow foamy solid, melting range 70-71 °C, new compound, R f = 7.54-7.49(m,2H),7.45(t,J=7.7Hz,1H),7.42-7.35(m,3H),7.33-7.28(m,1H),7.25-7.20(m,2H),7.20-7.14(m,2H),4.73 -4.62(m,2H),4.15(d,J=11.3Hz,1H),3.99(d,J=11.3Hz,1H),3.60(d,J=13.4Hz,1H),3.30(d,J=13.5Hz,1H),2.56(s,3H). 13 C10 NMR (100MHz, CDCl3) δ 197.3, 193.4, 165.1, 137.7, 137.1, 134.2, 133.0, 132.8, 132.54, 132.47, 132.0, 130.5, 129.3, 128.8, 128.5, 128.3, 128.0, 127.0, 125.5, 118.2, 69.6, 67.3, 42.8, 41.5, 26.8. HPLC: Chiralpak AD-H column, 230nm, 30℃, n-hexane / isopropanol = 60 / 40, flow rate = 0.8mL / min, retention time 10.3min (major) and 18.0min. HRMS C10 29 H 25 N₂O₄[M+H] + Theoretical value: 465.1809; Actual value: 465.1803.

[0091] (-)-N-(5-(2-Naphthoyl)-3-benzyl-3-cyano-3,6-dihydro-2H-pyran-4-yl)benza mide(3ka):

[0092] 59.8 mg, 63% yield, pale yellow foamy solid, melting range 67-68 °C, new compound, R f = (m,4H),7.42-7.30(m,4H),7.29-7.24(m,2H),7.22-7.14(m,2H),4.78(d,J=16.5Hz,1H),4.67(d,J=16. 6Hz, 1H), 4.17 (d, J = 11.3Hz, 1H), 3.99 (d, J = 11.3Hz, 1H), 3.67 (d, J = 13.4Hz, 1H), 3.33 (d, J = 13.4Hz, 1H). 13 C10 NMR (100MHz, CDCl3) δ 194.5, 165.4, 135.4, 134.5, 134.4, 133.5, 132.9, 132.4, 132.3, 130.6, 129.9, 129.4, 129.1, 128.6, 128.5, 128.2, 127.9, 127.1, 127.0, 125.9, 124.3, 118.4, 69.4, 67.5, 42.7, 41.0. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 18.6min and 23.0min (major). HRMS C10 31 H 28 N3O3[M+H] + Theoretical value: 490.2125; Actual value: 490.2121.

[0093] (-)-N-(3-Benzyl-3-cyano-5-(thiophene-2-carbonyl)-3,6-dihydro-2H-pyran-4-yl)benzamide(3la): 31.4 mg, 37% yield, white frothy solid, melting range 72-73 °C, new compound, R f = (m,5H),7.41-7.29(m,5H),7.07(dd,J=4.8,3.9Hz,1H),4.82(d,J=16.3Hz,1H),4.68(d,J=16.3Hz, 1H), 4.12 (d, J = 11.2Hz, 1H), 3.91 (d, J = 11.2Hz, 1H), 3.63 (d, J = 13.5Hz, 1H), 3.28 (d, J = 13.5Hz, 1H). 13 C10 NMR (100MHz, CDCl3) δ 185.4, 165.4, 142.7, 134.8, 134.3, 133.3, 133.1, 132.8, 132.5, 130.6, 129.1, 128.7, 128.2, 128.1, 127.3, 126.1, 118.4, 69.1, 67.3, 42.6, 40.7. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 17.6min and 23.1min (major). HRMS C10 25 H 21 N₂O₃S[M+H] + Theoretical value: 429.1267; Actual value: 429.1271.

[0094] (+)-N-(3-Cyano-5-(3-fluorobenzoyl)-3-methyl-3,6-dihydro-2H-pyran-4-yl)benzamide(3ma):

[0095] 31.7 mg, 43% yield, white frothy solid, melting range 65-66 °C, new compound, R f = 7.21-7.15(m,1H),4.65(d,J=16.4Hz,1H),4.50(d,J=16.4Hz,1H),4.15(d,J=11.2Hz,1H),3.93(d,J=11.2Hz,1H),1.75(s,3H). 13 C NMR (100MHz, CDCl3) δ 193.5 (d, 4 J C-F =2.0Hz), 165.8, 162.7 (d, 1 J C-F =247.4Hz), 139.3(d, 3 J C-F =6.4Hz),135.9,132.9,132.7,130.4(d,3 J C-F =7.6Hz),129.0,127.4,124.5,124.1(d, 4 J C-F =3.0Hz), 119.88, 119.86 (d, 2 J C-F =21.2Hz), 115.1(d, 2 J C-F =22.5Hz),72.5,67.1,36.6,21.6. 19 F NMR (376MHz, CDCl3) δ-111.29. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 60 / 40, flow rate = 0.8mL / min, retention time 10.0min (major) and 11.3min. HRMS C 21 H 18 FN2O3[M+H] + Theoretical value: 365.1296; Actual value: 365.1303.

[0096] (+)-N-(3-Cyano-5-(3-fluorobenzoyl)-3-phenyl-3,6-dihydro-2H-pyran-4-yl)benzamide(3na):

[0097] 44.9 mg, 53% yield, yellow frothy solid, melting range 76-77 °C, new compound, R f = 7.30-7.22(m,4H),7.19-7.13(m,1H),4.75(s,2H),4.38(d,J=11.4Hz,1H),4.00(d,J=11.4Hz,1H). 13 C NMR (100MHz, CDCl3) δ 192.5 (d, 4 J C-F =2.2Hz), 165.1, 162.7(d, 1 J C-F =246.9Hz), 139.4(d, 3 J C-F =6.4Hz),133.4,132.9,132.5,132.2,130.3(d, 3 J C-F =7.5Hz),129.7,129.5,128.8,126.98,126.96,126.1,124.3(d, 4 JC-F =3.1Hz), 119.7(d, 2 J C-F =21.1Hz), 118.6, 115.3(d, 2 J C-F =22.7Hz), 75.0, 67.3, 47.1. 19 F NMR (376MHz, CDCl3) δ -111.66. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 60 / 40, flow rate = 0.8mL / min, retention times 12.5min (major) and 17.7min. HRMS C 26 H 20 FN2O3[M+H] + Theoretical value: 427.1452; Actual value: 427.1459.

[0098] (-)-N-(3-Cyano-5-(3-fluorobenzoyl)-3-(4-methylbenzyl)-3,6-dihydro-2H-pyran-4-yl)benzamide (3oa): 50.4 mg, 55% yield, yellow foamy solid, melting range 4H),7.11(tdd,J=8.3,2.6,0.8Hz,1H),4.72-4.59(m,2H),4.17(d,J=11.2Hz,1H),3 .99(d,J=11.2Hz,1H),3.53(d,J=13.5Hz,1H),3.28(d,J=13.5Hz,1H),2.32(s,3H). 13 C NMR (100MHz, CDCl3) δ 192.6 (d, 4 J C-F =2.1Hz), 165.0, 162.5(d, 1 J C-F =246.4Hz), 139.1(d, 3 J C-F =6.4Hz),138.4,132.7,132.5,132.4,131.6,130.3,130.1,130.0,128.6,127.0,125.6,124.3(d, 4 J C-F =2.9Hz), 119.6(d, 2 J C-F =21.2Hz), 118.3, 115.3(d, 2 J C-F=22.4Hz),69.7,67.3,42.9,41.5,21.2. 19 F NMR (376MHz, CDCl3) δ-112.18. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 13.5min and 15.6min (major). HRMS C 28 H 24 FN2O3[M+H] + Theoretical value: 455.1765; Actual value: 455.1773.

[0099] (-)-N-(3-([1,1'-Biphenyl]-4-ylmethyl)-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)benzamide (3pa): 59.1 mg, 57% yield, pale yellow foamy solid. Solid, melting range 71-72℃, new compound, R f =0.32 (petroleum ether / acetone 3 / 1), 95.5:4.5er, [α] 20 D = -53.04 (c 1.18, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.78(brs,1H),7.65(d,J=8.3Hz,2H),7.60(d,J=8.3Hz,2H),7. 57-7.50(m,3H),7.48-7.42(m,3H),7.40-7.30(m,3H),7.25-7.20(m,2H),7.20-7.15 (m,2H),7.15-7.09(m,1H),4.72(d,J=16.6Hz,1H),4.66(d,J=16.5Hz,1H),4.22(d,J =11.2Hz,1H),4.02(d,J=11.2Hz,1H),3.65(d,J=13.4Hz,1H),3.36(d,J=13.4Hz,1H). 13 C NMR (100MHz, CDCl3) δ 192.7 (d, 4 J C-F =2.2Hz), 165.1, 162.5(d, 1 J C-F =246.5Hz),141.4,140.2,139.1(d, 3 J C-F=6.3Hz),133.2,132.7,132.6,132.5,130.9,130.2(d, 3 J C-F =7.7Hz),129.0,128.7,127.9,127.8,127.1,126.9,125.3,124.3(d, 4 J C-F =2.8Hz), 119.7(d, 2 J C-F =21.4Hz), 118.2, 115.3 (d, 2 J C-F =22.4Hz),69.6,67.3,42.8,41.4. 19 F NMR (376MHz, CDCl3) δ-112.01. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 14.7min and 17.2min (major). HRMS C 33 H 26 FN2O3[M+H] + Theoretical value: 517.1922; Actual value: 517.1928.

[0100] (-)-N-(3-Cyano-5-(3-fluorobenzoyl)-3-(naphthalen-2-ylmethyl)-3,6-dihydro-2H-pyran-4-yl)benzamide (3qa): 53.4 mg, 54% yield, pale yellow foamy solid. 7.56-7.47(m,3H),7.45-7.39(m,1H),7.33(tt,J=7.3,1.6Hz,1H),7.30-7.24(m,1H),7.13-7.02(m,5H),4.73(d,J=16.5Hz, 1H), 4.65 (d, J = 16.6Hz, 1H), 4.22 (d, J = 11.2Hz, 1H), 4.01 (d, J = 11.2Hz, 1H), 3.76 (d, J = 13.5Hz, 1H), 3.48 (d, J = 13.5Hz, 1H). 13 C NMR (100MHz, CDCl3) δ 192.7 (d, 4 J C-F =2.2Hz), 165.1, 162.5(d, 1 J C-F =247.1Hz), 139.2(d,3 J C-F =6.4Hz),133.5,133.1,132.9,132.4,131.7,130.1(d, 3 J C-F =7.7Hz),129.5,129.2,128.5,128.0,127.9,127.8,126.85,126.81,126.7,125.0,124.2(d, 4 J C-F =3.0Hz), 119.7(d, 2 J C-F =21.4Hz), 118.3, 115.3 (d, 2 J C-F =22.4Hz),69.7,67.3,42.8,41.8. 19 F NMR (376MHz, CDCl3) δ -111.77. HPLC: Chiralpak AD-H column, 230nm, 30℃, n-hexane / isopropanol = 60 / 40, flow rate = 0.8mL / min, retention time 10.5min (major) and 14.2min. HRMS C 31 H 24 FN2O3[M+H] + Theoretical value: 491.1765; Actual value: 491.1761.

[0101] (-)-(R)-N-(3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)acetamide (3gb): 57.7mg, 76% yield, yellow foamy solid, melting range (td,J=8.3,2.4Hz,1H),6.87(brs,1H),4.71(d,J=16.6Hz,1H),4.48(d,J=16.6Hz,1H),4.08(d,J= 11.3Hz,1H),3.87(d,J=11.3Hz,1H),3.40(d,J=13.5Hz,1H),3.23(d,J=13.5Hz,1H),1.56(s,3H). 13 C NMR (100MHz, CDCl3) δ192.1,168.3,162.6(d, 1 J C-F =246.6Hz), 138.9(d, 3 J C-F=6.0Hz),134.1,131.0,130.4,130.2(d, 3 J C-F =7.7Hz),129.1,128.3,124.5(d, 4 J C-F =2.4Hz), 119.9(d, 2 J C-F =21.3Hz), 118.3, 115.5(d, 2 J C-F =22.3Hz),69.0,67.1,42.5,41.1,23.2. 19 F NMR (376MHz, CDCl3) δ -111.82. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 12.9min and 14.6min (major). HRMS C 22 H 20 FN2O3[M+H] + Theoretical value: 379.1452; Actual value: 379.1451.

[0102] (-)-N-(3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)isobutyramide (3gc): 37.4mg, 46% yield, pale yellow foamy solid, melting range [missing information]. 7.20(tdd,J=8.3,2.6,0.9Hz,1H),6.45(brs,1H),4.66(d,J=16.7Hz,1H),4.60(d,J=16.5Hz,1H),4.12(d,J=11.2Hz,1H),3.93(d,J= 11.2Hz,1H),3.44(d,J=13.5Hz,1H),3.27(d,J=13.5Hz,1H),1.87(hept,J=6.9Hz,1H),0.67(d,J=6.9Hz,3H),0.60(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ 191.9 (d, 4 J C-F =2.2Hz), 174.4, 162.6(d, 1 J C-F =246.3Hz), 139.1(d, 3 J C-F=6.4Hz),134.2,130.6,130.4,130.0(d, 3 J C-F =7.7Hz),129.4,128.5,125.9,124.5(d, 4 J C-F =2.9Hz), 119.7(d, 2 J C-F =21.3Hz), 118.3, 115.6 (d, 2 J C-F =22.4Hz),69.5,67.2,42.9,41.9,36.0,18.6,18.5. 19 F NMR (376MHz, CDCl3) δ-112.33. HPLC: Chiralpak ID column, 230nm, 30℃, n-hexane / isopropanol = 60 / 40, flow rate = 0.8mL / min, retention times 11.3min (major) and 14.7min. HRMS C 24 H 24 FN2O3[M+H] + Theoretical value: 407.1765; Actual value: 407.1773.

[0103] (-)-N-(3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)-2-methylbenzamide (3gd): 52.5mg, 58% yield, yellow foamy solid, melting range Hz,1H),7.00(t,J=7.6Hz,1H),6.85(brs,1H),6.45(dd,J=7.6,0.8Hz,1H),4.71(d,J=16.8Hz,1H),4.65(dd,J=16.7,0 .9Hz,1H),4.15(d,J=11.3Hz,1H),3.97(d,J=11.3Hz,1H),3.47(d,J=13.5Hz,1H),3.34(d,J=13.5Hz,1H),2.18(s,3H). 13 C NMR (100MHz, CDCl3) δ 192.1 (d, 4 J C-F =2.1Hz), 167.4, 162.7(d, 1 J C-F =246.9Hz), 138.8(d, 3 J C-F=6.4Hz),137.2,134.0,133.9,131.4,130.9,130.6,130.33(d, 3 J C-F =7.3Hz),130.34,129.3,128.5,127.6,126.0,125.7,124.8(d, 4 J C-F =2.9Hz), 120.1(d, 2 J C-F =21.4Hz), 118.3, 115.7 (d, 2 J C-F =22.4Hz),69.1,67.2,42.8,41.4,19.7. 19 F NMR (376MHz, CDCl3) δ -111.76. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 10.1min and 19.9min (major). HRMS C 28 H 24 FN2O3[M+H] + Theoretical value: 455.1765; Actual value: 455.1770.

[0104] (-)-N-(3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)-3-methylbenzamide (3ge): 55.9 mg, 61% yield, yellow foamy solid, melting range 7.38-7.29(m,2H),7.26-7.21(m,1H),7.18-7.09(m,2H),7.07-6.96(m,2H),4.69(d,J=16.6Hz,1H),4.64(d,J=16.7 Hz,1H),4.16(d,J=11.2Hz,1H),3.98(d,J=11.2Hz,1H),3.57(d,J=13.5Hz,1H),3.31(d,J=13.5Hz,1H),2.29(s,3H). 13 C NMR (100MHz, CDCl3) δ 192.7 (d, 4 J C-F =2.1Hz), 165.4, 162.5(d, 1 J C-F =246.7Hz), 139.2(d, 3 JC-F =6.3Hz),138.6,134.3,133.3,132.72,132.65,130.5,130.1(d, 3 J C-F =7.5Hz),129.3,128.5,128.4,127.6,125.5,124.3(d, 4 J C-F =2.9Hz), 124.0, 119.6(d, 2 J C-F =21.3Hz), 118.2, 115.3(d, 2 J C-F =22.5Hz),69.5,67.3,42.8,41.6,21.3. 19 F NMR (376MHz, CDCl3) δ-112.05. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 12.5min and 14.8min (major). HRMS C 28 H 24 FN2O3[M+H] + Theoretical value: 455.1765; Actual value: 455.1764.

[0105] (-)-N-(3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)-4-methylbenzamide (3gf): 22.4mg, 25% yield, pale yellow foamy solid, melting range (m,3H),4.69(d,J=16.5Hz,1H),4.62(d,J=16.5Hz,1H),4.15(d,J=11.2Hz,1H),3. 96(d,J=11.2Hz,1H),3.58(d,J=13.5Hz,1H),3.30(d,J=13.5Hz,1H),2.34(s,3H). 13 C NMR (100MHz, CDCl3) δ 192.7 (d, 4 J C-F =2.3Hz), 165.0, 162.4(d, 1 J C-F =246.4Hz), 143.2, 139.2 (d, 3 J C-F=6.4Hz),134.2,133.2,130.4,130.0(d, 3 J C-F =7.7Hz),129.8,129.23,129.20,128.3,127.0,124.5,124.1(d, 4 J C-F =2.9Hz), 119.5(d, 2 J C-F =21.3Hz), 118.1, 115.1 (d, 2 J C-F =22.5Hz),69.3,67.2,42.7,41.4,21.5. 19 F NMR (376MHz, CDCl3) δ-112.04. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 15.0min and 17.9min (major). HRMS C 28 H 24 FN2O3[M+H] + Theoretical value: 455.1765; Actual value: 455.1773.

[0106] (-)-N-(3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)-3

[0107]

[0108] -methoxybenzamide (3 gg): 60.6 mg, 64% yield, pale yellow foamy solid, melting range 56-57 °C, new compound, R f =0.35 (petroleum ether / acetone 3 / 1), 95:5e.r., [α] 20 D = -73.76 (c 1.21, CHCl3). 1HNMR(400MHz, CDCl3)δ7.84(brs,1H),7.53-7.47(m,3H),7.44-7.37(m,3H),7.36-7. 30(m,2H),7.19-7.10(m,2H),6.96(dd,J=8.2,2.3Hz,1H),6.93-6.88(m,1H),6.71(d, J=7.6Hz,1H),4.69(d,J=16.6Hz,1H),4.63(d,J=16.6Hz,1H),4.15(d,J=11.2Hz,1H) ,3.96(d,J=11.2Hz,1H),3.75(s,3H),3.57(d,J=13.5Hz,1H),3.30(d,J=13.5Hz,1H). 13 C NMR (100MHz, CDCl3) δ 192.7 (d, 4 J C-F =2.1Hz), 165.1, 162.5(d, 1 J C-F =246.7Hz), 159.8, 139.2 (d, 3 J C-F =6.3Hz),134.2,134.1,132.9,130.4,130.2(d, 3 J C-F =7.8Hz),129.6,129.3,128.4,125.5,124.2(d, 4 J C-F =2.9Hz), 119.7(d, 2 J C-F =21.2Hz),119.0,118.6,118.2,115.3(d, 2 J C-F =22.4Hz),112.2,69.4,67.2,55.5,42.7,41.4. 19 F NMR (376MHz, CDCl3) δ -111.91. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 13.8min and 17.6min (major). HRMS C 28 H 24 FN₂O₄[M+H] + Theoretical value: 471.1715; Actual value: 471.1721.

[0109] (-)-N-(3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)-3-bromobenzamide (3gh): 61.5 mg, 59% yield, white foamy solid, melting range 4.17(d,J=11.2Hz,1H), 4.00(d,J=11.2Hz,1H), 3.58(d,J=13.4Hz,1H), 3.32(d,J=13.5Hz,1H). 13 C NMR (100MHz, CDCl3) δ 192.6 (d, 4 J C-F =2.1Hz), 163.8, 162.5(d, 1 J C-F =246.9Hz), 138.9(d, 3 J C-F =6.4Hz),135.4,134.5,134.2,132.0,130.4,130.25,130.16,129.9,129.5,128.7,127.1,125.6,124.3(d, 4 J C-F =3.1Hz), 122.7, 119.9 (d, 2 J C-F =21.1Hz), 118.2, 115.4 (d, 2 J C-F =22.5Hz),112.2,69.8,67.2,42.8,42.0. 19 F NMR (376MHz, CDCl3) δ -111.80. HPLC: Chiralpak AD-H column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 9.6min (major) and 17.4min. HRMS C 27 H 21 BrFN2O3[M+H] + Theoretical value: 519.0714 79 Br)and 521.0698( 81 Br), actual value 519.0712 ( 79 Br)and 521.0697( 81 Br).

[0110] (+)-2-((3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)carbamoyl)phenyl acetate(3gi): 41.1 mg, 41% yield, white foamy solid, melt 2H),7.24-7.14(m,4H),7.03(d,J=8.2Hz,1H),4.86(d,J=16.7Hz,1H),4.47(d,J=16.8Hz,1H),4.13(d ,J=11.4Hz,1H),3.90(d,J=11.4Hz,1H),3.38(d,J=13.6Hz,1H),3.25(d,J=13.6Hz,1H),2.32(s,3H). 13 C NMR (100MHz, CDCl3) δ 191.7 (d, 4 J C-F =1.7Hz),168.8,163.6,162.7(d, 1 J C-F =246.8Hz), 148.3, 138.9 (d, 3 J C-F =6.1Hz),134.0,133.0,130.5,130.4,130.3,129.7,129.0,128.1,127.6,126.1,125.8,124.6(d, 4 J C-F =3.0Hz), 123.5, 120.1(d, 2 J C-F =21.4Hz), 118.4, 115.5 (d, 2 J C-F =22.5Hz),68.7,67.2,42.7,40.4,21.3. 19 F NMR (376MHz, CDCl3) δ -111.65. HPLC: Chiralpak IC column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 13.2min and 21.5min (major). HRMSC 29 H 24 FN2O5[M+H] + Theoretical value: 499.1664; Actual value: 499.1665.

[0111] (-)-N-(3-Benzyl-3-cyano-5-(3-fluorobenzoyl)-3,6-dihydro-2H-pyran-4-yl)cinnamamide (3gj): 65.9mg, 71% yield, pale yellow solid, melting range 82-83℃, fresh. Hz,1H),6.09(d,J=15.6Hz,1H),4.73(d,J=16.5Hz,1H),4.51(d,J=16.5Hz,1H),4.10(d ,J=11.3Hz,1H),3.90(d,J=11.3Hz,1H),3.50(d,J=13.5Hz,1H),3.28(d,J=13.5Hz,1H). 13 C NMR (100MHz, CDCl3) δ 192.4 (d, 4 J C-F =2.0Hz), 164.0, 162.6(d, 1 J C-F =246.6Hz), 143.8, 139.1 (d, 3 J C-F =6.3Hz),134.1,132.1,130.5,130.4,130.2(d, 3 J C-F =7.6Hz),129.1,128.9,128.2,128.1,125.7,124.5(d, 4 J C-F =2.8Hz), 119.8(d, 2 J C-F =21.2Hz),118.9,118.4,115.5(d, 2 J C-F =22.4Hz),68.9,67.3,42.5,40.7. 19 F NMR (376MHz, CDCl3) δ -111.87. HPLC: Chiralpak AD-H column, 230nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.8mL / min, retention times 12.2min (major) and 20.9min. HRMS C 29 H 24 FN2O3[M+H] + Theoretical value: 467.1765; Actual value: 467.1757.

[0112] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for synthesizing chiral cyano-containing all-carbon quaternary cyclic compounds, characterized in that, Includes the following steps: The solvent, oxidant, alkynyl malononitrile compound, carboxylic acid compound, palladium salt and chiral dinitrogen ligand are mixed, reacted, dried and separated to obtain a chiral cyano-containing all-carbon quaternary carbon cyclic compound.

2. The method according to claim 1, characterized in that, The alkynyl malononitrile compound is selected from at least one of compounds having the structure of Formula I: The carboxylic acid compound is selected from at least one of compounds having the structure of Formula II: The palladium salt is selected from at least one of palladium trifluoroacetate, palladium acetate, or palladium acetylacetonate; The chiral dinitrogen ligand is selected from (S)-AdPyox, (S)-tBuPyox, (S)-iPrPyox, (S)-BnPyox, (S)-PhPyox, (S,R)-InPyox, (R a ,S,S)-C3-ACBP or (R p At least one of )-COXPY; The chiral, cyano-containing, all-carbon quaternary cyclic compound is selected from at least one of compounds having the structure of Formula III: The solvent is selected from at least one of toluene, ethyl acetate, 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane; The oxidant is selected from oxygen and / or benzoquinone.

3. The method according to claim 1, characterized in that, The molar ratio of the carboxylic acid compound to the alkynyl malononitrile compound is 3 to 25:1; The molar ratio of the oxidant to the alkynyl malononitrile compound is 0.1 to 1:1; The molar ratio of the palladium salt to the alkynyl malononitrile compound is 0.1–0.15:1; The molar ratio of the chiral dinitrogen ligand to the alkynyl malononitrile compound is 0.11–0.165:1; The ratio of the solvent to the alkynyl malononitrile compound is 1 ml: 0.1 mmol to 2 ml: 0.1 mmol.

4. The method according to claim 1, characterized in that, The reaction temperature is 60℃~80℃; The reaction time is 72–98 hours.

5. The method according to claim 1, characterized in that, The drying temperature is 20℃~30℃; The drying time is 10 min to 30 min.

6. The method according to claim 1, characterized in that, Includes the following steps: The palladium salt and chiral dinitrogen ligand are mixed with a solvent and stirred. Then, an alkynyl malononitrile compound and a carboxylic acid compound are added, reacted, dried, and separated to obtain the chiral cyano-containing all-carbon quaternary carbon cyclic compound.

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