Preparation method of chiral spiro skeleton and application of chiral spiro skeleton in ligand synthesis

Abstract

The invention relates to the technical field of organic chemistry, in particular to a preparation method of a chiral spiro skeleton and application of the chiral spiro skeleton in ligand synthesizing.The preparation method comprises the following steps that an amido diene compound shown in the formula I and an aldehyde compound shown in the formula III react under the action of a transition metal catalyst and a chiral phosphine ligand, and the chiral spiro skeleton is obtained. The alkenyl-substituted polycyclic nitrogen heterocyclic ring as shown in a formula IV is obtained; or the amido diene compound as shown in the formula II and the aldehyde compound as shown in the formula III are reacted under the action of the transition metal catalyst and the chiral phosphine ligand to obtain the alkenyl-substituted polycyclic nitrogen heterocyclic ring as shown in the formula V. The method is high in atom economy, and water is the only by-product; meanwhile, the system is simple and efficient, the actual operation is simple and convenient, multiple rings are constructed in one step, and the step economy is high; a chiral quaternary carbon center can be constructed, and enantioselectivity is high.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and in particular to a method for preparing a chiral spirocyclic skeleton and its application in ligand synthesis. Background Technology

[0002] Spirocyclic compounds have wide applications in bioactive compounds and molecular catalysts. Among them, polyspirocyclic compounds, as one of the representative spirocyclic compounds, are commonly found in natural products and pharmaceuticals, such as the following compounds:

[0003]

[0004] Studies have found that spirocyclic structures, due to their unique three-dimensional structure and rigid framework, often increase the solubility of compounds and reduce conformational entropy, making the introduction of chiral nitrogen-based spirocyclic compounds crucial for medicinal chemistry research. This skeletal feature also fixes the three-dimensional spatial positions of functional groups, thus expanding the application of spirocyclic compounds in computer-aided drug screening. Furthermore, polyspirocyclic compounds can act as organic catalysts to achieve asymmetric reactions. They can also serve as ligands to realize transition metal-catalyzed organic reactions, demonstrating the broad application potential of these frameworks.

[0005] The synthesis of chiral polyspirocyclic compounds has always been a crucial research area in organic synthetic chemistry. Over the past few decades, chemists have utilized traditional methods such as radical coupling, olefin metathesis, cycloaddition, nucleophilic substitution, and the Pauson-Khand reaction to construct spirocyclic skeletons. However, these methods suffer from drawbacks such as long synthetic steps and low atom economy, significantly limiting their application. In recent years, several asymmetric catalytic reactions for constructing polyspirocyclic compounds have been reported, primarily including tandem reactions catalyzed by small organic molecule catalysts and transition metal-catalyzed azido-acetylation cyclization reactions. However, existing asymmetric synthetic methods still have some shortcomings: 1) complex reactants; 2) difficulties in divergent synthesis; and 3) limited reaction types. Therefore, developing novel catalytic synthetic methods to achieve modular synthesis of chiral polyspirocyclic compounds is of great significance. Summary of the Invention

[0006] In view of this, the technical problem to be solved by the present invention is to provide a method for preparing a chiral spirocyclic framework and its application in ligand synthesis. This method has good substrate adaptability, can prepare a variety of azaspirocyclic structures, and the only byproduct is water, which meets the requirements of green chemistry.

[0007] This invention provides a method for preparing a chiral spirocyclic skeleton, comprising the following steps:

[0008] The aminodiene compound shown in Formula I and the aldehyde compound shown in Formula III are reacted under the action of a transition metal catalyst and a chiral phosphine ligand to obtain the alkenyl-substituted polycyclic nitrogen heterocycle shown in Formula IV; or the aminodiene compound shown in Formula II and the aldehyde compound shown in Formula III are reacted under the action of a transition metal catalyst and a chiral phosphine ligand to obtain the alkenyl-substituted polycyclic nitrogen heterocycle shown in Formula V.

[0009]

[0010] in, Selected from unsaturated rings;

[0011] n1 and n2 are independent integers selected from 0 to 10;

[0012] R 1 R 2 The following groups are independently selected from hydrogen, substituted or unsubstituted: alkyl (C1-C30), cycloalkyl (C3-C30), or aryl (C6-C30);

[0013] R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Independently selected from hydrogen, halogen, substituted or unsubstituted groups of the following: C1-C30 alkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl, nitro, ester or amino; wherein, R 3 and R 4 R 4 and R 5 R 5 and R 6 R 7 and R 8 R 8 and R 9 Or R 9 and R 10 It can be connected as an alicyclic or aromatic ring;

[0014] The substitution is by one or more of the following substituents: halogen, nitro, ester, amino, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl or C4-C30 heteroaryl.

[0015] X is independently selected from O or NR. 11 The R 11Selected from H, alkylsulfonyl groups of C1 to C40, or arylsulfonyl groups of C6 to C60.

[0016] The Preferably, it is a six-membered unsaturated ring, more preferably a six-membered aromatic ring, and most preferably a benzene ring or a pyridine ring.

[0017] The n1 and n2 are independently selected from any integer from 0 to 10, preferably any integer from 0 to 5, and more preferably any integer from 0 to 2. For example, they can be 0, 1 or 2.

[0018] The R 1 R 2 The independent preferred group is hydrogen, or a substituted or unsubstituted group of the following: C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C12 aryl.

[0019] More preferably, the R 1 R 2 Independent protecting groups selected from amino groups, including but not limited to benzyl (Bn), benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (BOC), p-methoxybenzyl (PMB), etc.

[0020] The R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Independently selected from hydrogen, halogen, substituted or unsubstituted groups of the following: C1-C30 alkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl, nitro, ester or amino; wherein, R 3 and R 4 R 4 and R 5 R 5 and R 6 R 7 and R 8 R 8 and R 9 Or R 9 and R 10 It can be connected as an alicyclic or aromatic ring.

[0021] Preferably, the R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10The following groups, selected independently from hydrogen, halogen, substituted or unsubstituted: C1-C3 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C6-C12 aryl, nitro, ester, amino.

[0022] More preferably, the R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 The following groups, selected independently from hydrogen, halogen, substituted or unsubstituted: C1-C3 alkyl, C1-C3 alkoxy, cyclopropyl, cyclobutyl, cyclohexyl or phenyl, nitro, ester, amino.

[0023] More preferably, the R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted groups of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, ester, amino, nitro.

[0024] Among them, R 3 and R 4 R 4 and R 5 R 5 and R 6 R 7 and R 8 R 8 and R 9 Or R 9 and R 10 It can be connected as a C5-C10 alicyclic ring or a C6-C12 aromatic ring, preferably as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl ring.

[0025] Preferably, the above substitution is performed by one or more of the following substituents: halogen, nitro, ester, amino, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl or C4-C30 heteroaryl.

[0026] More preferably, the above substitution is by one or more of the following substituents: halogen, nitro, ester, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl or C4-C12 heteroaryl.

[0027] More preferably, the above substitution is performed by one or more of the following substituents: halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, phenyl.

[0028] In this invention, the ester group refers to -COO-Rx, and the Rx is preferably a substituted or unsubstituted C1 to C30 alkyl group, more preferably a substituted or unsubstituted C1 to C6 alkyl group, and even more preferably a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl group.

[0029] X is independently selected from O or NR. 11 .

[0030] Preferably, the R 11 Selected from H, C1-C40 alkylsulfonyl groups or C6-C60 arylsulfonyl groups; more preferably, the R 11 Selected from H, C1-C10 alkylsulfonyl groups or C6-C12 arylsulfonyl groups, more preferably, the R 11 Selected from H, C1-C6 alkylsulfonyl groups, or C6-C12 arylsulfonyl groups. In some specific embodiments, the R... 11 Selected from H, p-toluenesulfonyl or methanesulfonyl.

[0031] In some specific embodiments, the aminodiene compound represented by Formula I has any of the following structures:

[0032] ;

[0033] R 1 The scope is the same as described above.

[0034] In some specific embodiments, the aminodiene compound represented by Formula I has any of the following structures:

[0035]

[0036] In some specific embodiments, the aminodiene compound represented by Formula II has the following structure:

[0037]

[0038] R 2 The scope is the same as described above.

[0039] In some specific embodiments, the aminodiene compound represented by Formula II has the following structure:

[0040]

[0041] In some specific embodiments, the aldehyde compound represented by Formula III has any of the following structures:

[0042] .

[0043] The above preparation method is preferably carried out in a protective atmosphere. The present invention does not impose any special limitation on the protective atmosphere, which can be a protective atmosphere well known to those skilled in the art, including but not limited to nitrogen, argon, etc.

[0044] The transition metal catalyst is preferably a transition metal catalyst containing palladium, including but not limited to one or more of palladium chloride, palladium bromide, palladium iodide, palladium acetate, palladium trifluoroacetate, palladium diacetonitrile chloride, allyl palladium chloride, palladium acetylacetonate, and tris(dibenzylindeneacetone)palladium; in a preferred embodiment of the present invention, the transition metal catalyst is preferably palladium acetate, palladium bromide, palladium trifluoroacetate, allyl palladium chloride, or palladium acetylacetonate.

[0045] The preferred chiral phosphine ligands are 5-(11bS)-5H-bibenzo[b,f]aza-4-binaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphatidyl, (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphatidylcycloheptyl-4-yl)-5H-dibenzo[B,F]azapyrrolidone, (R)-(6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine), (S)-N,N-dimethyl-1-[(R)-2-(diphenylphosphino)ferrocene]ethylamine, (R)-6, One or more of 6'-bis(diphenylphosphine)-2,2',3,3'-tetrahydro-5,5'-di-1,4-benzodioctyl; in a preferred embodiment of the present invention, the chiral phosphine ligand is preferably 5-(11bS)-5H-bibenzo[b,f]aza-4-binaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphatidyl or (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphatidyl-4-yl)-5H-dibenzo[B,F]azapyrrolidone.

[0046] The solvent for the reaction is preferably one or more of tetrahydrofuran, trifluorotoluene, dichloromethane, dichloroethane, chlorobenzene, N,N-dimethylformamide, acetonitrile, and toluene, more preferably dichloromethane or trifluorotoluene.

[0047] Preferably, the amount of the transition metal catalyst is 0.1% to 10% of the molar amount of the aminodiene compound shown in Formula I, more preferably 1% to 5%.

[0048] The amount of the chiral phosphine ligand is preferably 0.2% to 20% of the molar amount of the aminodiene compound shown in Formula I, more preferably 1% to 15%.

[0049] The amount of the transition metal catalyst is preferably 0.1% to 10% of the molar amount of the aminodiene compound shown in Formula II, more preferably 1% to 5%.

[0050] The amount of the chiral ligand is preferably 0.2% to 20% of the molar amount of the aminodiene compound shown in Formula II, more preferably 1% to 15%.

[0051] The molar ratio of the transition metal catalyst to the chiral phosphine ligand is preferably 1.5:1 to 1:1.5; more preferably 1:1 to 1:1.3.

[0052] The reaction temperature is preferably 0~100℃; more preferably 40~80℃, and for example, it can be 40, 50, 60, 70, or 80℃.

[0053] The reaction time is preferably 0~48h; more preferably 12~36h, and for example, it can be 12, 24, or 36h.

[0054] Vacuum degassing is preferred before the reaction.

[0055] After the reaction, the mixture is preferably cooled to room temperature and purified by column chromatography to obtain an alkenyl-substituted polyspirocyclic nitrogen heterocycle as shown in formula (IV) or (V).

[0056] The eluent for column chromatography purification is preferably petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is selected according to the type of X; when X is O, the volume ratio of petroleum ether to ethyl acetate is preferably (5-30):1, more preferably (10-20):1, and even more preferably 15:1; when X is NR... 10 When the volume ratio of petroleum ether to ethyl acetate is preferably (3-5):1.

[0057] The present invention also provides a chiral spirocyclic skeleton compound having the structure shown in Formula IV or Formula V:

[0058]

[0059] in, n1, n2, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 The range of X is as described above.

[0060] In some specific embodiments, the chiral spirocyclic skeleton compound has any of the following structures:

[0061] .

[0062] This invention uses the above-mentioned chiral spirocyclic skeleton compounds as raw materials and, through multiple transformation steps, prepares a series of azaspirocyclic chiral ligands with the structures shown in Formulas VI to XI:

[0063]

[0064] Wherein, n1, n2, R 1 R 8 R 9 R 10 The range of X is the same as described above;

[0065] R 5’ R 6’ Each group is independently selected from the following substituted or unsubstituted groups: C1-C30 alkyl, C3-C30 cycloalkyl, C6-C30 aryl, or C4-C30 heteroaryl; preferably, R 5’ R 6’ Each group is independently selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C12 aryl, or C4-C12 heteroaryl; more preferably, R 5’ R 6’ Each of the following groups, individually selected from substituted or unsubstituted groups, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl.

[0066] R 7’ R 8’ The following groups, individually selected from hydrogen, substituted or unsubstituted: C1–C30 alkyl, C3–C30 cycloalkyl, C6–C30 aryl, or C4–C30 heteroaryl; R 7’ and R 8’ It can be connected as an alicyclic or aromatic ring; preferably, R7’ R 8’ The following groups, individually selected independently from hydrogen, substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C12 aryl or C4-C12 heteroaryl; R 7’ and R 8’ It can be connected as a C5-C10 alicyclic ring or a C6-C12 aromatic ring; more preferably, R 7’ R 8’ The following groups, individually selected from hydrogen, substituted or unsubstituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or pyridyl. 7’ and R 8’ It can be linked as cyclopentyl, cyclohexyl, phenyl, or naphthyl.

[0067] R 9’ R 10’ Each group is independently selected from the following substituted or unsubstituted groups: C1-C30 alkyl, C3-C30 cycloalkyl, C6-C30 aryl, or C4-C30 heteroaryl; preferably, R 9’ R 10’ Each group is independently selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C12 aryl, or C4-C12 heteroaryl; more preferably, R 9’ R 10’ Each of the following groups, individually selected from substituted or unsubstituted groups, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl.

[0068] The substitution is performed by one or more of the following substituents: halogen, nitro, amino, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl, or C4-C30 heteroaryl; preferably, the substitution is performed by one or more of the following substituents: halogen, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, or C4-C12 heteroaryl; more preferably, the substitution is performed by one or more of the following substituents: halogen, nitro, amino, ester, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, phenyl.

[0069] The ester groups mentioned above are the same as those described previously.

[0070] * indicates that the absolute configuration of the chiral carbon atom in the oxazoline structure is either R or S configuration.

[0071] In some specific embodiments, the azaspirocyclic chiral ligand has any of the following structures:

[0072] .

[0073] The present invention also provides a method for preparing the above-mentioned azaspirocyclic chiral ligand.

[0074] When the R 5’ R 6’ When the ligand is aryl, the preparation method of the polyspirocyclic chiral phosphorus nitrogen ligand of formula VI includes the following steps:

[0075]

[0076] Starting with the spirocyclic compound in Formula IV, hydrogenation was carried out under ruthenium catalysis to obtain hydrogenated azaspirocyclic 2;

[0077] Hydrogenated azaspirocyclic 2 is deprotected by sulfuric acid to give spirocyclic phenol 3;

[0078] Spirocyclic phenol 3 reacts with trifluoromethanesulfonic anhydride to give spirocyclic sulfonate 4;

[0079] Sulfonate 4 undergoes a coupling reaction with diarylphosphine oxide under palladium catalysis to yield a spirocyclic pentavalent phosphine structure 5;

[0080] The above-mentioned spirocyclic pentavalent phosphine structure 5 was reduced by trichlorosilane to obtain nitrogen heterocyclic polyspirocyclic phosphorus nitrogen ligand 6.

[0081] When the R 1 When the group is benzyl, the method for preparing the chiral spirocyclic skeleton compound represented by Formula VII includes the following steps:

[0082]

[0083] Starting with the spirocyclic compound in Formula IV, hydrogenation under palladium catalysis yields hydrogenated azaspirocyclic compound 8;

[0084] The hydrogenated azaspirocyclic 8 was debenzed under the action of palladium on carbon and hydrogen to give spirocyclic secondary amine intermediate 9;

[0085] The above-mentioned spirocyclic secondary amine 9 reacts with di-tert-butyl dicarbonate to obtain the protected secondary amine intermediate 10;

[0086] The above intermediate 10 undergoes ester hydrolysis under alkaline conditions to yield benzoic acid intermediate 11;

[0087] Intermediate 13 was prepared by reacting benzoic acid intermediate 11 with amino alcohol compound 12 under the action of a condensing agent.

[0088] The above intermediate 13 was dehydrated by methanesulfonyl chloride to obtain oxazoline intermediate 14;

[0089] The above-mentioned oxazoline intermediate 14 was finally deprotected to obtain the polyspirocyclic oxazoline ligand 15.

[0090] Using the synthesized 15 as a starting material, the spirocyclic oxazoline phosphorus nitrogen ligand shown in Formula VIII was obtained according to the following synthetic route:

[0091]

[0092] When the R 1 When the group is benzyl, the method for preparing the chiral spirocyclic skeleton compound represented by Formula IX includes the following steps:

[0093]

[0094] Starting from the synthesized compound 5, debenzylation was carried out under the action of palladium on carbon and hydrogen to obtain spirocyclic secondary amine intermediate 17;

[0095] The above-mentioned spirocyclic secondary amine intermediate 17 was reduced by trichlorosilane to obtain nitrogen-containing polyspirocyclic phosphide 18;

[0096] Chiral spirocyclic diphosphorus ligand 19 was obtained under the action of disubstituted phosphorus chloride.

[0097] When the R 1 It is benzyl. The preparation method of the chiral spirocyclic skeleton compound of formula X, which is a pyridine ring, includes the following steps:

[0098]

[0099] Starting with the spirocyclic compound in Formula IV, hydrogenation was carried out under ruthenium catalysis to obtain hydrogenated azaspirocyclic compound 20;

[0100] Starting with the synthesized compound 20, debenzylation was performed under the action of palladium on carbon and hydrogen to obtain spirocyclic secondary amine intermediate 21;

[0101] The above-mentioned spirocyclic secondary amine intermediate 21 was subjected to disubstituted phosphorus chloride to obtain chiral spirocyclic pyridine phosphorus ligand 22.

[0102] When the R 5’ R 6’ When the ligand is aryl, the preparation method of the multispirocyclic chiral phosphorus-nitrogen ligand shown in Formula XI includes the following steps:

[0103]

[0104] Starting with the spirocyclic compound in Formula IV, hydrogenation was carried out under palladium catalysis to obtain hydrogenated azaspirocyclic 23.

[0105] The above-mentioned azaspirocyclic 23 was reduced by lithium aluminum hydride to obtain spirocyclic benzyl alcohol intermediate 24;

[0106] The above-mentioned spirocyclic benzyl alcohol intermediate 24 undergoes a chlorination reaction with thionyl chloride to give intermediate benzyl chloride 25;

[0107] The above intermediate benzyl chloride 25 undergoes a nucleophilic substitution reaction with a borane-protected phosphine hydrogen to give chiral phosphine intermediate 26;

[0108] Chiral phosphine intermediate 26 was deprotected by triethylenediamine to prepare chiral spirocyclic pyridine phosphine ligand 27.

[0109] This invention also provides the application of the above-mentioned azaspirocyclic chiral ligands in transition metal-catalyzed asymmetric allyl substitution, hydrogenation, hydroamylation, carboamylation, and carbonylation reactions.

[0110] Specifically, the present invention provides a chiral catalyst comprising the above-mentioned azaspirocyclic chiral ligand and a transition metal catalyst.

[0111] The preferred molar ratio of the azaspirocyclic chiral ligand to the transition metal catalyst is (1~1.5):1.

[0112] The transition metals include, but are not limited to, one or more of the following: rhodium di(1,5-cyclooctadiene)tetrafluoroborate ([Rh(COD)2]BF4), ruthenium trichloride, tris(triphenylphosphine) dichloride, p-methylisopropylbenzene ruthenium(II) dichloride dimer, (1,5-cyclooctadiene) dichloride, palladium chloride, palladium acetylacetonate, tetratriphenylphosphine palladium, bis(triphenylphosphine) dichloride palladium, allyl palladium chloride, palladium acetate, palladium diacetonitrile chloride, palladium iodide, palladium bromide, and palladium trifluoroacetate.

[0113] In the above-mentioned asymmetric allyl substitution, hydrogenation, hydroamylation, carbamate, and carbonylation reactions, the amount of the azaspirocyclic chiral ligand added is preferably 1% to 15% of the molar amount of the reactants, more preferably 6%; the amount of the transition metal catalyst added is preferably 1% to 10% of the molar amount of the reactants, more preferably 5%.

[0114] In the above-mentioned asymmetric allyl substitution, hydrogenation, hydroamination, carboamineation, and carbonylation reactions, the reaction temperature is preferably 15~40℃, more preferably 15~25℃, and can be, for example, 15, 20, 25, 30, 35, or 40℃. The reaction time is preferably 4~24h, more preferably 8~12h, and can be, for example, 8, 12, 18, or 24h.

[0115] In some specific embodiments, the chiral spirocyclic ligands prepared in this invention are applied to the asymmetric substitution reaction of allyl acetate, exhibiting excellent catalytic performance and achieving high yields and selectivity.

[0116] Compared with existing technologies, this invention provides a method for preparing a chiral spirocyclic framework. The method is highly atom-economical, with water as the only byproduct. At the same time, the system is simple, efficient, and easy to operate. Multiple rings can be constructed in one step, resulting in high step economy. Furthermore, it can construct chiral quaternary carbon centers with high enantioselectivity. In addition, the nitrogen-containing heterocyclic framework constructed by this invention has multiple controllable groups and can undergo various functional group transformations, providing a platform for the subsequent development of novel spirocyclic ligands.

[0117] This invention also provides a class of azaspirocyclic ligands having the structures shown in formulas (VI-XI). These chiral ligands can form chiral catalysts with transition metals, exhibiting excellent catalytic performance. The ligands provided by this invention have a rigid structure, providing a stable coordination environment and improving catalyst efficiency. The nitrogen atoms in this azaspirocyclic framework can coordinate with metal catalysts and also form hydrogen bonds with certain reaction feedstocks, acting as a proton shuttle, and hold promise for application in asymmetric catalytic reactions with certain inert substrates. Attached Figure Description

[0118] Figure 1 The above is the 1H NMR spectrum of the azaspirocyclic compound obtained in Example 1 of this invention;

[0119] Figure 2 The image shows the carbon NMR spectrum of the azaspirocyclic compound obtained in Example 1 of this invention.

[0120] Figure 3 The high-performance liquid chromatogram of the azaspirocyclic compound obtained in Example 1 of this invention;

[0121] Figure 4 The 1H NMR spectrum of the spirocyclic phosphorus nitrogen ligand obtained in Example 19 of this invention;

[0122] Figure 5 The image shows the phosphine NMR spectrum of the spirocyclic phosphorus nitrogen ligand obtained in Example 19 of this invention.

[0123] Figure 6 The image shows the 1H NMR spectrum of the spirocyclic oxazoline ligand obtained in Example 28 of this invention. Detailed Implementation

[0124] To further illustrate the present invention, a detailed description is provided below with reference to embodiments. However, it should be understood that these descriptions are merely for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims.

[0125] There are no particular restrictions on the source of any raw materials used in this invention; they can be purchased from the market or prepared using conventional methods known to those skilled in the art.

[0126] Example 1

[0127]

[0128] Under a nitrogen atmosphere, palladium acetylacetone (3.0 mg), 5-(11bS)-5H-biphenyl[b,f]aza-4-binaphthene[2,1-d:1',2'-f][1,3,2]dioxaphosphatide (12.2 mg), and dichloromethane (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (45 mg) and salicylaldehyde (30 mg) were added, the mixture was degassed under vacuum, and stirred at 80 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 23% yield with 93% enantioselectivity.

[0129] The nitrogen-containing spirocyclic compound obtained in Example 1 was analyzed using nuclear magnetic resonance (NMR), and its proton NMR spectrum is shown below. Figure 1 As shown, its carbon NMR spectrum was obtained as follows. Figure 2 As shown, the results are as follows:

[0130] 1 H NMR (400 MHz, CDCl3) δ7.24(d, J=5.0 Hz, 4H), 7.22–7.10(m, 3H), 6.86–6.75 (m, 2H), 5.96–5.79 (m, 2H), 5.00–4.90 (m, 1H), 3.98 (d, J=13.5 Hz,1H), 3.19 (d, J = 11.0 Hz, 2H), 2.82 (dt, J = 11.5, 4.4 Hz, 1H), 2.18 – 2.02(m, 3H), 1.97 (dt, J = 13.7, 4.6 Hz, 1H), 1.76–1.65 (m, 1H), 1.56 (q, J =4.4, 3.8 Hz, 2H), 1.32–1.23 (m, 1H), 1.13 (dt, J = 13.4, 4.8 Hz, 1H); 13C NMR(101 MHz, CDCl3) δ 153.4, 141.1, 131.5, 130.6, 128.9, 128.3, 128.1, 126.5,126.3, 122.2, 119.0, 116.5, 72.6, 65.5, 58.9, 50.6, 33.7, 30.8, 29.1, 22.1,20.8;HRMS (ESI) calcd for C 23 H 26 NO [M+H] + : 332.2009, found: 332.2005.

[0131] The azaspirocyclic compound obtained in Example 1 was analyzed using high performance liquid chromatography (HPLC), and its HPLC chromatogram is shown below. Figure 3 As shown.

[0132] Example 2

[0133]

[0134] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and dichloromethane (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (45 mg) and salicylaldehyde (30 mg) were added, the mixture was degassed under vacuum, and stirred at 80 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 78% yield with 94% enantioselectivity.

[0135] Example 3

[0136]

[0137] Under a nitrogen atmosphere, palladium acetate (2.2 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazenecyclohep-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg) and dichloromethane (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (45 mg) and salicylaldehyde (30 mg) were added, and the mixture was degassed under vacuum and stirred at 80 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 75% yield with 98% enantioselectivity.

[0138] Example 4

[0139]

[0140] Under a nitrogen atmosphere, palladium bromide (2.7 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazenecyclohepten-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and dichloromethane (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (45 mg) and salicylaldehyde (30 mg) were added, the mixture was degassed under vacuum, and stirred at 80 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 23% yield with an enantioselectivity of 83%.

[0141] Example 5

[0142]

[0143] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (45 mg) and salicylaldehyde (30 mg) were added, the mixture was degassed under vacuum, and stirred at 80 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 90% yield with 94% enantioselectivity.

[0144] Example 6

[0145]

[0146] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (45 mg) and salicylaldehyde (30 mg) were added, the mixture was degassed under vacuum, and stirred at 70 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 92% yield with 99% enantioselectivity.

[0147] Example 7

[0148]

[0149] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (45 mg) and 2-hydroxy-5-methoxybenzaldehyde (36 mg) were added, the mixture was degassed under vacuum, and stirred at 70 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 15:1) was performed to give the azaspirocyclic compound in 62% yield with 98% enantioselectivity.

[0150] The nitrogen-containing spirocyclic compounds obtained in Example 7 were analyzed using nuclear magnetic resonance, and the results were as follows: 1H NMR(400 MHz, CDCl3) δ 7.31–7.21 (m, 4H), 7.18 (t, J = 6.5 Hz, 1H), 6.85 (s, 1H), 6.81–6.69 (m, 2H), 5.92–5.78 (m, 2H), 4.81 (s, 1H), 4.05 (d, J = 13.6 Hz, 1H), 3.75 (s, 3H), 3.41–3.21 (m, 2H), 2.79 (dt, J = 9.9, 4.5 Hz, 1H), 2.24–2.13 (m, 1H), 2.12–2.02 (m, 2H), 1.95 (dt, J = 13.6, 5.3 Hz, 1H), 1.80 (s,1H), 1.64–1.47 (m, 2H), 1.32–1.26 (m, 1H), 1.16 (dt, J = 13.1, 5.3 Hz, 1H); 13 CNMR (101 MHz, CDCl3) δ 152.6, 147.4, 141.1, 130.2, 128.3, 128.1, 126.9,126.6, 123.4, 117.0, 116.2, 114.3, 73.4, 64.7, 59.2, 55.7, 49.7, 33.7, 30.8,29.2, 22.2, 20.4;HRMS (ESI) calcd for C 24 H 28 NO2 [M+H] + : 362.2115, found:362.2119.

[0151] Example 8

[0152]

[0153] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (43 mg) and salicylaldehyde (30 mg) were added, the mixture was degassed under vacuum, and stirred at 70 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 86% yield with enantioselectivity >99%.

[0154] The nitrogen-containing spirocyclic compound obtained in Example 8 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.29–7.12 (m, 7H), 6.99–6.80 (m, 2H), 6.11–6.00 (m, 1H), 6.00–5.89 (m, 1H), 4.49 (d, J = 5.0 Hz, 1H), 4.32 (d, J = 12.5 Hz, 1H), 3.12(dd, J = 12.5, 2.3 Hz, 1H), 2.96–2.83 (m, 2H), 2.25–2.13 (m, 3H), 1.83–1.73(m, 1H), 1.71–1.63 (m, 1H), 1.62–1.56 (m, 1H), 1.30 (dt, J = 13.7, 4.5 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 153.6, 139.9, 133.7, 132.1, 129.1, 128.5,128.1, 126.7, 124.1, 120.1, 119.4, 116.7, 72.1, 68.4, 57.3, 50.7, 40.0, 30.7,25.6, 23.7;HRMS (ESI) calcd for C 22 H 24 NO [M+H] + : 318.1852, found: 318.1853.

[0155] Example 9

[0156]

[0157] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (45 mg) and 3-hydroxy-2-pyridinecarboxaldehyde (30 mg) were added, followed by degassing under vacuum and stirring at 70 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 10:1) was performed to give the azaspirocyclic compound in 42% yield with 98% enantioselectivity.

[0158] The nitrogen-containing spirocyclic compound obtained in Example 9 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (500 MHz, CDCl3) δ 8.20 (dd, J = 4.0, 2.0 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.26 – 7.21 (m, 1H), 7.09 – 7.03 (m, 2H), 5.97 –5.84 (m, 2H), 4.57 (d, J = 13.2 Hz, 1H), 4.19 (d, J = 5.1 Hz, 1H), 3.88 (d, J= 13.2 Hz, 1H), 3.80 (s, 1H), 3.16 – 3.09 (m, 1H), 2.43 (td, J = 12.7, 2.8Hz, 1H), 2.04 – 1.95 (m, 3H), 1.94 – 1.82 (m, 2H), 1.48 – 1.41 (m, 1H), 1.18– 1.06 (m, 2H); 13 C NMR (126 MHz, CDCl3) δ 149.8, 145.5, 141.2, 140.2, 132.3,129.6, 128.0, 126.6, 124.2, 123.0, 122.5, 78.2, 65.7, 57.1, 52.4, 36.0, 31.0,21.9, 20.2, 18.9;HRMS (ESI) calcd for C 22 H 25 N2O [M+H] + : 333.1961, found:333.1967.

[0159] Example 10

[0160]

[0161] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (55 mg) and salicylaldehyde (30 mg) were added, the mixture was degassed under vacuum, and stirred at 70 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 81% yield with 98% enantioselectivity.

[0162] The nitrogen-containing spirocyclic compound obtained in Example 10 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, CDCl3) δ 7.62 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 7.3 Hz, 3H), 7.34(t, J = 7.3 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.24–7.19 (m, 1H), 7.08–7.01(m, 2H), 6.94–6.87 (m, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.69 (dd, J = 8.1, 1.1Hz, 1H), 5.86–5.68 (m, 2H), 5.41–5.31 (m, 1H), 4.44 (s, 1H), 4.38 (s, 2H), 3.79 (d, J = 16.0 Hz, 1H), 3.59 (d, J = 16.0 Hz, 1H), 2.57–2.47 (m, 1H), 2.20–2.08 (m, 2H), 1.96–1.85 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 153.2, 139.3,138.3, 134.2, 128.9, 128.8, 127.5, 127.4, 127.3, 126.8, 126.1, 125.7, 125.5,124.7, 124.7, 122.6, 119.2, 116.3, 75.9, 60.4, 53.0, 46.7, 36.9, 33.0, 22.4;HRMS (ESI) calcd for C 27 H 26 NO [M+H]+ : 380.2009, found: 380.2014.

[0163] Example 11

[0164]

[0165] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyridine (12.4 mg) and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (45 mg) and N-(2-formylphenyl)-p-toluenesulfonamide (66 mg) were added, the mixture was degassed under vacuum, and stirred at 70 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 10:1) was performed to give the azaspirocyclic compound in 74% yield with 96% enantioselectivity.

[0166] The nitrogen-containing spirocyclic compound obtained in Example 11 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(500 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.32 – 7.25 (m, 5H), 7.18 (t, J= 6.7 Hz, 1H), 7.11 (dd, J = 20.9, 7.9 Hz, 4H), 7.00 (t, J = 7.4 Hz, 1H), 6.03 (d, J = 9.3 Hz, 1H), 5.78 (dd, J = 9.9, 5.0 Hz, 1H), 4.95 (s, 1H), 3.54 (d, J = 13.6 Hz, 1H), 2.98 – 2.84 (m, 3H), 2.32 (s, 3H), 1.99 – 1.78 (m, 5H),1.55 (d, J = 8.1 Hz, 1H), 1.20 – 1.12 (m, 1H), 1.02 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 143.1, 139.2, 139.1, 135.7, 131.7, 129.4, 129.0, 128.8, 128.4,128.1, 127.8, 127.2, 126.5, 123.9, 71.9, 59.7, 54.0, 52.4, 39.0, 31.9, 30.9,21.5, 21.19, 21.15;HRMS (ESI) calcd for C 30 H 33 N₂O₂S [M+H] + : 485.2257, found:485.2260.

[0167] Example 12

[0168]

[0169] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyridine (12.4 mg) and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (55 mg) and N-(2-formylphenyl)-p-toluenesulfonamide (66 mg) were added, the mixture was degassed under vacuum, and stirred at 70 °C for 12 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 10:1) was performed to give the azaspirocyclic compound in 70% yield with 94% enantioselectivity.

[0170] The nitrogen-containing spirocyclic compound obtained in Example 12 was analyzed using nuclear magnetic resonance, and the results were as follows: 11H NMR (400 MHz, CDCl3) δ 7.67 – 7.59 (m, 2H), 7.31 (t, J = 7.0 Hz, 4H), 7.26 (t, J = 7.4 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.95 – 6.84 (m, 2H), 6.83 – 6.76 (m, 3H), 6.66 (d, J = 8.2 Hz, 2H), 5.76 – 5.68 (m, 2H), 5.59 (d, J = 10.8 Hz, 1H), 4.38 (s, 1H), 4.17 – 4.05 (m, 2H), 3.35 (d, J = 16.3 Hz, 1H), 3.24 (d, J = 16.3 Hz, 1H), 2.36 (dd, J = 12.9, 5.4 Hz, 1H), 2.24 – 2.17 (m, 1H), 2.15 (s, 5H); 13 13C NMR (101 MHz, CDCl3) δ 143.3, 140.0, 139.9, 136.2, 136.2, 135.7, 130.6, 130.1, 130.0, 129.4, 129.3, 128.5, 128.5, 127.9, 127.7, 127.4, 127.2, 127.1, 126.8, 126.3, 122.9, 119.0, 60.0, 56.7, 47.0, 37.3, 35.6, 23.4, 21.4; HRMS (ESI) calcd for C 34 H 33 N2O2S [M+H] + : 533.2257, found: 533.2271。

[0171] Example 13

[0172]

[0173] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (48 mg) and a salicylaldehyde derivative (44 mg) were added, followed by degassing under vacuum and stirring at 70 °C for 24 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 70% yield with 99% enantioselectivity.

[0174] The nitrogen-containing spirocyclic compound obtained in Example 13 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, CDCl3) δ 7.28-7.06 (m, 6H), 6.62 (t, J = 7.8 Hz, 2H), 6.03 (dt, J =9.7, 3.3 Hz, 1H), 5.98-5.89 (m, 1H), 5.20 (s, 2H), 4.57 (d, J = 5.1 Hz, 1H), 4.14 (d, J = 13.1 Hz, 1H), 3.46 (d, J = 17.7 Hz, 4H), 3.28 (d, J = 13.2 Hz, 1H), 2.87 (td, J = 9.2, 3.6 Hz, 1H), 2.33-2.22 (m, 1H), 2.18-2.10 (m, 2H),1.84-1.53 ​​(m, 4H); 13 C NMR (101 MHz, CDCl3) δ 157.2, 154.4, 140.8, 133.6,129.0, 128.3, 128.0, 126.5, 124.1, 110.4, 109.8, 104.6, 94.7, 71.4, 62.0,57.4, 56.5, 49.9, 39.1, 31.0, 25.5, 23.6; HRMS (ESI) calcd for C 24 H 28 NO3 [M+H] + : 378.2064, found: 378.2073.

[0175] Example 14

[0176]

[0177] Under a nitrogen atmosphere, palladium acetylacetonate (3.0 mg), (S)-5-(8,9,10,11,12,13,14,15-octahydrodinaphthalo[2,1-D:1',2'-F][1,3,2]dioxaphosphazene-hept-4-yl)-5H-dibenzo[B,F]azapyrrolidone (12.4 mg), and trifluorotoluene (1.0 mL) were added to a Young's tube, and the reaction was carried out at 40 °C for 30 min. After cooling to room temperature, aminodiene (42 mg) and a salicylaldehyde derivative (43 mg) were added, followed by degassing under vacuum and stirring at 70 °C for 24 h. After cooling to room temperature, column chromatography (petroleum ether:ethyl acetate = 20:1) was performed to give the azaspirocyclic compound in 81% yield with 95% enantioselectivity.

[0178] The nitrogen-containing spirocyclic compound obtained in Example 14 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.7 Hz, 1H), 7.27-7.09 (m, 6H), 6.98 (d, J =8.1 Hz, 1H), 6.01-5.93 (m, 1H), 5.88 (dd, J = 9.8, 3.0 Hz, 1H), 5.12 (d, J =4.1 Hz, 1H), 4.12 (s, 1H), 3.90 (s, 3H), 3.55 (d, J = 13.7 Hz, 1H), 3.12 (d,J = 13.6 Hz, 1H), 2.87 (d, J = 11.3 Hz, 1H), 2.26 (t, J = 11.9 Hz, 1H), 2.10-2.01 (m, 1H), 1.78-1.64 (m, 1H), 1.47 (d, J = 13.7 Hz, 1H), 1.31 (dt, J =13.2, 6.7 Hz, 2H), 1.13 (dd, J = 13.2, 5.4 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ168.1, 154.0, 141.5, 132.4, 130.8, 128.4, 128.3, 127.9, 126.3, 125.6, 123.9,121.5, 121.0, 70.8, 63.0, 57.4, 52.5, 52.0, 30.8, 29.3, 21.7, 21.4; HRMS(ESI) calcd for C 24 H26 NO3 [M+H] + : 376.1913, found: 376.1916.

[0179] Example 15

[0180]

[0181] Take a clean 100mL Schlenk bottle, heat it with a hot gun to remove water, and add 1 (0.39 g) Hoveyda-Grubbs 2 under nitrogen protection. nd Catalyst (31 mg), methanol / tetrahydrofuran mixed solvent (10 mL, 1 / 20), sodium borohydride (0.19 g) were slowly added at 0 °C. The reaction was stirred vigorously at room temperature for 12 hours, followed by careful quenching with acetone in an ice bath. Extraction with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography (petroleum ether:ethyl acetate = 20:1) yielded the target product, 0.28 g, yield: 72%.

[0182] The nitrogen-containing spirocyclic compound obtained in Example 15 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, CDCl3) δ 7.31 (d, J = 4.5 Hz, 4H), 7.28–7.23 (m, 1H), 7.16–7.11 (m,1H), 6.71 (dq, J = 7.5, 1.5 Hz, 2H), 4.95–4.85 (m, 2H), 4.26 (d, J = 3.8 Hz, 1H), 4.11 (td, J = 7.0, 3.8 Hz, 1H), 3.73–3.66 (m, 2H), 3.49 (s, 3H), 2.71 (ddt, J = 43.8, 12.4, 7.1 Hz, 2H), 1.97–1.89 (m, 1H), 1.86–1.78 (m, 1H),1.75–1.48 (m, 10H); 13C NMR (125 MHz, CDCl3) δ159.6, 156.8, 138.2, 131.2,128.8, 128.4, 127.4, 112.4, 110.5, 110.3, 95.5, 76.1, 63.8, 56.4, 55.8, 50.9,40.2, 31.0, 29.8, 26.6, 24.6, 22.1, 19.6; HRMS (ESI) calcd for C 25 H 32 NO3 [M+H] + :394.2382, found: 394.2380.

[0183] Example 16

[0184]

[0185] Take a clean 100 mL Schlenk flask, heat it with a hot gun to remove water, add 2 (0.28 g) of methanol / tetrahydrofuran mixed solvent (8 mL, 1 / 2) under nitrogen protection, slowly add concentrated sulfuric acid (0.52 mL) at 0 °C, react at room temperature for 12 hours, and then carefully quench the reaction with saturated sodium bicarbonate solution under ice bath. Extract with ethyl acetate (10 mL x 3), combine the organic phases, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 5:1) to give the target product, 0.21 g, yield: 85%.

[0186] The nitrogen-containing spirocyclic compound obtained in Example 16 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, CDCl3) δ 7.35–7.18 (m, 6H), 6.88 (dd, J = 8.8, 1.1 Hz, 1H), 6.52(dd, J = 9.1, 1.1 Hz, 1H), 4.87 (d, J = 3.7 Hz, 1H), 4.26–4.19 (m, 1H), 3.72 (dt, J = 12.5, 0.8 Hz, 1H), 3.59 (dd, J = 12.4, 0.8 Hz, 1H), 2.89–2.82 (m,1H), 2.71–2.64 (m, 1H), 1.87–1.60 (m, 11H), 1.58–1.47 (m, 1H); 13C NMR (100MHz, CDCl3) δ159.2, 155.7, 138.0, 130.8, 128.0, 127.4, 116.8, 115.6, 111.4,78.4, 66.8, 56.7, 52.3, 43.2, 31.4, 30.9, 30.2, 23.3, 23.2, 22.4; HRMS (ESI)calcd for C 23 H 28 NO2 [M+H] + : 350.2120, found: 350.2125.

[0187] Example 17

[0188]

[0189] Take a clean 50 mL Schlenk flask, heat it with a hot gun to remove water, and add 0.21 g of methyl methacrylate (MCP), 8 mL of dichloromethane (1 / 2), and 0.14 g of pyridine under nitrogen protection. Slowly add 0.26 g of trifluoromethanesulfonic anhydride at 0 °C and react at room temperature for 5 hours. Then, carefully quench the reaction with a saturated sodium bicarbonate solution in an ice bath. Extract with dichloromethane (10 mL x 3), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain the target product, 0.26 g, yield: 89%.

[0190] The nitrogen-containing spirocyclic compound obtained in Example 17 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, CDCl3) δ7.29 (pdd, J = 9.6, 6.7, 4.4 Hz, 6H), 7.13 (dd, J = 8.3,1.0 Hz, 1H), 6.97 (dd, J = 8.9, 0.9 Hz, 1H), 4.71 (d, J = 3.7 Hz, 1H), 4.16(ddd, J = 7.7, 6.6, 3.8 Hz, 1H), 3.73 (d, J = 0.9 Hz, 2H), 2.73–2.66 (m, 1H), 2.63–2.58 (m, 1H), 1.82–1.47 (m, 12H); 13C NMR (100 MHz, CDCl3) δ157.0, 147.5,139.1, 129.1, 128.8, 128.7, 126.9, 121.1, 118.4, 117.1, 115.6, 78.8, 63.2,57.2, 51.1, 42.8, 32.7, 32.0, 30.6, 23.4, 22.6, 22.6; HRMS (ESI) calcd forC 24 H 27 F3NO4S [M+H] + : 482.1613, found: 482.1620.

[0191] Example 18

[0192]

[0193] Take a clean 50 mL Schlenk flask, heat it with a hot gun to remove water, and add 4 (0.26 g), palladium acetate (12 mg), 1,4-bis(diphenylphosphine)butane (23 mg), N,N-diisopropylethylamine (0.28 g), diphenylphosphine oxide (0.16 g), and dimethyl sulfoxide (6 mL) under nitrogen protection. React at 100 °C for 24 hours. Cool the reaction to room temperature, dilute with ethyl acetate (6 mL), and wash five times with 10 mL of saturated brine. Dry the organic phase with anhydrous sodium sulfate and remove the solvent under reduced pressure. Column chromatography (petroleum ether:ethyl acetate = 1:1) yields the target product, 0.19 g, yield: 66%.

[0194] The nitrogen-containing spirocyclic compound obtained in Example 18 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, CDCl3) δ 7.82 (dd, J = 8.8, 1.1 Hz, 1H), 7.73–7.63 (m, 4H), 7.59–7.50 (m, 2H), 7.49–7.40 (m, 4H), 7.35–7.19 (m, 6H), 6.94 (dd, J = 8.5, 1.1Hz, 1H), 4.33 (d, J = 3.7 Hz, 1H), 4.14 (ddd, J = 8.1, 6.1, 3.8 Hz, 1H), 3.83–3.60 (m, 2H), 2.75–2.60 (m, 2H), 1.87–1.52 (m, 11H), 1.49–1.36 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 157.3, 138.6, 133.2, 132.4, 131.8, 131.4, 128.7,128.7, 128.5, 128.1, 128.1, 120.8, 117.7, 78.8, 67.2, 57.4, 50.6, 44.2, 32.7,32.6, 32.4, 23.5, 23.2, 22.3; 31 P NMR (162 MHz, CDCl3) δ 29.2; HRMS (ESI) calcdfor C 35 H 37 NO2P [M+H] + : 534.2562, found: 534.2571.

[0195] Example 19

[0196]

[0197] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, and add 0.19 g of 5, 0.14 g of triethylamine, and 2.5 mL of mesitylene under nitrogen protection. Slowly add 0.19 g of trichlorosilane at 0 °C, and react at 140 °C for 5 hours. Then, carefully quench the reaction with a saturated sodium hydroxide solution in an ice bath. Extract with ethyl acetate (10 mL x 3), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain the target product, 0.18 g, yield: 95%.

[0198] The nitrogen-containing spirocyclic compound obtained in Example 19 was analyzed using nuclear magnetic resonance, and the results were as follows: 1H NMR(400 MHz, CDCl3) δ 7.35-7.13 (m, 15H), 7.06 (t, J = 7.8 Hz, 1H), 6.84 (d, J =8.0 Hz, 1H), 6.45 (dd, J = 7.0, 4.2 Hz, 1H), 5.19 (s, 1H), 4.03 (d, J = 13.7Hz, 1H), 3.93 (d, J = 4.3 Hz, 1H), 3.47 (dd, J = 13.7, 2.9 Hz, 1H), 2.92 (d,J = 10.7 Hz, 1H), 2.30 (td, J = 12.2, 2.9 Hz, 1H), 2.21 (d, J = 12.9 Hz, 1H),1.93 (d, J = 14.0 Hz, 1H), 1.73-1.60 (m, 2H), 1.50-1.41 (m, 2H), 1.40-1.33(m, 1H), 1.31-1.20 (m, 2H), 1.09 (td, J = 14.0, 4.8 Hz, 1H), 0.95 (td, J =13.3, 4.4 Hz, 1H), 0.41 (d, J = 13.8 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 155.1(d, J C-P = 8.4 Hz), 142.0 (d, J C-P = 3.4 Hz), 139.3 (d, J C-P = 12.1 Hz), 137.0(d, J C-P = 11.7 Hz), 136.7 (d, J C-P = 9.8 Hz), 134.2 (d, J C-P = 19.9 Hz), 133.8(d, J C-P = 19.4 Hz), 128.7, 128.6 (d, J C-P = 11.1 Hz), 128.5 (d, J C-P = 3.6 Hz),128.3 (d, J C-P = 7.2 Hz), 128.1 (d, J C-P = 22.8 Hz), 126.3, 126.0 (d, J C-P=27.1 Hz), 125.2, 117.3, 72.7, 64.1 (d, J C-P = 20.0 Hz), 57.1 (d, J C-P = 7.7Hz), 52.7, 34.5 (d, J C-P = 1.8 Hz), 32.3 (d, J C-P = 29.4 Hz), 27.2, 21.4, 20.3,20.1; 31 P NMR (162 MHz, CDCl3) δ -16.1; HRMS (ESI) calcd for C 35 H 37 NOP [M+H] + :518.2607, found: 518.2626.

[0199] Example 20

[0200]

[0201] Take a clean 50 mL Schlenk flask, heat it with a hot gun to remove water, and add 4 (0.26 g), palladium acetate (12 mg), 1,4-bis(diphenylphosphine)butane (23 mg), N,N-diisopropylethylamine (0.28 g), diarylphosphine oxide (0.19 g), and dimethyl sulfoxide (6 mL) under nitrogen protection. React at 100 °C for 24 hours. After cooling to room temperature, dilute with ethyl acetate (6 mL) and wash five times with 10 mL of saturated brine. Dry the organic phase with anhydrous sodium sulfate and remove the solvent under reduced pressure. Column chromatography (petroleum ether:ethyl acetate = 1:1) yields the target product, 0.21 g, yield: 70%.

[0202] The nitrogen-containing spirocyclic compound obtained in Example 20 was analyzed using nuclear magnetic resonance, and the results were as follows: 11H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.8, 1.1 Hz, 1H), 7.58 – 7.52 (m, 4H), 7.34– 7.20 (m, 6H), 7.16 – 7.08 (m, 4H), 6.94 (dd, J = 8.4, 1.1 Hz, 1H), 4.35 (d,J = 3.8 Hz, 1H), 4.14 (ddd, J = 8.1, 6.1, 3.7 Hz, 1H), 3.80 – 3.66 (m, 2H),2.74 – 2.59 (m, 2H), 2.34 (d, J = 0.8 Hz, 6H), 1.85 – 1.75 (m, 3H), 1.75 –1.52 (m, 8H), 1.48 – 1.38 (m, 1H); 13 13C NMR (100 MHz, CDCl3) δ 157.3, 138.9,138.3, 133.2, 131.2, 129.2, 128.7, 128.6, 128.5, 128.1, 127.6, 120.8, 117.7,79.0, 68.2, 57.2, 50.6, 44.2, 32.9, 32.4, 32.0, 23.5, 23.2, 22.6, 21.1; 31 31P NMR(162 MHz, CDCl3) δ 29.2. HRMS (ESI) calcd for C 24 H 26 NO3 [M+H] + : 376.1913,found: 376.1916. HRMS (ESI) calcd for C 37 H<​​​​​​​​​​​Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, and add 0.21 g of 7, 0.14 g of triethylamine, and 3 mL of mesitylene under nitrogen protection. Slowly add 0.19 g of trichlorosilane at 0 °C, and react at 140 °C for 5 hours. Then, carefully quench the reaction with a saturated sodium hydroxide solution in an ice bath. Extract with ethyl acetate (10 mL x 3), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain the target product, 0.19 g, yield: 92%.

[0206] The nitrogen-containing spirocyclic compound obtained in Example 21 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 8.6, 1.1 Hz, 1H), 7.34 – 7.20 (m, 10H), 7.07– 6.97 (m, 5H), 4.41 (d, J = 3.7 Hz, 1H), 4.14 (td, J = 7.1, 3.8 Hz, 1H),3.81 – 3.65 (m, 2H), 2.70 – 2.58 (m, 2H), 2.36 – 2.29 (m, 6H), 1.83 – 1.75(m, 2H), 1.74 – 1.53 (m, 9H), 1.49 – 1.37 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ158.9, 138.9, 137.8, 136.9, 136.5, 129.8, 129.0, 128.7, 128.5, 128.5, 127.2,121.4, 117.7, 78.8, 65.8, 57.2, 50.6, 44.2, 32.6, 32.4, 32.0, 23.5, 23.2,22.6, 21.1; 31 P NMR (162 MHz, CDCl3) δ -13.3; HRMS (ESI) calcd for C 37 H 41 NOP [M+H] + : 546.2926, found: 546.2929.

[0207] Example 22

[0208]

[0209] Take a clean 50 mL beaker, add 0.5 g of acetone, 0.1 g of palladium hydroxide on carbon, and 13 mL of ethyl acetate. Place the beaker in a high-pressure reactor, purge with hydrogen three times, and then purge with hydrogen at 20 atm. Stir at room temperature for 12 hours. After the reaction, release the hydrogen, filter the mixture, recover the palladium hydroxide on carbon, remove the solvent from the filtrate under reduced pressure, and perform column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain the target product, 0.45 g, yield: 90%.

[0210] The nitrogen-containing spirocyclic compound obtained in Example 22 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 8.6, 1.8 Hz, 1H), 7.34 – 7.28 (m, 4H), 7.27– 7.17 (m, 2H), 6.86 (dd, J = 8.9, 1.8 Hz, 1H), 4.92 (d, J = 3.8 Hz, 1H), 4.16 (ddd, J = 7.7, 6.6, 3.7 Hz, 1H), 3.92 (s, 3H), 3.70 (qt, J = 12.4, 0.9Hz, 2H), 2.96 (ddd, J = 9.5, 5.9, 5.0 Hz, 1H), 2.85 (ddd, J = 9.5, 5.9, 5.0Hz, 1H), 1.84 (ddd, J = 13.3, 5.9, 5.0 Hz, 2H), 1.80 – 1.72 (m, 3H), 1.72 –1.58 (m, 4H), 1.46 – 1.36 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 167.5, 152.9,138.5, 129.4, 128.3, 128.1, 127.4, 127.1, 123.5, 122.7, 117.5, 78.8, 66.3,56.7, 51.9, 48.6, 44.6, 34.2, 31.8, 31.8, 23.3, 22.6; HRMS (ESI) calcd forC 24 H 28 NO3 [M+H] + : 378.2069, found: 378.2063.

[0211] Example 23

[0212]

[0213] Take a clean 50 mL beaker, add 0.45 g of 10, 0.1 g of palladium on carbon, and 8 mL of methanol / ethyl acetate mixed solvent (4 / 1). Place the mixture in a high-pressure reactor, purge with hydrogen three times, and then purge with hydrogen at 20 atm. Stir at 70°C for 12 hours. After the reaction, cool to room temperature, release the hydrogen, filter the mixture, recover the palladium on carbon, remove the solvent from the filtrate under reduced pressure, and perform column chromatography (methanol:dichloromethane = 1:10) to obtain the target product, 0.29 g, yield: 84%.

[0214] The nitrogen-containing spirocyclic compound obtained in Example 23 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 8.6, 1.8 Hz, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.86 (dd, J = 8.9, 1.8 Hz, 1H), 6.29 (dt, J = 8.0, 6.1 Hz, 1H), 4.81 (dd, J =8.2, 3.8 Hz, 1H), 4.30 (ddd, J = 8.3, 5.7, 3.8 Hz, 1H), 3.93 (s, 3H), 2.96 –2.74 (m, 2H), 2.06 – 1.93 (m, 1H), 1.90 (dd, J = 3.8, 3.1 Hz, 1H), 1.76 (dd,J = 3.8, 2.9 Hz, 1H), 1.73 – 1.46 (m, 6H), 1.42 – 1.31 (m, 1H); 13 C NMR (100MHz, CDCl3) δ 167.3, 154.0, 128.8, 126.8, 125.8, 124.5, 116.2, 77.7, 55.9,52.1, 46.1, 41.4, 32.8, 31.9, 29.7, 22.9, 22.8; HRMS (ESI) calcd for C 17 H 22 NO3[M+H] + : 288.1600, found: 288.1611.

[0215] Example 24

[0216]

[0217] Take a clean 100 mL Schlenk flask, heat it with a hot gun to remove water, and add 11 (0.29 g), triethylamine (0.4 mL), and dichloromethane (15 mL) under nitrogen protection. Slowly add di-tert-butyl dicarbonate (0.26 g) at 0 °C and react at room temperature for 1 hour. Extract with dichloromethane (10 mL x 3), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product, 0.37 g, yield: 95%.

[0218] The nitrogen-containing spirocyclic compound obtained in Example 24 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, CDCl3) δ 7.88 (dd, J = 8.6, 1.8 Hz, 1H), 7.17 (t, J = 8.7 Hz, 1H), 6.86 (dd, J = 8.9, 1.8 Hz, 1H), 5.14 (d, J = 3.7 Hz, 1H), 4.25 (ddd, J = 8.4,5.9, 3.8 Hz, 1H), 3.92 (s, 3H), 3.59 (ddd, J = 9.5, 6.4, 5.5 Hz, 1H), 3.50 (ddd, J = 9.5, 6.3, 5.4 Hz, 1H), 2.00 – 1.77 (m, 6H), 1.76 – 1.51 (m, 4H), 1.47 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 167.3, 155.1, 153.8, 129.4, 127.5,123.4, 119.4, 117.6, 80.0, 78.0, 63.8, 51.9, 46.4, 42.1, 32.6, 31.4, 30.8,28.5, 23.3, 22.6; HRMS (ESI) calcd for C 22 H 30 NO5 [M+H] + : 388.2124, found:388.2125.

[0219] Example 25

[0220]

[0221] Take a clean 100 mL Schlenk flask, heat it with a hot gun to remove water, and add 0.37 g of 12, 5 mL of methanol, and 5 mL of 30% potassium hydroxide aqueous solution under nitrogen protection. React at 80 °C for 12 hours. After the reaction is complete, cool to room temperature, neutralize with dilute hydrochloric acid at 0 °C, extract with ethyl acetate (10 mL x 3), combine the organic phases, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography (methanol:dichloromethane = 1:10) to obtain the target product, 0.34 g, yield: 91%.

[0222] The nitrogen-containing spirocyclic compound obtained in Example 25 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, CDCl3) δ 7.87 (dd, J = 9.1, 1.8 Hz, 1H), 7.18 (t, J = 8.9 Hz, 1H), 6.86 (dd, J = 8.8, 1.8 Hz, 1H), 5.14 (d, J = 3.7 Hz, 1H), 4.25 (ddd, J = 8.4,5.9, 3.7 Hz, 1H), 3.54 (dddd, J = 38.5, 9.5, 6.4, 5.5 Hz, 2H), 1.97 (dd, J =6.3, 5.4 Hz, 1H), 1.94 – 1.77 (m, 5H), 1.73 – 1.51 (m, 4H), 1.47 (s, 9H); 13 CNMR (100 MHz, CDCl3) δ 168.1, 155.1, 153.4, 129.4, 126.5, 123.5, 123.4,117.5, 80.0, 78.0, 63.8, 46.4, 42.1, 31.7, 31.5, 31.4, 28.5, 23.3, 22.6; HRMS(ESI) calcd for C 21 H 28 NO5 [M+H] + : 374.1967, found: 374.1966.

[0223] Example 26

[0224]

[0225] Take a clean 100 mL Schlenk flask, heat it with a hot gun to remove water, and add 13 (0.34 g), chiral amino alcohol 14 (0.37 g), 1-hydroxybenzotriazole (0.3 g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.52 g), and tetrahydrofuran (20 mL) under nitrogen protection. Stir at 0 °C for 1 hour, then react at room temperature for 12 hours. After the reaction is complete, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target product, 0.4 g, yield: 88%.

[0226] The nitrogen-containing spirocyclic compound obtained in Example 26 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 11.0 Hz, 1H), 7.80 (dd, J = 8.9, 1.8 Hz, 1H), 7.33 – 7.27 (m, 4H), 7.23 – 7.12 (m, 2H), 6.91 (dd, J = 8.9, 1.8 Hz, 1H), 4.99 – 4.89 (m, 2H), 4.80 (t, J = 6.2 Hz, 1H), 4.24 – 4.08 (m, 3H), 3.63 (ddd, J = 9.5, 6.4, 5.5 Hz, 1H), 3.50 (ddd, J = 9.4, 6.3, 5.4 Hz, 1H), 2.02(dd, J = 6.4, 5.5 Hz, 1H), 1.99 – 1.72 (m, 5H), 1.69 – 1.49 (m, 4H), 1.46 (s,9H); 13 C NMR (100 MHz, CDCl3) δ 166.6, 154.5, 154.0, 140.8, 131.7, 128.8,128.5, 128.2, 127.2, 123.0, 122.8, 117.7, 79.1, 76.9, 64.4, 63.2, 54.4, 45.4,44.1, 32.9, 32.4, 31.7, 28.0, 23.5, 22.6. HRMS (ESI) calcd for C 29 H 37 N₂O₅ [M+H] + : 493.2702, found: 493.2710.

[0227] Example 27

[0228]

[0229] Take a clean 100 mL Schlenk flask, heat it with a hot gun to remove water, and add 15 (0.4 g), triethylamine (0.34 mL), and dichloromethane (17 mL) under nitrogen protection. Slowly add methanesulfonyl chloride (0.1 mL) at 0 °C, stir at 0 °C for 0.5 hours, and then react at room temperature for 8 hours. After the reaction is complete, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product, 0.31 g, yield: 80%.

[0230] The nitrogen-containing spirocyclic compound obtained in Example 27 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, CDCl3) δ 7.56 (dd, J = 7.6, 1.8 Hz, 1H), 7.37 – 7.27 (m, 5H), 7.24(dd, J = 8.9, 7.5 Hz, 1H), 7.02 (dd, J = 8.8, 1.8 Hz, 1H), 5.51 – 5.36 (m,1H), 5.03 (d, J = 3.8 Hz, 1H), 4.64 (d, J = 6.9 Hz, 1H), 4.52 (d, J = 6.0 Hz,1H), 4.07 (ddd, J = 8.5, 5.9, 3.8 Hz, 1H), 3.56 (dddd, J = 39.3, 9.5, 6.3,5.5 Hz, 2H), 2.03 – 1.77 (m, 6H), 1.73 – 1.50 (m, 4H), 1.46 (s, 9H); 13 C NMR(100 MHz, CDCl3) δ 158.9, 154.6, 153.0, 136.0, 128.8, 128.4, 128.3, 126.2,124.8, 124.0, 123.7, 117.7, 79.1, 77.5, 70.4, 63.2, 58.4, 44.5, 43.9, 32.7,32.4, 31.1, 28.0, 23.5, 22.8. HRMS (ESI) calcd for C 29 H 35 N₂O₄ [M+H] + : 475.2597, found: 475.2600.

[0231] Example 28

[0232]

[0233] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, add 0.31 g of 16 and 7 mL of dichloromethane under nitrogen protection, and slowly add 1 mL of trifluoroacetic acid at 0 °C. React at room temperature for 1 hour. After the reaction is complete, neutralize the reaction with saturated sodium bicarbonate solution, extract with dichloromethane (10 mL x 3), combine the organic phases, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and column chromatography (methanol:dichloromethane = 1:10) to obtain the target product, 0.23 g, yield: 94%.

[0234] The nitrogen-containing spirocyclic compound obtained in Example 28 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (500 MHz, CDCl3) δ 7.40 (dd, J = 7.7, 1.2 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.26– 7.21 (m, 3H), 7.15 (t, J = 7.9 Hz, 1H), 6.99 (dd, J = 8.2, 1.1 Hz, 1H), 5.40 (dd, J = 10.1, 8.6 Hz, 1H), 4.68 (dd, J = 10.2, 8.3 Hz, 1H), 4.09 (t, J= 8.4 Hz, 1H), 3.96 (s, 1H), 3.65 (s, 1H), 2.89 (td, J = 8.9, 3.8 Hz, 1H),2.75 – 2.67 (m, 1H), 1.92 (d, J = 13.9 Hz, 1H), 1.77 (dt, J = 13.2, 8.2 Hz,1H), 1.72 – 1.65 (m, 2H), 1.64 – 1.52 (m, 2H), 1.48 – 1.41 (m, 1H), 1.37 –1.29 (m, 2H), 1.12 – 1.07 (m, 1H); 13 C NMR (126 MHz, CDCl3) δ 164.2, 154.5,142.6, 128.7, 128.5, 127.8, 127.5, 126.4, 123.3, 122.4, 120.5, 73.7, 73.6,70.7, 61.6, 43.1, 40.0, 34.2, 30.5, 26.7, 23.1, 20.0; HRMS (ESI) calcd forC 24 H27 N₂O₂ [M+H] + : 375.2073, found: 375.2077.

[0235] The proton NMR spectrum of compound 17 is shown below. Figure 6 As shown.

[0236] Example 29

[0237]

[0238] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, and add 17 (0.1 g), ultra-dry toluene (3 mL), and N,N-diisopropylethylamine (0.12 mg) under nitrogen protection. Stir the reaction mixture at room temperature for 15 minutes, then add diphenylphosphine chloride (0.17 g) at 0 °C and maintain the reaction at 0 °C for 12 hours. After the reaction is complete, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain the target product, 0.12 g, yield: 74%.

[0239] The nitrogen-containing spirocyclic compound obtained in Example 29 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 7.6, 1.8 Hz, 1H), 7.45 – 7.37 (m, 2H), 7.36– 7.20 (m, 14H), 6.98 (dd, J = 8.8, 1.8 Hz, 1H), 5.45 (dd, J = 6.8, 6.0 Hz,1H), 4.85 (d, J = 3.8 Hz, 1H), 4.64 (d, J = 6.9 Hz, 1H), 4.52 (d, J = 6.0 Hz,1H), 4.16 (ddd, J = 8.0, 6.2, 3.8 Hz, 1H), 2.97 (dddd, J = 40.3, 9.5, 6.3,5.5 Hz, 2H), 2.18 (dd, J = 6.4, 5.5 Hz, 1H), 1.93 – 1.48 (m, 8H), 1.46 – 1.32(m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.9, 153.5, 138.3, 134.7, 132.3, 128.8,128.6, 128.6, 127.9, 127.7, 127.6, 126.0, 125.8, 124.0, 117.7, 79.0, 70.4,68.2, 58.4, 50.3, 44.2, 32.9, 32.4, 31.1, 23.5, 22.6; 31 P NMR (162 MHz, CDCl3)δ 47.6; HRMS (ESI) calcd for C 36 H 36 N₂O₂P [M+H] + : 559.2914, found: 559.2930.

[0240] Example 30

[0241]

[0242] Take a clean 50 mL Schlenk flask, heat it with a hot gun to remove water, and add 4 (0.26 g), palladium acetate (12 mg), 1,4-bis(diphenylphosphine)butane (23 mg), N,N-diisopropylethylamine (0.28 g), diarylphosphine oxide (0.22 g), and dimethyl sulfoxide (6 mL) under nitrogen protection. React at 100 °C for 24 hours. After cooling to room temperature, dilute with ethyl acetate (6 mL) and wash five times with 10 mL of saturated brine. Dry the organic phase with anhydrous sodium sulfate and remove the solvent under reduced pressure. Column chromatography (petroleum ether:ethyl acetate = 1:1) yields the target product, 0.24 g, yield: 68%.

[0243] The nitrogen-containing spirocyclic compounds obtained in Example 30 were analyzed using nuclear magnetic resonance, and the results were as follows: 1H NMR(400 MHz, CDCl3) δ 7.57 (dd, J = 8.8, 1.2 Hz, 1H), 7.34 – 7.20 (m, 6H), 7.13(d, J = 2.2 Hz, 4H), 6.94 (dd, J = 8.3, 1.2 Hz, 1H), 6.52 (t, J = 2.1 Hz,2H), 4.50 (d, J = 3.8 Hz, 1H), 4.16 (ddd, J = 8.1, 6.1, 3.8 Hz, 1H), 3.85 (s,12H), 3.79 – 3.67 (m, 2H), 2.71 – 2.56 (m, 2H), 1.87 – 1.59 (m, 11H), 1.50 –1.36 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 159.5, 158.6, 139.5, 134.6, 133.1,128.9, 128.7, 128.5, 127.3, 127.0, 120.8, 117.1, 108.1, 101.8, 78.1, 68.2,57.7, 55.6, 51.5, 44.2, 32.4, 32.2, 32.0, 23.5, 23.3, 23.2; 31 P NMR (162 MHz, CDCl3) δ 29.2; HRMS (ESI) calcd for C 39 H 45 NO6P [M+H] + : 654.2984, found:654.2990.

[0244] Example 31

[0245]

[0246] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, and add 19 (0.24 g), triethylamine (0.14 g), and mesitylene (3 mL) under nitrogen protection. Slowly add trichlorosilane (0.19 g) at 0 °C, and react at 140 °C for 5 hours. Then, carefully quench the reaction with a saturated sodium hydroxide solution in an ice bath. Extract with ethyl acetate (10 mL x 3), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target product, 0.21 g, yield: 90%.

[0247] The nitrogen-containing spirocyclic compound obtained in Example 31 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, Chloroform-d) δ 7.44 (dd, J = 8.6, 1.1 Hz, 1H), 7.37 – 7.17 (m,6H), 7.10 (d, J = 2.2 Hz, 4H), 7.00 (dd, J = 8.5, 1.2 Hz, 1H), 6.49 (t, J =2.2 Hz, 2H), 4.68 (d, J = 3.8 Hz, 1H), 4.16 (td, J = 7.1, 3.8 Hz, 1H), 3.83(s, 14H), 2.70 – 2.52 (m, 2H), 1.87 – 1.55 (m, 11H), 1.54 – 1.35 (m, 1H); 13 CNMR (100 MHz, Chloroform-d) δ 158.5, 158.1, 139.5, 136.9, 136.6, 129.3,128.7, 128.5, 127.2, 127.0, 121.4, 117.1, 108.0, 101.4, 78.4, 68.1, 57.2,55.4, 51.5, 44.2, 32.2, 32.0, 31.2, 23.5, 23.3, 23.2.; 31 P NMR (162 MHz, Chloroform-d) δ -13.3; HRMS (ESI) calcd for C 39 H 45 NO5P [M+H] + : 638.3035, found:638.3038.

[0248] Example 32

[0249]

[0250] Take a clean ampoule, add 0.27 g of acetal (P), 50 mg of palladium on carbon, and 4 mL of methanol / ethyl acetate mixed solvent (4 / 1). Place the ampoule in a high-pressure reactor, purge with hydrogen three times, and then purge with hydrogen at 20 atm. Stir at 70°C for 12 hours. After completion, cool to room temperature, release the hydrogen, filter the mixture, recover the palladium on carbon, remove the solvent from the filtrate under reduced pressure, and perform column chromatography (methanol:dichloromethane = 1:10) to obtain the target product, 0.19 g, yield: 84%.

[0251] The nitrogen-containing spirocyclic compound obtained in Example 32 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, Chloroform-d) δ 7.76 (dd, J = 8.8, 1.1 Hz, 1H), 7.71 – 7.60 (m,4H), 7.53 – 7.37 (m, 6H), 7.19 (t, J = 8.6 Hz, 1H), 6.91 (dd, J = 8.3, 1.1Hz, 1H), 5.41 (dt, J = 8.6, 5.5 Hz, 1H), 4.54 (dd, J = 8.6, 3.7 Hz, 1H), 4.20 (ddd, J = 7.3, 6.7, 3.8 Hz, 1H), 2.98 (dddd, J = 29.6, 6.9, 5.6, 4.1 Hz, 2H),1.83 – 1.54 (m, 11H), 1.53 – 1.29 (m, 1H); 13 C NMR (100 MHz, Chloroform-d) δ159.2, 135.4, 132.2, 132.1, 131.2, 128.9, 128.7, 128.6, 119.7, 117.7, 76.8,65.0, 46.1, 44.3, 32.9, 31.0, 30.0, 25.2, 23.4, 23.3.; 31 P NMR (162 MHz, Chloroform-d) δ 29.2; HRMS (ESI) calcd for C 28 H 31 NO2P [M+H] + : 444.2092, found:444.2088.

[0252] Example 33

[0253]

[0254] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, and add 21 (0.19 g), triethylamine (0.42 g), and mesitylene (3 mL) under nitrogen protection. Slowly add trichlorosilane (0.56 g) at 0 °C, and react at 140 °C for 5 hours. Then, carefully quench the reaction with a saturated sodium hydroxide solution in an ice bath. Extract with ethyl acetate (10 mL x 3), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography (methanol:dichloromethane = 1:10) to obtain the target product, 0.16 g, yield: 90%.

[0255] The nitrogen-containing spirocyclic compound obtained in Example 33 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, Chloroform-d) δ 7.54 (ddd, J = 11.9, 8.2, 1.3 Hz, 5H), 7.45 – 7.21(m, 7H), 6.91 (dd, J = 8.3, 1.1 Hz, 1H), 5.44 (dt, J = 8.8, 5.6 Hz, 1H), 4.58(dd, J = 8.7, 3.7 Hz, 1H), 4.27 (ddd, J = 8.3, 5.6, 3.8 Hz, 1H), 3.01 (tdd, J= 6.7, 5.6, 4.1 Hz, 2H), 2.06 – 1.91 (m, 1H), 1.81 (dd, J = 8.9, 6.3 Hz, 1H),1.76 – 1.38 (m, 10H); 13 C NMR (100 MHz, Chloroform-d) δ 159.2, 136.5, 134.1,133.9, 132.1, 129.8, 128.6, 128.0, 119.1, 117.7, 77.2, 64.5, 46.1, 44.3,32.9, 31.5, 30.0, 25.2, 23.3, 23.3; 31 P NMR (162 MHz, Chloroform-d) δ -13.3; HRMS (ESI) calcd for C 28 H 31 NOP [M+H] + : 428.2143, found: 428.2140.

[0256] Example 34

[0257]

[0258] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, and add 22 (0.16 g), ultra-dry toluene (3 mL), and N,N-diisopropylethylamine (98 mg) under nitrogen protection. Stir the reaction mixture at room temperature for 15 minutes, then add diphenylphosphine chloride (0.17 g) at 0 °C and maintain the reaction at 0 °C for 12 hours. After the reaction is complete, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product, 0.17 g, yield: 74%.

[0259] The nitrogen-containing spirocyclic compound obtained in Example 34 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.62 – 7.51 (m, 4H), 7.48 – 7.15 (m, 18H), 7.00 (dd, J = 8.5, 1.2 Hz, 1H), 4.50 (d, J = 3.8 Hz, 1H), 4.14 (ddd, J = 8.3, 5.8,3.8 Hz, 1H), 3.02 – 2.90 (m, 2H), 2.17 – 1.91 (m, 1H), 1.80 – 1.41 (m, 11H); 13 C NMR (100 MHz, Chloroform-d) δ 158.1, 139.1, 136.9, 136.5, 133.7, 131.5,129.8, 129.3, 128.6, 128.6, 128.1, 127.2, 120.0, 117.1, 79.0, 63.3, 51.0,44.2, 32.6, 32.4, 32.0, 24.5, 23.5, 22.8; 31 P NMR (162 MHz, Chloroform-d) δ62.5, -13.3; HRMS (ESI) calcd for C 40 H 40 NOP2 [M+H] + : 612.2585, found: 612.2577.

[0260] Example 35

[0261]

[0262] Take a clean 100mL Schlenk bottle, heat it with a hot gun to remove water, and add 24g (0.17g) of Hoveyda-Grubbs 2 under nitrogen protection. nd Catalyst (31 mg), methanol / tetrahydrofuran mixed solvent (5 mL, 1 / 20), sodium borohydride (0.11 g) were slowly added at 0 °C, and the reaction was stirred vigorously at room temperature for 12 hours. The reaction was then carefully quenched with acetone in an ice bath. Extraction with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography (petroleum ether:ethyl acetate = 5:1) yielded the target product, 0.12 g, yield: 70%.

[0263] The nitrogen-containing spirocyclic compound obtained in Example 35 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, Chloroform-d) δ 8.80 (dd, J = 5.0, 1.9 Hz, 1H), 7.42 (dd, J = 8.6,5.1 Hz, 1H), 7.36 – 7.28 (m, 4H), 7.28 – 7.21 (m, 1H), 7.15 (dd, J = 8.6, 1.9Hz, 1H), 4.59 (d, J = 3.8 Hz, 1H), 4.23 (ddd, J = 7.7, 6.3, 3.7 Hz, 1H), 3.66(dd, J = 3.5, 0.9 Hz, 2H), 2.84 – 2.61 (m, 2H), 1.88 – 1.56 (m, 11H), 1.56 –1.39 (m, 1H); 13 C NMR (100 MHz, Chloroform-d) δ 147.7, 146.5, 137.6, 137.4,127.9, 127.9, 127.8, 124.2, 115.5, 78.0, 62.6, 57.2, 52.1, 46.4, 31.5, 31.4,29.7, 23.5, 23.1, 23.0; HRMS (ESI) calcd for C 22 H 27 N2O [M+H] + : 335.2123, found:335.2130.

[0264] Example 36

[0265]

[0266] Take a clean ampoule, add 25g (0.12g), palladium on carbon (50mg), and a methanol / ethyl acetate mixed solvent (4mL, 4 / 1). Place the mixture in a high-pressure reactor, purge with hydrogen three times, and then purge with hydrogen at 20 atm. Stir at 70°C for 12 hours. After completion, cool to room temperature, release the hydrogen, filter the mixture, recover the palladium on carbon, remove the solvent from the filtrate under reduced pressure, and perform column chromatography (methanol:dichloromethane = 1:10) to obtain the target product, 70mg, yield: 82%.

[0267] The nitrogen-containing spirocyclic compound obtained in Example 36 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, Chloroform-d) δ 8.65 (dd, J = 5.0, 1.8 Hz, 1H), 7.41 (dd, J = 8.6,5.0 Hz, 1H), 7.22 (dd, J = 8.6, 1.8 Hz, 1H), 4.93 (dt, J = 8.8, 6.4 Hz, 1H), 4.76 (dd, J = 8.9, 3.7 Hz, 1H), 4.33 (ddd, J = 8.0, 5.9, 3.7 Hz, 1H), 2.97 (dtd, J = 28.4, 6.6, 4.1 Hz, 2H), 1.85 – 1.58 (m, 9H), 1.57 – 1.33 (m, 2H); 13 CNMR (100 MHz, Chloroform-d) δ 149.2, 141.8, 136.9, 124.1, 113.8, 78.1, 64.3,44.6, 43.2, 31.5, 29.8, 29.1, 25.3, 23.4, 22.7.; HRMS (ESI) calcd for C 15 H 21 N₂O[M+H] + : 245.1654, found: 245.1655.

[0268] Example 37

[0269]

[0270] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, and add 26 (70 mg), ultra-dry toluene (2 mL), and N,N-diisopropylethylamine (98 mg) under nitrogen protection. Stir the reaction mixture at room temperature for 15 minutes, then add diphenylphosphine chloride (0.17 g) at 0 °C and maintain the reaction at 0 °C for 12 hours. After the reaction is complete, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target product, 87 mg, yield: 70%.

[0271] The nitrogen-containing spirocyclic compound obtained in Example 37 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, Chloroform-d) δ 8.76 (dd, J = 5.0, 1.8 Hz, 1H), 7.54 – 7.25 (m,11H), 7.17 (dd, J = 8.6, 1.9 Hz, 1H), 4.66 (d, J = 3.8 Hz, 1H), 4.16 (ddd, J= 8.2, 5.9, 3.7 Hz, 1H), 2.94 – 2.68 (m, 2H), 1.85 – 1.32 (m, 12H); 13 C NMR(100 MHz, Chloroform-d) δ 146.7, 144.7, 137.9, 135.4, 132.1, 128.6, 127.8,123.4, 117.9, 77.5, 67.0, 52.5, 42.7, 33.1, 32.6, 32.0, 23.4, 23.3, 23.3; 31 PNMR (162 MHz, Chloroform-d) δ 62.5; HRMS (ESI) calcd for C 27 H 30 N2OP [M+H] + :429.2096, found: 429.2098.

[0272] Example 38

[0273]

[0274] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, add 0.19 g of ultra-dry tetrahydrofuran (4 mL) under nitrogen protection, and then add 1 mL of a 1 M solution of lithium aluminum hydride in tetrahydrofuran dropwise at 0 °C. React at 50 °C for 12 hours. After the reaction is complete, carefully quench the reaction with potassium hydroxide solution at 0 °C. Extract with ethyl acetate (10 mL x 3), combine the organic phases, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 3:1) to give the target product, 0.15 g, yield: 88%.

[0275] The nitrogen-containing spirocyclic compound obtained in Example 38 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, Chloroform-d) δ 7.35 – 7.26 (m, 4H), 7.26 – 7.19 (m, 2H), 7.16 (dq,J = 8.6, 1.1 Hz, 1H), 6.89 (dd, J = 8.8, 1.3 Hz, 1H), 4.82 (t, J = 6.7 Hz,1H), 4.74 – 4.58 (m, 2H), 4.50 (d, J = 3.8 Hz, 1H), 4.16 (ddd, J = 8.5, 5.8,3.7 Hz, 1H), 3.71 (dt, J = 12.4, 0.9 Hz, 1H), 3.58 (dt, J = 12.4, 0.9 Hz,1H), 2.96 (ddd, J = 9.5, 5.9, 5.0 Hz, 1H), 2.72 (ddd, J = 9.5, 5.9, 5.0 Hz,1H), 2.02 (dddd, J = 12.6, 9.8, 7.5, 5.8 Hz, 1H), 1.87 – 1.41 (m, 9H); 13 C NMR(100 MHz, Chloroform-d) δ 153.9, 138.1, 133.8, 128.0, 127.4, 127.4, 127.1,126.0, 114.8, 78.4, 63.9, 63.6, 56.7, 50.3, 44.6, 33.2, 31.4, 30.9, 23.3,22.4; HRMS (ESI) calcd for C 23 H 28 NO2 [M+H] +: 350.2120, found: 350.2123.

[0276] Example 39

[0277]

[0278] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, and add 0.15 g of 28, 5 mL of ultra-dry dichloromethane, and 80 mg of pyridine under nitrogen protection. Then, add 0.1 mL of dimethyl sulfoxide dropwise at 0 °C and react at room temperature for 12 hours. After the reaction is complete, carefully quench the reaction with sodium bicarbonate solution at 0 °C. Extract with dichloromethane (10 mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain the target product, 0.15 g, yield: 93%.

[0279] The nitrogen-containing spirocyclic compound obtained in Example 39 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, Chloroform-d) δ 7.40 – 7.18 (m, 7H), 6.98 – 6.85 (m, 1H), 4.55 –4.38 (m, 3H), 4.16 (ddd, J = 8.5, 5.8, 3.8 Hz, 1H), 3.82 – 3.60 (m, 2H), 2.96(ddd, J = 9.4, 5.8, 5.0 Hz, 1H), 2.66 (ddd, J = 9.5, 5.9, 5.0 Hz, 1H), 2.02(dddd, J = 12.7, 9.7, 7.6, 5.8 Hz, 1H), 1.87 – 1.43 (m, 9H); 13 C NMR (100 MHz, Chloroform-d) δ 154.1, 138.1, 132.8, 128.4, 128.2, 128.1, 128.0, 127.4,125.3, 117.2, 78.4, 63.8, 56.7, 50.3, 44.6, 40.8, 33.2, 31.8, 30.9, 23.3,22.3; HRMS (ESI) calcd for C 23 H 28 NO2 [M+H] + : 368.1781, found: 368.1788.

[0280] Example 40

[0281]

[0282] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, add 0.12 g of borane-protected phosphine hydrogen and 4 mL of ultra-dry tetrahydrofuran under nitrogen protection, then add 0.24 mL of n-butyllithium in n-hexane (concentration 2.5 M) dropwise at -78 °C, and react at -78 °C for 20 minutes. Then add 2g of tetrahydrofuran solution (0.15 g of 2g dissolved in 1 mL of tetrahydrofuran), and react at room temperature for 8 hours. After the reaction is complete, carefully quench the reaction with ammonium chloride solution at 0 °C. Ethyl acetate (10 mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 5:1) to give the target product, 0.17 g, yield: 79%.

[0283] The nitrogen-containing spirocyclic compound obtained in Example 40 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR(400 MHz, Chloroform-d) δ 7.41 – 7.14 (m, 17H), 7.00 (dd, J = 8.7, 1.4 Hz, 1H), 4.46 (d, J = 3.8 Hz, 1H), 4.14 (td, J = 7.0, 3.8 Hz, 1H), 3.86 – 3.60 (m, 7H), 2.77 (dddd, J = 47.9, 9.5, 5.8, 5.0 Hz, 2H), 1.85 – 1.54 (m, 9H), 1.51 – 1.39 (m, 1H); 13 C NMR (100 MHz, Chloroform-d) δ 157.3, 138.6, 137.5,134.2, 132.8, 129.9, 128.7, 128.7, 128.7, 128.4, 125.1, 122.8, 117.9, 79.4,68.1, 57.4, 47.7, 44.2, 40.1, 33.9, 32.7, 32.6, 23.5, 22.3.; 31 P NMR (162 MHz, Chloroform-d) δ -12.3; HRMS (ESI) calcd for C 35 H 40 BNOP [M+H] + : 532.2941, found:532.2941.

[0284] Example 41

[0285]

[0286] Take a clean 25 mL Schlenk flask, heat it with a hot gun to remove water, add 30 (0.17 g) and diethylamine (1 mL) under nitrogen protection, and react at 50 °C for 8 hours. After the reaction is complete, remove the solvent under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 20:1) gives the target product, 0.16 g, yield: 95%.

[0287] The nitrogen-containing spirocyclic compound obtained in Example 41 was analyzed using nuclear magnetic resonance, and the results were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.20 (m, 17H), 7.00 (dd, J = 8.6, 1.4 Hz, 1H), 4.46 (d, J = 3.8 Hz, 1H), 4.14 (td, J = 7.0, 3.8 Hz, 1H), 3.83 – 3.57(m, 4H), 2.95 (ddd, J = 9.4, 5.9, 5.0 Hz, 1H), 2.72 (ddd, J = 9.5, 5.9, 5.0Hz, 1H), 1.85 – 1.54 (m, 9H), 1.53 – 1.39 (m, 1H); 13 C NMR (100 MHz, Chloroform-d) δ 157.3, 138.6, 137.5, 134.2, 132.8, 130.1, 128.7, 128.7,128.5, 127.0, 125.1, 124.1, 117.9, 78.8, 68.1, 57.4, 47.7, 44.2, 40.1, 33.9,33.1, 32.9, 23.5, 22.3; 31 P NMR (162 MHz, Chloroform-d) δ -12.3; HRMS (ESI)calcd for C 35 H 37 NOP [M+H] + : 518.2613, found: 518.2623.

[0288] Example 42

[0289] Asymmetric etherification of allyl acetate:

[0290]

[0291] Inside a glove box, 0.01 mmol [Pd(allyl)Cl]₂ and 0.012 mmol of the chiral ligand were dissolved in a Schlenk tube containing 1 mL of dichloromethane. After stirring at room temperature for 20 minutes, 0.2 mmol of allyl acetate, 0.4 mmol of ethanol, and 0.3 mmol of potassium carbonate were added. The reaction was then carried out at room temperature for 12 hours. After the reaction was complete, the target product was obtained by silica gel column chromatography. The optical purity of the product was analyzed by HPLC.

[0292] The selection of chiral ligands and the results of asymmetric catalysis are shown in Table 1.

[0293] Table 1 Results of asymmetric catalysis

[0294]

[0295] The results in Table 1 show that the chiral spirocyclic ligands prepared in this application exhibit excellent catalytic performance in the asymmetric substitution reaction of allyl acetate, and the reaction achieves high yield and selectivity.

[0296] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing a chiral spirocyclic skeleton, comprising the following steps: The aminodiene compound shown in Formula I and the aldehyde compound shown in Formula III are reacted under the action of a transition metal catalyst and a chiral phosphine ligand to obtain the alkenyl-substituted polycyclic nitrogen heterocycle shown in Formula IV; or the aminodiene compound shown in Formula II and the aldehyde compound shown in Formula III are reacted under the action of a transition metal catalyst and a chiral phosphine ligand to obtain the alkenyl-substituted polycyclic nitrogen heterocycle shown in Formula V. in, Selected from unsaturated rings; Where n1 and n2 are independently selected from any integers from 0 to 10; R 1 R 2 The following groups are independently selected from hydrogen, substituted or unsubstituted: alkyl groups of C1 to C30, cycloalkyl groups of C3 to C30, or aryl groups of C6 to C30; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Independently selected from hydrogen, halogen, substituted or unsubstituted groups of the following: C1-C30 alkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl, nitro, ester or amino; wherein, R 3 and R 4 R 4 and R 5 R 5 and R 6 R 7 and R 8 R 8 and R 9 Or R 9 and R 10 It can be connected as an alicyclic or aromatic ring; The substitution is by one or more of the following substituents: halogen, nitro, ester, amino, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl or C4-C30 heteroaryl. X is independently selected from O or NR. 11 The R 11 It is selected from H, alkyl sulfonyl groups of C1 to C40 or aryl sulfonyl groups of C6 to C60.

2. The method for preparing the chiral spirocyclic skeleton according to claim 1, characterized in that, The It is a benzene ring or a pyridine ring; n1 and n2 are independent integers selected from 0 to 2.

3. The method for preparing the chiral spirocyclic skeleton according to claim 1, characterized in that, The R 1 R 2 The following groups are independently selected from hydrogen, substituted or unsubstituted: alkyl groups of C1 to C6, cycloalkyl groups of C3 to C6, or aryl groups of C6 to C12; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 The following groups are independently selected from hydrogen, halogen, substituted or unsubstituted groups: C1-C3 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C6-C12 aryl, nitro, ester, amino; Wherein, the substitution is by one or more of the following substituents: halogen, nitro, ester, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl or C4-C12 heteroaryl. X is independently selected from O or NR. 11 The R 11 Selected from H, alkyl sulfonyl groups of C1 to C10 or aryl sulfonyl groups of C6 to C12.

4. The method for preparing the chiral spirocyclic skeleton according to claim 1, characterized in that, The aminodiene compounds represented by Formula I have any of the following structures: The aminodiene compounds represented by Formula II have the following structures: The aldehyde compounds represented by Formula III have any of the following structures: 。 5. A chiral spirocyclic skeleton compound having the structure shown in Formula IV or Formula V: in, n1, n2, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 The scope of X is as described in any one of claims 1 to 4.

6. The chiral spirocyclic skeleton compound according to claim 5, characterized in that, It has any of the following structures: 。 7. A chiral ligand of a nitrogen-based spirocyclic ring, characterized in that, It has the structure shown in Equations VI to XI: Wherein, n1, n2, R 1 R 8 R 9 R 10 The scope of X is as described in any one of claims 1 to 4; R 5’ R 6’ Each of the following groups, whether substituted or unsubstituted, is independently selected: alkyl (C1-C30), cycloalkyl (C3-C30), aryl (C6-C30), or heteroaryl (C4-C30); R 7’ R 8’ The following groups, individually selected independently from hydrogen, substituted or unsubstituted: C1–C30 alkyl, C3–C30 cycloalkyl, C6–C30 aryl, or C4–C30 heteroaryl; R 7’ and R 8’ It can be connected as an alicyclic or aromatic ring; R 9’ R 10’ Each of the following groups, whether substituted or unsubstituted, is independently selected: alkyl (C1-C30), cycloalkyl (C3-C30), aryl (C6-C30), or heteroaryl (C4-C30); The substitution is by one or more of the following substituents: halogen, nitro, amino, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl or C4-C30 heteroaryl. * indicates that the absolute configuration of the chiral carbon atom in the oxazoline structure is either R or S configuration.

8. The azaspirocyclic chiral ligand according to claim 7, characterized in that, The R 5’ R 6’ Each of the following groups, whether substituted or unsubstituted, is independently selected: alkyl (C1-C6), cycloalkyl (C3-C6), aryl (C6-C12), or heteroaryl (C4-C12); R 7’ R 8’ The following groups, individually selected independently from hydrogen, substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C12 aryl or C4-C12 heteroaryl; R 7’ and R 8’ It can be connected as a C5-C10 alicyclic ring or a C6-C12 aromatic ring; R 9’ R 10’ Each of the following groups, whether substituted or unsubstituted, is independently selected: alkyl (C1-C6), cycloalkyl (C3-C6), aryl (C6-C12), or heteroaryl (C4-C12); The substitution is achieved by one or more of the following substituents: halogen, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, or C4-C12 heteroaryl.

9. The azaspirocyclic chiral ligand according to claim 7, characterized in that, It has any of the following structures: 。 10. The use of the azaspirocyclic chiral ligand according to any one of claims 7 to 9 in transition metal-catalyzed asymmetric allyl substitution, hydrogenation, hydroamylation, carboamylation, and carbonylation reactions.

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