1,1'-spirobis tetralin-8,8'-diol derivatives, processes for their preparation, monophosphine ligands prepared therefrom and processes and uses thereof

Abstract

The present disclosure belongs to the technical field of organic synthesis, and particularly relates to a 1,1'-spirobistetralin-8,8'-diol derivative, a preparation method thereof, a monophosphine ligand prepared therefrom, and a preparation method and application thereof. The 1,1'-spirobistetralin-8,8'-diol derivative is a compound shown in formula I or a stereoisomer thereof, and is obtained via a preparation route taking compound II or compound II' as a key intermediate. The monophosphine ligand prepared based on the 1,1'-spirobistetralin-8,8'-diol derivative is a compound shown in formula III or a stereoisomer thereof, and can be used as a ligand in a metal-catalyzed asymmetric hydroacylation reaction, an asymmetric hydrogenation reaction, an asymmetric allyl alkylation reaction or an asymmetric allyl amination reaction, and has economic practicability and industrial application prospects.

Description

Technical Field

[0001] This disclosure belongs to the field of organic synthesis technology, specifically relating to a 1,1'-spirobistetrahydronaphthalene-8,8'-diol derivative, its preparation method, the monophosphine ligand prepared therefrom, its preparation method, and its application. Background Technology

[0002] 3,3',4,4'-Tetrahydro-2H,2'H-1,1'-spirobenaphthalene-8,8'-diol (SBITOL, also known as 1,1'-spirobadione-8,8'-diol) is a class of dominant chiral spirocyclic diphenols, and its derived ligands exhibit excellent stereoselectivity in asymmetric catalysis. Ligand properties can be further regulated by modifying the substituents of its core; however, existing synthetic routes are subject to stringent conditions and poor functional group compatibility, making it difficult to introduce diverse substituents into aromatic or alicyclic rings. This hinders the efficient preparation of substituted derivatives and restricts the development and application of ligand libraries for this type of skeleton. Summary of the Invention

[0003] To achieve the above objectives, the embodiments of this disclosure adopt the following technical solutions: In a first aspect, this disclosure provides compounds of Formula I or their stereoisomers: , in: R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

[0004] In some embodiments of this disclosure, the compound of formula I is represented by formula I-1: , in: R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

[0005] In some embodiments of this disclosure, the compound of formula I-1 is represented by formula I-1-1: , R1 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; R7, R8, R9, R 10 When the hydrogen is present, R1 and R6 are not both hydrogen and not both bromine.

[0006] In some embodiments of this disclosure, compound I-1-1 is selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , or .

[0007] In some embodiments of this disclosure, the compound of formula I-1 is represented by formula I-1-2: , R1 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R3 and R4 are simultaneously selected from halogens, C1-C4 alkyl groups, 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings, wherein the 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings are not substituted, or are substituted by halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, or phenyl groups. R7, R8, R9, R 10 It can be either hydrogen or methyl.

[0008] In some embodiments of this disclosure, compound I-1-2 is selected from any of the following compounds: , , , , or .

[0009] In some embodiments of this disclosure, the compound of formula I-1 is represented by formula I-1-3: , R2 and R5 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 and R5 cannot be hydrogen simultaneously.

[0010] In some embodiments of this disclosure, compound I-1-3 is selected from the following compounds: .

[0011] Secondly, this disclosure provides a method for preparing compound I-1-1, comprising the following steps: Reaction route 1: , R1 and R6 are both selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; Reaction route 2-1: , Wherein, R is H or benzyl, X is bromine or iodine, and R1 and R6 are simultaneously selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; Reaction route 2-2: , Wherein, R is methyl, methoxymethyl, trimethylsilyl or tert-butyldimethylsilyl, X is bromine or iodine, and R1 and R6 are simultaneously selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; Reaction route 3: , R1 and R6 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both hydrogen and not both bromine; When R7, R8, R9, R 10 When the methyl group is present, the cyclopropanating agent is isopropyl diphenylsulfonium tetrafluoroborate; Compound IV, Compound VII, or Compound XII react with the cyclopropanating agent under the action of strong base 1, wherein strong base 1 is an alkali metal hydride, alkali metal alkoxide, amino base, amino base, organolithium reagent, or inorganic strong base; When R7, R8, R9, R 10 When the cyclopropanating agent is hydrogen, it is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, a dihalomethane, or a diazomethane compound; when the cyclopropanating agent is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, compound IV, compound VII, or compound XII react with the cyclopropanating agent under the action of a strong base 1, wherein the strong base 1 is an alkali metal hydride, an alkali metal alkoxide, an amino base, an amino base, an organolithium reagent, or an inorganic strong base; when the cyclopropanating agent is a dihalomethane, and the dihalomethane is diiodomethane, compound IV, compound VII, or compound XII react with diiodomethane under the action of zinc; when the dihalomethane is dibromomethane, compound IV, compound VII, or compound XII react with dibromomethane under the action of diethylzinc. The coupling reagent is an aromatic boric acid reagent, a C1-C4 alkyl boric acid reagent, an organozinc reagent, a Grignard reagent, or an organotin reagent. The aromatic boric acid reagent has a parent ring selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered fused heterocyclic aromatic rings substituted with boric acid, potassium trifluoroborate, or pinacol borate. The C1-C4 alkyl boric acid reagent is a C1-C4 alkyl-substituted boric acid, potassium trifluoroborate, or pinacol borate. The organozinc reagent is R'-zinc halide. The Grignard reagent is R'-magnesium halide, the organotin reagent is R'-tri-n-butyltin, the halogen atom is independently selected from chlorine, bromine, and iodine, and R' is selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, 8-10 membered heterocyclic aromatic rings, or C1-C4 alkyl groups; the 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings are not substituted, or are substituted by halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, or phenyl groups.

[0012] In some embodiments of this disclosure, the preparation method of compound I-1-1 includes the following steps: When R1 and R6 are the same, the reaction route 3 is as follows: , R1 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 is neither hydrogen nor bromine; When R1 and R6 are different, the reaction route 3 is as follows: , R1 and R6 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both hydrogen and not both bromine.

[0013] Thirdly, this disclosure provides a method for preparing compound I-1-2, comprising the following steps: using compound I-1-1 as a raw material, compound I-1-2 is prepared by reaction, and the reaction route is as follows: , R1 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; X is selected from halogens; R3 and R4 are simultaneously selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; The coupling reagent is an aromatic boric acid reagent, a C1-C4 alkyl boric acid reagent, an organozinc reagent, a Grignard reagent, or an organotin reagent. The aromatic boric acid reagent has a parent ring selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered fused heterocyclic aromatic rings substituted with boric acid, potassium trifluoroborate, or pinacol borate. The C1-C4 alkyl boric acid reagent is a C1-C4 alkyl-substituted boric acid, potassium trifluoroborate, or pinacol borate. The organozinc reagent is R'-zinc halide. The Grignard reagent is R'-magnesium halide, the organotin reagent is R'-tri-n-butyltin, the halogen atom is independently selected from chlorine, bromine, and iodine, and R' is selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, 8-10 membered heterocyclic aromatic rings, or C1-C4 alkyl groups; the 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings are not substituted, or are substituted by halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, or phenyl groups.

[0014] Fourthly, this disclosure provides a method for preparing compound I-1-3, comprising the following steps: , R2 and R5 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 and R5 cannot be hydrogen simultaneously; When R7, R8, R9, R 10 When the methyl group is present, the cyclopropanating agent is isopropyl diphenylsulfonium tetrafluoroborate; compound XVI reacts with the cyclopropanating agent under the action of strong base 1, wherein strong base 1 is an alkali metal hydride, alkali metal alkoxide, amino base, amino base, organolithium reagent or inorganic strong base; When R7, R8, R9, R 10 When the cyclopropanating agent is hydrogen, it is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, a dihalomethane, or a diazomethane compound; when the cyclopropanating agent is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, compound XVI reacts with the cyclopropanating agent under the action of a strong base 1, wherein the strong base 1 is an alkali metal hydride, an alkali metal alkoxide, an amino base, an amino base, an organolithium reagent, or an inorganic strong base; when the cyclopropanating agent is a dihalomethane, and the dihalomethane is diiodomethane, compound XVI reacts with diiodomethane under the action of zinc; when the dihalomethane is dibromomethane, compound XVI reacts with dibromomethane under the action of diethylzinc.

[0015] In some embodiments of this disclosure, the preparation method of compound I-1-3 includes the following steps: When R2 and R5 are the same, the route is as follows: , R2 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 is not hydrogen; When R2 and R5 are different, the route is as follows: , R2 and R5 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl, and R2 and R5 are not both hydrogen, nor are they both bromine; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 and R5 cannot be hydrogen simultaneously.

[0016] In some embodiments of this disclosure, the cyclopropanating agent is isopropyl diphenylsulfonium tetrafluoroborate, trimethylsulfonium oxide, or trimethylsulfonium. The trimethylsulfonium oxide is trimethyl sulfoxide, trimethyl sulfonium chloride, trimethyl sulfonium bromide, or trimethylsulfonium methanesulfonate. The trimethylsulfonium is trimethylsulfonium iodide, trimethylsulfonium bromide, trimethylsulfonium chloride, trimethylsulfonium tetrafluoroborate, trimethylsulfonium hexafluorophosphate, trimethylsulfonium trifluoromethanesulfonate, trimethylsulfonium p-toluenesulfonic acid, or trimethylmethylsulfonium sulfate. The strong base 1 is sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium amino, diisopropylaminolithium, hexamethyldisilamide lithium, hexamethyldisilamide sodium, hexamethyldisilamide potassium, n-butyllithium, sodium hydroxide, or potassium hydroxide. Compounds IV, VII, and XII are also mentioned. The amount of compound XVI is 1 molar equivalent, the amount of the cyclopropanating agent is 2-6 molar equivalent, and the amount of strong base 1 is 2-6 molar equivalent; the reaction solvent is one or more of anhydrous dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, sulfolane, acetonitrile, 2-methyltetrahydrofuran, and tert-butanol; the reaction temperature is 0-80℃; Alternatively, the cyclopropanating agent may be a dihalomethane. When the dihalomethane is diiodomethane, the amount of diiodomethane used is 2-10 molar equivalents, the amount of zinc used is 2-20 molar equivalents, and the reaction solvent is one or more of diethyl ether, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, n-hexane, or chloroform, with a reaction temperature of -20 to 60°C. When the dihalomethane is dibromomethane, the amount of dibromomethane used is 2-8 molar equivalents, the amount of diethylzinc used is 2-20 molar equivalents, and the reaction solvent is one or more of diethyl ether, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, n-hexane, or chloroform, with a reaction temperature of -20 to 60°C. Alternatively, the cyclopropanating agent may be a diazonium methane compound, which may be diazonium methane or trimethylsilyl diazonium methane; the reaction may be carried out under light, heat, or a transition metal catalyst; the transition metal catalyst may be rhodium acetate dimer, copper acetylacetonate, copper bis(trifluoromethanesulfonyl)imide, or palladium bis(dibenzylacetone); the amount of the diazonium methane compound used is 2-6 molar equivalents, and the amount of the transition metal catalyst used is 0.01-10 molar equivalents; the reaction solvent may be one or more of diethyl ether, tetrahydrofuran, dichloromethane, toluene, or 1,2-dichloroethane; and the reaction temperature may be -20 to 60°C.

[0017] In some embodiments of this disclosure, when the coupling agent is an aromatic boric acid or a C1-C4 alkyl boric acid, the catalyst a is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, XPhos-Pd-G2, SPhos-Pd-G2, PEPPSI™-IPr, palladium acetate, tris(dibenzylacetone)palladium, or palladium dichloride; when catalyst a is an acetonitrile complex of palladium acetate, tris(dibenzylacetone)palladium, palladium dichloride, or palladium dichloride, catalyst a... It forms a catalytic system in combination with an organophosphorus ligand; the organophosphorus ligand is at least one of bidentate phosphine ligands or monodentate phosphine ligands, wherein the bidentate phosphine ligand is 1,1'-bis(diphenylphosphino)ferrocene, 9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthracene, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, or 1 4-Bis(diphenylphosphine)butane, wherein the monodentate phosphine ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, n-butylbis(1-adamantyl)phosphine, triphenylphosphine, tri(o-tolyl)phosphine, tri-tert-butylphosphine, or tricyclohexylphosphine, wherein the organophosphine ligand and catalyst a The molar ratio of palladium is 1:1 to 4; the base 2 is cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, triethylamine, or diisopropylethylamine; the amount of compound V, compound X, compound X', or compound I-1-2 is 1 molar equivalent; the amount of coupling agent is 2 to 10 molar equivalents; the amount of catalyst a is 1 to 50 mol% of compound V, compound X, compound X', or compound I-1-2; the amount of base 2 is 2 to 10 molar equivalents; the reaction solvent is 1,4-dioxane / water, toluene / water, tetrahydrofuran / water, ethylene glycol dimethyl ether / water, N,N-dimethylformamide / water, ethanol, methanol / water, or acetonitrile / water; When the coupling agent is an organozinc reagent, Grignard reagent, or organotin reagent, the catalyst a is 1,3-bis(diphenylphosphine propane) nickel dichloride or tetra-triphenylphosphine palladium, the amount of compound V, compound X, compound X', or compound I-1-2 is 1 molar equivalent, the amount of the coupling agent is 2 to 10 molar equivalents, the amount of catalyst a is 1 to 50 mol% of compound V, compound X, compound X', or compound I-1-2, and the reaction solvent is tetrahydrofuran or toluene.

[0018] In some embodiments of this disclosure, catalyst b is palladium on carbon, palladium hydroxide / carbon, platinum / carbon, platinum oxide, Raney nickel, platinum black, ruthenium dioxide, Raney cobalt, Wilkinson catalyst, Crabtree catalyst, rhodium / carbon, ruthenium / carbon, iridium / carbon, or palladium black; when catalyst b is palladium on carbon or palladium hydroxide / carbon, the palladium loading is 1-30 wt%, and the amount of catalyst b added is 3-50 wt% of compound II, compound VIII, or compound II'; the hydrogen source is hydrogen or a hydrogen transfer reagent, and the hydrogen pressure is 1-100 atm; the compound II, compound VIII, or compound II' The amount of the hydrogen transfer reagent used is 1 molar equivalent, and the hydrogen transfer reagent is ammonium formate, formic acid, hydrazine hydrate, cyclohexene or isopropanol, and the amount of the hydrogen transfer reagent used is 4 to 100 molar equivalents; the reaction solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, 1,4-dioxane, glacial acetic acid, toluene, and N,N-dimethylformamide; the reaction temperature is 0 to 100°C.

[0019] In some embodiments of this disclosure, catalyst c is boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, methanesulfonic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, polyphosphoric acid, aluminum trichloride, zinc chloride, ferric chloride, titanium tetrachloride, tin tetrachloride, trimethylsilyl trifluoromethanesulfonate, boron tribromide, scandium trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, ethyl polyphosphoric acid, trimethylsilyl polyphosphoric acid, phosphorus pentoxide, or Amberlyst-15; the reaction solvent is sulfuric acid, hydrobromic acid, hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, polyphosphoric acid, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, 1,4-dioxane, chloroform, xylene, nitrobenzene, 1,1,2,2-tetrachloroethane, or tetrahydrofuran; and compounds VI, XI, XI', and XIII are also mentioned. The amount of compound XVII is 1 molar equivalent, and the amount of catalyst c is 0.01~50 molar equivalent; the reaction temperature is -40~120℃.

[0020] In some embodiments of this disclosure, when the halogenating agent is N-bromosuccinimide, N-bromophthalimide, N-iodosuccinimide, iodine, bromine, pyridinium tribromide, or tetrabutylammonium tribromide, the compound IX, compound IX', or compound I-1-1 The amount of the catalyst is 1 molar equivalent, and the amount of the halogenated reagent is 2-3 molar equivalents; when the halogenated reagent is an alkali metal halide / hydrogen peroxide, the alkali metal halide is sodium bromide, potassium bromide, potassium iodide, or sodium iodide, the amount of the alkali metal halide is 2-3 molar equivalents, and the amount of hydrogen peroxide is 2-6 molar equivalents; when the halogenated reagent is 1,3-dibromo-5,5-dimethylhydantoin or dibromoisocyanuric acid, the amount of the halogenated reagent is 1.0-1.5 molar equivalents; the catalyst d is a hydrobromic acid-acetic acid solution, hydrobromic acid aqueous solution, hydroiodic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid, glacial acetic acid, methanesulfonic acid, camphorsulfonic acid, phosphoric acid, or trifluoromethanesulfonic acid, and the amount of catalyst d added is 1-30% of compound IX, compound IX', or compound I-1-1. mol%; the reaction solvent is one or more of anhydrous dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, 1,2-dichloroethane, chloroform, glacial acetic acid, dimethyl sulfoxide, N,N-dimethylformamide, methanol, water, toluene, and xylene; the reaction temperature is -40~50℃.

[0021] In some embodiments of this disclosure, when R is methyl, the deprotecting agent is boron tribromide, hydrobromic acid, aluminum trichloride, trimethylsilicon iodide, boron trichloride, or pyridine hydrochloride, the amount of compound I-1-1' is 1 molar equivalent, the amount of the deprotecting agent is 2-10 molar equivalents, the reaction solvent is dichloromethane or dichloroethane, and the reaction temperature is -78 to 50°C; when R is methoxymethyl, the deprotecting agent is concentrated hydrochloric acid, hydrobromic acid, or trifluoroacetic acid, and the amount of the deprotecting agent is 0. The reaction solvent is one or more of methanol, ethanol, tert-butanol, chloroform, dichloromethane, and 1,4-dioxane, and the reaction temperature is -40 to 100°C. When R is trimethylsilyl or tert-butyldimethylsilyl, the deprotecting agent is tetrabutylammonium fluoride, cesium fluoride, potassium fluoride, or sodium fluoride, and the amount of the deprotecting agent is 1 to 10 molar equivalents. The reaction solvent is tetrahydrofuran, N,N-dimethylformamide, or 1,4-dioxane, and the reaction temperature is -40 to 50°C.

[0022] In some embodiments of this disclosure, the base 3 is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, triethylamine, diisopropylethylamine, tetramethylguanidine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; the amount of compound XIV, compound XV, compound XVIII, or compound XIX is 1 molar equivalent, the amount of acetone is 0.5 molar equivalent, and the amount of base 3 is 1 to 3 molar equivalent; the reaction solvent is one or more of anhydrous ethanol, methanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, water, ethylene glycol dimethyl ether, acetonitrile, tert-butanol, 2-methyltetrahydrofuran, and N-methylpyrrolidone; the reaction temperature is -20 to 60°C.

[0023] In some embodiments of this disclosure, the intermediate compound or its stereoisomer obtained by the above preparation method is described by formula II or formula II': or , in: R1, R2, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both hydrogen and not both bromine, and R2 and R5 are not both hydrogen.

[0024] Fifthly, this disclosure provides a monophosphine ligand prepared from the aforementioned compound I, wherein the monophosphine ligand is a compound of formula III or a stereoisomer thereof: , Wherein: R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen; R 11 and R 12 Alkyl groups selected independently from C1-C6, or , or R 11 and R 12 Form with the attached nitrogen atom , , , or .

[0025] In some embodiments of this disclosure, the monophosphine ligand of Formula III is selected from any of the following compounds: , , , , or , R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring. The 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

[0026] In some embodiments of this disclosure, the monophosphine ligand is selected from any of the following compounds: , , , , , , , , , , , or .

[0027] Sixthly, this disclosure provides a method for preparing the above-mentioned monophosphine ligand, comprising the following steps: Compound I reacts with tris(dimethylamino)phosphine to give the monophosphine ligand compound III-1, as shown in the following reaction route: , Compound I reacts with phosphorus trichloride and organic amine compound XX to give monophosphine ligand compound III, as shown in the following reaction route: , Alternatively, compound I reacts with phosphorus trichloride, organic amine compound XX, and n-butyllithium to yield monophosphine ligand compound III, as shown in the following reaction route:

[0028] Among them, R 11 and R 12 Simultaneously selected from methyl or , or R 11 and R 12 Form with the attached nitrogen atom , , , or ; R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

[0029] In some embodiments of this disclosure, in the step of reacting compound I with tris(dimethylamino)phosphine to obtain monophosphine ligand compound III-1, the amount of compound I used is 1 molar equivalent, the amount of tris(dimethylamino)phosphine added is 1 to 5 molar equivalents, the reaction solvent is anhydrous toluene, anhydrous dichloromethane, anhydrous 1,2-dichloroethane or anhydrous tetrahydrofuran, and the reaction temperature is 0 to 110°C; In the step of reacting compound I with phosphorus trichloride and organic amine compound XX to obtain monophosphine ligand compound III, the amount of phosphorus trichloride and organic amine compound XX is 1.0~10.0 molar equivalents, the base 4 is triethylamine, the amount of base 4 is 1.0~10.0 molar equivalents, the reaction solvent is anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous 1,2-dichloroethane or anhydrous toluene, and the reaction temperature is -78~50℃; In the step of reacting compound I with phosphorus trichloride, organic amine compound XX, and n-butyllithium to obtain monophosphine ligand compound III, the amounts of phosphorus trichloride, organic amine compound XX, base 4, and n-butyllithium are 1 to 5 molar equivalents, the reaction solvent is anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous 1,2-dichloroethane, or anhydrous toluene, and the reaction temperature is -78 to 30°C.

[0030] In a seventh aspect, this disclosure provides applications of the monophosphine ligands described above, wherein the monophosphine ligands are complexed with metal salts of gold, copper, rhodium, ruthenium, iridium, nickel, molybdenum, palladium, or cobalt to prepare catalysts; or the monophosphine ligands are used in metal-catalyzed asymmetric hydroacylation reactions, asymmetric hydrogenation reactions, asymmetric allyl alkylation reactions, or asymmetric allyl amination reactions.

[0031] Beneficial effects: This disclosure provides a 1,1'-spirobistetrahydronaphthalene-8,8'-diol derivative, its preparation method, a monophosphine ligand prepared therefrom, and its preparation method and applications. The 1,1'-spirobistetrahydronaphthalene-8,8'-diol derivative is a compound of Formula I or its stereoisomer, obtained via a preparation route using compound II or compound II' as a key intermediate. This disclosure provides multiple feasible preparation routes, all of which can prepare the 1,1'-spirobistetrahydronaphthalene-8,8'-diol derivative from cyclopropane ketone compounds of Formula II or Formula II'. These routes are relatively short, have relatively mild reaction conditions, good functional group compatibility, and can achieve the preparation of multiple substituents at different positions on the aromatic ring of 1,1'-spirobistetrahydronaphthalene-8,8'-diol.

[0032] The monophosphine ligands prepared based on the 1,1'-spirobistetrahydronaphthalene-8,8'-diol derivative are compounds of Formula III or their stereoisomers. They can be used as ligands for metal-catalyzed asymmetric hydroacylation, asymmetric hydrogenation, asymmetric allyl alkylation, or asymmetric allyl amination reactions. The ee value of the reaction products can reach 99%, and the stereoselectivity is better than that of monophosphine ligands of 1,1'-spirobistetrahydronaphthalene-8,8'-diol (SBITOL). They have economic practicality and promising prospects for industrial application. Detailed Implementation

[0033] The present disclosure is further described below with reference to specific embodiments, but the embodiments are merely exemplary and do not constitute any limitation on the scope of the present disclosure. Those skilled in the art should understand that modifications or substitutions to the details and form of the technical solutions of the present disclosure can be made without departing from the spirit and scope of the present disclosure, but all such modifications and substitutions fall within the protection scope of the present disclosure.

[0034] The following describes the 1,1'-spirobistetrahydronaphthalene-8,8'-diol derivative provided in the embodiments of this disclosure, its preparation method, the monophosphine ligand prepared therefrom, its preparation method, and its application.

[0035] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0036] In embodiments of this disclosure, the terms “comprising,” “including,” “having,” “containing,” or any other variation thereof are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may also include other elements not expressly listed or elements inherent to such a composition, step, method, article, or apparatus.

[0037] In this disclosure, unless otherwise stated, the numerical range "a~b" represents a shortened representation of any combination of real numbers between a and b, where a and b are both real numbers. For example, the numerical range "0~80" means that all real numbers between "0~80" have been listed herein, and "0~80" is simply a shortened representation of these numerical combinations.

[0038] In the embodiments of this disclosure, "stereoisomer" refers to a compound having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, and trans-restricted isomers. The term "stereoisomer" here also includes "pure stereoisomers" of the aforementioned stereoisomers and mixtures of various stereoisomers in different proportions. Specifically, this disclosure protects the above-mentioned single configurations, racemic mixtures, and stereoisomers mixed in any proportion. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.), and can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.

[0039] In embodiments of this disclosure, the term "chiral" refers to a molecule that has the property of not being able to overlap with its mirror image; while "chiral" refers to a molecule that can overlap with its mirror image.

[0040] In this disclosure, the term "enantiomer" refers to two non-overlapping but mirror-image isomers of a compound.

[0041] In embodiments of this disclosure, the term "diastereomer" refers to a stereoisomer with two or more chiral centers whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical operations such as electrophoresis and chromatography, for example, HPLC.

[0042] In the embodiments of this disclosure, enantiomeric excess (ee%) is a key parameter in organic chemistry describing the enantiomeric composition of a compound. It represents the percentage of excess of one enantiomeric compound relative to another, and is calculated using the formula ee = ([R] - [S]) / ([R] + [S]) × 100%. This parameter is directly determined by chromatography, circular dichroism (CD) spectroscopy, or optical rotation determination, and is used to characterize the optical purity of chiral compounds.

[0043] In embodiments of this disclosure, unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds where hydrogen is replaced by deuterium or tritium, or where carbon is enriched. 13 C or 14 Compounds having the structure disclosed herein, other than those with carbon substitution of C, are within the scope of this disclosure. The compounds of this disclosure optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may use isotopes such as, for example, deuterium (… 2 H), tritium ( 3 H), iodine 125 ( 125 I) or carbon 14 ( 14 C) Mark. Use 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br and 125 Isotopic substitutions of I are all considered. All isotopic variants of the compounds disclosed herein, whether or not they are radioactive, are covered within the scope of this disclosure.

[0044] In embodiments of this disclosure, the term "substitution" means that one or more hydrogen atoms in the given structure are replaced by a specific substituent. The one or more substituents may be different from each other or they may be the same.

[0045] In embodiments of this disclosure, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0046] In the embodiments of this disclosure, the term "hydroxyl group" refers to the -OH group.

[0047] In embodiments of this disclosure, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 6 carbon atoms, more preferably alkyl groups containing 1 to 3 carbon atoms. The alkyl group can be straight-chain or branched. For example, the term "C1-C6 alkyl" refers to an alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion of an alkoxy group (i.e., an alkyl group) has the same definition as above. For example, the term "C1-C6 alkyl"... 1- "C3 alkyl" refers to an alkyl group containing 1, 2, or 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

[0048] In embodiments of this disclosure, the term "alkoxy" refers to -O-alkyl. The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-"; it is further preferred to be "C1-C3 alkoxy". Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.

[0049] In the embodiments of this disclosure, the term "aromatic ring" refers to an aromatic hydrocarbon group containing a conjugated π system, such as a benzene ring, a cyclopentadienyl anion ring, etc.

[0050] In the embodiments of this disclosure, the term "fused aromatic ring" refers to an aromatic hydrocarbon group formed by the fusion of two or more aromatic rings sharing two adjacent carbon atoms, such as naphthyl, anthracene, phenanthrene, etc.

[0051] In embodiments of this disclosure, the term "aromatic heterocycle" refers to a monocyclic system containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and it may be unsubstituted or substituted. Examples of aromatic heterocycles include, but are not limited to, pyrroleyl, furanyl, imidazolyl, furazolidone, isothiazolyl, isoxazolyl, oxazolyl, pyridine, pyridazine, pyrimidine, pyrazine, etc.

[0052] In the embodiments of this disclosure, the term "fused cyclic heteroaromatic ring" refers to a fused cyclic group that contains at least one heteroatom selected from N, O, and S in addition to carbon atoms and has aromaticity. It is formed by the fusion of an aromatic ring with an aromatic heterocycle or multiple aromatic heterocycles, such as quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzothiophenyl, purineyl, etc.

[0053] In the embodiments of this disclosure, "trimethyl sulfoxide" is also referred to as "trimethyl iodosulfonium oxide" and "trimethyl bromide" is also referred to as "trimethyl bromide".

[0054] In the embodiments disclosed herein, “XPhos-Pd-G2” refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0055] In the embodiments disclosed herein, “SPhos-Pd-G2” refers to chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II).

[0056] In the embodiments disclosed herein, “PEPPSI™-IPr” refers to [1,3-bis(2,6-diisopropylbenzyl)imidazol-2-pyridyl](3-chloropyridine)palladium dichloride.

[0057] In the embodiments disclosed herein, "XPhos" refers to 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0058] In this embodiment of the disclosure, "SPhos" refers to 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl.

[0059] In the embodiments disclosed herein, "Wilkinson catalyst" refers to rhodium tri(triphenylphosphine) chloride, which is a monovalent rhodium complex type hydrogenation reaction catalyst.

[0060] In the embodiments disclosed herein, "Crabtree catalyst" refers to an iridium-based organometallic catalyst with the chemical name hexafluorophosphate (tricyclohexylphosphine)(1,5-cyclooctadiene)(pyridine)iridium.

[0061] In the embodiments disclosed herein, "Amberlyst-15" refers to a macroporous strong acid cation exchange resin, the chemical composition of which is a polymer of styrene and divinylbenzene crosslinked together, and contains sulfonic acid groups.

[0062] In the embodiments disclosed herein, the bidentate phosphine ligand “2,2'-bis(diphenylphosphino)-1,1'-binaphthyl” includes its racemic form and any enantiomer.

[0063] The following provides a detailed description of the 1,1'-spirobistetrahydronaphthalene-8,8'-diol derivative provided in the embodiments of this disclosure, its preparation method, the monophosphine ligand prepared therefrom, its preparation method, and its application.

[0064] A compound of Formula I or a stereoisomer thereof: , in: R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring. The 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, or phenyl. Specifically, it can be para-substituted, ortho-substituted, or meta-substituted, and can be substituted by one or more identical or different substituents. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

[0065] Compound I can be prepared according to the following route: .

[0066] In some embodiments of this disclosure, the compound of formula I is described by formula I-1: , in: R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

[0067] In some embodiments of this disclosure, the compound of formula I-1 is represented by formula I-1-1: , R1 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; R7, R8, R9, R 10 When the hydrogen is present, R1 and R6 are not both hydrogen and not both bromine.

[0068] In some embodiments of this disclosure, the compound of formula I-1 is described by formula I-1-2: , R1 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R3 and R4 are simultaneously selected from halogens, C1-C4 alkyl groups, or 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings, wherein the 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings are not substituted, or are substituted by halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, or phenyl groups. R7, R8, R9, R 10 It can be either hydrogen or methyl.

[0069] In some embodiments of this disclosure, the compound of formula I-1 is described by formula I-1-3: , R2 and R5 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 and R5 cannot be hydrogen simultaneously.

[0070] The preparation method of the above compound I-1-1 includes the following steps: Reaction route 1: , R1 and R6 are both selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; Reaction route 2-1: , Wherein, R is H or benzyl, X is bromine or iodine, and R1 and R6 are simultaneously selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; Reaction route 2-2: , Wherein, R is methyl, methoxymethyl, trimethylsilyl or tert-butyldimethylsilyl, X is bromine or iodine, and R1 and R6 are simultaneously selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; Reaction route 3: , R1 and R6 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both hydrogen and not both bromine; When R7, R8, R9, R 10 When the methyl group is present, the cyclopropanating agent is isopropyl diphenylsulfonium tetrafluoroborate; Compound IV, Compound VII, or Compound XII react with the cyclopropanating agent under the action of strong base 1, wherein strong base 1 is an alkali metal hydride, alkali metal alkoxide, amino base, amino base, organolithium reagent, or inorganic strong base; When R7, R8, R9, R 10 When the cyclopropanating agent is hydrogen, it is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, a dihalomethane, or a diazomethane compound; when the cyclopropanating agent is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, compound IV, compound VII, or compound XII react with the cyclopropanating agent under the action of strong base 1, wherein strong base 1 is an alkali metal hydride, an alkali metal alkoxide, an amino base, an amino base, an organolithium reagent, or an inorganic strong base; The cyclopropanizing agent is a dihalomethane. When the dihalomethane is diiodomethane, compound IV, compound VII, or compound XII react with diiodomethane in the presence of zinc. When the dihalomethane is dibromomethane, compound IV, compound VII, or compound XII react with dibromomethane in the presence of diethylzinc. The coupling reagent is an aromatic boric acid reagent, a C1-C4 alkyl boric acid reagent, an organozinc reagent, a Grignard reagent, or an organotin reagent; the aromatic boric acid reagent has a parent ring selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, 8-10 membered heterocyclic aromatic rings substituted with boric acid, potassium trifluoroborate, or pinacol borate ester; the C1-C4 alkyl boric acid reagent is a C1-C4 alkyl-substituted boric acid, potassium trifluoroborate, or pinacol borate ester; the organozinc reagent is R'-zinc halide. The Grignard reagent is R'-magnesium halide, the organotin reagent is R'-tri-n-butyltin, the halogen atom is independently selected from chlorine, bromine, and iodine, and R' is selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, 8-10 membered heterocyclic aromatic rings, or C1-C4 alkyl groups; the 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings are not substituted, or are substituted by halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, or phenyl groups.

[0071] The aromatic boric acid reagents may specifically be phenylboronic acid, 1-naphthoboronic acid, quinoline-6-boronic acid, potassium phenyltrifluoroborate, potassium (1-naphtho)trifluoroborate, pinacol ester (7-methoxy-1-naphthyl)boronic acid or other aromatic boric acid reagents; The C1-C4 alkylboronic acid reagents may specifically be methylboronic acid, ethylboronic acid, n-propylboronic acid, isopropylboronic acid, n-butylboronic acid, isobutylboronic acid, potassium methyltrifluoroborate, potassium ethyltrifluoroborate, potassium n-propyltrifluoroborate, potassium isopropyltrifluoroborate, potassium butyltrifluoroborate, potassium (isobutyl)trifluoroborate, pinacol methylboronate, pinacol ethylboronate, pinacol butylboronate, or other alkylboronic acid reagents. The organozinc reagent may specifically be methyl zinc chloride, 2-propyl zinc bromide, tert-butyl zinc bromide, phenyl zinc bromide, 2-pyridyl zinc bromide, or other organozinc reagents; The Grignard reagent may specifically be methyl magnesium bromide, propyl magnesium chloride, n-butyl magnesium bromide, phenyl magnesium bromide, 2-naphthyl magnesium bromide, 4-methyl-1-naphthyl magnesium bromide, or other Grignard reagents; The organotin reagent may specifically be tributylphenyltin, tributyl(1-naphthyl)tin, tri-n-butyl-2-pyridyltin, 2-tributylmethyltinylthiophene, or other organotin reagents.

[0072] In some embodiments of this disclosure, when R1 and R6 are the same, the reaction route 3 is as follows: , R1 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 is neither hydrogen nor bromine; When R1 and R6 are different, the reaction route 3 is as follows: , R1 and R6 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both hydrogen and not both bromine.

[0073] The preparation method of the above compound I-1-2 includes the following steps: Using the above-mentioned compound I-1-1 as a starting material, compound I-1-2 was prepared by reaction, and the reaction route is as follows: , R1 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; X is selected from halogens; R3 and R4 are simultaneously selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; The coupling reagent is an aromatic boric acid reagent, a C1-C4 alkyl boric acid reagent, an organozinc reagent, a Grignard reagent, or an organotin reagent. The aromatic boric acid reagent has a parent ring selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, and 8-10 membered heterocyclic aromatic rings substituted with boric acid, potassium trifluoroborate, or pinacol borate. The C1-C4 alkyl boric acid reagent is a C1-C4 substituted boric acid, potassium trifluoroborate, or pinacol borate. The organozinc reagent is R'-zinc halide. The Grignard reagent is R'-magnesium halide, the organotin reagent is R'-tri-n-butyltin, the halogen atom is independently selected from chlorine, bromine, and iodine, and R' is selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, 8-10 membered heterocyclic aromatic rings, or C1-C4 alkyl groups; the 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings are not substituted, or are substituted by halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, or phenyl groups.

[0074] The preparation method of the above compound I-1-3 includes the following steps: , R2 and R5 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy or 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 and R5 cannot be hydrogen simultaneously; When R7, R8, R9, R 10When the methyl group is present, the cyclopropanating agent is isopropyl diphenylsulfonium tetrafluoroborate; compound XVI reacts with the cyclopropanating agent under the action of strong base 1, wherein strong base 1 is an alkali metal hydride, alkali metal alkoxide, amino base, amino base, organolithium reagent or inorganic strong base; When R7, R8, R9, R 10 When the cyclopropanating agent is hydrogen, it is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, a dihalomethane, or a diazomethane compound; when the cyclopropanating agent is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, compound XVI reacts with the cyclopropanating agent under the action of a strong base 1, wherein the strong base 1 is an alkali metal hydride, an alkali metal alkoxide, an amino base, an amino base, an organolithium reagent, or an inorganic strong base; when the cyclopropanating agent is a dihalomethane, and the dihalomethane is diiodomethane, compound XVI reacts with diiodomethane under the action of zinc; when the dihalomethane is dibromomethane, compound XVI reacts with dibromomethane under the action of diethylzinc.

[0075] In some embodiments of this disclosure, when R2 and R5 are the same, the above reaction route is as follows: , R2 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy or 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 is not hydrogen; When R2 and R5 are different, the route is as follows: , R2 and R5 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy or 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl, and R2 and R5 are not both hydrogen, nor are they both bromine; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10When both are hydrogen, R2 and R5 cannot be hydrogen simultaneously.

[0076] In some embodiments of this disclosure, the cyclopropanating agent is isopropyl diphenylsulfonium tetrafluoroborate, trimethylsulfonium oxide, or trimethylsulfonium; the amount of compound IV, compound VII, compound XII, or compound XVI is 1 molar equivalent; the amount of the cyclopropanating agent is 2 to 6 molar equivalents, specifically 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 molar equivalents or any value between two of these; the amount of strong base 1 is 2 to 6 molar equivalents, specifically 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 molar equivalents or any value between two of these; the reaction solvent is anhydrous dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, sulfolane, acetonitrile, 2-methyltetrahydrofuran, or tert-butyl One or more alcohols are used; the reaction temperature is 0~80℃, preferably 50℃, and can specifically be 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 46℃, 47℃, 48℃, 49℃, 50℃, 51℃, 52℃, 53℃, 54℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃ or any value between two of these; when anhydrous dimethyl sulfoxide, 1,4-dioxane, sulfolane, or tert-butanol are used as the reaction solvent, the minimum reaction temperature is higher than the solvent melting point temperature; when tetrahydrofuran is used as the reaction solvent, the maximum reaction temperature is the solvent boiling point temperature; When the cyclopropanating agent is a dihalomethane, and the dihalomethane is diiodomethane, then compounds IV, VII, and XII... The amount of compound XVI used is 1 molar equivalent; the amount of diiodomethane used is 2 to 10 molar equivalents, specifically 2, 3, 4, 5, 6, 7, 8, 9, 10 molar equivalents or any value between two of these; the amount of zinc used is 2 to 20 molar equivalents, specifically 2, 5, 7, 10, 12, 15, 18, 20 molar equivalents or any value between two of these; the reaction solvent is one or more of diethyl ether, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, n-hexane, or chloroform; the reaction temperature is -20 to 60°C, specifically -20°C, -10°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C or any value between two of these; when diethyl ether or dichloromethane is used as the reaction solvent, the highest reaction temperature is the boiling point of the solvent; The cyclopropanizing agent is a dihalomethane. When the dihalomethane is dibromomethane, the amount of compound IV, compound VII, compound XII, or compound XVI is 1 molar equivalent, and the amount of dibromomethane is 2-8 molar equivalents, specifically 2, 3, 4, 5, 6, 7, 8 molar equivalents or any value between two values; the amount of diethylzinc is 2-20 molar equivalents, specifically 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 12, 15, 18, 20 molar equivalents or any value between two values; the reaction solvent... The solvent is one or more of diethyl ether, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, n-hexane, or chloroform. The reaction temperature is -20 to 60°C, specifically -20°C, -10°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, or any value between two of these. When diethyl ether or dichloromethane is used as the reaction solvent, the maximum reaction temperature is the boiling point of the solvent. The cyclopropanizing agent is a diazonium methane compound, specifically diazonium methane or trimethylsilyl diazonium methane; the reaction is carried out under light, heat, or a transition metal catalyst; the transition metal catalyst is rhodium acetate dimer, copper acetylacetone, copper bis(trifluoromethanesulfonyl)imide, or palladium bis(dibenzylacetone); the amount of compound IV, compound VII, compound XII, or compound XVI is 1 molar equivalent; the amount of the diazonium methane compound is 2-6 molar equivalents, specifically 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 molar equivalents or any value between two of these; the amount of the transition metal catalyst is 0.01-10 molar equivalents, specifically 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 8, 10 molar equivalents or any value between two of these. The reaction solvent is one or more of diethyl ether, tetrahydrofuran, dichloromethane, toluene, or 1,2-dichloroethane; the reaction temperature is -20 to 60°C, specifically -20°C, -10°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, or any two values; when diethyl ether or dichloromethane is used as the reaction solvent, the highest reaction temperature is the boiling point of the solvent.

[0077] In some embodiments of this disclosure, when the coupling agent is an aromatic boric acid reagent or a C1-C4 alkyl boric acid reagent, the amount of compound V, compound X, compound X', or compound I-1-2 is 1 molar equivalent, and the amount of the coupling agent is 2 to 10 molar equivalents, specifically 2, 3, 4, 5, 6, 7, 8, 9, 10 molar equivalents or any value between two of these; the amount of catalyst a is 1 to 50 mol% of compound V, compound X, compound X', or compound I-1-2, specifically 1 mol%, 3 mol%, 5 mol%, 7 mol%, 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%. The amount of alkali 2 used is 2 to 10 molar equivalents, specifically 2, 3, 4, 5, 6, 7, 8, 9, 10 molar equivalents or any value between two values.

[0078] In some embodiments of this disclosure, when the coupling agent is an organozinc reagent, Grignard reagent, or organotin reagent, the amount of compound V, compound X, compound X', or compound I-1-2 is 1 molar equivalent, and the amount of the coupling agent is 2 to 10 molar equivalents, specifically 2, 3, 4, 5, 6, 7, 8, 9, 10 molar equivalents or any value between two of these; the amount of catalyst a is 1 to 50 mol% of compound V, compound X, compound X', or compound I-1-2, specifically 1 mol%, 3 mol%, 5 mol%, 7 mol%, 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, or any value between two of these.

[0079] In some embodiments of this disclosure, catalyst b is palladium on carbon or palladium hydroxide / carbon, with a palladium loading of 1-30 wt%, specifically 1 wt%, 3 wt%, 5 wt%, 7.5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, or any value between two of these. The amount of catalyst b added is compound II, compound VIII, or compound II'. The concentration is 3-50 wt%, preferably 10-15 wt%, specifically 3 wt%, 5 wt%, 7.5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, or any value between any two values; the pressure of the hydrogen gas is 1-100 atm, specifically 1 atm, 2 atm, 3 atm, 4 atm, 5 atm, 10 atm, 15 atm, 20 atm, 25 atm, 30 atm, 35 atm, 40 atm, 45 atm, 50 atm, 60 atm, 70 atm, 80 atm, 90 atm, 100 atm, or any value between any two values; the compound II, compound VIII, or compound II' The amount used is 1 molar equivalent, and the hydrogen transfer reagent is ammonium formate, formic acid, hydrazine hydrate, cyclohexene or isopropanol. The amount of hydrogen transfer reagent used is 4 to 100 molar equivalents, specifically 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100 molar equivalents or any value between two values. The reaction solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, 1,4-dioxane, glacial acetic acid, toluene, and N,N-dimethylformamide; the reaction temperature is 0~100℃, specifically 0℃, 5℃, 10℃, 15℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, or any value between two of these; when 1,4-dioxane or glacial acetic acid is used as the reaction solvent, the minimum reaction temperature is higher than the solvent's melting point temperature; when methanol, ethanol, isopropanol, tetrahydrofuran, or ethyl acetate is used as the reaction solvent, the maximum reaction temperature is the solvent's boiling point temperature.

[0080] In some embodiments of this disclosure, the amount of compound VI, compound XI, compound XI', compound XIII or compound XVII is 1 molar equivalent, and the amount of catalyst c is 0.01 to 50 molar equivalents, specifically 0.01, 0.05, 0.1, 0.3, 0.5, 0.8, 1, 2, 3, 4, 5, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50 molar equivalents or any value between two of these. The catalyst c is boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, methanesulfonic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, polyphosphoric acid, aluminum trichloride, zinc chloride, ferric chloride, titanium tetrachloride, tin tetrachloride, trimethylsilyl trifluoromethanesulfonate, boron tribromide, scandium trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, ethyl polyphosphoric acid ester, trimethylsilyl polyphosphoric acid ester, phosphorus pentoxide, or Amberlyst-15; when catalyst c is boron trifluoride diethyl ether complex or boron trifluoride tetrahydrofuran complex, it can also serve as a reaction solvent; The reaction solvent can be sulfuric acid, hydrobromic acid, hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, polyphosphoric acid, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, 1,4-dioxane, chloroform, xylene, nitrobenzene, 1,1,2,2-tetrachloroethane, or tetrahydrofuran; when the reaction solvent is sulfuric acid, hydrobromic acid, or hydrochloric acid, the concentration is 0.1~5M; The reaction temperature is -40~120℃, preferably 60℃, and can specifically be -40℃, -30℃, -20℃, -10℃, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 56℃, 57℃, 58℃, 59℃, 60℃, 61℃, 62℃, 63℃, 64℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, 120℃ or any value between two of these. When sulfuric acid, hydrobromic acid, hydrochloric acid, trifluoroacetic acid, polyphosphoric acid, 1,2-dichloroethane, 1,4-dioxane, xylene, or nitrobenzene are used as reaction solvents, the minimum reaction temperature is higher than the solvent melting point temperature; when sulfuric acid, hydrobromic acid, hydrochloric acid, trifluoroacetic acid, dichloromethane, 1,2-dichloroethane, toluene, 1,4-dioxane, chloroform, or tetrahydrofuran are used as reaction solvents, the maximum reaction temperature is the solvent boiling point temperature.

[0081] In some embodiments of this disclosure, when the halogenating agent is N-bromosuccinimide, N-bromophthalimide, N-iodosuccinimide, iodine, bromine, pyridinium tribromide, or tetrabutylammonium tribromide, the amount of compound IX, compound IX', or compound I-1-1 is 1 molar equivalent, and the amount of the halogenating agent is 2 to 3 molar equivalents, specifically 2, 2.3, 2.5, 2.8, 3 molar equivalents, or any value between two of these. When the halogenating agent is an alkali metal halide / hydrogen peroxide, the alkali metal halide is sodium bromide, potassium bromide, potassium iodide, or sodium iodide, and the amount of the alkali metal halide is 2-3 molar equivalents, specifically 2, 2.3, 2.5, 2.8, 3 molar equivalents or any value between two such values; the amount of hydrogen peroxide is 2-6 molar equivalents, specifically 2, 2.5, 2.8, 3, 3.5, 4, 4.5, 4.8, 5, 5.5, 6 molar equivalents or any value between two such values; the hydrogen peroxide is a 30wt% aqueous solution of hydrogen peroxide. When the halogenated reagent is 1,3-dibromo-5,5-dimethylhydantoin or dibromoisocyanuric acid, the amount of the halogenated reagent used is 1.0 to 1.5 molar equivalents, specifically 1.0, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5 molar equivalents or any value between two of these. The catalyst d is a hydrobromic acid-acetic acid solution, a hydrobromic acid aqueous solution, hydroiodic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid, glacial acetic acid, methanesulfonic acid, camphorsulfonic acid, phosphoric acid, or trifluoromethanesulfonic acid, wherein the concentration of the hydrobromic acid-acetic acid solution is 33wt%, the concentration of the hydrobromic acid aqueous solution is 48wt%, the concentration of the hydrochloric acid aqueous solution is 37wt%, and the sulfuric acid is 98wt% concentrated sulfuric acid. The amount of catalyst d added is 1 to 30 mol% of compound IX, compound IX' or compound I-1-1, specifically 1 mol%, 5 mol%, 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, or any value between two of these. When glacial acetic acid is used as both catalyst d and reaction solvent, the amount of glacial acetic acid added is 5 to 30 times the mass of compound IX or compound I-1-1; The reaction solvent is one or more selected from anhydrous dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, 1,2-dichloroethane, chloroform, glacial acetic acid, dimethyl sulfoxide, N,N-dimethylformamide, methanol, water, toluene, and xylene. The reaction temperature is -40~50℃, specifically -40℃, -30℃, -20℃, -10℃, -5℃, 0℃, 5℃, 10℃, 15℃, 20℃, and 21℃. The minimum reaction temperature is 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 35℃, 40℃, 45℃, 50℃, or any two of these values. When 1,4-dioxane, 1,2-dichloroethane, glacial acetic acid, dimethyl sulfoxide, water, or xylene is used as the reaction solvent, the minimum reaction temperature is higher than the solvent melting point. When anhydrous dichloromethane is used as the reaction solvent, the maximum reaction temperature is the solvent boiling point.

[0082] In some embodiments of this disclosure, R is methyl, the deprotecting agent is boron tribromide, hydrobromic acid, aluminum trichloride, trimethylsilicon iodide, boron trichloride, or pyridine hydrochloride, the amount of compound I-1-1' is 1 molar equivalent, and the amount of the deprotecting agent is 2 to 10 molar equivalents, specifically 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, or any value between two of these; the reaction solvent is dichloromethane. The reaction can be with alkane or dichloroethane, and the reaction temperature is -78 to 50°C. Specifically, it can be -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, or any value between two of these. When dichloroethane is used as the reaction solvent, the minimum reaction temperature is higher than the solvent's melting point temperature. When dichloromethane is used as the reaction solvent, the maximum reaction temperature is the solvent's boiling point temperature. In some embodiments of this disclosure, R is methoxymethyl, the deprotecting agent is concentrated hydrochloric acid, hydrobromic acid, or trifluoroacetic acid, the concentration of concentrated hydrochloric acid is 37 wt%, and the concentration of the aqueous hydrobromic acid solution is 48 wt%; the amount of the deprotecting agent is 0.1 to 10 molar equivalents, specifically 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or any value between two of these; the reaction solvent is one or more of methanol, ethanol, tert-butanol, chloroform, dichloromethane, and 1,4-dioxane, and the reaction temperature is -40 to 100°C. The reaction temperature can be -40℃, -30℃, -20℃, -10℃, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, or any value between two of these. When tert-butanol or 1,4-dioxane is used as the reaction solvent, the minimum reaction temperature is higher than the solvent's melting point. When methanol, ethanol, tert-butanol, chloroform, or dichloromethane is used as the reaction solvent, the maximum reaction temperature is the solvent's boiling point. In some embodiments of this disclosure, R is trimethylsilyl or tert-butyldimethylsilyl, the deprotecting agent is tetrabutylammonium fluoride, cesium fluoride, potassium fluoride, or sodium fluoride, and the amount of the deprotecting agent is 1 to 10 molar equivalents, specifically 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, or any value between two of these. The reaction solvent is tetrahydrofuran, N,N- The reaction temperature is -40 to 50°C, specifically -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, or any value between two of these. When 1,4-dioxane is used as the reaction solvent, the minimum reaction temperature is higher than the solvent melting point temperature.

[0083] In some embodiments of this disclosure, the amount of compound XIV, compound XV, compound XVIII or compound XIX is 1 molar equivalent, the amount of acetone is 0.5 molar equivalent, and the amount of base 3 is 1 to 3 molar equivalents, specifically 1, 1.3, 1.5, 2, 2.2, 2.5, 2.8, 3.0 molar equivalents or any value between two of these. The reaction solvent is one or more of the following: anhydrous ethanol, methanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, water, ethylene glycol dimethyl ether, acetonitrile, tert-butanol, 2-methyltetrahydrofuran, and N-methylpyrrolidone; the reaction temperature is -20 to 60°C, specifically -20°C, -10°C, -5°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 10°C, 15°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, or any two values; when 1,4-dioxane, dimethyl sulfoxide, water, or tert-butanol is used as the reaction solvent, the minimum reaction temperature is higher than the solvent melting point temperature.

[0084] A monophosphine ligand, prepared from compound I described above, wherein the monophosphine ligand is a compound of formula III or a stereoisomer thereof: , Wherein: R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen; R 11 and R 12 Alkyl groups selected independently from C1-C6, or , or R 11 and R 12 Form with the attached nitrogen atom , , , or .

[0085] In some embodiments of this disclosure, the monophosphine ligand of Formula III is selected from any of the following compounds: , , , , or , R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring. The 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

[0086] A method for preparing the above-mentioned monophosphine ligand includes the following steps: Compound I reacts with tris(dimethylamino)phosphine or dichloro(dimethylamino)phosphine to give the monophosphine ligand compound III-1, as shown in the following reaction route: , Compound I reacts with phosphorus trichloride and organic amine compound XX to give monophosphine ligand compound III, as shown in the following reaction route: , Alternatively, compound I reacts with phosphorus trichloride, organic amine compound XX, and n-butyllithium to yield monophosphine ligand compound III, as shown in the following reaction route: , Among them, R 11 and R 12 Simultaneously selected from methyl or , or R 11 and R 12 Form with the attached nitrogen atom , , , or ; R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

[0087] In some embodiments of this disclosure, the compound XX may specifically be dimethylamine, bis(1-phenylethyl)amine, , , , or .

[0088] In some embodiments of this disclosure, in the step of reacting compound I with tris(dimethylamino)phosphine to obtain monophosphine ligand compound III-1, the amount of compound I used is 1 molar equivalent, and the amount of tris(dimethylamino)phosphine added is 1 to 10 molar equivalents, specifically 1, 1.5, 2, 2.5, 3, 4, 5, 7, 10 molar equivalents or any value between two of these; the reaction solvent is anhydrous toluene, anhydrous dichloromethane, anhydrous 1,2-dichloroethane, or anhydrous tetrahydrofuran, and the reaction temperature is 0 to 110°C, specifically 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C or any value between two of these; when anhydrous dichloromethane, anhydrous 1,2-dichloroethane, or anhydrous tetrahydrofuran is used as the reaction solvent, the highest reaction temperature is the boiling point temperature of the solvent.

[0089] In some embodiments of this disclosure, in the step of reacting compound I with phosphorus trichloride and organic amine compound XX to obtain monophosphine ligand compound III, the base 4 is triethylamine, and the amounts of phosphorus trichloride, organic amine compound XX, and base 4 are 1.0 to 10.0 molar equivalents, specifically 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 molar equivalents or any value between two of these; the reaction solvent is anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous 1,2-dichloroethane, or anhydrous toluene, and the reaction temperature is -78 to 50°C, preferably 0°C, specifically -78°C, -7... 0℃, -60℃, -50℃, -40℃, -30℃, -20℃, -10℃, -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 10℃, 20℃, 30℃, 40℃, 50℃, or any value between two of these; when anhydrous 1,2-dichloroethane is used as the reaction solvent, the minimum reaction temperature is higher than the solvent's melting point temperature; when dichloromethane is used as the reaction solvent, the maximum reaction temperature is the solvent's boiling point temperature.

[0090] In some embodiments of this disclosure, compound I reacts with phosphorus trichloride, organic amine compound XX, and n-butyllithium to yield monophosphine ligand compound III. In the steps, the amounts of phosphorus trichloride, organic amine compound XX, base 4, and n-butyllithium are 1 to 5 molar equivalents, specifically 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 molar equivalents or any value between two of these; the reaction solvent is anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous 1,2-dichloroethane, or anhydrous toluene, and the reaction temperature is -78 to 30°C, preferably 0°C, specifically -78°C, -70°C, -50°C, -30°C, -10°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 10°C, 20°C, 30°C or any value between two of these; when anhydrous 1,2-dichloroethane is used as the reaction solvent, the minimum reaction temperature is higher than the solvent melting point temperature.

[0091] An application of the aforementioned monophosphine ligand, wherein the monophosphine ligand is complexed with a metal salt of gold, copper, rhodium, ruthenium, iridium, nickel, molybdenum, palladium or cobalt to prepare a catalyst; or the monophosphine ligand is used for metal-catalyzed asymmetric hydroacylation, asymmetric hydrogenation, asymmetric allyl alkylation or asymmetric allyl amination reactions.

[0092] The abbreviations for the reaction reagents mentioned in the instructions are as follows: Me: Methyl group; Ph: phenyl; nBu: n-Butyl; TMSOI: Trimethyl sulfoxide; NBS: N-bromosuccinimide; TfOH: Trifluoromethanesulfonic acid; DMSO: Dimethyl sulfoxide; DPPF palladium dichloride: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; Rh(COD)2BF4: Rhodium (I) bis(1,5-cyclooctadiene)tetrafluoroborate; Rh(NBD)2BF4: Rhodium bis(biscyclopentadiene)tetrafluoroborate; [Rh(COD)Cl]2: (1,5-cyclooctadiene)rhodium(I) dimer.

[0093] The features and performance of this disclosure are further described in detail below with specific examples.

[0094] Example 1: Preparation of compound I-1-1-1

[0095] Preparation of compound V-1

[0096] Trimethyl sulfoxide (4.84 g, 22.0 mmol, 2.2 equiv) and sodium hydride (60% mineral oil dispersion, 1.76 g, 44.0 mmol, 4.4 equiv) were added to a reaction flask, followed by anhydrous dimethyl sulfoxide (40 mL). The mixture was stirred at room temperature for 30 min until a grayish-white suspension was formed. Separately, compound IV-1 (4.24 g, 10.0 mmol, 1 equiv) was dissolved in anhydrous dimethyl sulfoxide (20 mL) and slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was placed in a 50°C oil bath and stirred. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 4:1, v / v) continued until the spot of starting compound IV-1 disappeared (40 min). The reaction was quenched by adding saturated brine (100 mL) after cooling to room temperature. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (100 mL × 2) and saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to give 3.00 g of bis[2-(5-hydroxy-2-bromo)cyclopropyl] ketone (V-1), with a yield of 66%.

[0097] HRMS (ES+) calcd for [M + H] + C19 H 17 Br2O3, m / z: 452.9518, found:452.9519. Preparation of compound II-1

[0098] Under nitrogen protection, bis[2-(5-hydroxy-2-bromo)cyclopropyl] ketone (compound V-1, 4.52 g, 10.0 mmol, 1.0 eq), phenylboronic acid (3.66 g, 30.0 mmol, 3.0 eq), DPPF palladium dichloride (366 mg, 0.50 mmol, 5 mol%), and cesium carbonate (26.06 g, 80.0 mmol, 8.0 eq) were added sequentially to a dry two-necked Schlenk flask. 1,4-Dioxane (80 mL) and water (20 mL) were then added and stirred to dissolve. The reaction mixture was degassed by bubbling with nitrogen for 15 minutes, and then heated to 100 °C (internal temperature) under a nitrogen atmosphere. The reaction mixture was stirred for 12–24 hours, and TLC was used to monitor the reaction (evolving solvent: petroleum ether / ethyl acetate = 3:1, v / v) until the starting material disappeared.

[0099] The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (80 mL × 2). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 5:1, v / v) to give the target product bis[2-(4-hydroxy-[1,1'-biphenyl]-2-yl)cyclopropyl] ketone (compound II-1), a white solid, 3.30 g, yield 74%.

[0100] HRMS (ESI) calcd for [M+H] + C 31 H 27 O3, m / z: 447.1955, found: 447.1954. Preparation of compound VI-1

[0101] In a reaction flask, bis[2-(4-hydroxy-[1,1'-biphenyl]-2-yl)cyclopropyl]methyl ketone (compound II-1, 4.46 g, 10.0 mmol, 1 equiv), 10% palladium-on-carbon catalyst (446 mg, water content approximately 50%, amounting to 10% of the substrate mass), and methanol solvent (50 mL) were added sequentially. The mixture was stirred to ensure uniform dispersion of the substrate. The reaction flask was purged with nitrogen once, then purged with hydrogen three times. Finally, the reaction was carried out under the protection of a hydrogen balloon (approximately 1 atm) with stirring at room temperature (20–30 °C). The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was stopped after the starting materials were completely converted (24 hours). The reaction solution was filtered under reduced pressure with diatomaceous earth to remove the palladium-carbon catalyst. The filter cake was washed with methanol 2-3 times. The filtrates were combined and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography to obtain the target ring-opening product 1,7-bis(2-phenyl-5-hydroxyphenyl)-4-heptanone (compound VI-1), which was a white solid, 4.01 g, with a yield of 89%.

[0102] HRMS (ESI) calcd for [M+H] + C 31 H 31 O3, m / z: 451.2268, found:451.2267. Preparation of compound I-1-1-1

[0103] Under nitrogen protection, compound VI-1 (2.25 g, 5.0 mmol, 1 equiv) was added to a dry reaction flask, followed by the addition of boron trifluoride diethyl ether (BF3·Et2O, 10 mL, serving as both solvent and Lewis acid catalyst). After stirring to dissolve, the reaction solution was heated to 60 °C (external bath temperature), and the reaction was maintained at this temperature with stirring. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) continued until the spot of starting compound VI-1 disappeared (approximately 12 h). After cooling to room temperature, the reaction solution was slowly poured into ice water (150 mL) under an ice-water bath, and stirred vigorously for 30 min. Extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 1). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to give 1.92 g of 5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound I-1-1-1), with a yield of 88%.

[0104] HRMS (ESI) calcd for [M+H] + C 31 H 29 O2, m / z: 433.2163, found: 433.2160. Example 2: Preparation of compound I-1-1-1

[0105] The preparation steps of compound II-1 are as follows:

[0106] Under nitrogen protection, bis[2-(5-hydroxy-2-bromophenyl)cyclopropyl] ketone (compound V-1, 4.52 g, 10.0 mmol, 1.0 eq), Ni(dppp)Cl2 (27 mg, 0.05 mmol, 0.5 mol%), and anhydrous tetrahydrofuran (80 mL) were added sequentially to a 250 mL dry two-necked Schlenk flask and stirred until dissolved. The reaction system was cooled to an internal temperature of 0–5 °C, and a tetrahydrofuran solution of magnesium phenyl bromide (PhMgBr, 1.0 M in THF, 45.0 mL, 45.0 mmol, 4.5 eq) was slowly added dropwise, controlling the dropping rate to keep the internal temperature below 5 °C. After the addition was complete, the reaction system was slowly heated to room temperature and stirred for 2 h, followed by heating to 60 °C for 8–12 h (TLC monitoring, developing solvent: petroleum ether / ethyl acetate = 3:1, v / v).

[0107] After the reaction was complete, the reaction solution was cooled to 0°C, and the reaction was quenched by slowly adding saturated ammonium chloride aqueous solution (50 mL). The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed successively with saturated brine (50 mL), then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1, v / v) to give a white solid bis(2-(4-hydroxy-[1,1'-biphenyl]-2-yl)cyclopropyl) ketone (compound II-1), 3.57 g, yield 80%.

[0108] HRMS (ESI) calcd for [M+H] + C 31 H 27 O3, m / z: 447.1955, found:447.1955. The steps for preparing compound V-1 from compound IV-1, compound VI-1 from compound II-1, and compound I-1-1-1 from compound VI-1 were carried out according to the conditions of Example 1, to obtain 5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound I-1-1-1).

[0109] Example 3: Preparation of compound I-1-1-1

[0110] The preparation steps of compound II-1 are as follows:

[0111] Under nitrogen protection, the substrate bis[2-(5-hydroxy-2-bromophenyl)cyclopropyl] ketone (compound V-1, 4.52 g, 10.0 mmol, 1.0 eq), Pd(PPh3)4 (578 mg, 0.50 mmol, 5 mol%), and anhydrous THF (100 mL) were added to a dry 250 mL three-necked flask and stirred until dissolved. The reaction system was cooled to an internal temperature of 0–5 °C, and a tetrahydrofuran solution of phenyl zinc bromide (PhZnBr, 1.0 M in THF, 45.0 mL, 45.0 mmol, 4.5 eq) was slowly added dropwise, controlling the dropping rate to keep the internal temperature below 5 °C. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 1 h, followed by heating to 60 °C for 12–18 h (TLC monitoring, developing solvent: petroleum ether / ethyl acetate = 3:1, v / v).

[0112] After the reaction was complete, the reaction solution was cooled to 0°C, and the reaction was quenched by slowly adding saturated ammonium chloride aqueous solution (50 mL). The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed successively with saturated brine (50 mL), then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1, v / v) to give 3.34 g of a white solid bis(2-(4-hydroxy-[1,1'-biphenyl]-2-yl)cyclopropyl) ketone (compound II-1), yield 75%.

[0113] HRMS (ESI) calcd for [M+H] + C 31 H 27 O3, m / z: 447.1955, found:447.1955. The steps for preparing compound V-1 from compound IV-1, compound VI-1 from compound II-1, and compound I-1-1-1 from compound VI-1 were carried out according to the conditions of Example 1, to obtain 5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound I-1-1-1).

[0114] Example 4: Preparation of compound I-1-1-1

[0115] The preparation steps of compound II-1 are as follows:

[0116] Under nitrogen protection, the substrate bis[2-(5-hydroxy-2-bromophenyl)cyclopropyl] ketone (compound V-1, 4.52 g, 10.0 mmol, 1.0 eq), Pd(PPh3)4 (578 mg, 0.50 mmol, 5 mol%), and anhydrous toluene (120 mL) were added to a dry 250 mL three-necked flask and stirred until dissolved. Tributylphenyltin (PhSnBu3, 14.0 mL, 44.0 mmol, 4.4 eq) was added and stirred until homogeneous. The reaction system was heated to 100 °C and refluxed for 12–24 h (TLC monitoring, developing solvent: petroleum ether / ethyl acetate = 3:1, v / v).

[0117] After the reaction was complete, the reaction solution was cooled to room temperature, and 80 mL of saturated potassium fluoride aqueous solution was added. The mixture was stirred vigorously at room temperature for 1 h to precipitate the organotin byproduct. The filtrate was filtered with diatomaceous earth as an aid, and the organic phase was separated from the filtrate. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed successively with saturated brine (60 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1, v / v) to give 3.79 g of bis(2-(4-hydroxy-[1,1'-biphenyl]-2-yl)cyclopropyl) methyl ketone (compound II-1), a white solid, with a yield of 85%.

[0118] HRMS (ESI) calcd for [M+H] + C 31 H 27 O3, m / z: 447.1955, found:447.1955. The steps for preparing compound V-1 from compound IV-1, compound VI-1 from compound II-1, and compound I-1-1-1 from compound VI-1 were carried out according to the conditions of Example 1, to obtain 5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound I-1-1-1).

[0119] Example 5: Preparation of compound I-1-1-1

[0120] Preparation of compound VIII-1

[0121] Add trimethyl thionyl chloride (3.86 g, 30.0 mmol, 3 equiv) and potassium tert-butoxide (4.49 g, 40.0 mmol, 4 equiv) to a reaction flask, then add anhydrous dimethyl sulfoxide (40 mL) and stir at room temperature for 30 min until a suspension is formed. Separately, dissolve compound VII-1 (2.66 g, 10.0 mmol, 1 equiv) in anhydrous dimethyl sulfoxide (20 mL) and slowly add it dropwise to the above reaction solution. After the addition is complete, place the reaction solution at room temperature and stir. Monitor the reaction by TLC (developing solvent: petroleum ether / ethyl acetate = 4:1, v / v) until the spot of starting compound VII-1 disappears (approximately 40 min). The reaction was quenched by adding saturated brine (100 mL) after cooling to room temperature. The mixture was extracted with methyl tert-butyl ether (50 mL × 2). The organic phases were combined and washed successively with water (100 mL × 2) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to give bis[2-(3-hydroxyphenyl)cyclopropyl] ketone (compound VIII-1), 1.76 g of white solid, with a yield of 60%.

[0122] HRMS (ES+) calcd for [M + H] + C 19 H 19 O3, m / z: 295.1329, found: 295.1328. Preparation of compound IX-1

[0123] The prepared bis[2-(3-hydroxyphenyl)cyclopropyl] ketone (compound VIII-1, 2.94 g, 10.0 mmol, 1 equiv), 10% palladium-on-carbon catalyst (441 mg, water content approximately 50%, 15% of the substrate mass), and isopropanol solvent (50 mL) were added sequentially to a reaction flask. The mixture was stirred to ensure uniform dispersion of the substrate. Ammonium formate (3.78 g, 60 mmol, 6 equiv) was added, and the reaction was stirred at room temperature (20–30 °C). The reaction progress was monitored by thin-layer chromatography (TLC), and the reaction was stopped after the starting material was completely converted (24 hours). The reaction solution was filtered through diatomaceous earth under reduced pressure to remove the palladium-on-carbon catalyst. The filter cake was washed 2–3 times with isopropanol. The filtrates were combined, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain the target ring-opening product 1,7-bis(3-hydroxyphenyl)-4-heptanone (compound IX-1), 2.40 g, with a yield of 80%.

[0124] HRMS (ES+) calcd for [M + H] + C 19 H 23 O3, m / z: 299.1642, found: 299.1640. Preparation of compound X-1

[0125] Compound IX-1 (2.98 g, 10.0 mmol, 1 equiv) and anhydrous tetrahydrofuran (50 mL) were added to a dry reaction flask and stirred thoroughly. The reaction flask was placed in a cryogenic bath and cooled to an internal temperature of 0°C. Concentrated hydrochloric acid (36–37 wt%, 170 μL, 20 mol%) was added, followed by N-iodosuccinimide (5.62 g, 25 mmol, 2.5 equiv) in three batches, with an interval of approximately 5 min between each batch. After the addition was complete, the reaction mixture was stirred at 0°C for 10 min, then placed at room temperature (20–30°C) and stirred continuously. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 2:1, v / v) was performed until the starting spot disappeared (approximately 1 h). After the reaction was complete, saturated sodium sulfite aqueous solution (50 mL) was added to the reaction solution to quench the reaction, and the mixture was brought to room temperature and stirred for 15 min. Tetrahydrofuran was removed by vacuum distillation. The residue was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed successively with water (100 mL × 2) and saturated brine (100 mL × 1). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1, v / v) to give 4.02 g of 1,7-bis(2-iodo-5-hydroxyphenyl)-4-heptanone (compound X-1), with a yield of 73%.

[0126] HRMS (ES+) calcd for [M + H] + C 19 H 21 I2O3, m / z: 550.9575, found:550.9577. Preparation of compound XI-1

[0127] Under nitrogen protection, 1,7-bis(2-iodo-5-hydroxyphenyl)-4-heptanone (compound X-1, 5.50 g, 10.0 mmol, 1.0 eq), phenylboronic acid (3.66 g, 30.0 mmol, 3.0 eq), Pd(Ph3P)4 (578 mg, 0.50 mmol, 5 mol%), and cesium carbonate (13.03 g, 40.0 mmol, 4.0 eq) were added sequentially to a dry two-necked Schlenk flask. 1,4-Dioxane (80 mL) and water (20 mL) were then added, and the mixture was stirred to dissolve. The reaction mixture was degassed by bubbling with nitrogen for 15 minutes, and then heated to 80 °C (internal temperature) under nitrogen atmosphere. The reaction mixture was stirred for 12–24 hours, and TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) was performed until the starting material disappeared.

[0128] The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (80 mL × 2). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 5:1, v / v) to give the target product 1,7-bis(2-phenyl-5-hydroxyphenyl)-4-heptanone (compound XI-1), a white solid, 3.69 g, yield 82%.

[0129] HRMS (ESI) calcd for [M+H] + C 31 H 31 O3, m / z: 451.2268, found:451.2267. Preparation of compound I-1-1-1

[0130] Under nitrogen protection, compound XI-1 (2.25 g, 5.0 mmol, 1 equiv) was added to a dry reaction flask, followed by 10 mL of trifluoromethanesulfonic acid (used as both solvent and Lewis acid catalyst). After stirring to dissolve, the reaction solution was heated to 40 °C (external bath temperature), and the reaction was maintained at this temperature with stirring. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) was performed until the spot of compound XI-1 disappeared (approximately 12 h). After cooling to room temperature, the reaction solution was slowly poured into ice water (150 mL) under an ice-water bath, and stirred vigorously for 30 min. Extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to give 1.84 g of 5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobenaphthalene-8,8'-diol (compound I-1-1-1), with a yield of 84%.

[0131] HRMS (ES+) calcd for [M + H] + C 31 H 29 O2, m / z: 433.2163, found: 433.2160. Example 6: Preparation of compound I-1-1-2

[0132] Preparation of compound II-2

[0133] Add trimethyl sulfoxide (4.4 g, 20.0 mmol, 2 equiv) and potassium tert-butoxide (4.48 g, 40.0 mmol, 4 equiv) to a reaction flask, then add anhydrous N,N-dimethylformamide (40 mL) and stir at room temperature for 30 min until a suspension is formed. Separately, dissolve compound XII-1 (2.94 g, 10.0 mmol, 1 equiv) in anhydrous N,N-dimethylformamide (20 mL) and slowly add it dropwise to the above reaction solution. After the addition is complete, place the reaction solution at 70 °C and stir. Monitor by TLC (developing solvent: petroleum ether / ethyl acetate = 4:1, v / v) until the spot of starting compound XII-1 disappears (approximately 40 min). The reaction was quenched by adding saturated brine (100 mL) after cooling to room temperature. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (100 mL × 2) and saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to give compound II-2, 2.10 g, with a yield of 65%.

[0134] HRMS (ESI) calcd for [M+H] + C 21 H 23 O3, m / z: 323.1642, found:323.1651. Compound XII-1 can be obtained through the following preparation route:

[0135] Potassium hydroxide (3.65 g, 65.0 mmol, 1.3 equiv) and anhydrous ethanol (20 mL) were added to a dry reaction flask and stirred until dissolved under an ice-water bath. 2-Methyl-5-hydroxybenzaldehyde (compound XIV-1, 6.81 g, 50.0 mmol, 1 equiv) was added to the system, and a paste gradually formed under stirring. After the internal temperature dropped to 0–5 °C, acetone (1.45 g, 1.84 mL, 25.0 mmol, 0.5 equiv) was slowly added dropwise, completing the addition in approximately 30 min. The ice-water bath was removed, and the mixture was heated to 60 °C and stirred for 8 h. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 2:1, v / v) continued until the spot of compound XIV-1 disappeared. Add 100 mL of ice water to the above reaction solution, slowly add 4 mL of glacial acetic acid to neutralize, stir vigorously for 10 min, and let the resulting suspension stand in an ice-water bath for 20 min. Filter, wash the filter cake successively with water (20 mL × 3) and ethanol-water mixed solvent (EtOH / H2O = 1:2, v / v, 20 mL × 2), and dry under vacuum at 40-60 °C to obtain compound XII-1, 6.62 g, with a yield of 90%, which can be directly added to the next reaction.

[0136] HRMS (ESI) calcd for [M+H] + C 19 H 19 O3, m / z: 295.1329, found:295.1330. Preparation of compound XIII-1

[0137] Compound II-2 (3.22 g, 10.0 mmol, 1 equiv), 10% palladium-on-carbon catalyst (322 mg, water content approximately 50%, 10% of substrate mass), and methanol solvent (50 mL) were added sequentially to a reaction vessel, and the mixture was stirred to ensure uniform dispersion of the substrate. The reaction vessel was purged with nitrogen once, then purged with hydrogen three times, and finally reacted under hydrogen (100 atm) protection at room temperature (20–30 °C) with stirring. The reaction progress was monitored by thin-layer chromatography (TLC), and the reaction was stopped after complete conversion of the starting material (4 hours). The reaction solution was filtered through diatomaceous earth under reduced pressure to remove the palladium-on-carbon catalyst. The filter cake was washed 2–3 times with methanol, and the filtrates were combined and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography to obtain the target ring-opening product compound XIII-1, 2.65 g, with a yield of 82%.

[0138] HRMS (ES+) calcd for [M + H]+ C 21 H 27 O3, m / z: 327.1955, found: 327.1955. Preparation of compound I-1-1-2

[0139] Under nitrogen protection, compound XIII-1 (1.63 g, 5.0 mmol, 1 equiv) was added to a dry reaction flask, followed by the addition of boron trifluoride diethyl ether (BF3·Et2O, 10 mL, serving as both solvent and Lewis acid catalyst). After stirring to dissolve, the reaction solution was heated to 60 °C (external bath temperature), and the reaction was maintained at this temperature with stirring. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) was performed until the spot of starting compound XIII-1 disappeared (approximately 12 h). After cooling to room temperature, the reaction solution was slowly poured into ice water (150 mL) under an ice-water bath, and stirred vigorously for 30 min. Extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 1). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from a dichloromethane:petroleum ether system to give 1.31 g of 5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound I-1-1-2), with a yield of 85%.

[0140] HRMS (ES+) calcd for [M + H] + C 21 H 25 O2, m / z: 309.1850, found: 309.1850. Example 7: Preparation of compound I-1-1-3

[0141] Preparation of compound II-3

[0142] Add trimethyl sulfoxide (4.84 g, 22.0 mmol, 2.2 equiv) and sodium hydride (60% mineral oil dispersion, 1.76 g, 44.0 mmol, 4.4 equiv) to a reaction flask, then add anhydrous dimethyl sulfoxide (40 mL) and stir at room temperature for 30 min until a suspension is formed. Separately, take (1... E 4E 1-(5-hydroxy-2-methylphenyl)-5-(4-hydroxy-[1,1'-biphenyl]-2-yl)-1,4-pentadien-3-one (compound XII-2, 3.56 g, 10.0 mmol, 1 equiv) was dissolved in anhydrous dimethyl sulfoxide (20 mL) and slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was placed in an oil bath at 50 °C and stirred. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 4:1, v / v) continued until the spot of the starting compound XII-2 disappeared (approximately 40 min). The reaction was quenched by adding saturated brine (100 mL) after cooling to room temperature. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (100 mL × 2) and saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to give compound II-3, 2.31 g, with a yield of 60%.

[0143] HRMS (ESI) calcd for [M+H] + C 26 H 25 O3, m / z: 385.1799, found:385.1795. Compound XII-2 can be obtained through the following preparation route:

[0144] 2-Methyl-5-hydroxybenzaldehyde (compound XIV-1, 1.36 g, 10.0 mmol, 1.0 equiv) was added to a dry round-bottom flask and dissolved in anhydrous ethanol (20 mL). Acetone (2.90 g, 3.7 mL, 50.0 mmol, 5 equiv) was added and stirred until dissolved. The internal temperature was maintained at 0–5 °C, and 10% potassium hydroxide aqueous solution (15 mL, 28 mmol KOH) was slowly added dropwise over 15 minutes. After the addition was complete, the reaction mixture was stirred at 0–5 °C for 2 hours. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 2:1, v / v) showed complete conversion of the starting material. Water (50 mL) was added to dilute the reaction system, and the pH was adjusted to 2–3 with 3 mol / L hydrochloric acid while stirring. The mixture was extracted with ethyl acetate (30 mL × 2), and the organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to give the intermediate ( E)-4-(5-hydroxy-2-methylphenyl)-3-buten-2-one (compound XV-1) is a yellow solid, 1.51 g, yield 86%.

[0145] Add the intermediate to a dry round-bottom flask. E 4-(5-hydroxy-2-methylphenyl)-3-buten-2-one (compound XV-1, 1.41 g, 8.0 mmol, 1.0 equiv) was dissolved in anhydrous ethanol (20 mL), and 4-hydroxy-[1,1'-biphenyl]-2-carboxaldehyde (1.58 g, 8.0 mmol, 1.0 equiv) was added and stirred to dissolve. The internal temperature was maintained at 0–5 °C, and 10% potassium hydroxide aqueous solution (15 mL, 28 mmol KOH) was slowly added dropwise over 15 minutes. After the addition was complete, the reaction was stirred at 0–5 °C for 2 hours. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 2:1, v / v) showed complete conversion of the starting material. Water (50 mL) was added to dilute the reaction system, and the pH was adjusted to 2–3 with 3.0 M hydrochloric acid under stirring. A large amount of solid precipitated, which was filtered. The filter cake was washed with water (20 mL × 2), dried, and the product (1) was obtained. E 4 E 1-(5-hydroxy-2-methylphenyl)-5-(4-hydroxy-[1,1'-biphenyl]-2-yl)-1,4-pentadien-3-one (compound XII-2) is a yellow solid, 2.28 g, yield 80%.

[0146] HRMS (ESI) calcd for [M+H] + C 24 H 21 O3, m / z:357.1486, found:357.1486. Preparation of compound XIII-2

[0147] Compound II-3 (3.85 g, 10.0 mmol, 1 equiv), 10% palladium-on-carbon catalyst (578 mg, approximately 50% water content, 15% of the substrate mass), and solvent 1,4-dioxane (50 mL) were added sequentially to a reaction flask, and the mixture was stirred to ensure uniform dispersion of the substrate. A hydrazine hydrate aqueous solution (80% mass concentration, 2.4 mL, 40 mmol, 4 equiv) was added, and the mixture was stirred at 100 °C. The reaction progress was monitored by thin-layer chromatography (TLC), and the reaction was stopped after complete conversion of the starting material (8 hours). The reaction solution was filtered through diatomaceous earth under reduced pressure to remove the palladium-on-carbon catalyst. The filter cake was washed 2-3 times with tetrahydrofuran. The filtrates were combined, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain the target ring-opening product compound XIII-2, 3.3 g, in 85% yield.

[0148] HRMS (ESI) calcd for [M+H] + C 26 H 29 O3, m / z: 389.2112, found:389.2110. Preparation of compound I-1-1-3

[0149] Under nitrogen protection, compound XIII-2 (1.94 g, 5.0 mmol, 1 equiv) and anhydrous 1,2-dichloroethane (20 mL) were added to a dry reaction flask, followed by the addition of boron trifluoride diethyl ether (BF3·Et2O, 2.84 g, 20.0 mmol, 4 equiv). After stirring to dissolve, the reaction solution was heated to 60 °C (external bath temperature), and the reaction was maintained at this temperature with stirring. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) continued until the spot of starting compound XIII-2 disappeared (approximately 12 h). After cooling to room temperature, the reaction solution was slowly poured into ice water (150 mL) under an ice-water bath and stirred vigorously for 30 min. Extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 1), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to give compound I-1-1-3, 1.56 g, with a yield of 84%.

[0150] HRMS (ESI) calcd for [M+H + C 26 H 27O2, m / z: 371.2006, found:371.2005. Example 8: Preparation of compound I-1-1-4

[0151] Preparation of compound VIII-1

[0152] Trimethylsulfonium iodide (4.49 g, 22.0 mmol, 2.2 equiv) and sodium hydride (60% mineral oil dispersion, 1.76 g, 44.0 mmol, 4.4 equiv) were added to a reaction flask, followed by anhydrous dimethyl sulfoxide (40 mL). The mixture was stirred at room temperature for 30 min until a suspension was formed. Separately, compound VII-1 (2.66 g, 10.0 mmol, 1 equiv) was dissolved in anhydrous dimethyl sulfoxide (20 mL) and slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was placed in a 50°C oil bath and stirred. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 4:1, v / v) continued until the spot of starting compound VII-1 disappeared (approximately 40 min). The reaction solution was cooled to room temperature, and the reaction was quenched by adding saturated brine (100 mL). The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (100 mL × 2) and saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to give compound VIII-1, 1.85 g, with a yield of 63%.

[0153] HRMS (ES+) calcd for [M + H] + C 19 H 19 O3, m / z: 295.1329, found: 295.1328. Preparation of compound IX-1

[0154] The prepared bis[2-(3-hydroxyphenyl)cyclopropyl] ketone (compound VIII-1, 2.94 g, 10.0 mmol, 1 equiv), 10% palladium-on-carbon catalyst (441 mg, water content approximately 50%, 15% of the substrate mass), and solvent 1,4-dioxane (50 mL) were added sequentially to a reaction flask, and the mixture was stirred to ensure uniform dispersion of the substrate. A hydrazine hydrate aqueous solution (80% mass concentration, 2.4 mL, 40 mmol, 4 equiv) was added, and the reaction was stirred at 100 °C. The reaction progress was monitored by thin-layer chromatography (TLC), and the reaction was stopped after the starting material was completely converted (8 hours). The reaction solution was filtered under reduced pressure with diatomaceous earth to remove the palladium-on-carbon catalyst. The filter cake was washed 2-3 times with tetrahydrofuran. The filtrates were combined and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography to obtain the target ring-opening product 1,7-bis(3-hydroxyphenyl)-4-heptanone (compound IX-1), 2.46 g, with a yield of 82%.

[0155] HRMS (ES+) calcd for [M + H] + C 19 H 23 O3, m / z: 299.1642, found: 299.1640. Preparation of compound X-2

[0156] Compound IX-1 (2.98 g, 10.0 mmol, 1 equiv) and anhydrous dichloromethane (50 mL) were added to a dry reaction flask and stirred thoroughly. The reaction flask was placed in a cryogenic bath and cooled to an internal temperature of 0°C. HBr (180 μL, 33% in HOAc, 10 mol%) was added, followed by the addition of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 3.00 g, 10.5 mmol, 1.05 equiv) in three batches, with an interval of approximately 5 min between each addition. After the addition was complete, the reaction mixture was stirred at 0°C for 10 min, then placed at room temperature (20–30°C) and stirred continuously. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 2:1, v / v) was performed until the starting spot disappeared (approximately 1 h). After the reaction was complete, saturated sodium sulfite aqueous solution (50 mL) was added to the reaction solution to quench the reaction, and the mixture was brought to room temperature and stirred for 15 min. Dichloromethane was removed by vacuum distillation. The residue was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed successively with water (100 mL × 2) and saturated brine (100 mL × 1). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1, v / v) to give 3.36 g of 1,7-bis(2-bromo-5-hydroxyphenyl)-4-heptanone (compound X-2), with a yield of 78%.

[0157] HRMS (ES+) calcd for [M + H] + C 19 H 21 Br2O3, m / z: 456.9832, found:456.9830. Preparation of compound XI-2

[0158] Under nitrogen protection, 1,7-bis(2-bromo-5-hydroxyphenyl)-4-heptanone (compound X-2, 4.55 g, 10.0 mmol, 1.0 eq), potassium butyltrifluoroborate (8.15 g, 50.0 mmol, 5.0 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (732 mg, 1 mmol, 10 mol%), and potassium tert-butoxide (6.73 g, 60.0 mmol, 6.0 eq) were added sequentially to a dry two-necked Schlenk flask. Methanol (80 mL) and water (20 mL) were added, and the mixture was stirred to dissolve. The reaction mixture was degassed by bubbling with nitrogen for 15 minutes, and then heated to 60 °C (internal temperature) under nitrogen atmosphere. The reaction mixture was stirred for 12–24 hours, and TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) was performed until the starting material disappeared.

[0159] The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (80 mL × 2). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 5:1, v / v) to give the target product 1,7-bis(2-butyl-5-hydroxyphenyl)-4-heptanone (compound XI-2), 3.28 g, yield 80%.

[0160] HRMS (ESI) calcd for [M+H] + C 27 H 39 O3, m / z: 411.2894, found: 411.2892. Preparation of compound I-1-1-4

[0161] Under nitrogen protection, compound XI-2 (2.05 g, 5.0 mmol, 1 equiv) and anhydrous 1,2-dichloroethane (20 mL) were added to a dry reaction flask, followed by the addition of boron trifluoride diethyl ether (BF3·Et2O, 2.84 g, 20.0 mmol, 4 equiv). After stirring to dissolve, the reaction solution was heated to 60 °C (external bath temperature), and the reaction was maintained at this temperature with stirring. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) continued until the spot of the starting compound XI-2 disappeared (approximately 12 h). After cooling to room temperature, the reaction solution was slowly poured into ice water (150 mL) under an ice-water bath and stirred vigorously for 30 min. Extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 1). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to give 1.67 g of 5,5'-dibutyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobenaphthalene-8,8'-diol (compound I-1-1-4), with a yield of 85%.

[0162] HRMS (ESI) calcd for [M+H] + C 27 H 37 O2, m / z: 393.2789, found:393.2788. Example 9: Preparation of compound I-1-1-5

[0163] Preparation of compound II-4

[0164] Under nitrogen protection, compound XII-3 (3.15 g, 10.0 mmol, 1 equiv) was added to a reaction flask, followed by anhydrous dichloromethane (20 mL), and stirred to dissolve. Then, dirhodium tetraacetate (0.46 g, 1.0 mmol, 0.1 equiv) was added. The mixture was stirred and cooled to 0–10 °C, and diazonium diethyl ether solution (1 mol / L, 30 mL, 30 mmol, 3 equiv) was slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was placed at room temperature (20–30 °C) and stirred for 2 h. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 2:1, v / v) was performed until the spot of the starting compound XII-3 disappeared. The reaction was quenched by adding saturated ammonium chloride aqueous solution (200 mL), and extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed successively with water (200 mL × 2) and saturated brine (200 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1, v / v) to give compound II-4, 2.40 g, with a yield of 70%.

[0165] HRMS (ESI) calcd for [M+H] + C 20 H 20 ClO3, m / z:343.1096, found:343.1095. Compound XII-3 can be obtained through the following preparation route:

[0166] 2-Methyl-5-hydroxybenzaldehyde (compound XIV-1, 1.36 g, 10.0 mmol, 1.0 equiv) was added to a dry round-bottom flask and dissolved in anhydrous ethanol (20 mL). Acetone (2.90 g, 3.7 mL, 50.0 mmol, 5 equiv) was added and stirred until dissolved. The internal temperature was maintained at 0–5 °C, and 10% potassium hydroxide aqueous solution (15 mL, 28 mmol KOH) was slowly added dropwise over 15 minutes. After the addition was complete, the reaction mixture was stirred at 0–5 °C for 2 hours. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 2:1, v / v) showed complete conversion of the starting material. Water (50 mL) was added to dilute the reaction system, and the pH was adjusted to 2–3 with 3 mol / L hydrochloric acid while stirring. The mixture was extracted with ethyl acetate (30 mL × 2), and the organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to give the intermediate (E )-4-(5-hydroxy-2-methylphenyl)-3-buten-2-one (compound XV-1) is a yellow solid, 1.51 g, yield 86%.

[0167] Add the intermediate to a dry round-bottom flask. E 4-(5-hydroxy-2-methylphenyl)-3-buten-2-one (compound XV-1, 1.41 g, 8.0 mmol, 1.0 equiv) was dissolved in anhydrous ethanol (20 mL), and 2-chloro-5-hydroxybenzaldehyde (1.25 g, 8.0 mmol, 1.0 equiv) was added and stirred until dissolved. The internal temperature was maintained at 0–5 °C, and 10% potassium hydroxide aqueous solution (15 mL, 28 mmol KOH) was slowly added dropwise over 15 minutes. After the addition was complete, the reaction mixture was stirred at 0–5 °C for 2 hours. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 2:1, v / v) showed complete conversion of the starting material. Water (50 mL) was added to dilute the reaction system, and the pH was adjusted to 2–3 with 3.0 M hydrochloric acid while stirring. A large amount of solid precipitated, which was filtered. The filter cake was washed with water (20 mL × 2) and dried to give the product compound XII-3, 2.14 g, with a yield of 85%.

[0168] HRMS (ESI) calcd for [M+H] + C 18 H 16 ClO3, m / z:315.0783, found:315.0780. Preparation of compound XIII-3

[0169] Compound II-4 (3.43 g, 10.0 mmol, 1 equiv), 10% palladium-on-carbon catalyst (343 mg, approximately 50% water content, 10% of the substrate mass), and isopropanol solvent (50 mL) were added sequentially to a reaction vessel, and the mixture was stirred to ensure uniform dispersion of the substrate. The reaction vessel was purged with vacuum and nitrogen once, then purged with vacuum and hydrogen three times. Finally, the reaction was carried out under hydrogen (approximately 50 atm) protection at 60°C with stirring. The reaction progress was monitored by thin-layer chromatography (TLC), and the reaction was stopped after the starting material was completely converted (6 hours). The reaction solution was filtered through diatomaceous earth under reduced pressure to remove the palladium-on-carbon catalyst. The filter cake was washed 2-3 times with isopropanol. The filtrates were combined, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain the target ring-opening product compound XIII-3, 2.95 g, with a yield of 85%.

[0170] HRMS (ESI) calcd for [M+H]+ C 20 H 24 ClO3, m / z: 347.1409, found:347.1405. Preparation of compound I-1-1-5

[0171] Under nitrogen protection, compound XIII-3 (1.73 g, 5.0 mmol, 1 equiv), aluminum trichloride (2.66 g, 20.0 mmol, 4 equiv), and 1,2-dichloroethane (20 mL) were added to a dry reaction flask. After stirring to dissolve, the reaction solution was heated to 60 °C (external bath temperature), and the reaction was maintained at this temperature with stirring. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) was performed until the spot of starting compound XIII-3 disappeared (approximately 12 h). After cooling to room temperature, the reaction solution was slowly poured into ice water (150 mL) under ice-water bath cooling, and stirred vigorously for 30 min. Extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 1), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to give compound I-1-1-5, 1.40 g, in 85% yield.

[0172] HRMS (ESI) calcd for [M+H] + C 20 H 22 ClO2, m / z: 329.1303, found:329.1300. Example 10: Preparation of compound I-1-1-6

[0173] Preparation of compound V-2

[0174] Trimethyl sulfoxide (4.84 g, 22.0 mmol, 2.2 equiv) and sodium hydride (60% mineral oil dispersion, 1.76 g, 44.0 mmol, 4.4 equiv) were added to a reaction flask, followed by anhydrous dimethyl sulfoxide (40 mL). The mixture was stirred at room temperature for 30 min until a grayish-white suspension was formed. Separately, compound IV-2 (5.18 g, 10.0 mmol, 1 equiv) was dissolved in anhydrous dimethyl sulfoxide (20 mL) and slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was placed in a 50°C oil bath and stirred. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 4:1, v / v) continued until the spot of starting compound IV-2 disappeared (40 min). The reaction was quenched by adding saturated brine (100 mL) after cooling to room temperature. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (100 mL × 2) and saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to give 3.39 g of bis[2-(5-hydroxy-2-iodo)cyclopropyl] ketone (V-2), with a yield of 62%.

[0175] HRMS (ES+) calcd for [M + H] + C 19 H 17 I2O3, m / z: 546.9262, found:546.9260. Preparation of compound II-5

[0176] Under a nitrogen atmosphere, bis[2-(5-hydroxy-2-iodo)cyclopropyl] ketone (compound V-2, 5.46 g, 10.0 mmol, 1.0 eq), potassium carbonate (6.91 g, 50.0 mmol, 5.0 eq), 1-naphthoic acid (5.16 g, 30.0 mmol, 3.0 eq), palladium acetate (45 mg, 200 µmol), n-butyldi(1-adamantyl)phosphine (10.8 mg, 30 µmol), water (50 mL), and ethylene glycol dimethyl ether (50 mL) were added to a round-bottom flask. The resulting solution was rapidly degassed by an oil pump and purged with nitrogen through a double-row tube. After five purgings, the solution was stirred at 90 °C for 24 hours under a nitrogen atmosphere. The solution was cooled to room temperature, and 200 mL of saturated ammonium chloride aqueous solution was added to the reaction mixture. Extraction was then performed using dichloromethane (3 × 80 mL). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to obtain the crude substance. The crude substance was then purified by silica gel column chromatography to give compound II-5, 3.55 g, with a calculated yield of 65%.

[0177] HRMS (ESI) calcd for [M+H] + C 39 H 31 O3, m / z: 547.2268, found:547.22685. Preparation of compound VI-2

[0178] Compound II-5 (5.46 g, 10.0 mmol, 1 equiv), 10% palladium-on-carbon catalyst (546 mg, approximately 50% water content, 10% of the substrate mass), and methanol (50 mL) were added sequentially to a reaction flask. The mixture was stirred to ensure uniform dispersion of the substrate. The reaction flask was purged under vacuum and nitrogen once, then purged under vacuum and hydrogen three times. Finally, the reaction was carried out under the protection of a hydrogen balloon (approximately 1 atm) with stirring at room temperature (20–30 °C). The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was stopped after the starting material was completely converted (24 hours). The reaction solution was filtered through diatomaceous earth under reduced pressure to remove the palladium-on-carbon catalyst. The filter cake was washed 2–3 times with methanol. The filtrates were combined, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain the target ring-opening product, compound VI-2, as a white solid, 4.79 g, with a yield of 87%.

[0179] HRMS (ESI) calcd for [M+H] + C 39 H 35O3, m / z: 551.2581, found:551.2581. Preparation of compound I-1-1-6

[0180] Under nitrogen protection, compound VI-2 (2.75 g, 5.0 mmol, 1 equiv) was added to a dry reaction flask, followed by the addition of boron trifluoride diethyl ether (BF3·Et2O, 10 mL, serving as both solvent and Lewis acid catalyst). After stirring to dissolve, the reaction solution was heated to 60 °C (external bath temperature), and the reaction was maintained at this temperature with stirring. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) continued until the spot of starting compound VI-2 disappeared (approximately 12 h). After cooling to room temperature, the reaction solution was slowly poured into ice water (150 mL) under an ice-water bath, and stirred vigorously for 30 min. Extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 1), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to give product compound I-1-1-6, 2.26 g, yield 85%.

[0181] HRMS (ESI) calcd for [M+H] + C 39 H 33 O2, m / z: 533.2476, found:533.2475. Example 11: Preparation of compound I-1-1-7

[0182] Preparation of compound V-2

[0183] Compound V-2 was prepared according to the conditions of Example 10.

[0184] HRMS (ES+) calcd for [M + H] + C 19 H 17 I2O3, m / z: 546.9262, found:546.9260. Preparation of compound II-6

[0185] Under nitrogen protection, bis[2-(5-hydroxy-2-iodo)cyclopropyl] ketone (compound V-2, 5.46 g, 10.0 mmol, 1.0 eq), (1-methyl-1H-indol-5-yl)boronic acid (5.25 g, 30.0 mmol, 3.0 eq), DPPF palladium dichloride (366 mg, 0.50 mmol, 5 mol%), and cesium carbonate (13.03 g, 40.0 mmol, 4.0 eq) were added sequentially to a dry two-necked Schlenk flask. 1,4-Dioxane (80 mL) and water (20 mL) were added and stirred to dissolve. The reaction mixture was degassed by bubbling with nitrogen for 15 minutes, then heated to 100 °C (internal temperature) under a nitrogen atmosphere and stirred for 12–24 hours, monitored by TLC (evolving solvent: petroleum ether / ethyl acetate = 3:1, v / v) until the starting material disappeared.

[0186] The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (80 mL × 2). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 5:1, v / v) to give compound II-6, 4.03 g, yield 73%.

[0187] HRMS (ESI) calcd for [M+H] + C 37 H 33 N2O3, m / z: 553.2486, found:553.2486. Preparation of compound VI-3

[0188] Compound II-6 (5.52 g, 10.0 mmol, 1 equiv), 10% palladium-on-carbon catalyst (552 mg, approximately 50% water content, 10% of the substrate mass), and methanol (50 mL) were added sequentially to a reaction flask. The mixture was stirred to ensure uniform dispersion of the substrate. The reaction flask was purged with nitrogen once, then purged with hydrogen three times. Finally, the reaction was carried out under the protection of a hydrogen balloon (approximately 1 atm) at room temperature (20–30 °C) with stirring. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was stopped after the starting material was completely converted (24 hours). The reaction solution was filtered through diatomaceous earth under reduced pressure to remove the palladium-on-carbon catalyst. The filter cake was washed 2–3 times with methanol. The filtrates were combined, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound VI-3, 4.84 g, with a yield of 87%.

[0189] HRMS (ESI) calcd for [M+H] + C 37 H 37 N2O3, m / z: 557.2799, found:557.2799. Preparation of compound I-1-1-7

[0190] Under nitrogen protection, compound VI-3 (2.78 g, 5.0 mmol, 1 equiv) was added to a dry reaction flask, followed by the addition of boron trifluoride diethyl ether (BF3·Et2O, 10 mL, serving as both solvent and Lewis acid catalyst). After stirring to dissolve, the reaction solution was heated to 60 °C (external bath temperature), and the reaction was maintained at this temperature with stirring. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) was performed until the spot of starting compound VI-3 disappeared (approximately 12 h). After cooling to room temperature, the reaction solution was slowly poured into ice water (150 mL) under an ice-water bath, and stirred vigorously for 30 min. Extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 1), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to give product compound I-1-1-7, 1.40 g, yield 52%.

[0191] HRMS (ESI) calcd for [M+H] + C 37 H 35 N2O2, m / z: 539.2694, found:539.2694. Example 12: Preparation of compound I-1-1-8

[0192] Preparation of compound V-2

[0193] Compound V-2 was prepared according to the conditions of Example 10.

[0194] HRMS (ES+) calcd for [M + H] + C 19 H 17 I2O3, m / z: 546.9262, found:546.9260. Preparation of compound II-7

[0195] Under nitrogen protection, bis[2-(5-hydroxy-2-iodo)cyclopropyl] methyl ketone (compound V-2, 5.46 g, 10.0 mmol, 1.0 eq), quinoline-6-boronic acid (5.19 g, 30.0 mmol, 3.0 eq), DPPF palladium dichloride (366 mg, 0.50 mmol, 5 mol%), and cesium carbonate (13.03 g, 40.0 mmol, 4.0 eq) were added sequentially to a dry two-necked Schlenk flask. 1,4-dioxane (80 mL) and water (20 mL) were added and stirred to dissolve. The reaction mixture was degassed by bubbling with nitrogen for 15 minutes, then heated to 100 °C (internal temperature) under nitrogen atmosphere and stirred for 12–24 hours, monitored by TLC (evolving solvent: petroleum ether / ethyl acetate = 3:1, v / v) until the starting material disappeared.

[0196] The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (80 mL × 2). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 5:1, v / v) to give compound II-7, 4.11 g, yield 75%.

[0197] HRMS (ESI) calcd for [M+H] + C 37 H 29 N2O3, m / z: 549.2173, found:549.2172. Preparation of compound VI-4

[0198] Compound II-7 (5.48 g, 10.0 mmol, 1 equiv), 10% palladium-on-carbon catalyst (548 mg, approximately 50% water content, 10% of the substrate mass), and methanol (50 mL) were added sequentially to a reaction flask. The mixture was stirred to ensure uniform dispersion of the substrate. The reaction flask was purged with nitrogen once, then purged with hydrogen three times. Finally, the reaction was carried out under the protection of a hydrogen balloon (approximately 1 atm) at room temperature (20–30 °C) with stirring. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was stopped after the starting material was completely converted (24 hours). The reaction solution was filtered through diatomaceous earth under reduced pressure to remove the palladium-on-carbon catalyst. The filter cake was washed 2–3 times with methanol. The filtrates were combined, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound VI-4, 4.69 g, with a yield of 85%.

[0199] HRMS (ESI) calcd for [M+H] + C 37 H 33 N2O3, m / z: 553.2486, found:553.2486. Preparation of compound I-1-1-8

[0200] Under nitrogen protection, compound VI-4 (2.76 g, 5.0 mmol, 1 equiv) was added to a dry reaction flask, followed by the addition of boron trifluoride diethyl ether (BF3·Et2O, 10 mL, serving as both solvent and Lewis acid catalyst). After stirring to dissolve, the reaction solution was heated to 60 °C (external bath temperature), and the reaction was maintained at this temperature with stirring. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 3:1, v / v) continued until the spot of starting compound VI-4 disappeared (approximately 12 h). After cooling to room temperature, the reaction solution was slowly poured into ice water (150 mL) under an ice-water bath, and stirred vigorously for 30 min. Extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 1), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to give product compound I-1-1-8, 1.63 g, yield 61%.

[0201] HRMS (ESI) calcd for [M+H] + C 37 H 31 N2O2, m / z: 535.2381, found:535.2380. Example 13: Preparation of compound I-1-1-9

[0202] Preparation of compound V-3

[0203] Isopropyl diphenylsulfonium tetrafluoroborate (6.96 g, 22.0 mmol, 2.2 equiv) and sodium hydride (60% mineral oil dispersion, 1.76 g, 44.0 mmol, 4.4 equiv) were added to a reaction flask, followed by anhydrous dimethyl sulfoxide (40 mL). The mixture was stirred at room temperature for 30 min until a suspension was formed. Separately, compound IV-1 (4.24 g, 10.0 mmol, 1 equiv) was dissolved in anhydrous dimethyl sulfoxide (20 mL) and slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was placed in a 50°C oil bath and stirred. TLC monitoring (developing solvent: petroleum ether / ethyl acetate = 4:1, v / v) continued until the spot of starting compound IV-1 disappeared (40 min). The reaction was quenched by adding saturated brine (100 mL) after cooling to room temperature. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (100 mL × 2) and saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to give compound V-3, 3.25 g, with a yield of 64%.

[0204] HRMS (ES+) calcd for [M + H] + C 23 H 25 Br2O3, m / z: 509.0145, found:509.0145. Preparation of compound II-8

[0205] Compound II-8 was prepared using compound V-3 as a raw material according to the process for preparing compound II-1 in Example 1.

[0206] HRMS (ESI) calcd for [M+H] + C 35 H 35 O3, m / z: 503.2581, found:503.2580. Preparation of compound VI-5

[0207] Compound VI-5 was prepared using compound II-8 as a raw material according to the process for preparing compound VI-1 in Example 1.

[0208] HRMS (ESI) calcd for [M+H] + C 35 H 39 O3, m / z: 507.2894, found:507.2894. Preparation of compound I-1-1-9

[0209] Compound I-1-1-9 was prepared using compound VI-5 as a raw material according to the process for preparing compound I-1-1-1 in Example 1.

[0210] HRMS (ESI) calcd for [M+H] + C 35 H 37 O2, m / z: 489.2789, found:489.2788. Example 14: Preparation of compounds ( R )-Ⅰ-1-1-1 and compound ( S )-Ⅰ-1-1-1

[0211] Step 1: Synthesis ( S )- and ( R )-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((1 R ,2 S 5 R )-2-Isopropyl-5-methylcyclohexyl)bis(carbonate)

[0212] Under nitrogen protection, triethylamine (2.0 mL) was added to a solution of rac-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (864 mg, 2.0 mmol) in dichloromethane (20 mL), and the mixture was stirred until completely dissolved. Then, chloroformic acid (-)-menthol ester (1.4 g, 6.4 mmol) was added in portions, with the internal temperature controlled to not exceed 30 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours.

[0213] After the reaction was complete, the mixture was washed successively with water (15 mL × 2), dilute hydrochloric acid (1 mol / L, 15 mL × 2), and saturated brine (15 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / toluene = 1:10, V / V), and the less polar fraction was collected to give a white solid ( R )-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((1 R ,2 S 5 R )-2-isopropyl-5-methylcyclohexyl)bis(carbonate) (748 mg, yield 94%); collect the more polar fractions, S )-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((1 R ,2 S 5 R 2-Isopropyl-5-methylcyclohexyl)bis(carbonate) (756 mg, 95% yield).

[0214] ( R )-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((1 R ,2 S 5 R 2-Isopropyl-5-methylcyclohexyl)bis(carbonate): HRMS (ESI) calcd for [M+H] + C 53 H 65 O6,m / z: 797.4776, found:797.4771. ( S )-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((1 R ,2 S 5 R 2-Isopropyl-5-methylcyclohexyl)bis(carbonate): HRMS (ESI) calcd for [M+H] + C 53 H 65 O6,m / z: 797.4776, found:797.4775. Step 2: ( R)-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (( R )-Ⅰ-1-1-1)

[0215] Under nitrogen protection, sodium hydroxide (400 mg, 10 mmol) was dissolved in a mixed solvent of water (2 mL) and methanol (20 mL), and then added ( R )-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((1 R ,2 S 5 R 2-Isopropyl-5-methylcyclohexyl)bis(carbonate) (797 mg, 1.0 mmol). The reaction was heated to reflux with stirring for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with dichloromethane (20 mL × 2), discarding the organic phase. The aqueous phase was acidified with 6 mol / L hydrochloric acid to pH ≈ 1~2, precipitating a white precipitate, which was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1:6, V / V). The resulting white solid was recrystallized from dichloromethane-n-hexane to obtain ( R 5,5'-Diphenyl-3,3',4,4'-Tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (392 mg, 91% yield, 99% ee).

[0216] Step 3: Synthesis ( S )-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (( S )-Ⅰ-1-1-1)

[0217] Under nitrogen protection, sodium hydroxide (400 mg, 10 mmol) was dissolved in a mixed solvent of water (2 mL) and methanol (20 mL), and then added ( S )-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((1 R ,2 S 5 R2-Isopropyl-5-methylcyclohexyl)bis(carbonate) (797 mg, 1.0 mmol). The reaction was heated to reflux with stirring for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with dichloromethane (20 mL × 2), discarding the organic phase. The aqueous phase was acidified with 6 mol / L hydrochloric acid to pH ≈ 1~2, precipitating a white precipitate, which was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1:6, V / V). The resulting white solid was recrystallized from dichloromethane-n-hexane to obtain ( S 5,5'-Diphenyl-3,3',4,4'-Tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (375 mg, 87% yield, 99% ee).

[0218] Example 15: Preparation of compounds ( R )-I-1-1-2 and compound ( S )-I-1-1-2

[0219] Step 1: Synthesis ( S )- and ( R )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate)

[0220] Under nitrogen protection, triethylamine (2.0 mL) was added to a 20 mL solution of rac-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (compound I-1-1-2, 616 mg, 2.0 mmol) in dichloromethane and stirred until completely dissolved. Then, triethylamine (2.0 mL) was added in portions. S Add 1.6 g (6.4 mmol) of camphorsulfonyl chloride (1-(+)-10-)-, keeping the internal temperature below 30°C. After addition, stir the reaction mixture at room temperature for 12 hours.

[0221] After the reaction was complete, the mixture was washed successively with water (15 mL × 2), dilute hydrochloric acid (1 mol / L, 15 mL × 2), and saturated brine (15 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / toluene = 1:10, V / V), and the less polar fraction was collected to give a white solid ( R )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate) (699 mg, 95% yield); collect the more polar fractions, ( S 5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate) (707 mg, 96% yield).

[0222] ( R 5,5'-Dimethyl-3,3',4,4'-Tetrahydro-2H,2'H-1,1'-Spirodi[naphthalene]-8,8'-Dimethylbis((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate): HRMS (ESI) calcd for [M+H] + C 41 H 53 O8S2, m / z: 737.3176, found:737.3177. ( S 5,5'-Dimethyl-3,3',4,4'-Tetrahydro-2H,2'H-1,1'-Spirodi[naphthalene]-8,8'-Dimethylbis((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate): HRMS (ESI) calcd for [M+H] + C 41 H 53 O8S2, m / z: 737.3176, found:737.3182. Step 2: Synthesis ( R )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (( R )-I-1-1-2)

[0223] Under nitrogen protection, sodium hydroxide (2.0 g, 50 mmol) was dissolved in a mixed solvent of water (5 mL) and methanol (50 mL), and then (…) was added. R 7,7-Dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate) (737 mg, 1.0 mmol). The mixture was heated to reflux with stirring for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by vacuum distillation. Water (20 mL) was added to the residue, and the mixture was extracted with dichloromethane (20 mL × 2), discarding the organic phase. The aqueous phase was acidified with 6 mol / L hydrochloric acid to pH ≈ 1~2, precipitating a white precipitate, which was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under vacuum. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1:6, V / V), and the resulting white solid was recrystallized from dichloromethane-n-hexane to obtain ( R )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (compound( R )-I-1-1-2, 283 mg, yield 92%, 99% ee).

[0224] Step 3: Synthesis ( S )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (( S )-I-1-1-2)

[0225] Under nitrogen protection, sodium hydroxide (2.0 g, 50 mmol) was dissolved in a mixed solvent of water (5 mL) and methanol (50 mL), and then (…) was added. S7,7-Dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-dimethylbis((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate) (737 mg, 1.0 mmol). The mixture was heated to reflux with stirring for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by vacuum distillation. Water (20 mL) was added to the residue, and the mixture was extracted with dichloromethane (20 mL × 2), discarding the organic phase. The aqueous phase was acidified with 6 mol / L hydrochloric acid to pH ≈ 1~2, precipitating a white precipitate, which was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under vacuum. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1:6, V / V), and the resulting white solid was recrystallized from dichloromethane-n-hexane to obtain ( S )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (compound( S )-I-1-1-2, 287 mg, yield 93%, 99% ee).

[0226] Example 16: Preparation of compound I-1-2'-1

[0227] Preparation of compound I-1-2-1

[0228] Under a nitrogen atmosphere, ( R )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (compound( R (I-1-1-2, 1.54 g, 5.0 mmol, >99% ee) was dissolved in dichloromethane (50 mL), and p-toluenesulfonic acid (475 mg, 2.5 mmol) was added. The mixture was cooled to 0 °C, and N-iodosuccinimide (2.47 g, 11.0 mmol) was added in portions over 15 minutes. The mixture was then brought back to room temperature and stirred for about 2 hours. After the reaction was completed as monitored by TLC, the reaction was quenched by adding saturated sodium thiosulfate aqueous solution (20 mL). The organic phase was separated by liquid chromatography, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane = 10:1, v / v) to obtain compound ( R )-Ⅰ-1-2-1, white solid 2.52 g, calculated yield 90%, ee value > 99%.

[0229] 1 H NMR (400 MHz, CDCl3) δ 7.55 (s, 2H), 4.75 (s, 2H), 2.95–2.88 (m,2H), 2.70–2.61 (m, 2H), 2.24 (s, 6H), 2.21–2.18 (m, 2H), 2.10 (dt, J = 13.8,6.9 Hz, 2H), 1.96–1.85 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 152.5, 136.5, 132.0, 130.0, 128.5, 85.0, 39.0, 32.7, 27.5, 19.8, 18.9. HRMS (ES + ) Calcd for C 21 H 23 O2I2 [M+H] + Found: 560.9782, Found: 560.9785. Preparation of compound I-1-2'-1

[0230] Under a nitrogen atmosphere, add ( R )-7,7'-Diiodo-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirobis[naphthalene]-8,8'-diol (compound( R The reaction mixture consisted of 560 mg (1.0 mmol, >99% ee), potassium carbonate (691 mg, 5.0 mmol), phenylboronic acid (1.22 g, 10.0 mmol), palladium acetate (4.5 mg, 20 µmol), n-butylbis(1-adamantyl)phosphine (10.8 mg, 30 µmol), water (5.0 mL), and ethylene glycol dimethyl ether (5.0 mL). The resulting solution was rapidly degassed with an oil pump and purged with nitrogen in a double-row tube. After five purgings, the mixture was stirred at 90°C for 24 hours under a nitrogen atmosphere. The solution was cooled to room temperature, and 20 mL of saturated ammonium chloride aqueous solution was added to the reaction mixture. Extraction was then performed using dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain the target compound (…). R )-Ⅰ-1-2'-1, a white solid, was 299 mg, with a calculated yield of 65%.

[0231] 1 H NMR (400 MHz, CDCl3) δ 7.47–7.44 (m, 4H), 7.38–7.34 (m, 4H), 7.28–7.24 (m, 2H), 7.05 (s, 2H), 4.65 (s, 2H), 2.75–2.58 (m, 4H), 2.25 (s, 6H), 2.15–1.95 (m, 4H), 1.90–1.78 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 151.0, 143.5, 136.5, 131.5, 131.0, 129.3,128.6, 128.0, 127.5, 127.2, 126.5, 126.0, 39.0, 32.5, 27.0, 19.5, 18.5. HRMS (ES + ) Calcd for C 33 H 33 O2 [M+H] + Found: 461.2475, Found: 461.2480. Example 17: Preparation of compound I-1-3-1

[0232] Preparation of compound II'-1

[0233] Compound XVI-1 (2.98 g, 10.0 mmol, 1 equiv) was used as a starting material, and potassium tert-butoxide (6.72 g, 60.0 mmol, 6 equiv) was used as a starting material. The remaining conditions were the same as those for preparing compound II-2 in Example 6 to prepare compound II'-1.

[0234] HRMS (ESI) calcd for [M+H] + C 19 H 19 O5, m / z: 327.1227, found:327.1225. Compound XVI-1 can be prepared using compound XVIII-1 (6.9 g, 50.0 mmol, 1 equiv) as a starting material, potassium hydroxide (7.01 g, 125 mmol, 2.5 equiv), and other conditions as described in Example 6 for the preparation of compound XII-1. .

[0235] HRMS (ESI) calcd for [M+H] + C 17 H 15 O5, m / z: 299.0914, found:299.0914. Preparation of compound XVII-1

[0236] Compound XVII-1 was prepared from compound II'-1 using the same process as that used to prepare compound XIII-1 in Example 6.

[0237] HRMS (ES+) calcd for [M + H] + C 19 H 23 O5, m / z: 331.1540, found: 331.1540. Preparation of compound I-1-3-1

[0238] Compound I-1-3-1 was prepared by using compound XVII-1 as a raw material according to the process for preparing compound I-1-1-2 in Example 6.

[0239] HRMS (ES+) calcd for [M + H] + C 19 H 21 O4, m / z: 313.1435, found: 313.1435. Example 18: Preparation of phosphoramide ligand III-1-1

[0240] Under a nitrogen atmosphere, Ph-SBITOL (compound I-1-1-1, 4.33 g, 10.0 mmol, 1.0 equiv) was added to a dry 100 mL round-bottom flask and dissolved in anhydrous toluene (20 mL). Tris(dimethylamino)phosphine (1.96 g, 2.18 mL, 12.0 mmol, 1.2 equiv) was added, and the mixture was stirred at 100 °C for 2 hours. TLC monitoring (eluent: petroleum ether / ethyl acetate = 2:1, v / v) showed complete conversion of the starting material, followed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to give the product as a white solid, 3.54 g, yield 70%.

[0241] HRMS (ESI) calcd for [M+H] + C 33 H 33 NO2P, m / z: 506.2243, found: 506.2237. Example 19: Preparation of phosphoramide ligands ( R )-Ⅲ-1-2

[0242] Under nitrogen protection, at room temperature, towards ( R )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound( R In a solution of 616 mg, 2.0 mmol, 1 eq) of 1-I-1-1-2 in anhydrous toluene (4 mL), tris(dimethylamino)phosphine ((Me₂N)₃P, 359 mg, 2.2 mmol, 1.1 eq) was added. After the addition was complete, the reaction mixture was heated to 100 °C and stirred. The reaction was monitored by TLC until complete (approximately 12 h, developing solvent: petroleum ether / ethyl acetate = 5:1). The mixture was diluted with ethyl acetate (40 mL), washed successively with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give a white solid product containing phosphorus amide ligand ( R )-Ⅲ-1-2 (495 mg, yield 65%).

[0243] 1H NMR (400 MHz, CDCl3): δ 7.05 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 8.1Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 8.1 Hz, 1H), 2.94–2.90 (m,4H), 2.25 (s, 6H), 2.16 (s, 6H), 1.99–1.88 (m, 4H), 1.83–1.79 (m, 2H), 1.73–1.72 (m, 2H); 31 P NMR (162 MHz, CDCl3): δ 119.8; 13 C NMR (100 MHz, CDCl3): δ 126.8, 126.4, 126.3, 125.9, 122.3, 122.0,41.6, 37.7, 37.6, 35.2, 29.7, 29.6, 22.9, 18.5, 15.5. HRMS (ESI) calcd for [M+H] + C 23 H 29 NO2P, m / z: 382.1930,found:382.1922. Example 20: Preparation of phosphoramide ligands ( R )-Ⅲ-1-2

[0244] Under nitrogen protection, at 0°C, towards ( R )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound( RIn a solution of 10 mL of anhydrous tetrahydrofuran containing 1-Ⅰ-1-1-2 (616 mg, 2.0 mmol, 1 eq) and triethylamine (2.8 mL, 20 mmol), dichloro(dimethylamino)phosphine (Me2NPCl2, 870 mg, 6.0 mmol, 3 eq) was added. After addition, the reaction mixture was heated to room temperature and stirred. The reaction was monitored by TLC until complete (approximately 1 h, eluent: petroleum ether / ethyl acetate = 5:1). The mixture was diluted with ethyl acetate (40 mL), washed successively with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give a white solid product containing phosphorus amide ligand ( R )-Ⅲ-1-2 (457 mg, yield 60%).

[0245] HRMS (ESI) calcd for [M+H] + C 23 H 29 NO2P, m / z: 382.1930, found:382.1922. Example 21: Preparation of phosphoramide ligands ( R,R N ,R N )-Ⅲ-2-1

[0246] Under nitrogen protection, at 0°C, towards ( R )-5,5'-diphenyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound( R In a solution of anhydrous tetrahydrofuran (33 mL) containing 1-I-1-1-1 (865 mg, 2.0 mmol, 1 eq) and triethylamine (425 mg, 4.2 mmol, 2.1 eq), phosphorus trichloride (PCl3, 0.20 mL, 2.3 mmol, 1.17 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 20 h. The solution was filtered under nitrogen protection to remove insoluble matter, and the filtrate was cooled to -78 °C and then added dropwise (… R , R )-bis-(1-phenylethyl)aminolithium tetrahydrofuran solution [from ( R , RThe reaction was prepared by reacting bis-(1-phenylethyl)amine (450 mg, 2.0 mmol) with a cyclohexane solution of n-butyllithium (1.1 mL, 2 mol / L, 2.2 mmol, 1.1 eq) in anhydrous tetrahydrofuran (25 mL) at -30 °C. After the reaction was completed, the reaction solution was slowly raised to room temperature and stirred overnight (about 12 h). The solvent was removed by vacuum distillation, and the residue was filtered through a short silica gel column (eluent: ethyl acetate / petroleum ether = 1:20) to give a colorless oily substance, which slowly solidified into a white solid upon standing. The phosphoramidite ligand ( R,R N ,R N )-Ⅲ-2-1 (898.4 mg, yield 65.5%).

[0247] HRMS (ESI) calcd for [M+H] + C 47 H 45 NO2P, m / z: 686.3183, found: 686.3180. Example 22: Preparation of phosphoramide ligands ( R,R N ,R N )-Ⅲ-2-2

[0248] Under nitrogen protection, at 0°C, towards ( R )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound( R In a solution of anhydrous tetrahydrofuran (33 mL) containing 1-I-1-1-2 (616 mg, 2.0 mmol, 1 eq) and triethylamine (425 mg, 4.2 mmol, 2.1 eq), phosphorus trichloride (PCl3, 0.20 mL, 2.3 mmol, 1.17 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 20 h. The solution was filtered under nitrogen protection to remove insoluble matter, and the filtrate was cooled to -78 °C and then added dropwise (… R , R )-bis-(1-phenylethyl)aminolithium tetrahydrofuran solution [from ( R , RThe reaction was prepared by reacting bis-(1-phenylethyl)amine (450 mg, 2.0 mmol) with a cyclohexane solution of n-butyllithium (1.1 mL, 2 mol / L, 2.2 mmol, 1.1 eq) in anhydrous tetrahydrofuran (25 mL) at -30 °C. After the reaction was completed, the reaction solution was slowly raised to room temperature and stirred overnight (about 12 h). The solvent was removed by vacuum distillation, and the residue was filtered through a short silica gel column (eluent: ethyl acetate / petroleum ether = 1:20) to give a colorless oily substance, which slowly solidified into a white solid upon standing. The phosphoramidite ligand ( R,R N ,R N )-Ⅲ-2-2 (747 mg, yield 66.5%).

[0249] HRMS (ESI) calcd for [M+H] + C 37 H 41 NO2P, m / z: 562.2869, found:562.2875. Example 23: Preparation of phosphoramide ligands ( R,R N ,R N )-Ⅲ-2-2

[0250] Step 1: Preparation of [bis(α-methylbenzyl)amino]phosphorus dichloride Under nitrogen protection, at -78℃, towards ( R , R To a solution of 1-bis-(1-phenylethyl)amine (0.46 mL, approximately 450 mg, 2.0 mmol) in anhydrous tetrahydrofuran (3.0 mL), a hexane solution of n-butyllithium (2.4 M, 0.92 mL, 2.2 mmol, 1.1 eq) was slowly added dropwise. After addition, the mixture was stirred at -78 °C for 30 min, then brought to room temperature. In a separate reaction flask, under nitrogen protection, a solution of phosphorus trichloride (0.23 mL, approximately 357 mg, 2.6 mmol, 1.3 eq) in anhydrous tetrahydrofuran (2.0 mL) was cooled to -78 °C, and a solution of aminolithium prepared by the above method was slowly added dropwise. After addition, the reaction mixture was slowly brought to room temperature and stirred overnight (approximately 12 h). The mixture was concentrated under reduced pressure, and residual phosphorus trichloride was removed by repeated dilution with anhydrous tetrahydrofuran (5.0 mL × 3) and evaporation under reduced pressure. The crude product obtained was dissolved in anhydrous tetrahydrofuran (2.0 mL), which is [( R , RA tetrahydrofuran solution of phosphorus dichloride (approximately 6.0 mL total volume, approximately 0.33 M concentration) was stored at 0°C under nitrogen protection and used directly for the next reaction.

[0251] Step 2: Phosphoramide ligand ( R,R N ,R N Preparation of )-Ⅲ-2-2 Under nitrogen protection, at 0℃, ( R )-5,5'-dimethyl-3,3',4,4'-tetrahydro-2H,2'H-1,1'-spirodin-8,8'-diol (compound( R Add the intermediate 1,1-dichloro-N,N-bis(()-Ⅰ-1-1-2, 154 mg, 0.5 mmol, 1 eq) prepared above to an anhydrous tetrahydrofuran (5 mL) solution of triethylamine (505 mg, 5 mmol, 10 eq). R A tetrahydrofuran solution (1.5 mL, approximately 0.5 mmol) of 1-phenylethylphosphonamine was added. After addition, the reaction mixture was heated to room temperature and stirred. The reaction was monitored by TLC until complete (approximately 1 h, developing solvent: petroleum ether / ethyl acetate = 5:1). The mixture was diluted with ethyl acetate (20 mL), washed successively with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a white powdery solid containing phosphoramide ligands (…). R,R N , R N )-Ⅲ-2-2 (232 mg, yield 83%).

[0252] HRMS (ESI) calcd for [M+H] + C 37 H 41 NO2P, m / z: 562.2869, found:562.2875. Example 24: Preparation of phosphoramide ligand III-3-1

[0253] With compounds ( R Using phosphorus trichloride, tetrahydropyrrole, and n-butyllithium as raw materials, phosphorus amide ligands were prepared according to Example 22. R,R N ,RN The phosphoramid ligand Ⅲ-3-1 was prepared using the process of )-Ⅲ-2-2.

[0254] HRMS (ESI) calcd for [M+H] + C 25 H 31 NO2P, m / z: 408.2014, found:407.2014. Example 25: Asymmetric hydrogenation of dehydroamino acid 8a

[0255] Under a nitrogen atmosphere, Rh(COD)₂BF₄ (4.0 mg, 0.01 mmol) and a phosphorus amide ligand compound ( R )-Ⅲ-1-2 (7.6 mg, 0.02 mmol) was dissolved in 1.0 mL of dry dichloromethane and stirred at room temperature for 0.5 hours to give a dichloromethane solution of the chiral rhodium compound. Under a nitrogen atmosphere, 0.2 mmol of compound 8a (44.0 mg, 0.2 mmol) was dissolved in 2.0 mL of toluene in a hydrogenation reaction tube, and 0.1 mL of the above dichloromethane solution of the chiral rhodium compound was added. The hydrogenation reaction tube was transferred to an autoclave and purged with hydrogen (10 atm) for reaction. After 8 hours, the autoclave was opened, and the crude material was purified by silica gel column chromatography to give the target product 9a, a white solid of 43.6 mg, with a calculated yield of 99%.

[0256] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included high-performance liquid chromatography (HPLC) to determine the ee value and nuclear magnetic resonance (NMR) to determine the proton and carbon spectra. The analysis results are as follows: 1. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel Chiralpak ® AD-H column; 10% i -PrOH hexanes; 1.0 mL / min; retention times: 9.4 min (major), 13.0 min (minor). Calculated ee: 99%.

[0257] 2. Proton and carbon spectra obtained from nuclear magnetic resonance analysis.

[0258] 1 H NMR (400 MHz, CDCl3) d7.32 – 7.19 (m, 3H), 7.12 – 7.05 (m, 2H), 6.05 (s, 1H), 4.92 – 4.83 (m, 1H), 3.71 (s, 2H), 3.18 – 3.02 (m, 2H), 1.97(s, 2H). 13 C NMR (101 MHz, CDCl3) d 172.1, 169.6, 135.8, 129.2, 128.5, 127.1, 53.1, 52.2, 37.8, 23.0. Comparative compound test: Under the same test conditions, the asymmetric hydrogenation reaction of dehydroamino acid 8a was carried out using SBITOL-derived monophosphine ligands to obtain the target product 9a, 42.7 mg of white solid, with a calculated yield of 97% and an ee value of 93% ee.

[0259]

[0260] Example 26: Asymmetric hydrogenation of dehydroamino acid 8b

[0261] Under a nitrogen atmosphere, Rh(NBD)₂BF₄ (3.7 mg, 0.01 mmol) and a phosphorus amide ligand compound ( R )-Ⅲ-1-2 (7.6 mg, 0.02 mmol) was dissolved in 1.0 mL of dry dichloromethane and stirred at room temperature for 0.5 hours to obtain a dichloromethane solution of the chiral rhodium compound. Under a nitrogen atmosphere, 8b (94.2 mg, 0.6 mmol) was dissolved in 6.0 mL of toluene in a hydrogenation reaction tube, and 0.3 mL of the above dichloromethane solution of the chiral rhodium compound was added. The hydrogenation reaction tube was transferred to an autoclave and purged with hydrogen (5 atm) for reaction. After 12 hours, the autoclave was opened, and the crude material was purified by silica gel column chromatography to obtain 94.5 mg of the target product 9b as a white solid, with a calculated yield of 99%.

[0262] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included high-performance liquid chromatography (HPLC) to determine the ee value and nuclear magnetic resonance (NMR) to determine the proton and carbon spectra. The analysis results are as follows: 1. High-performance liquid chromatography (HPLC) analysis to determine ee value: chiral column Daicel Chiralcel® OD-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention time: 13.8 min (major), 20.6 min (minor). The calculated ee value was 99%.

[0263] 2. Nuclear magnetic resonance analysis of proton, carbon, infrared and high-resolution mass spectrometry.

[0264] 1 H NMR (400 MHz, CDCl3) δ 6.16 (s, 1H), 4.61 – 4.51 (m, 1H), 3.72 (s,3H), 2.01 (s, 3H), 1.92 – 1.79 (m, 1H), 1.77 – 1.62 (m, 1H), 0.88 (t, J = 7.5Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.04, 169.79, 53.15, 52.25, 25.55, 23.09,9.41. Comparative compound test: Under the same test conditions, the asymmetric hydrogenation reaction of dehydroamino acid 8b was carried out using SBITOL-derived monophosphine ligands to obtain the target product 9b, a white solid of 93.6 mg, with a calculated yield of 98% and an ee value of 92% ee.

[0265]

[0266] Example 27: Asymmetric hydrogenation of dehydroamino acids at 8c

[0267] Under a nitrogen atmosphere, Rh(NBD)₂BF₄ (3.7 mg, 0.01 mmol) and a phosphorus amide ligand compound ( R)-Ⅲ-1-2 (7.6 mg, 0.02 mmol) was dissolved in 1.0 mL of dry dichloromethane and stirred at room temperature for 0.5 hours to obtain a dichloromethane solution of the chiral rhodium compound. Under a nitrogen atmosphere, 8c (114.3 mg, 0.8 mmol) was dissolved in 8.0 mL of toluene in a hydrogenation reaction tube, and 0.4 mL of the above dichloromethane solution of the chiral rhodium compound was added. Hydrogen gas (1 atm) was introduced into the hydrogenation reaction tube, and the reaction was carried out under a hydrogen atmosphere for 24 hours. The crude product was then purified by silica gel column chromatography to obtain 114.8 mg of the target product 9c, a colorless oily liquid, with a calculated yield of 99%.

[0268] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included high-performance liquid chromatography (HPLC) to determine the ee value and nuclear magnetic resonance (NMR) to determine the proton and carbon spectra. The analysis results are as follows: 1. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel Chiralcel ® OD-H column; 5% i -PrOH hexanes; 1.0 mL / min; retention times: 15.1 min (major), 18.6 min (minor). Calculated result: 99% ee.

[0269] 2. Proton and carbon NMR spectra 1 H NMR (400 MHz, CDCl3) 6.24 (s, 1H), 4.69 – 4.44 (m, 1H), 3.72 (s, 3H), 1.99 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 173.6, 169.6, 52.4, 47.9, 23.0, 18.4. Comparative compound test: Under the same test conditions, the asymmetric hydrogenation reaction of dehydroamino acid 8c was carried out using SBITOL-derived monophosphine ligands to obtain the target product 9c, a white solid of 113.7 mg, with a calculated yield of 98% and an ee value of 90%ee.

[0270]

[0271] Example 28: Hydroacylation reaction of salicylaldehyde and unsaturated sulfides

[0272] Hydroacylation of salicylaldehyde with unsaturated sulfides: Under a nitrogen atmosphere, [Rh(COD)Cl]₂ (4.9 mg, 0.01 mmol) and a phosphoramidite ligand compound ( R , R N , R N )-Ⅲ-2-2 (11.2 mg, 0.02 mmol) was dissolved in dichloromethane (2.0 mL). Potassium phosphate (4.2 mg, 0.02 mmol) and salicylaldehyde 8d (22 μL, 0.2 mmol) were added sequentially to the solution. The solution was cooled to 0 °C, and then unsaturated sulfide 8e (46 μL, 0.3 mmol) was added. The reaction was stirred at 0 °C for 72 hours. After the reaction was completed as monitored by TLC, the reaction solution was evaporated and subjected to silica gel column chromatography to obtain 52.4 mg of the target product 9d, a colorless oily liquid, with a calculated yield of 91%.

[0273] After this step is completed, in order to further verify that the purified compound is indeed the target product to be prepared in this embodiment, the obtained product is analyzed. High performance liquid chromatography is used to determine the ee value, and nuclear magnetic resonance hydrogen spectroscopy is used to determine the ratio of branched product to linear product. b : l The analysis of the test is as follows: 1. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel Chiralpak® OD-H column; 1% i -PrOH hexanes; 1.0 mL / min; retention times: 9.5 min (major), 10.3 min (minor). Calculated result: 97% ee.

[0274] 2. Proton and carbon NMR spectra Nuclear magnetic resonance hydrogen spectroscopy analysis ( b : l The ratio is 15:1; 1 H NMR (400 MHz, CDCl3) d12.47 (s, 1H), 7.77 – 7.70 (m, 1H), 7.50 –7.41 (m, 1H), 7.35 – 7.22 (m, 4H), 7.20 – 7.11 (m, 1H), 7.02 – 6.95 (m, 1H),3.82 – 3.69 (m, 1H), 3.04 – 2.88 (m, 2H), 2.28 – 2.15 (m, 1H), 1.84 – 1.71(m, 1H), 1.24 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 209.7, 163.1, 136.4, 135.8, 129.8, 129.1, 128.9, 126.0, 118.9, 118.7, 118.4, 38.7, 32.5, 31.2, 17.5. Comparative compound testing: Under identical testing conditions, the hydroacylation reaction of salicylaldehyde 8d and unsaturated sulfide 8e was carried out using SBITOL-derived monophosphine ligands, yielding the target product 9d, a white solid of 42.4 mg, with a calculated yield of 74%. The ratio of branched to linear products was (…). b : l The ratio is 7:1, and the ee value is 82% ee.

[0275]

[0276] Example 29: Hydroacylation reaction of 2-hydroxy-1-naphthaldehyde with unsaturated sulfides

[0277] Hydroacylation of 2-hydroxy-1-naphthaldehyde with unsaturated sulfides: Under a nitrogen atmosphere, [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol) and a phosphoramidite ligand compound ( R , R N , R N)-Ⅲ-2-1 (6.9 mg, 0.01 mmol) was dissolved in 2.0 mL of dichloromethane. Potassium phosphate (2.1 mg, 0.01 mmol), 2-hydroxy-1-naphthaldehyde 8f (34.6 mg, 0.2 mmol), and unsaturated sulfide 8e (46 μL, 0.3 mmol) were added sequentially to the solution. The reaction was stirred at room temperature for 72 hours. After the reaction was complete as monitored by TLC, the reaction solution was purified by solvent evaporation and then subjected to silica gel column chromatography to obtain 63.8 mg of the target product 9e as a colorless oily liquid, with a calculated yield of 95%.

[0278] After this step is completed, in order to further verify that the purified compound is indeed the target product to be prepared in this embodiment, the obtained product is analyzed, and the specific rotation is tested, the ee value is determined by high performance liquid chromatography, and the ratio of branched product to linear product is determined by nuclear magnetic resonance spectroscopy. b : l The analysis of the test is as follows: 1. Specific rotation [α] measured by the D line at 23 ℃ D 23 +50.1 ( c = 1.0, CH2Cl2). 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel Chiralpak ® OD-H column; 2% i -PrOH hexanes; 1.0 mL / min; retention times: 32.5 min (minor), 34.9 min (major). Calculated result: 92% ee; 1H NMR spectroscopy analysis ( b : l The ratio is 13.7:1.

[0279] 2. Nuclear magnetic resonance analysis including proton, carbon, infrared, and high-resolution mass spectrometry. Nuclear magnetic resonance hydrogen spectroscopy analysis ( b : l The ratio is 13.7:1; 1 H NMR (400 MHz, CDCl3) d 11.89 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.79 (d, J= 8.0 Hz, 1H), 7.58 – 7.50 (m, 1H), 7.45 – 7.36 (m, 1H), 7.26 – 7.08 (m, 6H), 4.03 – 3.86 (m, 1H), 2.86 (t, J = 7.4Hz, 2H), 2.25 – 2.12 (m, 1H), 1.92 – 1.81 (m, 1H), 1.32 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 211.6, 161.1, 136.5, 135.7, 131.4, 129.2(2C), 128.8, 128.6, 127.9, 126.0, 124.3, 123.9, 119.3, 115.9, 43.7, 33.9,31.3, 17.5. IR (thin film) 3058, 2972, 2357, 1677, 1512, 1264, 1177, 1091, 825,738 cm -1 . HRMS (CI + ) Calcd for C 21 H 21 O2S [M+H] + : 337.1257, Found: 337.1255. Comparative compound testing: Under identical testing conditions, the hydroacylation reaction of 2-hydroxy-1-naphthaldehyde 8f and unsaturated sulfide 8e was carried out using SBITOL-derived monophosphine ligands to give the target product 9e, a white solid of 57.8 mg, with a calculated yield of 86% and an ee value of 70% ee. The ratio of branched to linear products (…) b : l The ratio is 8.2:1.

[0280]

Claims

1. The compound or its stereoisomer as shown in Formula I: ， in: R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

2. The compound of formula I or its stereoisomers according to claim 1, characterized in that, The compound described in Formula I is represented by Formula I-1: ， in: R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

3. The compound of formula I or its stereoisomers according to claim 2, characterized in that, The compound described in Formula I-1 is represented by Formula I-1-1: ， R1 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both hydrogen and not both bromine.

4. The compound of formula I or its stereoisomers according to claim 3, characterized in that, The compound I-1-1 is selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , or .

5. The compound of formula I or its stereoisomers according to claim 2, characterized in that, The compound described in Formula I-1 is represented by Formula I-1-2: ， R1 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R3 and R4 are simultaneously selected from halogens, C1-C4 alkyl groups, 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings, wherein the 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings are not substituted, or are substituted by halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, or phenyl groups. R7, R8, R9, R 10 It can be either hydrogen or methyl.

6. The compound of formula I or its stereoisomers according to claim 5, characterized in that, Compound I-1-2 is selected from any of the following compounds: , , , , or .

7. The compound of formula I or its stereoisomers according to claim 2, characterized in that, The compound described in Formula I-1 is represented by Formula I-1-3: ， R2 and R5 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 and R5 cannot be hydrogen simultaneously.

8. The compound of formula I or its stereoisomers according to claim 7, characterized in that, Compound I-1-3 is selected from the following compounds: 。 9. A method for preparing compound I-1-1 as described in claim 3, characterized in that, The preparation method of compound I-1-1 includes the following steps: Reaction route 1: ， R1 and R6 are both selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; Reaction route 2-1: ， Wherein, R is H or benzyl, X is bromine or iodine, and R1 and R6 are simultaneously selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; Reaction route 2-2: ， Wherein, R is methyl, methoxymethyl, trimethylsilyl or tert-butyldimethylsilyl, X is bromine or iodine, and R1 and R6 are simultaneously selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; Reaction route 3: ， R1 and R6 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both hydrogen and not both bromine; When R7, R8, R9, R 10 When the methyl group is present, the cyclopropanating agent is isopropyl diphenylsulfonium tetrafluoroborate; Compound IV, Compound VII, or Compound XII react with the cyclopropanating agent under the action of strong base 1, wherein strong base 1 is an alkali metal hydride, alkali metal alkoxide, amino base, amino base, organolithium reagent, or inorganic strong base; When R7, R8, R9, R 10 When the cyclopropanating agent is hydrogen, it is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, a dihalomethane, or a diazomethane compound; when the cyclopropanating agent is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, compound IV, compound VII, or compound XII react with the cyclopropanating agent under the action of a strong base 1, wherein the strong base 1 is an alkali metal hydride, an alkali metal alkoxide, an amino base, an amino base, an organolithium reagent, or an inorganic strong base; when the cyclopropanating agent is a dihalomethane, and the dihalomethane is diiodomethane, compound IV, compound VII, or compound XII react with diiodomethane under the action of zinc; when the dihalomethane is dibromomethane, compound IV, compound VII, or compound XII react with dibromomethane under the action of diethylzinc. The coupling reagent is an aromatic boric acid reagent, a C1-C4 alkyl boric acid reagent, an organozinc reagent, a Grignard reagent, or an organotin reagent. The aromatic boric acid reagent has a parent ring selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered fused heterocyclic aromatic rings substituted with boric acid, potassium trifluoroborate, or pinacol borate. The C1-C4 alkyl boric acid reagent is a C1-C4 alkyl-substituted boric acid, potassium trifluoroborate, or pinacol borate. The organozinc reagent is R'-zinc halide. The Grignard reagent is R'-magnesium halide, the organotin reagent is R'-tri-n-butyltin, the halogen atom is independently selected from chlorine, bromine, and iodine, and R' is selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, 8-10 membered heterocyclic aromatic rings, or C1-C4 alkyl groups; the 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings are not substituted, or are substituted by halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, or phenyl groups.

10. The method for preparing compound I-1-1 according to claim 9, characterized in that, The preparation method of compound I-1-1 includes the following steps: When R1 and R6 are the same, the reaction route 3 is as follows: ， R1 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 is neither hydrogen nor bromine; When R1 and R6 are different, the reaction route 3 is as follows: ， R1 and R6 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both hydrogen and not both bromine.

11. A method for preparing compound I-1-2 as described in claim 5, characterized in that, The preparation method of compound I-1-2 includes the following steps: using compound I-1-1 as a raw material, compound I-1-2 is prepared by reaction, and the reaction route is as follows: ， R1 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; X is selected from halogens; R3 and R4 are simultaneously selected from C1-C4 alkyl, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; The coupling reagent is an aromatic boric acid reagent, a C1-C4 alkyl boric acid reagent, an organozinc reagent, a Grignard reagent, or an organotin reagent. The aromatic boric acid reagent has a parent ring selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered fused heterocyclic aromatic rings substituted with boric acid, potassium trifluoroborate, or pinacol borate. The C1-C4 alkyl boric acid reagent is a C1-C4 alkyl-substituted boric acid, potassium trifluoroborate, or pinacol borate. The organozinc reagent is R'-zinc halide. The Grignard reagent is R'-magnesium halide, the organotin reagent is R'-tri-n-butyltin, the halogen atom is independently selected from chlorine, bromine, and iodine, and R' is selected from 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, 8-10 membered heterocyclic aromatic rings, or C1-C4 alkyl groups; the 5-6 membered aromatic rings, 8-10 membered fused aromatic rings, 5-6 membered heterocyclic aromatic rings, or 8-10 membered heterocyclic aromatic rings are not substituted, or are substituted by halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, or phenyl groups.

12. A method for preparing compound I-1-3 as described in claim 7, characterized in that, The preparation method of compound I-1-3 includes the following steps: ， R2 and R5 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 and R5 cannot be hydrogen simultaneously; When R7, R8, R9, R 10 When the methyl group is present, the cyclopropanating agent is isopropyl diphenylsulfonium tetrafluoroborate; compound XVI reacts with the cyclopropanating agent under the action of strong base 1, wherein strong base 1 is an alkali metal hydride, alkali metal alkoxide, amino base, amino base, organolithium reagent or inorganic strong base; When R7, R8, R9, R 10 When the cyclopropanating agent is hydrogen, it is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, a dihalomethane, or a diazomethane compound; when the cyclopropanating agent is a trimethyl sulfonium oxide salt or a trimethyl sulfonium salt, compound XVI reacts with the cyclopropanating agent under the action of a strong base 1, wherein the strong base 1 is an alkali metal hydride, an alkali metal alkoxide, an amino base, an amino base, an organolithium reagent, or an inorganic strong base; when the cyclopropanating agent is a dihalomethane, and the dihalomethane is diiodomethane, compound XVI reacts with diiodomethane under the action of zinc; when the dihalomethane is dibromomethane, compound XVI reacts with dibromomethane under the action of diethylzinc.

13. The method for preparing compound I-1-3 according to claim 12, characterized in that, The preparation method of compound I-1-3 includes the following steps: When R2 and R5 are the same, the route is as follows: ， R2 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 is not hydrogen; When R2 and R5 are different, the route is as follows: , R2 and R5 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy or phenyl, and R2 and R5 are not both hydrogen, nor are they both bromine; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R2 and R5 cannot be hydrogen simultaneously.

14. The preparation method according to any one of claims 9, 10, 12 or 13, characterized in that, The cyclopropanizing agent is isopropyl diphenylsulfonium tetrafluoroborate, trimethylsulfonium oxide, or trimethylsulfonium. The trimethylsulfonium oxide is trimethyl sulfoxide, trimethyl sulfonium chloride, trimethyl sulfonium bromide, or trimethylsulfonium methanesulfonate. The trimethylsulfonium is trimethylsulfonium iodide, trimethylsulfonium bromide, trimethylsulfonium chloride, trimethyltetrafluoroborate sulfonium, trimethylsulfonium hexafluorophosphate, trimethylsulfonium trifluoromethanesulfonate, trimethylsulfonium p-toluenesulfonic acid, or trimethylmethylsulfonium sulfate. The strong base 1 is sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium amino, diisopropylaminolithium, hexamethyldisilamide lithium, hexamethyldisilamide sodium, hexamethyldisilamide potassium, n-butyllithium, sodium hydroxide, or potassium hydroxide. Compounds IV, VII, and XII are also mentioned. The amount of compound XVI is 1 molar equivalent, the amount of the cyclopropanating agent is 2-6 molar equivalent, and the amount of strong base 1 is 2-6 molar equivalent; the reaction solvent is one or more of anhydrous dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, sulfolane, acetonitrile, 2-methyltetrahydrofuran, and tert-butanol; the reaction temperature is 0-80℃; Alternatively, the cyclopropanating agent may be a dihalomethane. When the dihalomethane is diiodomethane, the amount of diiodomethane used is 2-10 molar equivalents, the amount of zinc used is 2-20 molar equivalents, and the reaction solvent is one or more of diethyl ether, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, n-hexane, or chloroform, with a reaction temperature of -20 to 60°C. When the dihalomethane is dibromomethane, the amount of dibromomethane used is 2-8 molar equivalents, the amount of diethylzinc used is 2-20 molar equivalents, and the reaction solvent is one or more of diethyl ether, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, n-hexane, or chloroform, with a reaction temperature of -20 to 60°C. Alternatively, the cyclopropanating agent may be a diazonium methane compound, which may be diazonium methane or trimethylsilyl diazonium methane; the reaction may be carried out under light, heat, or a transition metal catalyst; the transition metal catalyst may be rhodium acetate dimer, copper acetylacetonate, copper bis(trifluoromethanesulfonyl)imide, or palladium bis(dibenzylacetone); the amount of the diazonium methane compound used is 2-6 molar equivalents, and the amount of the transition metal catalyst used is 0.01-10 molar equivalents; the reaction solvent may be one or more of diethyl ether, tetrahydrofuran, dichloromethane, toluene, or 1,2-dichloroethane; and the reaction temperature may be -20 to 60°C.

15. The preparation method according to claim 9 or 11, characterized in that, When the coupling agent is an aromatic boric acid or a C1-C4 alkyl boric acid, catalyst a is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, XPhos-Pd-G2, SPhos-Pd-G2, PEPPSI™-IPr, palladium acetate, tris(dibenzylacetone)palladium, or palladium dichloride; when catalyst a is an acetonitrile complex of palladium acetate, tris(dibenzylacetone)palladium, palladium dichloride, or palladium dichloride, catalyst a... It forms a catalytic system in combination with an organophosphorus ligand; the organophosphorus ligand is at least one of bidentate phosphine ligands or monodentate phosphine ligands, wherein the bidentate phosphine ligand is 1,1'-bis(diphenylphosphino)ferrocene, 9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthracene, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, or 1 4-Bis(diphenylphosphine)butane, wherein the monodentate phosphine ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, n-butylbis(1-adamantyl)phosphine, triphenylphosphine, tri(o-tolyl)phosphine, tri-tert-butylphosphine, or tricyclohexylphosphine, wherein the organophosphine ligand and catalyst a The molar ratio of palladium is 1:1 to 4; the base 2 is cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, triethylamine, or diisopropylethylamine; the amount of compound V, compound X, compound X', or compound I-1-2 is 1 molar equivalent; the amount of coupling agent is 2 to 10 molar equivalents; the amount of catalyst a is 1 to 50 mol% of compound V, compound X, compound X', or compound I-1-2; the amount of base 2 is 2 to 10 molar equivalents; the reaction solvent is 1,4-dioxane / water, toluene / water, tetrahydrofuran / water, ethylene glycol dimethyl ether / water, N,N-dimethylformamide / water, ethanol, methanol / water, or acetonitrile / water; When the coupling agent is an organozinc reagent, Grignard reagent, or organotin reagent, the catalyst a is 1,3-bis(diphenylphosphine propane) nickel dichloride or tetra-triphenylphosphine palladium, the amount of compound V, compound X, compound X', or compound I-1-2 is 1 molar equivalent, the amount of the coupling agent is 2 to 10 molar equivalents, the amount of catalyst a is 1 to 50 mol% of compound V, compound X, compound X', or compound I-1-2, and the reaction solvent is tetrahydrofuran or toluene.

16. The preparation method according to any one of claims 9, 10, 12 or 13, characterized in that, The catalyst b is palladium on carbon, palladium hydroxide / carbon, platinum / carbon, platinum oxide, Raney nickel, platinum black, ruthenium dioxide, Raney cobalt, Wilkinson catalyst, Crabtree catalyst, rhodium / carbon, ruthenium / carbon, iridium / carbon, or palladium black; when catalyst b is palladium on carbon or palladium hydroxide / carbon, the palladium loading is 1~30wt%, and the amount of catalyst b added is 3~50wt% of compound II, compound VIII, or compound II'; the hydrogen source is hydrogen or a hydrogen transfer reagent, and the hydrogen pressure is 1~100 atm; the compound II, compound VIII, or compound II' The amount of the hydrogen transfer reagent used is 1 molar equivalent, and the hydrogen transfer reagent is ammonium formate, formic acid, hydrazine hydrate, cyclohexene or isopropanol, and the amount of the hydrogen transfer reagent used is 4 to 100 molar equivalents; the reaction solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, 1,4-dioxane, glacial acetic acid, toluene, and N,N-dimethylformamide; the reaction temperature is 0 to 100°C.

17. The preparation method according to any one of claims 9, 10, 12 or 13, characterized in that, The catalyst c is a boron trifluoride diethyl ether complex, a boron trifluoride tetrahydrofuran complex, methanesulfonic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, polyphosphoric acid, aluminum trichloride, zinc chloride, ferric chloride, titanium tetrachloride, tin tetrachloride, trimethylsilyl trifluoromethanesulfonate, boron tribromide, scandium trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, ethyl polyphosphoric acid, trimethylsilyl polyphosphoric acid, phosphorus pentoxide, or Amberlyst-15; the reaction solvent is sulfuric acid, hydrobromic acid, hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, polyphosphoric acid, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, 1,4-dioxane, chloroform, xylene, nitrobenzene, 1,1,2,2-tetrachloroethane, or tetrahydrofuran; and compounds VI, XI, XI', XIII, or XVII are also mentioned. The amount of the catalyst used is 1 molar equivalent, and the amount of the catalyst c is 0.01~50 molar equivalent; the reaction temperature is -40~120℃.

18. The preparation method according to claim 9 or 11, characterized in that, When the halogenating agent is N-bromosuccinimide, N-bromophthalimide, N-iodosuccinimide, iodine, bromine, pyridinium tribromide, or tetrabutylammonium tribromide, then compound IX, compound IX', or compound I-1-1 The amount of the catalyst is 1 molar equivalent, and the amount of the halogenated reagent is 2-3 molar equivalents; when the halogenated reagent is an alkali metal halide / hydrogen peroxide, the alkali metal halide is sodium bromide, potassium bromide, potassium iodide, or sodium iodide, the amount of the alkali metal halide is 2-3 molar equivalents, and the amount of hydrogen peroxide is 2-6 molar equivalents; when the halogenated reagent is 1,3-dibromo-5,5-dimethylhydantoin or dibromoisocyanuric acid, the amount of the halogenated reagent is 1.0-1.5 molar equivalents; the catalyst d is a hydrobromic acid-acetic acid solution, hydrobromic acid aqueous solution, hydroiodic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid, glacial acetic acid, methanesulfonic acid, camphorsulfonic acid, phosphoric acid, or trifluoromethanesulfonic acid, and the amount of catalyst d added is 1-30% of compound IX, compound IX', or compound I-1-1. mol%; the reaction solvent is one or more of anhydrous dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, 1,2-dichloroethane, chloroform, glacial acetic acid, dimethyl sulfoxide, N,N-dimethylformamide, methanol, water, toluene, and xylene; the reaction temperature is -40~50℃.

19. The preparation method according to claim 9, characterized in that, When R is methyl, the deprotecting agent is boron tribromide, hydrobromic acid, aluminum trichloride, trimethylsilicon iodide, boron trichloride, or pyridine hydrochloride, the amount of compound I-1-1' is 1 molar equivalent, the amount of the deprotecting agent is 2-10 molar equivalents, the reaction solvent is dichloromethane or dichloroethane, and the reaction temperature is -78 to 50°C; when R is methoxymethyl, the deprotecting agent is concentrated hydrochloric acid, hydrobromic acid, or trifluoroacetic acid, and the amount of the deprotecting agent is 0.1-10 molar equivalents. The reaction solvent is one or more of methanol, ethanol, tert-butanol, chloroform, dichloromethane, and 1,4-dioxane, and the reaction temperature is -40 to 100°C. When R is trimethylsilyl or tert-butyldimethylsilyl, the deprotecting agent is tetrabutylammonium fluoride, cesium fluoride, potassium fluoride, or sodium fluoride, and the amount of the deprotecting agent is 1 to 10 molar equivalents. The reaction solvent is tetrahydrofuran, N,N-dimethylformamide, or 1,4-dioxane, and the reaction temperature is -40 to 50°C.

20. The preparation method according to claim 10 or 13, characterized in that, The base 3 is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, triethylamine, diisopropylethylamine, tetramethylguanidine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; the amount of compound XIV, compound XV, compound XVIII, or compound XIX is 1 molar equivalent, the amount of acetone is 0.5 molar equivalent, and the amount of base 3 is 1 to 3 molar equivalent; the reaction solvent is one or more of anhydrous ethanol, methanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, water, ethylene glycol dimethyl ether, acetonitrile, tert-butanol, 2-methyltetrahydrofuran, and N-methylpyrrolidone; the reaction temperature is -20 to 60°C.

21. The intermediate compound or its stereoisomer obtained by the preparation method according to any one of claims 9, 10, 12 or 13, characterized in that, The intermediate compound is described by formula II or formula II': or , in: R1, R2, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both hydrogen and not both bromine, and R2 and R5 are not both hydrogen.

22. A monophosphine ligand, characterized in that, The monophosphine ligand is prepared from compound I according to claim 1, wherein the monophosphine ligand is a compound of formula III or a stereoisomer thereof. ， Wherein: R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, or phenyl; R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen; R 11 and R 12 Alkyl groups selected independently from C1-C6, or , or R 11 and R 12 Form with the attached nitrogen atom , , , or .

23. The monophosphine ligand according to claim 22, characterized in that, The monophosphine ligand of Formula III is selected from any of the following compounds: , , , , or , R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring. The 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

24. The monophosphine ligand according to claim 23, characterized in that, The monophosphine ligand is selected from any of the following compounds: , , , , , , , , , , or .

25. A method for preparing the monophosphine ligand as described in claim 23, characterized in that, Includes the following steps: Compound I reacts with tris(dimethylamino)phosphine to give the monophosphine ligand compound III-1, as shown in the following reaction route: ， Compound I reacts with phosphorus trichloride and organic amine compound XX to give monophosphine ligand compound III, as shown in the following reaction route: ， Alternatively, compound I reacts with phosphorus trichloride, organic amine compound XX, and n-butyllithium to yield monophosphine ligand compound III, as shown in the following reaction route: ， Among them, R 11 and R 12 Simultaneously selected from methyl or , or R 11 and R 12 Form with the attached nitrogen atom , , , or ; R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy, 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring, wherein the 5-6 membered aromatic ring, 8-10 membered fused aromatic ring, 5-6 membered aromatic heterocycle, or 8-10 membered fused heteroaromatic ring is not substituted, or is substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, or phenyl. R7, R8, R9, R 10 It can be either hydrogen or methyl; When R2, R3, R4, R5, R7, R8, R9, R 10 When both are hydrogen, R1 and R6 are not both bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 They are not both hydrogen.

26. The preparation method according to claim 25, characterized in that, In the step of reacting compound I with tris(dimethylamino)phosphine to obtain monophosphine ligand compound III-1, the amount of compound I used is 1 molar equivalent, the amount of tris(dimethylamino)phosphine added is 1 to 5 molar equivalents, the reaction solvent is anhydrous toluene, anhydrous dichloromethane, anhydrous 1,2-dichloroethane or anhydrous tetrahydrofuran, and the reaction temperature is 0 to 110°C; In the step of reacting compound I with phosphorus trichloride and organic amine compound XX to obtain monophosphine ligand compound III, the amount of phosphorus trichloride and organic amine compound XX is 1.0~10.0 molar equivalents, the base 4 is triethylamine, the amount of base 4 is 1.0~10.0 molar equivalents, the reaction solvent is anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous 1,2-dichloroethane or anhydrous toluene, and the reaction temperature is -78~50℃; In the step of reacting compound I with phosphorus trichloride, organic amine compound XX, and n-butyllithium to obtain monophosphine ligand compound III, the amounts of phosphorus trichloride, organic amine compound XX, base 4, and n-butyllithium are 1 to 5 molar equivalents, the reaction solvent is anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous 1,2-dichloroethane, or anhydrous toluene, and the reaction temperature is -78 to 30°C.

27. An application of the monophosphine ligand as described in any one of claims 22-24, characterized in that, The monophosphine ligand is complexed with metal salts of gold, copper, rhodium, ruthenium, iridium, nickel, molybdenum, palladium or cobalt to prepare a catalyst; or the monophosphine ligand is used for metal-catalyzed asymmetric hydroacylation, asymmetric hydrogenation, asymmetric allyl alkylation or asymmetric allyl amination reactions.

Images