Chiral ligand ppbox, process for its preparation and use in asymmetric catalytic conversions

Abstract

The application discloses a kind of chiral ligand PPBOX, its preparation method and application in asymmetric catalytic conversion, specifically related to a kind of compound as shown in formula I as chiral ligand in reaction, the reaction is reaction A, reaction B or reaction C;Reaction A: copper catalyst catalyzed tension release driven remote leaving group participated asymmetric propargyl amination, reaction B: copper catalyst catalyzed tension release driven remote leaving group participated asymmetric alkylation reaction, reaction C: copper catalyst catalyzed asymmetric propargyl enoxy. Such chiral ligand has excellent catalytic efficiency and stereoselective effect in the three types of asymmetric conversion reactions.

Description

Technical Field

[0001] This invention relates to a chiral ligand PPBOX, its preparation method, and its application in asymmetric catalytic conversion. Background Technology

[0002] PyBOX-type chiral ligands, namely pyridine-bisoxazoline ligands, have a wide range of applications, especially in copper-catalyzed a series of asymmetric transformations (RSC Adv. 2018, 8, 31129-31193; Chem. Rev. 2019, 119, 4293-4356; Eur. J. Org. Chem. 2023 26, e202300728; Angew. Chem. Int. Ed. 2021, 60, 8488-8493; Angew. Chem. Int. Ed. 2023, 62, e202301470.). Among these, copper-catalyzed classical asymmetric propargyl substitution reactions and asymmetric propargyl substitution reactions involving long-range leaving groups are important pathways for constructing chiral alkyne units, attracting widespread attention due to their mild conditions, high stereoselectivity control, and inexpensive catalysts (Tetrahedron Lett. 2015, 56, 283-295; Synthesis 2017, 49, 790-801; Chem. Lett. 2021, 50, 1282-1288.). These reaction modes primarily rely on the use of PyBOX ligands. Although significant progress has been made in copper-catalyzed asymmetric propargyl substitution reactions in recent years, satisfactory results have still not been achieved in several important transformations. One major reason is the limited stereocontrol and catalytic efficiency of known PyBOX ligands, which require further improvement. Therefore, in-depth structural modification and optimization based on known chiral PyBOX ligands to develop novel PyBOX ligands with superior performance in relevant asymmetric transformations is of significant research value. Recently, we discovered that by introducing a phenolic unit at the para position of the pyridine skeleton in PyBOX-type chiral ligands, we can obtain PPBOX chiral ligands, which can be applied in asymmetric long-range substitution reactions driven by alkynyl copper for dearomatization and rearomatization (Angew. Chem. Int. Ed. 2023, 62, e202314517.). Prior to this work, attempts to introduce phenolic units at the para-position of the pyridine skeleton of PyBOX-type chiral ligands were only sporadic and primarily used as monomers for preparing polymers or macromolecules to participate in some transformations (Molecular Diversity, 2003, 6, 93–105; J.Org.Chem. 2005, 70, 5536-5544; Tetrahedron Lett. 2008, 49, 5355–5358; Eur.J.Org.Chem. 2012, 6145–6154; Euro.Poly.J. 2018, 109, 473–482). In summary, the variety of PPBOX ligands still needs further exploration to meet more applications of asymmetric transformations. Summary of the Invention

[0003] This invention addresses the shortcomings of known PyBOX-type chiral ligands in terms of stereocontrol and catalytic efficiency by providing a compound as shown in Formula I, its preparation method, and its applications. When applied to asymmetric transformation reactions catalyzed by three novel copper catalysts, this type of chiral ligand exhibits significantly improved catalytic efficiency and stereocontrol compared to known ligands, demonstrating great application potential and practical value.

[0004] This invention provides the application of a compound of Formula I as a chiral ligand in a reaction, wherein the reaction is reaction A, reaction B or reaction C;

[0005] Reaction A: Asymmetric propargyl amination catalyzed by copper catalyst and driven by strain release involving a long-range leaving group.

[0006]

[0007] Reaction B: A copper-catalyzed strain release-driven asymmetric alkylation reaction involving long-range leaving groups.

[0008]

[0009] Reaction C: Asymmetric propargyl olefin oxidation catalyzed by a copper catalyst;

[0010]

[0011] X is a leaving group; express or Configuration;

[0012]

[0013] n can be 1, 2, 3, or 4 independently;

[0014] R1 is independently C 1～6 Alkyl, with one or more R 1a Replacement C 1～6 Alkyl, C 6～10 aryl, or, by one or more R 1b Replacement C 6～10 Aryl;

[0015] R2 is independently H and C 1～6 Alkyl, C 1～6 Alkoxy, halogen, -CN, -C(=O)-R 2-1 C 6～10 aryl, with one or more R 2a Replacement C 1～6 Alkyl, with one or more R 2b Replacement C 1～6alkoxy, or, by one or more R 2c Replacement C 6～10 Aryl;

[0016] R 2-1 Independently for C 1～6 Alkyl or C 6～10 Aryl;

[0017] R 1a R 1b R 2a R 2b and R 2c Each independently constitutes a halogen, C 1～6 Alkyl, C 1～6 alkoxy- or halogen-substituted C 1～6 Alkyl or C 6～10 Aryl;

[0018] And / or, two R2 atoms together with the attached C atom form C 6～10 Aryl;

[0019] Alternatively, the three R2 atoms together with the attached C atoms form C. 13～20 Aryl.

[0020] In one possible solution, R1 is independently C. 1～6 Alkyl or C 6～10 Aryl.

[0021] In a certain scheme, R2 is independently H and C. 1～6 Alkyl, C 1～6 Alkoxy, halogen, -CN, -C(=O)-R 2-1 , by one or more R 2a Replacement C 1～6 Alkyl, or C 6～10 Aryl.

[0022] In one particular scheme, R 2-1 C 6～10 Aryl.

[0023] In one particular scheme, R 2a Independently halogen or C 6～10 Aryl.

[0024] In one scheme, R1 is independently methyl or phenyl.

[0025] In one scheme, R2 is independently F, Cl, Br, ethyl, tert-butyl, methoxy, -CN, isopropyl, CF3 or phenyl.

[0026] In one scheme, two R2 atoms together with the attached C atoms form In one scheme, three R2 atoms are formed together with the attached C atoms. In one embodiment, the compound represented by Formula I is represented by Formula I-1, I-2, I-3, or I-4:

[0027]

[0028] Wherein, n, R1, and R2 are as described in any one of Formula I of the present invention.

[0029] In one embodiment, the compound represented by Formula I is preferably:

[0030]

[0031] Wherein, n, R1, and R2 are as described in any one of Formula I of the present invention.

[0032] In one embodiment, the compound represented by Formula I has any of the following structures:

[0033]

[0034] Or its enantiomers.

[0035] In one embodiment, reaction A: asymmetric propargyl amination catalyzed by the copper catalyst and driven by strain release involving a long-range leaving group, comprises the following steps:

[0036] In a solvent, in the presence of a copper catalyst, the compound shown in Formula I above, and a basic reagent, compound 9-1 and compound 10-1 are reacted as shown below to give compound 11-1 or compound 11-2.

[0037]

[0038] X can be halogen, -OAc, -OBoc, -OBz, -OTs, -OTroc, -OP(O)(OR)2 or -OCO2R independently;

[0039] R is C 1～6 alkyl;

[0040] R a1 and R a2 Each is independently a C that is optionally substituted with one or more substituents. 6～10 Aryl;

[0041] R b1 and R b2 Each is independently H, and C is optionally substituted with one or more substituents. 6～10 aryl, C substituted with one or more substituents 1～6Alkyl, 3- to 10-membered cycloalkyl optionally substituted with one or more substituents, or C optionally substituted with one or more substituents 2～6 alkenyl;

[0042] Or R b1 and R b2 Together with the attached N atom, it forms a 5- to 16-membered heterocyclic alkyl group, optionally substituted with one or more substituents; the 5- to 16-membered heterocyclic alkyl group contains 1, 2, 3 or 4 N atoms, and is a monocyclic, bicyclic or tricyclic saturated or semi-saturated cyclic group.

[0043] In one embodiment, reaction B is an asymmetric alkylation reaction catalyzed by the copper catalyst and driven by a strain release involving a long-range leaving group, comprising the following steps:

[0044] In a solvent, in the presence of a copper catalyst, the above-described compound as shown in Formula I, a metal salt Lewis acid, and a basic reagent, compound 9-1 and compound 12-1 are reacted as shown below to give compound 13-1 or compound 13-2.

[0045]

[0046] X can be halogen, -OAc, -OBoc, -OBz, -OTs, -OTroc, -OP(O)(OR)2 or -OCO2R independently;

[0047] R is C 1～6 alkyl;

[0048] R a1 and R a2 Each is independently a C that is optionally substituted with one or more substituents. 6～10 Aryl;

[0049] R c1 and R c2 Each is independently H, or C optionally substituted with one or more substituents. 1～6 alkyl;

[0050] R c3 Independently, C is optionally substituted with one or more substituents. 6～10 Aryl, or, optionally, a 5- to 10-membered heteroaryl group substituted with one or more substituents.

[0051] In one embodiment, reaction C: the asymmetric propargyl olefin oxylation reaction catalyzed by the copper catalyst, comprises the following steps:

[0052] In a solvent, in the presence of a copper catalyst, the compound shown in Formula I above, a Lewis acid of metal salt and a basic reagent, compound 14-1 is reacted as shown below to give compound 15-1 or compound 15-2.

[0053]

[0054] R d1 Independently, C is optionally substituted with one or more substituents. 6～10 Aryl, or, optionally, 5- to 10-membered heteroaryl groups substituted with one or more substituents;

[0055] R d2 -C(=O)OC is optionally substituted with one or more substituents. 1～6 alkyl.

[0056] In one particular scheme, R a1 R a2 R b1 R b2 R c1 R c2 R c3 R d1 and R d2 In the case where the optional substitution is by one or more substituents, the substituents are independently C 1～6 Alkyl, C 1～6 Alkoxy, halogen, C 6～10 Aryl, -OH 3- to 10-membered cycloalkyl groups, -C(=O)OC 1～6 Alkyl, 5-10-membered heteroaryl, 3-16-membered heterocyclic alkyl or -O(CH2)mC 6～10 Aryl; the C 1～6 Alkyl, C 1～6 Alkoxy, C 6～10 Aryl, 3-10 membered cycloalkyl, -C(=O)OC 1～6 Alkyl, 5-10-membered heteroaryl, 3-16-membered heterocyclic alkyl or -O(CH2)mC 6～10 The aryl group may be optionally replaced by one or more R's;

[0057] The heteroatoms in the 5- to 10-membered heteroaryl groups are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three.

[0058] The heteroatoms in the 3- to 16-membered heterocyclic alkyl groups are independently selected from 1, 2, 3, or 4 of B, N, O, and S, and the number of heteroatoms is independently 1, 2, 3, or 4, and they are monocyclic, bicyclic, or tricyclic saturated or semi-saturated cyclic groups.

[0059] Ra21 R a22 and R a23 Each independently is H or C 1～6 alkyl;

[0060] m can be 1, 2, or 3 independently;

[0061] R' is independently of halogen, oxo, and C. 1～6 Alkyl, C 1～6 Alkoxy or optional 3- to 16-membered heterocyclic alkyl groups substituted with one or more R1';

[0062] R1' is C 1～6 alkyl.

[0063] In one particular scheme, R a1 and R a2 Each independently serves as an optional entity to be controlled by one or more Rs. a1-1 Replacement C 6～10 Aryl;

[0064] R a1-1 Independently for C 1～6 Alkyl, C 1～6 Alkoxy or halogen.

[0065] In one particular scheme, R b1 and R b2 Each is independently H, arbitrarily controlled by one or more R b1-1 Replacement C 6～10 aryl, optionally with one or more R b1-2 Replacement C 1～6 Alkyl, 3- to 10-membered cycloalkyl, or, optionally with one or more R b1-3 Replacement C 2～6 alkenyl;

[0066] R b1-1 Independently -OH, halogen, or -O(CH2)mC 6～10 Aryl; wherein, the -O(CH2)mC 6～10 C in aryl 6～10 The aryl group is replaced by one or more halogens;

[0067] m can be 1 or 2 independently;

[0068] R b1-2 Independently for optional use by one or more R b1-2-1 Replacement C 6～10 Aryl, -OH C 1～6 Alkoxy, 3- to 10-membered cycloalkyl, -C(=O)OC 1～6 Alkyl, 5- to 10-membered heteroaryl, or, optionally with one or more Rb1-2-2 Substituted 3- to 16-membered heterocyclic alkyl groups;

[0069] R b1-2-1 Independently for C 1～6 Alkoxy, or, optionally, by one or more R b1-2-1-1 Substituted 3- to 16-membered heterocyclic alkyl groups;

[0070] R a21 R a22 and R a23 Each independently is C 1～6 alkyl;

[0071] R b1-2-1-1 C 1～6 alkyl;

[0072] R b1-2-2 Independently for C 1～6 Alkyl or oxo;

[0073] R b1-3 -C(=O)OC 1～6 alkyl;

[0074] In one particular scheme, R b1 and R b2 Together with the attached N atom, it forms an optional structure controlled by one or more R atoms. b1-4 Substituted 5- to 16-membered heterocyclic alkyl groups;

[0075] R b1-4 It is oxygenated.

[0076] In one particular scheme, R c1 and R c2 Each independently is C 1～6 Alkyl group.

[0077] In one particular scheme, R c3 Independently for optional use by one or more R c3-1 Replacement C 6～10 Aryl, or 5- to 10-membered heteroaryl;

[0078] R c3-1 Independently for C 1～6 Alkyl, C 1～6 Alkoxy or halogen.

[0079] In one particular scheme, R d1 For optional use by one or more R d1-1 Replacement C 6～10 Aryl, or 5- to 10-membered heteroaryl;

[0080] R d1-1 -C(=O)OC 1～6 alkyl.

[0081] In one particular scheme, R d2 For optional use by one or more R d2-1 Substituted -C(=O)OC 1～6 alkyl;

[0082] R d2-1 Independently halogen or C 1～6 Alkyl group.

[0083] In one scheme, the C 1～6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-propyl.

[0084] In one scheme, the C 6～10 The aryl group can be phenyl or naphthyl independently.

[0085] In one scheme, the C 1～6 The alkoxy group is independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy or ethoxy.

[0086] In one embodiment, the halogen is independently F, Cl, Br or I, preferably F, Cl or Br.

[0087] In one embodiment, the halogen-substituted C 1～6 The halogen substitution in the alkyl group is independently fluorine substitution, chlorine substitution, bromine substitution or iodine substitution, preferably fluorine substitution.

[0088] In one embodiment, the halogenated C 1～6 The number of halogenated groups in the alkyl group can be 1, 2, or 3 independently, for example, 3.

[0089] In one scheme, the C 13～20 The aryl group is C 13～16 Aryl, for example

[0090] In one embodiment, the 3- to 10-membered cycloalkyl group is a 3- to 8-membered cycloalkyl group, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0091]

[0092] In one scheme, the C 2～6 The alkenyl group can be vinyl, propenyl, allyl, isopropenyl, n-butenyl, sec-butenyl, or isobutenyl; for example...

[0093] In one embodiment, the 5-16 membered heterocyclic alkyl group is an 8-14 membered heterocyclic alkyl group, containing 1, 2, or 3 N atoms, preferably a 9-10 membered bicyclic heterocyclic alkyl group or an 11-14 membered tricyclic heterocyclic alkyl group; for example

[0094] In one embodiment, the 3-16 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group, wherein the heteroatom is selected from one, two, or three of B, O, and S, and the number of heteroatoms is one, two, or three; for example

[0095] In one embodiment, the 3-16 membered heterocyclic alkyl group is a 3-12 membered heterocyclic alkyl group, wherein the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three; preferably, it is a 4-6 membered monocyclic heterocyclic alkyl group or a 9-11 membered bicyclic heterocyclic alkyl group; for example

[0096] In one embodiment, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom is selected from one or two of O and S, and the number of heteroatoms is independently one or two; for example

[0097] In one particular scheme, R a1 and R a2 Each independently

[0098] In one particular scheme, R b1 and R b2 Each independently -CH3、

[0099] In one particular scheme, R c1 and R c2 Each is independently -CH2CH3.

[0100] In one particular scheme, R c3 for

[0101] In one particular scheme, R d1 for In one particular scheme, R d2 for In one scheme, compound 9-1 is

[0102] In one scheme, compound 10-1 is

[0103]

[0104] In one scheme, compound 12-1 is

[0105] In one scheme, compound 14-1 is

[0106] In a given scheme, X is independently either -OBoc or -OAc.

[0107] In one embodiment, compound 9-1 is in the E configuration, Z configuration, or a mixture of Z / E; for example, the E configuration.

[0108] In one embodiment, in reaction A, when the compound represented by formula I is When, the compound is obtained

[0109] In one embodiment, in reaction A, when the compound represented by formula I is When, the compound is obtained

[0110] In one embodiment, in reaction B, when the compound represented by formula I is When, the compound is obtained

[0111] In one embodiment, in reaction B, when the compound represented by formula I is When, the compound is obtained

[0112] In one embodiment, during reaction C, when the compound represented by formula I is... When, the compound is obtained

[0113] In one embodiment, during reaction C, when the compound represented by formula I is... When, the compound is obtained

[0114] In one embodiment, in reaction A, the solvent is an ether solvent, such as methyl anisole or 1,4-dioxane.

[0115] In one embodiment, in reaction A, the copper catalyst is a monovalent or divalent copper salt; preferably copper hexafluorophosphate tetraacetonitrile (Cu(CH3CN)4PF6).

[0116] In one embodiment, reaction A further includes a Lewis acid of metal salt, which is bismuth trifluoromethanesulfonate (Bi(OTf)3) or lithium trifluoromethanesulfonate (LiOTf), for example, Bi(OTf)3.

[0117] In one embodiment, in reaction A, the basic reagent is an organic base, preferably a tertiary amine organic base; for example, diisopropylethylamine.

[0118] In one embodiment, the molar ratio of compound 9-1 to the copper catalyst in the reaction is 1:(0.01 to 0.5); for example, 1:0.05.

[0119] In one embodiment, in reaction A, the molar ratio of compound 9-1 to the compound shown in Formula I is 1:(0.01 to 1); preferably 1:(0.01 to 0.5); for example, 1:0.15.

[0120] In one embodiment, in reaction A, the molar ratio of compound 9-1 to compound 10-1 is 1:(0.5-2); for example, 1:1.

[0121] In one embodiment, in reaction A, the molar ratio of compound 9-1 to the Lewis acid of the metal salt is 1:(0.01 to 0.5); for example, 1:0.1.

[0122] In one embodiment, in reaction A, the molar ratio of compound 9-1 to the basic reagent is 1:(0.5-4); for example, 1:2.

[0123] In one embodiment, the temperature of reaction A is 25–80°C; for example, 50°C or 60°C.

[0124] In reaction A, the reaction time can be monitored by conventional means in the art (e.g., TLC, HPLC or LCMS), and the reaction endpoint is generally taken as when compound 9-1 disappears or no longer reacts. The reaction time is preferably 16 to 90 hours; for example, 24 hours or 72 hours.

[0125] In one embodiment, in reaction B, the solvent is an ether solvent, such as methyl anisole.

[0126] In one embodiment, in reaction B, the copper catalyst is a monovalent or divalent copper salt; preferably Cu(CH3CN)4PF6.

[0127] In one embodiment, in reaction B, the Lewis acid of the metal salt is Bi(OTf)3 or LiOTf, for example, Bi(OTf)3.

[0128] In one embodiment, in reaction B, the alkaline reagent is an organic base, preferably a piperidine-based organic base; for example, pentamethylpiperidine.

[0129] In one embodiment, in reaction B, the molar ratio of compound 9-1 to the copper catalyst is 1:(0.01 to 0.5); for example, 1:0.05.

[0130] In one embodiment, in reaction B, the molar ratio of compound 9-1 to the compound shown in Formula I is 1:(0.01 to 1); for example, 1:0.15.

[0131] In one embodiment, in reaction B, the molar ratio of compound 9-1 to compound 12-1 is 1:(1 to 6); for example, 1:3.

[0132] In one embodiment, in reaction B, the molar ratio of compound 9-1 to the Lewis metal salt is 1:(0.01 to 0.5); for example, 1:0.1.

[0133] In one embodiment, in reaction B, the molar ratio of compound 9-1 to the basic reagent is 1:(0.5-4); for example, 1:2.

[0134] In one embodiment, reaction B is carried out at a temperature of 25–80°C; for example, 50°C.

[0135] In reaction B, the reaction time can be monitored by conventional means in the art (e.g., TLC, HPLC or LCMS), and the reaction endpoint is generally taken as when compound 9-1 disappears or no longer reacts. The reaction time is preferably 40 to 90 hours; for example, 72 hours.

[0136] In one embodiment, in reaction C, the solvent is an alcohol solvent, such as n-butanol.

[0137] In one embodiment, in reaction C, the copper catalyst is a monovalent or divalent copper salt; preferably Cu(CH3CN)4PF6.

[0138] In one embodiment, in reaction C, the Lewis acid of the metal salt is Bi(OTf)3 or LiOTf, for example, LiOTf.

[0139] In one embodiment, in reaction C, the basic reagent is an organic base, preferably a tertiary amine organic base; for example, Et2NMe.

[0140] In one embodiment, in reaction C, the molar ratio of compound 14-1 to the copper catalyst is 1:(0.01 to 0.5); for example, 1:0.04.

[0141] In one embodiment, in reaction C, the molar ratio of compound 14-1 to the compound shown in Formula I is 1:(0.01 to 1); preferably 1:(0.06 to 0.5); for example 1:008 or 1:0.12.

[0142] In one embodiment, in reaction C, the molar ratio of compound 14-1 to the Lewis metal salt is 1:(1-6); preferably 1:(1.2-4); for example, 1:2.5.

[0143] In one embodiment, in reaction C, the molar ratio of compound 14-1 to the basic reagent is 1:(0.5-4); for example, 1:2.

[0144] In one embodiment, the temperature of reaction C is -15 to 40°C; preferably -10 to 25°C; for example, 0°C.

[0145] In reaction C, the reaction time can be monitored by conventional means in the art (e.g., TLC, HPLC or LCMS), and the reaction endpoint is generally taken as when compound 14-1 disappears or no longer reacts. The reaction time is preferably 0.5 to 4 days; for example, 1 day or 3 days.

[0146] The present invention also provides a chiral ligand, which is a compound as shown in formula II, III or IV;

[0147]

[0148] n can be 1, 2, 3, or 4 independently;

[0149] R3 is independently C 1～6 Alkyl, or, by one or more R 3a Replacement C 1～6 alkyl;

[0150] R4 is independently C 1～6 Alkyl, C 1～6 Alkoxy, halogen, -CN, -C(=O)-R 4-1 , by one or more R 4a Replacement C 1～6 Alkyl, or, by one or more R 4b Replacement C 1～6 Alkoxy;

[0151] R 4-1 Independently for C 1～6 Alkyl or C 6～10 Aryl;

[0152] R5 is a halogen;

[0153] R6 is independently C 6～10aryl, or, by one or more R 6a Replacement C 6～10 Aryl;

[0154] R7 is independently C 1～6 Alkyl, C 6～10 aryl, with one or more R 7a Replacement C 1～6 Alkyl, or, by one or more R 7b Replacement C 6～10 Aryl;

[0155] R 3a R 4a R 4b R 6a R 7a and R 7b Each independently constitutes a halogen, C 1～6 Alkyl, C 1～6 alkoxy- or halogen-substituted C 1～6 Alkyl or C 6～10 Aryl;

[0156] Or two R7 atoms together with the attached C atom form C 6～10 Aryl;

[0157] Or three R7 atoms together with the attached C atom form C 13～20 Aryl;

[0158] express or Configuration;

[0159] The compound shown in Formula II is not...

[0160] In one possible solution, R3 is C. 1～6 alkyl.

[0161] In one scheme, R4 is independently C. 1～6 Alkyl, C 1～6 Alkoxy, halogen, -CN, -C(=O)-R 4-1 , by one or more R 4a Replacement C 1～6 alkyl.

[0162] In one particular scheme, R 4-1 C 6～10 Aryl.

[0163] In one particular scheme, R 4a C 6～10 Aryl.

[0164] In one particular scheme, R6 is C6~C10 Aryl.

[0165] In one scheme, R7 is independently C. 1～6 Alkyl, C 6～10 aryl, with one or more R 7a Replacement C 1～6 alkyl.

[0166] In one particular scheme, R 7a It is a halogen.

[0167] In one particular scheme, R3 is a methyl group.

[0168] In one scheme, R4 is independently F, Br, ethyl, tert-butyl, methoxy, -CN, isopropyl,

[0169] In one particular scheme, R5 is Br.

[0170] In one particular scheme, R6 is a phenyl group.

[0171] In one scheme, R7 is independently CF3, phenyl, or tert-butyl.

[0172] In one scheme, two R7 atoms are formed together with the adjacent C atoms. In one scheme, three R7 atoms are formed together with the attached C atoms. In one embodiment, the chiral ligand has any of the following structures:

[0173]

[0174]

[0175] Or its enantiomers.

[0176] Terminology Definition

[0177] "-Ac" represents acetyl.

[0178] "-Boc" represents tert-butyloxycarbonyl.

[0179] "-Bz" represents benzoyl group.

[0180] "-Ts" indicates p-toluenesulfonyl group.

[0181] "-Troc" represents 2,2,2-trichloroethoxycarbonyl.

[0182] express or Configuration.

[0183] The term "one or more" refers to, for example, 1, 2 or 3.

[0184] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0185] The term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C40, C50, C6 ... 1～4 Or C 1～6 Alkyl groups are straight-chain or branched, saturated monovalent hydrocarbon groups. Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0186] The term "alkenyl" refers to an alkenyl group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C6 ... 2～6 A straight-chain or branched, unsaturated monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bonds. Alkenyl groups include, but are not limited to: vinyl, propenyl, allyl, isopropenyl, n-butenyl, sec-butenyl, or isobutenyl; for example...

[0187] The term "halogen-substituted C" 1～6 "Alkyl" refers to a C-aryl group that is optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl groups. Halogen-substituted C 1～6 Examples of alkyl groups include -CF3, etc.

[0188] The term "alkoxy" refers to the group R. X -O-,R X The definition is the same as the term "alkyl".

[0189] The term "oxo" refers to the =O group, where an oxygen atom replaces two hydrogen atoms on the same carbon atom; that is, a carbonyl group replaces a methylene group.

[0190] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C66). 6～10 C 13～20 Aromatic (aryl) is a cyclic, unsaturated monovalent hydrocarbon group, which can be monocyclic or polycyclic (e.g., two or three). In polycyclic forms, the monocyclic rings share two atoms and one bond. The aryl group is attached to the rest of the molecule through an aromatic ring. Aryl groups include, but are not limited to, phenyl, naphthyl, or... wait.

[0191] The term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of ring atoms (e.g., 3 to 8 or 3 to 10), which is monocyclic. Cycloalkyl groups include, but are not limited to: wait.

[0192] The term "heterocyclic alkyl" refers to a saturated or semi-saturated cyclic group having a specified number of ring atoms (e.g., 5–6, 8–14, 3–12, 3–16, or 5–16), wherein one, two, three, or four ring atoms are heteroatoms independently selected from B, N, O, and S, and the remainder are carbon atoms. It includes monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems can be fused or bridged ring systems; furthermore, heteroatoms can occupy the bonding positions between the heterocyclic alkyl group and the rest of the molecule. In bicyclic and tricyclic systems, some rings can be aromatic, while the rings directly bonded to the rest of the molecule are not aromatic. Examples of heterocyclic alkyl groups include, but are not limited to, those not specifically mentioned above. wait.

[0193] The term "heteroaromatic ring" refers to a cyclic group having a specified number of ring atoms (e.g., 5–6 or 5–10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic and possesses aromaticity (conforming to Hückel's rule). Heteroaromatic rings are linked to other segments of the molecule through aromatic rings. Heteroaromatic rings include, but are not limited to, those with aromaticity. wait.

[0194] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0195] The reagents and raw materials used in this invention are all commercially available.

[0196] The significant advancements of this invention lie in the synthesis of a series of phenol-substituted PPBOX chiral ligands, which, when applied to three novel asymmetric transformation reactions, exhibit excellent catalytic efficiency and stereocontrol. These improved chiral ligands hold promise for applications in a wider range of asymmetric catalytic syntheses. Detailed Implementation

[0197] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0198] Example 1: Synthesis of the new ligand 7a

[0199]

[0200] A 100 mL reaction flask was filled with compound 1 (2.3 g, 10 mmol) and 2a (1.7 mL, 22 mmol), and the mixture was heated and stirred at 100 °C for 2 h. The reaction was then allowed to return to room temperature to give intermediate 3a, which required no further purification. CHCl3 (15 mL) and SOCl2 (4.4 mL, 60 mmol) were then added to the reaction flask. The reaction was refluxed at 80 °C for 2 h. After the reaction was complete, the solution was concentrated and separated by column chromatography to give a white solid product 4a (3.0 g, 85% yield), which is a known compound (Chem. Commun, 2005, 3280–3282).

[0201] Take a 250 mL reaction flask, and under nitrogen protection, add NaH (1.3 g, 32 mmol, 60% dispersion in mineral oil) and dry THF (20 mL). While stirring, slowly add 4a (2.8 g, 7.9 mmol) of THF (40 mL). Then, react at 40 °C for 1 h. After the reaction is complete, filter, concentrate, and separate by column chromatography to obtain a white solid 5a (1.5 g, 68% yield), which is a known compound (Chem. Commun, 2005, 3280–3282).

[0202] Take a 4 mL reaction flask and add compounds 5a (56 mg, 0.20 mmol), 6a (0.30 mmol), Cs₂CO₃ (0.13 g, 0.40 mmol), and DMSO (0.50 mL) sequentially. The reaction is carried out at 80 °C for 24 h. After completion, quench with H₂O (5.0 mL), extract with ethyl acetate (10 mL × 3), dry to anhydrous sodium sulfate, concentrate, and separate by column chromatography. The crude product is then recrystallized from dichloromethane and petroleum ether to obtain pure compound 7a.

[0203] Compound 7a, white solid, yield 41%, [α] D 25 -24.7 (c 1.2, CHCl3). 1 H NMR(400MHz,chloroform-d)δ8.28(d,J=8.5Hz,1H),7.89(dd,J=8.7,3.1Hz,2H),7.68(s,2H),7.68-7.64(m,1H),7.57(t,J =7.5Hz,1H),7.28(d,J=8.7Hz,1H),4.57(t,J=8.1Hz,2H),4.43-4-34(m,2H),4.04(t,J=8.1Hz,2H),1.33(d,J=6.6Hz,6H). 13C NMR(101MHz,chloroform-d)δ164.90,161.96,148.93,148.20,133.18,132.44,129.95,128. 31,128.17,127.07,126.65,120.82,115.09,113.31,74.72,62.25,21.23.HRMS(ESI):[M+H] ⊕ calcd forC 23 H 21 O3N3Br ⊕ 466.0761, found 466.0764.

[0204] Using the appropriate raw materials, and referring to the reaction conditions and operating methods in Example 1, the following new ligands 7b-7j were prepared.

[0205] Example 2: New ligand 7b

[0206]

[0207] Compound 7b, white solid, yield 52%, [α] D 25 -39.3 (c 1.4, CHCl3). 1 H NMR(400MHz,chloroform-d)δ7.72(s,2H),7.45(dd,J=7.8,1.8Hz,1H),7.33–7.11(m,2H),6.92(dd,J=7.9,1. 5Hz,1H),4.59(t,J=8.1Hz,2H),4.46–4.33(m,2H),4.05(t,J=8.1Hz,2H),1.36(d,J=6.7Hz,6H),1.34(s,9H). 13 C NMR(101MHz,chloroform-d)δ165.59,162.08,152.56,148.84,141.88,127.97,127 .72,125.53,121.28,114.14,74.71,62.23,34.68,30.20,21.23.HRMS(ESI):[M+H] ⊕ calcd for C 23 H 28 O3N3 ⊕ 394.2125, found 394.2122.

[0208] Example 3: New ligand 7c

[0209]

[0210] Compound 7c, white solid, yield 36%, [α] D 25 -42.9 (c 0.5, CHCl3). 1 H NMR(400MHz,chloroform-d)δ7.71(s,2H),7.32(t,J=8.2Hz,1H),6.81(dd,J=8.2,2.3Hz,1H),6.68(dd,J=8.2,1.4Hz,1H), 6.64(t,J=2.3Hz,1H),4.58(t,J=8.0Hz,2H),4.46–4.34(m,2H),4.05(t,J=8.0Hz,2H),3.81(s,3H),1.35(d,J=6.7Hz,6H). 13 C NMR(101MHz,chloroform-d)δ165.63,162.03,161.31,154.81,148.83,130.77, 113.98,112.62,111.54,106.70,74.70,62.24,55.45,21.25.HRMS(ESI):[M+H] ⊕ calcd for C 20 H 22 O4N3 ⊕ 368.1605, found 368.1606.

[0211] Example 4: New ligand 7d

[0212]

[0213] Compound 7d, white solid, 40% yield, [α] D 25 -37.2 (c 1.1, CHCl3). 1 H NMR(400MHz,chloroform-d)δ7.65(s,2H),7.03(d,J=9.1Hz,2H),6.94(d,J=9.1Hz,2H),4.58( t,J=8.1Hz,2H),4.47–4.34(m,2H),4.05(t,J=8.1Hz,2H),3.84(s,3H),1.35(d,J=6.7Hz,6H). 13C NMR(101MHz,chloroform-d)δ166.38,162.08,157.35,148.73,146.98,121.80,115.41,113.41,74.68,62.23,55.62,21.26.HRMS(ESI):[M+H] ⊕ calcd for C 20 H 22 O4N3 ⊕ 368.1605, found 368.1605.

[0214] Example 5: New ligand 7e

[0215]

[0216] Compound 7e, white solid, yield 27%, [α] D 25 -65.0 (c 0.3, CHCl3). 1 H NMR(400MHz,chloroform-d)δ7.67(s,2H),7.17–7.06(m,4H),4.59(t,J=8.1Hz,2H),4.48–4.34(m,2H),4.05(t,J=8.1Hz,2H),1.35(d,J=6.6Hz,6H). 13 C NMR(101MHz,chloroform-d)δ165.79,161.97,160.18(d,J=244.9Hz),149.46,1 48.90, 122.28 (d, J = 8.5Hz), 117.12 (d, J = 23.6Hz), 113.53, 74.74, 62.25, 21.25. 19 F NMR(376MHz,chloroform-d)δ-116.43.HRMS(ESI):[M+H] ⊕ calcd for C 19 H 19 O3N3F ⊕ 356.1405, found 356.1403.

[0217] Example 6: New ligand 7f

[0218]

[0219] Compound 7f, white solid, yield 16%, [α] D 25 -37.4 (c 0.7, CHCl3).1 H NMR(400MHz,chloroform-d)δ7.77(s,2H),7.74(d,J=8.8Hz,2H),7.19(d,J=8.8Hz,2H) ,4.61(t,J=8.1Hz,2H),4.49–4.34(m,2H),4.07(t,J=8.1Hz,2H),1.36(d,J=6.6Hz,6H). 13 C NMR(126MHz,chloroform-d)δ164.00,161.79,157.65,149.34,134.76,120.84,118.11,114.79,109.28,74.91,62.33,21.34.HRMS(ESI):[M+H] ⊕ calcd for C 20 H 19 O3N4 ⊕ 363.1452, found 363.1454.

[0220] Example 7: 7g of new ligand

[0221]

[0222] Compound 7 g, white solid, yield 58%, [α] D 25 -48.0 (c 2.1, CHCl3). 1 H NMR(400MHz,chloroform-d)δ7.56(s,2H),7.30–7.25(m,1H),7.24–7.20(m,2H),4.57(t,J=8.0Hz,2H),4.49–4. 35(m,2H),4.04(t,J=8.0Hz,2H),2.89(hept,J=6.8Hz,2H),1.34(d,J=6.6Hz,6H),1.12(dd,J=6.9,3.3Hz,12H). 13 C NMR(101MHz,chloroform-d)δ166.31,162.02,148.76,146.97,140.95,126.91,124.86,112.23,74.66,62.19,27.11,23.26,21.23.HRMS(ESI):[M+H] ⊕ calcd for C 25 H 32 O3N3 ⊕ 422.2438, found 422.2435.

[0223] Example 8: New ligand 7h

[0224]

[0225] Compound 7h, white solid, yield 46%, [α] D 25 -44.9 (c 0.7, CHCl3), 1 H NMR(400MHz,chloroform-d)δ7.62(s,2H),7.01(d,J=8.0Hz,1H),6.84(s,1H),6.82(d,J=8.0Hz,1H),4.57(t,J=8.0Hz,2H) ,4.46–4.33(m,2H),4.04(t,J=8.0Hz,2H),3.75(s,3H),2.68(q,J=7.6Hz,2H),1.34(d,J=6.6Hz,6H),1.28(t,J=7.6Hz,3H). 13 C NMR(101MHz,chloroform-d)δ166.11,162.19,151.10,148.44,143.36,139.68,122.21 ,120.54,113.08,113.00,74.62,62.21,55.76,28.76,21.27,15.37.HRMS(ESI):[M+H] ⊕ calcd for C 22 H 26 O4N3 ⊕ 396.1918, found 396.1918.

[0226] Example 9: New ligand 7i

[0227]

[0228] Compound 7i, white solid, yield 28%, [α] D 25 -46.2 (c 0.4, CHCl3). 1H NMR(400MHz,chloroform-d)δ7.66(d,J=7.6Hz,2H),7.60(d,J=8.6Hz,1H),7.52–7.45(m,1H),7.47(s,2H),7.35(t,J=7.6Hz,2H),6.90(dd,J =8.6,2.4Hz,1H),6.68(d,J=2.4Hz,1H),4.55(t,J=8.0Hz,2H),4.44–4.33(m,2H),4.02(t,J=8.0Hz,2H),3.88(s,3H),1.33(d,J=6.6Hz,6H). 13 C NMR(101MHz,chloroform-d)δ193.59,165.18,163.52,161.82,153.44,148.54,137.89,133.13,132 .74,129.51,128.15,124.11,113.54,111.48,107.67,74.65,62.19,55.79,21.25.HRMS(ESI):[M+H] ⊕ calcd for C 27 H 26 O5N3 ⊕ 472.1867, found 472.1866.

[0229] Example 10: New ligand 7j

[0230]

[0231] Compound 7j, white solid, yield 54%, [α] D 25 -49.2 (c 1.7, CHCl3), 1 H NMR(400MHz,chloroform-d)δ7.52(s,2H),7.29–7.23(m,2H),7.21–7.16(m,2H),7.14–7.06(m,3H),6.97(d,J=9.3Hz,1H),4.58(t,J=

[0232] 8.0Hz,2H),4.46–4.32(m,2H),4.05(t,J=8.0Hz,2H),3.85(s,2H),1.35(d,J=6.7Hz,6H). 13C NMR(101MHz,chloroform-d)δ165.26,161.89,149.98,148.75,138.44,135.67,131.55,131.46, 128.85,128.54,128.42,126.45,122.51,113.12,74.72,62.24,36.05,21.27.HRMS(ESI):[M+H] ⊕ calcd for C 26 H 25 O3N3Cl ⊕ 462.1579, found 462.1581.

[0233] Example 11: Synthesis of the new ligand 7k

[0234]

[0235] Compound 1 (4.6 g, 20 mmol), 6k (4.9 g, 30 mmol), K2CO3 (5.5 g, 40 mmol), and DMF (60 mL) were added to a 250 mL reaction flask. The reaction was stirred at 80 °C until complete. The mixture was quenched with water, extracted with ethyl acetate (3 × 60 mL), dried over anhydrous Na2SO4, concentrated, and subjected to column chromatography to give compound 8k (2.35 g, 33% yield).

[0236] The intermediate 8K and amino alcohol 2B (2.0 g, 2.2 equiv) were added to a reaction flask, followed by the addition of toluene solvent. The reaction was stirred at 80 °C for 2 h. Subsequently, the toluene solvent was removed by concentration, and then dichloromethane (13 mL) and DAST (2.67 g, 2.5 equiv) were added at -20 °C, with stirring continued for 4 h. Afterward, the reaction was quenched with a saturated sodium carbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain pure compound 7K.

[0237] Compound 7K is a white solid with a yield of 8%, [α]. D 16 = -38.2 (c 3.0in CHCl3); 1 H NMR(400MHz, CDCl3)δ7.90(s,2H),7.60–7.46(m,2H),7.42–7.24(m,12H),5.4 3(dd,J=10.4,8.6Hz,2H), 4.91(dd,J=10.4,8.7Hz,2H), 4.41(t,J=8.7Hz,2H). 13C NMR (101MHz, CDCl3) δ165.01,163.12,154.10,149.04,141.50,131.11,128.81,127.83,1 26.79,123.78,122.60,122.57,117.79,117.76,114.75,75.59,70.33.HRMS(ESI):[M+H] ⊕ calcd for C 30 H 23 O3N3F3 ⊕ 530.1686, found 530.1679.

[0238] Using the appropriate raw materials and following the reaction conditions and operating methods in Example 11, the following new ligands 7l-7p were prepared.

[0239] Example 12: New ligand 7l

[0240]

[0241] Compound 7l, white solid, 1% overall yield, [α] D 16 = +11.3 (c 0.39in CHCl3); 1 H NMR (400MHz, CDCl3) δ8.31–8.15(m,3H),8.07(h,J=8.1Hz,5H),7.91(s,2H),7.77(d,J=8.3Hz ,1H),7.44–7.15(m,10H),5.37(t,J=9.5Hz,2H),4.87(t,J=9.6Hz,2H),4.37(t,J=8.7Hz,2H). 13 C NMR (101MHz, CDCl3) δ166.78,163.26,148.88,146.63,141.52,131.17,131.09,129.49,128.74,128.54,127.73,127.37,127.01,126 .79,126.54,126.16,125.74,125.65,125.42,124.56,123.29,120.15,118.47,114.17,75.46,70.31,58.20,8.13.HRMS(ESI):[M+H] ⊕ calcd for C 39 H 28 O3N3 ⊕ 586.2125, found 586.2117.

[0242] Example 13: New ligand 7m

[0243]

[0244] Compound 7m, white solid, overall yield 5%, [α] D 16 = -50.1 (c 0.70in CHCl3); 1 H NMR(400MHz, CDCl3)δ7.72(s,2H),7.47(dd,J=7.5,1.9Hz,1H),7.44–7.37(m,4H),7.37–7.33(m,4H),7.33–7.23(m, 9H), 7.17 (dd, J=8.0, 1.4Hz, 1H), 5.39 (dd, J=10.4, 8.5Hz, 2H), 4.86 (dd, J=10.4, 8.7Hz, 2H), 4.35 (t, J=8.6Hz, 2H). 13 C NMR (101MHz, CDCl3) δ165.35,163.26,150.23,148.32,141.64,136.74,134.63,131.85,129.37,129.00,128. 97,128.77,128.31,127.77,127.63,126.79,126.54,121.59,114.10,75.45,70.26,29.66.HRMS(ESI):[M+H] ⊕ calcd for C 35 H 28 O3N3 ⊕ 538.2125, found 538.2115.

[0245] Example 14: New ligand 7n

[0246]

[0247] Compound 7n, white solid, overall yield 3%, [α] D 16 = -31.2 (c 0.61in CHCl3); 1H NMR(400MHz, CDCl3)δ7.82(s,2H),7.36(dd,J=7.8,1.8Hz,1H),7.31–7.26(m ,4H),7.25–7.21(m,6H),7.21–7.17(m,1H),7.15(dd,J=7.7,1.8Hz,1H),7.0 9(td,J=7.5,1.5Hz,1H),6.86(dd,J=7.9,1.5Hz,1H),5.35(dd,J=10.4,8.7H z,2H),4.83(dd,J=10.4,8.7Hz,2H),4.33(t,J=8.7Hz,2H),1.27(s,9H).13C NMR (101MHz, CDCl3) δ165.73,163.34,152.52,148.73,141.88,141.54,128.80,128.04,127 .80,127.76,126.83,125.65,121.22,114.81,75.50,70.35,34.70,30.23.HRMS(ESI):[M+H] ⊕ calcd for C 33 H 32 O3N3 ⊕ 518.2438, found 518.2430.

[0248] Example 15: New ligand 7o

[0249]

[0250] Compound 7o, white solid, overall yield 2%, [α] D 16 = -27.8 (c 0.29in CHCl3); 1 H NMR(400MHz, CDCl3)δ7.81(s,2H),7.38–7.15(m,12H),7.00–6.90(m,2H),5.35(dd,J =10.4,8.6Hz,2H),4.82(dd,J=10.4,8.7Hz,2H),4.33(t,J=8.6Hz,2H),1.25(s,9H). 13 C NMR (101MHz, CDCl3) δ166.00,163.37,151.28,148.74,148.60,141.60,128.80,127.80 ,127.30,126.82,119.91,114.55,75.49,70.34,34.51,31.38,29.66.HRMS(ESI):[M+H]⊕ calcd for C 33 H 32 O3N3 ⊕ 518.2438, found 518.2432.

[0251] Example 16: New ligand 7p

[0252]

[0253] Compound 7p, white solid, 3% overall yield, [α] D 16 = -26.8 (c 0.14in CHCl3); 1 H NMR(400MHz, CDCl3)δ7.77(d,J=8.3Hz,1H),7.57–7.45(m,3H),7.38–7.19(m,11H) ,5.40(dd,J=10.4,8.6Hz,2H), 4.88(dd,J=10.4,8.7Hz,2H), 4.39(t,J=8.7Hz,2H). 13 C NMR (101MHz, CDCl3) δ166.4,163.3,148.8,141.5,135.3,128.8,128.1,127.8,126.9, 126.8,126.7,126.2,125.8,121.4,116.7,114.2,75.5,70.3,29.6.HRMS(ESI):[M+H] ⊕ calcd forC 33 H 32 O3N3 ⊕ 512.1969, found 512.1960.

[0254] Application Example 1: Asymmetric ring-opening propargyl amination reaction catalyzed by copper catalyst and chiral PPBOX ligand

[0255] Synthesis of compound 9a

[0256]

[0257] Take a 250 mL reaction flask, add a clean stir bar, 21 (5.1 g, 21 mmol), and ultra-dry THF (10 mL) as solvent. Then slowly add a PhMgBr THF solution (42 mL, 42 mmol, 2.0 equiv, 1 M in THF). Stir the reaction at room temperature for 16 h. After the reaction is complete, quench the reaction with saturated NH4Cl aqueous solution (50 mL) and extract with EtOAc (50 mL × 3). Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate and separate by column chromatography to give a yellow liquid product 22 (6.4 g, 95% yield). 1 H NMR(400MHz,chloroform-d)δ7.45(d,J=7.0Hz,2H),7.39–7.20 (m,8H),1.96(ddd,J=8.9,6.4,5.1 Hz,1H),1.92(s,1H),1.46(dt,J=8.7,5.1Hz,1H),0.98(ddd,J=8.7,6.4,5.1Hz,1H),0.92(dt,J=8.9,5.1Hz,1H),0.15(s,9H). 13 C NMR(101MHz,chloroform-d)δ146.7,146.4,128.3,128.1,127.6,127.2,127.1,126.4,109.1,80.8,76.7,32.4,11.9,5.6,0.3.HRMS(DART):[M+H] ⊕ calcd for C 21 H 25 OSi ⊕ 321.1669, found 321.1671.

[0258] Take a 50 mL reaction flask and add a clean stir bar, 22 (4.0 mmol), K2CO3 (1.1 g, 8.0 mmol, 2.0 equiv), and MeOH (10 mL) as solvents. Stir the reaction at room temperature for 3 h. After the reaction is complete, filter, concentrate the reaction solution, and separate by column chromatography to obtain a pale yellow liquid product 23 (0.90 g, yield 91%). 1 H NMR(400MHz,chloroform-d)δ7.43(d,J=7.2Hz,2H),7.39–7.20(m,8H),1.95(ddd,J=9.1,6.4,5.0Hz,1H),1.92(s,1H), 1.81(d,J=2.2Hz,1H), 1.45(dtd,J=8.5,5.0,2.2Hz,1H), 1.02(ddd,J=8.5,6.4,5.0Hz,1H), 0.92(dt,J=9.1,5.0Hz,1H). 13C NMR(101MHz,chloroform-d)δ146.8,146.4,128.3,128.1,127.6,127.2,127.1,126.4,86.6,76.5,64.5,31.9,11.4,4.3.HRMS(DART):[M+H] ⊕ calcd for C 18 H 17 O ⊕ 249.1274, found 249.1275.

[0259] Take a 50 mL reaction flask and add a clean stir bar, 23 (4.0 mmol), DMAP (0.24 g, 2.0 mmol, 0.5 equiv), Et3N (1.7 mL, 12 mmol, 3.0 equiv), and THF (10 mL) as solvents. Then add Boc2O (1.8 mL, 8.0 mmol, 2.0 equiv). Stir the reaction at room temperature for 8 h. After the reaction is complete, concentrate the reaction solution and separate it by alkaline Al2O3 column chromatography to obtain a white solid product 9a (1.1 g, yield 77%). 1 H NMR(400MHz,chloroform-d)δ7.39(d,J=7.0Hz,2H),7.32(t,J=7.3Hz,2H),7.29–7.21(m,6H) ,3.15–2.74(m,1H),1.83(d,J=1.7Hz,1H),1.40(s,9H),1.05–0.94(m,2H),0.68–0.59(m,1H). 13 C NMR(101MHz,chloroform-d)δ151.4,142.7,141.5,128.0,127.7,127.6,127.4,127.1,87.9,85.5,81.9,64.8,27.7,27.3,11.7,4.9.HRMS(DART):[M+NH4] ⊕ calcd for C 23 H 28 O3N ⊕ 366.2064, found366.2066.

[0260]

[0261] Under nitrogen protection, Cu(CH3CN)4PF6 (1.9 mg, 0.0050 mmol), chiral ligand 7j (6.9 mg, 0.015 mmol), and PhOMe (0.10 mL) were added to a 4 mL reaction flask. The reaction was stirred at room temperature for 10 min. Then, substrate 9a (35 mg, 0.10 mmol), amine 10a (11 mg, 0.10 mmol), diisopropylethylamine (DIPEA, 26 mg, 0.20 mmol), Bi(OTf)3 (6.7 mg, 0.010 mmol), and PhOMe (0.40 mL) were added sequentially to the reaction flask. The reaction was stirred at 50 °C for 72 h. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography to obtain product 11a.

[0262] Compound 11a, yellow solid, 74% yield. [α] D 25 -27.4(c 1.2,CHCl3)for 94:6er; 1 H NMR(500MHz,chloroform-d)δ7.46–7.41(m,2H),7.40–7.36(m,1H),7.31–7.23(m,7H),7.20(dd,J=7.8,1.8Hz,2H),6.89 –6.81(m,3H),6.17(t,J=7.3Hz,1H),4.63(td,J=7.7,2.3Hz,1H),2.84(s,3H),2.78–2.61(m,2H),2.37(d,J=2.3Hz,1H). 13 C NMR(101MHz,chloroform-d)δ149.87,144.09,142.35,139.77,129.82,129.12,128.32,128.08,127 .34,127.20,127.14,124.66,118.42,114.92,82.13,72.84,52.67,33.56,32.92.HRMS(ESI):[M+H] ⊕ calcd for C 25 H 24 N ⊕338.1903, found 339.1905. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40℃; 10% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 12.1min (major), 15.6min (minor).

[0263] Application Example 2 used the same substrate and ligands as in Application Example 1, and prepared the product under the reaction conditions shown below. The yields and enantioselectivity of the product are shown in the table below:

[0264]

[0265]

[0266]

[0267] Using the appropriate raw materials, and referring to the reaction conditions and operating methods in Application Example 1, the following compound 9b-9ak was prepared.

[0268] Application Example 3: Synthesis of Compound 9b

[0269]

[0270] Compound 9b is a yellow oily liquid in 69% yield, [α]. D 25 -8.2(c 1.5,CHCl3)for 95:5er; 1 HNMR(400MHz,chloroform-d)δ7.30(d,J=7.0Hz,4H),7.25–7.09(m,14H),6.97–6.93(m,2H),6.00(t,J=7.1Hz,1H),3.67(d,J=13.7Hz,2H), 3.48(ddd,J=9.0,6.9,2.2Hz,1H), 3.29(d,J=13.7Hz,2H), 2.49(dt,J=15.0,9.0Hz,1H), 2.39(dt,J=15.0,6.9Hz,1H), 2.24(d,J=2.2Hz,1H). 13C NMR(101MHz,chloroform-d)δ142.8,142.6,139.8,139.5,129.8,128.9,128.3,128. 2,128.1,127.3,127.0,127.0,126.1,81.4,73.1,54.6,51.9,33.7.HRMS(ESI):[M+H] ⊕ calcd for C 32 H 30 N ⊕ 428.2373, found 428.2371. HPLC analysis: ChiracelOJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40℃; 2% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 16.8min (minor), 19.6min (major).

[0271] Application Example 4: Synthesis of Compound 9c

[0272]

[0273] Compound 9c is a yellow oily liquid in 77% yield, [α]. D 25 -27.6(c 0.7,CHCl3)for 92:8er; 1 HNMR(400MHz,chloroform-d)δ7.37–7.28(m,7H),7.28–7.19(m,6H),7.12(d,J=6.5Hz,2H),6.17(t,J=7.1Hz,1H),3.63(d,J =13.2Hz,1H),3.51(td,J=7.5,2.2Hz,1H),3.45(d,J=13.2Hz,1H),2.48(t,J=7.5Hz,2H),2.31(d,J=2.2Hz,1H),2.18(s,3H). 13 C NMR(101MHz,chloroform-d)δ143.0,142.6,139.9,139.2,129.8,128.9,128.3,128.2,1 28.1,127.3,127.0,127.0,125.9,81.0,73.5,59.0,55.2,37.5,33.8.HRMS(DART):[M+H] ⊕calcd forC 26 H 26 N ⊕ 352.2060, found 352.2060. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 28.4min (minor), 32.1min (major).

[0274] Application Example 5: Synthesis of Compound 9d

[0275]

[0276] Compound 9d, a yellow liquid, 69% yield, [α] D 25 -36.0(c 1.6,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.30–7.08(m,13H),7.01(d,J=6.3Hz,2H),6.04( t,J=7.1Hz,1H),3.70(d,J=13.9Hz,1H),3.46(ddd,J=8.6,7.3,2.2Hz,1H),3.27 (d,J=13.9Hz,1H),2.46–2.33(m,3H),2.32–2.24(m,1H),2.17(d,J=2.2Hz,1H), 1.42–1.29(m,2H),1.30–1.22(m,1H),1.20–1.09(m,1H),0.77(t,J=7.3Hz,3H). 13 C NMR(101MHz,chloroform-d)δ142.7,142.7,140.0,139.9,129.8,128.9,128.2,128.1,127.3,127 .0,126.9,126.8,126.3,82.0,72.5,55.3,52.6,50.0,33.8,30.4,20.5,14.1.HRMS(DART):[M+H] ⊕ calcd for C 29 H 32 N ⊕394.2529, found 394.2532. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40°C; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 11.8min (minor), 13.2min (major).

[0277] Application Example 6: Synthesis of Compound 9e

[0278]

[0279] Compound 9e, a yellow liquid, in 65% yield, [α] D 25 -24.6(c 1.5,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.38–7.28(m,7H),7.28–7.18(m,8H),7.18–7.12(m,1H),7.12–7.07(m,4H),6.12(t,J=7.1Hz,1H),3.80(d,J=13.8Hz,1H ),3.55(ddd,J=8.3,7.8,2.2Hz,1H),3.37(d,J=13.8Hz,1H),2.67(dt,J=15 .2,7.8Hz,1H),2.58–2.41(m,5H),2.25(d,J=2.2Hz,1H),1.91–1.68(m,2H). 13 C NMR(101MHz,chloroform-d)δ142.8,142.6,142.4,139.9,139.8,129.8,128.9,128.3,128.3,128.2,128.2,128 .1,127.3,127.0,126.9,126.9,126.2,125.6,81.9,72.7,55.4,52.9,50.0,33.9,33.6,29.9.HRMS(DART):[M+H] ⊕ calcd for C 34 H 34 N ⊕456.2686, found 456.2682. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40℃; 5% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 17.4min (minor), 23.1min (major).

[0280] Application Example 7: Synthesis of Compound 9f

[0281]

[0282] Compound 9f, a yellow liquid, 45% yield, [α] D 25 -37.8(c 0.8,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.36–7.32(m,3H),7.32–7.24(m,7H),7.23–7.19(m,3H),7.13– 7.03(m,2H),6.16(t,J=7.0Hz,1H),3.81(d,J=14.9Hz,1H),3.69(d,J=14.9Hz,1H),3.64(ddd ,J=8.9,6.5,2.2Hz,1H),2.56–2.34(m,3H),2.26(d,J=2.2Hz,1H),2.16(d,J=12.5Hz,1H),1. 80–1.65(m,3H),1.60–1.52(m,1H),1.44–1.31(m,1H),1.27–1.14(m,2H),1.12–1.00(m,2H). 13 C NMR(101MHz,chloroform-d)δ142.8,142.5,141.3,140.0,129.8,128.3,128.1,128.1,127.3,126.9,126 .9,126.8,126.5,85.1,72.2,58.5,50.8,49.8,35.3,32.7,28.3,26.4,26.24,26.16.HRMS(DART):[M+H] ⊕ calcd for C 31 H 34 N ⊕420.2686, found 420.2687. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40°C; 2% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 12.4min (minor), 15.1min (major).

[0283] Application Example 8: Synthesis of Compound 9g

[0284]

[0285] Compound 9g, yellow liquid, yield 48%, [α] D 25 -28.2(c 1.1,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.04(d,J=8.2Hz,2H),6.10(t,J=7.0Hz,1H),3.72(d,J=14.7Hz,1H),3.65 –3.42(m,2H),2.89(hept,J=6.5Hz,1H),2.54–2.30(m,2H),2.19(d,J=2.2Hz,1H),1.01(t,J=6.5Hz,6H). 13 CNMR(101MHz,chloroform-d)δ142.8,142.6,141.1,140.0,129.9,128.4,128.2,128.10,128.07 ,127.3,127.0,126.9,126.7,126.6,84.9,72.5,50.5,49.1,35.2,22.3,16.9.HRMS(DART):[M+H] ⊕ calcd for C 28 H 30 N ⊕380.2373, found 380.2371. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40°C; 2% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 13.5min (minor), 14.9min (major).

[0286] Application Example 9: Synthesis of Compound 9h

[0287]

[0288] Compound 9h, yellow liquid, yield 64%, [α] D 25 -33.6(c 0.9,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.36–7.20(m,10H),7.20–7.05(m,7H),6.78–6.70(m,3H),6.16(t,J=7.3Hz,1H),4.63(ddd,J=8.9,7.4,2.3Hz, 1H), 4.56 (d, J=16.9Hz, 1H), 4.39 (d, J=16.9Hz, 1H), 2.67 (dt, J=14.7, 7.4Hz, 1H), 2.56 (ddd, J=14.7, 8.9, 7.4Hz, 1H), 2.32 (d, J=2.3Hz, 1H). 13 C NMR(101MHz,chloroform-d)δ148.4,144.1,142.3,139.7,139.6,129.7,129.0,128.34,128.30,128. 1,127.3,127.2,126.8,126.6,124.7,118.7,115.7,82.5,73.1,52.4,52.3,33.8.HRMS(DART):[M+H] ⊕ calcd for C 31 H 28 N ⊕414.2216, found414.2214. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40°C; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 14.5min (major), 15.5min (minor).

[0289] Application Example 10: Synthesis of Compound 9i

[0290]

[0291] Compound 9i, a yellow liquid, 51% yield, [α] D 25 -27.5(c 1.0,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.38–7.29(m,3H),7.28–7.05(m,11H),6.83–6.72(m,5H),6.15(t,J=7.3Hz,1H),4.60(td,J=7.7,2.3Hz,1H),4 .49(d,J=16.6Hz,1H),4.33(d,J=16.6Hz,1H),3.76(s,3H),2.66(dt,J=14.7,7.7Hz,1H),2.55(dt,J=14.7,7.7Hz,1H),2.33(d,J=2.3Hz,1H). 13 C NMR(101MHz,chloroform-d)δ158.4,148.4,144.0,142.3,139.7,131.5,129.7,128.9,128.3,128.1,1 28.0,127.3,127.1,124.8,118.8,116.0,113.8,82.6,73.1,55.2,52.4,51.8,33.8.HRMS(DART):[M+H] ⊕ calcd for C 32 H 30 ON ⊕444.2322, found 444.2322. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40℃; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 16.4min (major), 18.6min (minor).

[0292] Application Example 11: Synthesis of Compound 9j

[0293]

[0294] Compound 9j, yellow liquid, yield 61%, [α] D 25 -19.2(c 0.9,CHCl3)for 93:7er; 1 H NMR(400MHz,chloroform-d)δ7.35–7.16(m,13H),7.08–7.03(m,2H),6.83(d,J=8.1Hz,2H),6.63(d,J=8.1Hz,2H), 6.17(t,J=7.2Hz,1H),4.39(s,1H),4.38–4.17(m,3H),2.65–2.54(m,1H),2.54–2.44(m,1H),2.34(d,J=2.3Hz,1H). 13 C NMR(101MHz,chloroform-d)δ149.9,143.6,142.6,142.4,139.7,139.6,129.7,128.3,128.2,128.1 ,127.7,127.3,127.1,126.7,125.3,121.2,115.5,82.7,77.2,73.3,54.1,34.1.HRMS(DART):[M+H] ⊕ calcd forC 31 H 28 ON ⊕430.2165, found 430.2162. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40°C; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 70.9min (minor), 74.9min (major).

[0295] Application Example 12: Synthesis of Compound 9k

[0296]

[0297] Compound 9K is a yellow liquid in 58% yield, [α]. D 25 -43.1(c 1.1,CHCl3)for 91:9er; 1 H NMR(400MHz,chloroform-d)δ7.37–7.28(m,8H),7.28–7.20(m,3H),7.16(d,J=6.5Hz,2H) ,7.09(d,J=6.4Hz,2H),5.99(t,J=7.1Hz,1H),3.78(d,J=13.4Hz,1H),3.73–3.63(m,1H), 3.58(td,J=7.9,2.3Hz,1H),3.54–3.48(m,1H),3.46(d,J=13.4Hz,1H),2.75(ddd,J=14.2 ,9.8,4.8Hz,1H),2.56(dt,J=14.2,3.4Hz,1H),2.51–2.37(m,3H),2.29(d,J=2.3Hz,1H). 13 C NMR(101MHz,chloroform-d)δ143.7,142.3,139.6,138.7,129.7,129.0,128.5,128.2,128.1,1 27.4,127.2,127.1,127.1,125.1,81.3,73.1,58.7,55.3,52.7,51.8,33.6.HRMS(DART):[M+H] ⊕ calcd for C 27 H 28 N ⊕382.2165, found 382.2163. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at254nm, 40℃; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 29.9min (minor), 32.1min (major).

[0298] Application Example 13: Synthesis of Compound 9l

[0299]

[0300] Compound 9l, yellow liquid, yield 55%, [α] D 25 -32.8(c 0.8,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.39–7.35(m,2H),7.34–7.18(m,11H),7.07(d,J=6.2Hz,2H),6.09(t,J=7.1Hz,1H),3.74(d,J=13.6Hz,1H),3.44(ddd, J=8.9,7.1,2.2Hz,1H),3.31(d,J=13.6Hz,1H),2.49–2.33(m,2H),2.26(d, J=2.2Hz,1H),1.97(d,J=14.7Hz,1H),1.91(d,J=14.7Hz,1H),0.05(s,9H). 13 C NMR(101MHz,chloroform-d)δ142.7,142.6,139.9,139.7,129.8,128.9,128.2,128.1,128. 0,127.28,127.0,126.9,126.2,81.4,73.1,58.5,54.5,40.7,33.9,-1.3.HRMS(DART):[M+H] ⊕ calcd for C 29 H 34 NSi ⊕424.2455, found424.2453. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 11.8min (minor), 13.8min (major).

[0301] Application Example 14: Synthesis of Compound 9m

[0302]

[0303] Compound 9m, a yellow liquid, yield 64%, [α] D 25 -6.7(c 1.2,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.45(t,J=7.6Hz,4H),7.39–7.21(m,12H),7.21–7.14(m,2H),7.14–7.10(m,2H),6.19(t,J=7.3Hz,1H),4 .51(s,1H),3.63(td,J=7.8,2.2Hz,1H),2.52(dt,J=14.5,7.8Hz,1H),2.43(dt,J=14.5,7.8Hz,1H),2.30(d,J=2.2Hz,1H),2.06(s,3H). 13 C NMR(101MHz,chloroform-d)δ143.4,143.0,142.9,142.6,139.9,129.9,128.7,128.5,128.2,128.1,127.9 ,127.8,127.3,127.2,127.02,127.00,126.9,125.9,81.0,74.1,73.8,53.0,34.4,33.9.HRMS(DART):[M+H] ⊕ calcd for C 32 H 30 N ⊕428.2373, found428.2371. HPLC analysis: Chiracel AD-H+AD-H (the two columns were connected to each other); detected at 254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 13.5min (major), 14.8min (minor).

[0304] Application Example 15: Synthesis of Compound 9n

[0305]

[0306] Compound 9n, a yellow liquid, in 76% yield, [α] D 25 -14.3(c 0.6,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.38–7.33(m,2H),7.33–7.17(m,11H),7.08(d,J=6.2Hz,2H),6.14(t ,J=7.1Hz,1H),4.46(t,J=5.3Hz,1H),3.89(d,J=13.7Hz,1H),3.73–3.64(m,1H),3.60(ddd,J=8.4,7 .9,2.2Hz,1H),3.55–3.45(m,3H),3.45–3.35(m,1H),2.70(dd,J=14.1,5.3Hz,1H),2.58(dd,J=14.1 ,5.3Hz,1H),2.53–2.38(m,2H),2.25(d,J=2.2Hz,1H),1.18(t,J=7.0Hz,3H),1.10(t,J=7.0Hz,3H). 13 C NMR(101MHz,chloroform-d)δ142.7,142.7,139.9,139.7,129.8,129.0,128.17,128.15,128.0,127.3,1 27.0,126.9,126.2,103.0,82.0,72.6,62.7,61.8,56.7,53.6,53.5,34.0,27.7,15.3.HRMS(DART):[M+H] ⊕ calcd for C 31 H 36 O2N ⊕454.2741, found 454.2735. HPLC analysis: Chiracel AD-H+AD-H (the two columns were connected to each other); detected at 254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 15.1min (major), 16.8min (minor).

[0307] Application Example 16: Synthesis of Compound 9o

[0308]

[0309] Compound 9o, yellow liquid, 25 mg, yield 64%, [α] D 25 -46.6(c 1.3,CHCl3)for 94:6er; 1 HNMR(400MHz,chloroform-d)δ7.39–7.34(m,2H),7.34–7.20(m,11H),7.11(d,J=6.2Hz,2H ),6.17(t,J=7.1Hz,1H),3.92(d,J=13.9Hz,1H),3.81(td,J=8.3,7.9,2.2Hz,1H),3.30(d, J=13.9Hz,1H),2.69–2.40(m,3H),2.24(d,J=2.2Hz,1H),2.09(dd,J=12.9,7.6Hz,1H),0.9 0–0.78(m,1H),0.58–0.49(m,1H),0.44–0.35(m,1H),0.19–0.12(m,1H),0.08–0.01(m,1H). 13 C NMR(101MHz,chloroform-d)δ142.7,142.6,140.1,139.9,129.8,128.8,128.2,128.14,128.06,127 .3,127.0,126.9,126.8,126.4,81.9,72.7,55.2,54.9,52.4,33.8,9.7,5.7,2.3.HRMS(DART):[M+H] ⊕ calcd for C 29 H 30 N ⊕392.2373, found392.2371. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40°C; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 12.8min (minor), 14.5min (major).

[0310] Application Example 17: Synthesis of Compound 9p

[0311]

[0312] Compound 9p, a yellow liquid, in 52% yield, [α] D 25 -6.0(c 0.1,CHCl3)for 96:4er; 1 H NMR(400MHz,chloroform-d)δ7.38–7.17(m,13H),7.08(d,J=6.3Hz,2H),6.91(ddd,J=15.8,7.3,4 .2Hz,1H),6.11(t,J=7.2Hz,1H),6.05(d,J=15.8Hz,1H),4.19(q,J=7.1Hz,2H),3.75(d,J=13.8Hz, 1H),3.56(td,J=7.8,2.2Hz,1H),3.39(d,J=13.8Hz,1H),3.28(ddd,J=16.0,4.2,2.3Hz,1H),3.11 (dd,J=16.0,7.3Hz,1H),2.48(td,J=7.8,4.6Hz,2H),2.30(d,J=2.2Hz,1H),1.28(t,J=7.1Hz,3H). 13 C NMR(101MHz,chloroform-d)δ166.3,146.5,143.3,142.4,139.8,138.8,129.8,128.8,128.4,128.2,128.1, 127.3,127.2,127.1,127.0,125.4,122.8,81.1,73.4,60.3,55.3,52.7,51.5,33.8,14.2.HRMS(DART):[M+H] ⊕ calcd for C 31 H 32 O2N ⊕450.2428, found 450.2422. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40℃; 2% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 37.3min (minor), 45.5min (major).

[0313] Application Example 18: Synthesis of Compound 9q

[0314]

[0315] Compound 9q, a yellow liquid, in 67% yield, [α] D 25 -19.5(c 1.1,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.42(d,J=6.8Hz,2H),7.35–7.17(m,11H),7.07(d,J= 6.0Hz,2H),6.19(t,J=7.1Hz,1H),4.13(q,J=7.1Hz,2H),3.82(d,J=13.5Hz,1H),3. 65(ddd,J=8.4,7.9,2.2Hz,1H),3.49(d,J=13.5Hz,1H),3.30(d,J=17.0Hz,1H),3.2 3(d,J=17.0Hz,1H),2.64–2.39(m,2H),2.29(d,J=2.2Hz,1H),1.23(t,J=7.1Hz,3H). 13 C NMR(101MHz,chloroform-d)δ171.3,142.9,142.6,139.9,138.6,129.8,129.1,128.3,128.2,128.0, 127.4,127.2,127.0,126.9,125.6,81.2,73.3,60.5,55.8,53.0,52.2,33.8,14.2.HRMS(ESI):[M+H] ⊕ calcd for C 29 H 30 O2N ⊕424.2271, found 424.2264.HPLC analysis: ChiracelOJ-H column; detected at 254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 15.2min (minor), 18.4min (major).

[0316] Application Example 19: Synthesis of Compound 9r

[0317]

[0318] Compound 9r, a yellow liquid, in 43% yield, [α] D 25 -5.6(c 1.3,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.71(d,J=7.5Hz,1H),7.64(d,J=7.8Hz,1H),7.41–7.32(m,3 H),7.31–7.16(m,12H),7.02(dd,J=7.2,2.3Hz,2H),6.08(t,J=7.1Hz,1H),4.05(d,J=14.2H z,1H),3.74(t,J=14.2Hz,2H),3.60–3.51(m,1H),3.42(d,J=14.2Hz,1H),2.55(dt,J=15.9 ,8.1Hz,1H),2.45(dt,J=15.9,6.9Hz,1H),2.29(d,J=2.2Hz,1H),1.33(s,6H),1.32(s,6H). 13 C NMR(101MHz,chloroform-d)δ146.0,142.7,142.6,139.90,139.88,135.1,130.7,129.8,129.04,128.95,12 8.1,128.0,127.3,126.9,126.9,126.8,126.4,125.9,83.6,82.1,72.7,54.8,53.2,52.6,33.9,25.0,24.7. 11 B NMR(128MHz,chloroform-d)δ30.9.HRMS(DART):[M+H] ⊕ calcd for C 38 H 41 O2N 10 B ⊕553.3261, found 553.3264.

[0319] Application Example 20: Synthesis of Compound 9S

[0320]

[0321] Compound 9S, a yellow liquid, yield 67%, [α] D 25 -15.3(c 1.1,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.40–7.34(m,3H),7.33–7.17(m,11H),7.05(dd,J=7. 6,2.0Hz,2H),6.36–6.27(m,1H),6.21(d,J=3.2Hz,1H),6.11(t,J=7.1Hz,1H),3.79 (d,J=13.9Hz,1H),3.68(d,J=14.6Hz,1H),3.59(ddd,J=8.5,7.9,2.2Hz,1H),3.50( d,J=14.6Hz,1H),3.43(d,J=13.9Hz,1H),2.62–2.38(m,2H),2.30(d,J=2.2Hz,1H). 13 C NMR(101MHz,chloroform-d)δ153.0,142.8,142.7,141.9,139.9,139.3,129.8,128.8,128.3,128.2,1 28.0,127.4,127.0,126.9,125.9,110.2,108.2,81.3,73.1,54.7,52.4,47.5,33.7.HRMS(DART):[M+H] ⊕ calcd for C 30 H 28 ON ⊕ 418.2165, found 418.2161. HPLC analysis: ChiracelOJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 25.0min (minor), 29.6min (major).

[0322] Application Example 21: Synthesis of Compound 9t

[0323]

[0324] Compound 9t, a yellow liquid, yield 62%, [α] D 25 -31.3(c 0.4,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.40–7.15(m,13H),7.13–7.04(m,2H),6.12(t,J=7.2Hz,1H),5. 82(dddd,J=17.2,10.2,8.1,4.3Hz,1H),5.23(dq,J=17.2,1.7Hz,1H),5.11(dt,J=10.2,2.0Hz ,1H),3.80(d,J=13.9Hz,1H),3.61(td,J=7.9,2.2Hz,1H),3.33(d,J=13.9Hz,1H),3.19(ddt,J =14.2,4.3,2.0Hz,1H),2.91(dd,J=14.2,8.1Hz,1H),2.66–2.39(m,2H),2.27(d,J=2.2Hz,1H). 13 C NMR(101MHz,chloroform-d)δ142.8,142.6,139.9,139.6,136.5,129.8,128.8,128.2,128.2,128. 1,127.3,127.0,126.9,126.9,126.0,117.2,81.6,72.9,54.6,53.5,52.2,33.7.HRMS(DART):[M+H] ⊕ calcd for C 28 H 28 N ⊕ 378.2216, found 378.2215. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40°C; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 14.3min (minor), 16.7min (major).

[0325] Application Example 22: Synthesis of Compound 9u

[0326]

[0327] Compound 9u, a yellow liquid, yield 48%, [α] D 25 -29.8(c 1.2,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.83(d,J=8.0Hz,1H),7.58–7.50(m,1H),7.39–7.18(m,12 H),7.13–7.00(m,5H),6.88(s,1H),5.95(t,J=6.9Hz,1H),3.93(d,J=14.0Hz,1H),3.78(d ,J=13.3Hz,1H),3.70(s,3H),3.67–3.62(m,1H),3.60(d,J=14.0Hz,1H),3.34(d,J=13.3H z,1H),2.62(dt,J=16.3,8.3Hz,1H),2.52(dt,J=16.3,6.5Hz,1H),2.39(d,J=2.2Hz,1H). 13 C NMR(101MHz,chloroform-d)δ162.0,146.3,143.1,142.2,140.1,139.6,138.4,130.4,129.7,129.4,128.3,128.2,128.0,127. 4,127.2,127.1,127.0,126.1,125.5,122.3,121.7,120.3,114.2,80.5,74.0,54.9,52.5,52.4,33.4,29.3.HRMS(DART):[M+H] ⊕ calcd for C 36 H 33 ON2 ⊕ 509.2587, found 509.2585. HPLC analysis: Chiracel AD-H+AD-H (the two columns were connected to each other); detected at 254nm, 40℃; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 70.2min (major), 75.8min (minor).

[0328] Application Example 23: Synthesis of Compound 9v

[0329]

[0330] Compound 9v, a yellow liquid, 68% yield, [α] D 25 -11.1(c 0.7,CHCl3)for 91:9er; 1 H NMR(400MHz,chloroform-d)δ7.41–7.28(m,3H),7.28–7.15(m,9H),6.81–6.73(m,3H),6.16(t,J=7.3Hz,1H),4.45(td,J=7.7,2.3Hz,1H),3 .30–3.11(m,2H),2.69–2.52(m,2H),2.33(d,J=2.3Hz,1H),1.66–1.54(m,1H),1.52–1.40(m,1H),1.35–1.23(m,2H),0.89(t,J=7.4Hz,3H). 13 C NMR(101MHz,chloroform-d)δ148.2,143.9,142.4,139.8,129.8,129.0,128.3,128.1,127.3,127 .2,127.1,124.9,118.2,115.6,82.9,72.7,52.8,47.3,33.9,30.4,20.4,13.9.HRMS(DART):[M+H] ⊕ calcd for C 28 H 30 N ⊕ 380.2373, found 380.2373. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at254nm, 40℃; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 11.4min (major), 12.3min (minor).

[0331] Application Example 24: Synthesis of Compound 9w

[0332]

[0333] Compound 9w, yellow liquid, 26 mg, yield 70%, [α] D 25-12.3(c 0.9,CHCl3)for 92:8er; 1 HNMR(400MHz,chloroform-d)δ7.40–7.29(m,3H),7.29–7.19(m,5H),7.19–7.14(m,4H),6.89(dd,J=16.5,7.8Hz,3H),6.13(t,J=7.3Hz, 1H),4.42(td,J=7.7,2.3Hz,1H),3.75–3.62(m,2H),3.55–3.27(m,2H),2.76–2.52(m,2H),2.40(d,J=2.3Hz,1H),1.89(t,J=5.9Hz,1H). 13 C NMR(101MHz,chloroform-d)δ147.9,144.4,142.2,139.6,129.7,129.2,128.3,128.1,127.2 9,127.25,127.2,124.4,120.4,117.9,82.7,73.5,59.9,54.1,49.7,33.8.HRMS(ESI):[M+H] ⊕ calcd for C 26 H 26 ON ⊕ 368.2009, found 368.2011. HPLC analysis: Chiracel AD-H+AD-H (the two columns were connected to each other); detected at254nm, 40℃; 10% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 22.5min (minor), 24.4min (major).

[0334] Application Example 25: Synthesis of Compound 9x

[0335]

[0336] Compound 9x, yellow liquid, 30 mg, yield 85%, [α] D 25 -37.1(c 1.0,CHCl3)for 93:7er; 1HNMR(400MHz,chloroform-d)δ7.42–7.36(m,2H),7.36–7.30(m,1H),7.30–7.15(m,7H),7.10–7.03(m,2H),6.70(t,J=7.3Hz,1H),6.50(d,J=8 .0Hz,1H),6.22(t,J=7.1Hz,1H),4.39(td,J=7.9,2.2Hz,1H),3.43–3.19(m,2H),3.03–2.83(m,2H),2.73–2.54(m,2H),2.17(d,J=2.2Hz,1H). 13 C NMR(101MHz,chloroform-d)δ150.7,144.0,142.3,139.8,130.5,129.8,128.3,128.1,127.4,127.2 2,127.18,127.17,124.8,124.5,118.7,108.2,81.4,72.5,49.0,47.9,33.5,28.2.HRMS(ESI):[M+H] ⊕ calcd for C 26 H 24 N ⊕ 350.1903, found350.1902. HPLC analysis: Chiracel AD-H+AD-H (the two columns were connected to each other); detected at 254nm, 40°C; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 15.1min (minor), 17.4min (major).

[0337] Application Example 26: Synthesis of Compound 9y

[0338]

[0339] Compound 9y, a yellow liquid, in 64% yield, [α] D 25 -26.9(c 0.9,CHCl3)for 93:7er; 1H NMR(400MHz,chloroform-d)δ7.40–7.29(m,3H),7.28–7.12(m,9H),6.81–6.70(m,3H),6.17(t,J=7.3Hz,1H),5.85(ddt,J=17.3,10.4,5.5Hz,1H),5.19(dd ,J=17.3,1.9Hz,1H),5.09(dd,J=10.4,1.9Hz,1H),4.52(ddd,J=9.2,7.1,2.4 Hz,1H),3.90(tt,J=5.5,1.9Hz,2H),2.73–2.52(m,2H),2.33(d,J=2.4Hz,1H). 13 C NMR(101MHz,chloroform-d)δ148.3,144.1,142.3,139.7,135.9,129.8,128.9,128.3,128.1,12 7.3,127.2,127.1,124.7,118.4,116.1,115.3,82.6,72.9,52.0,50.6,33.9.HRMS(DART):[M+H] ⊕ calcd for C 27 H 26 N ⊕ 364.2060, found364.2059. HPLC analysis: Chiracel AD-H+AD-H (the two columns were connected to each other); detected at 254nm, 40℃; 2% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 12.7min (minor), 13.7min (major).

[0340] Application Example 27: Synthesis of Compound 9z

[0341]

[0342] Compound 9z, a yellow liquid, 84% yield, [α] D 25 -62.3(c 1.5,CHCl3)for 93:7er; 1H NMR(400MHz,chloroform-d)δ8.34(d,J=8.3Hz,1H),7.86(d,J=7.3Hz,1H),7.79(d, J=8.1Hz,1H),7.56–7.34(m,4H),7.32–7.22(m,3H),7.22–7.17(m,3H),7.10–6.99( m,4H),6.01(t,J=7.0Hz,1H),4.08(d,J=12.9Hz,1H),3.89(d,J=12.9Hz,1H),3.53( ddd,J=9.0,6.9,2.2Hz,1H),2.56–2.37(m,2H),2.36(d,J=2.2Hz,1H),2.21(s,3H). 13 C NMR(101MHz,chloroform-d)δ142.6,142.4,139.9,134.4,133.9,132.6,129.8,128.4,128.1,128.0,127.7,127 .3,126.94,126.85,126.0,125.8,125.6,125.13,125.11,80.9,73.7,58.2,54.6,36.7,33.6.HRMS(DART):[M+H] ⊕ calcd for C 30 H 28 N ⊕ 402.2216, found402.2215. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40°C; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 24.7min (minor), 26.0min (major).

[0343] Application Example 28: Synthesis of Compound 9aa

[0344]

[0345] Compound 9aa, a yellow liquid, 53% yield, [α] D 25 -41.2(c 0.2,CHCl3)for 92:8er; 1H NMR(400MHz,chloroform-d)δ7.40–7.27(m,4H),7.27–7.20(m,4H),7.20–7.17(m,2H),6.20(t,J=7.1Hz,1H),3.56(td,J= 7.8,2.2Hz,1H),2.45(t,J=7.5Hz,2H),2.41–2.25(m,4H),2.19(d,J=2.2Hz,1H),1.52–1.33(m,4H),0.86(t,J=7.4Hz,6H). 13 C NMR(101MHz,chloroform-d)δ142.8,142.6,140.1,129.9,128.2,128.0,127.3,1 27.0,126.9,126.5,82.7,72.0,53.5,53.1,33.9,21.6,11.9.HRMS(DART):[M+H] ⊕ calcd for C 24 H 30 N ⊕ 332.2373, found 332.2373. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 11.5min (minor), 12.1min (major).

[0346] Application Example 29: Synthesis of Compound 9ab

[0347]

[0348] Compound 9ab, a yellow liquid, 55% yield, [α] D 25 -9.0(c 0.6,CHCl3)for 93:7er; 1H NMR(400MHz,chloroform-d)δ7.41–7.35(m,2H),7.35–7.31(m,1H),7.30–7.21(m,5H),7.18(d,J=6.8Hz,2H),6.16(t,J=7.1Hz,1H ),4.72–4.52(m,4H),3.89(p,J=6.8Hz,1H),3.34(td,J=7.5,2.2Hz,1H),2.43(t,J=7.5Hz,2H),2.27(d,J=2.2Hz,1H),2.11(s,3H). 13 C NMR(101MHz,chloroform-d)δ143.6,142.4,139.8,129.8,128.3,128.1,127.3,127 .2,127.1,125.1,80.7,76.0,75.9,73.9,56.6,53.6,33.4,32.5.HRMS(DART):[M+H] ⊕ calcd forC 22 H 24 ON ⊕ 318.1852, found 318.1853. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40°C; 5% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 24.6min (minor), 26.7min (major).

[0349] Application Example 30: Synthesis of Compound 9ac

[0350]

[0351] Compound 9ac, a yellow liquid, in 66% yield, [α] D 25 -9.3(c 0.7,CHCl3)for 92:8er; 1H NMR(400MHz,chloroform-d)δ7.40–7.34(m,2H),7.32–7.14(m,8H),6.18(t,J=7.2 Hz,1H),5.80(dddd,J=17.3,10.1,7.3,5.6Hz,1H),5.20(dd,J=17.3,1.7Hz,1H),5 .12(d,J=10.1Hz,1H),3.57(td,J=7.8,2.3Hz,1H),3.08(dd,J=13.5,5.6Hz,1H),2 .97(dd,J=13.5,7.3Hz,1H),2.54–2.39(m,2H),2.29(d,J=2.3Hz,1H),2.17(s,3H). 13 C NMR(101MHz,chloroform-d)δ143.1,142.6,140.0,136.0,129.8,128.2,128.0,127.3 ,127.02,126.97,125.7,117.4,81.0,73.6,57.9,55.4,37.3,33.7.HRMS(DART):[M+H] ⊕ calcd for C 22 H 24 N ⊕ 302.1903, found 302.1903. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 30°C; 2% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 13.1min (minor), 13.8min (major).

[0352] Application Example 31: Synthesis of Compound 9ad

[0353]

[0354] Compound 9ad, a yellow liquid, yield 48%, [α] D 25 -28.7(c 0.4,CHCl3)for 93:7er; 1H NMR(400MHz,chloroform-d)δ7.39–7.33(m,2H),7.33–7.15(m,8H),6.19(t,J=7.1Hz,1H),5.76(dddd,J=17.2, 10.1,7.2,4.6Hz,1H),5.16(dq,J=17.2,1.8Hz,1H),5.01(dq,J=10.1,1.6Hz,1H),3.65(td,J=7.8,2.3Hz,1H), 3.24(ddd,J=15.4,4.6,1.8Hz,1H),3.16(dd,J=15.4,7.2Hz,1H),2.59–2.49(m,1H),2.46–2.37(m,2H),2.22(d ,J=2.3Hz,1H),2.05–1.98(m,1H),1.81–1.71(m,2H),1.69–1.62(m,1H),1.62–1.54(m,1H),1.37–0.99(m,5H). 13 C NMR(101MHz,chloroform-d)δ142.8,142.5,140.1,138.5,129.9,128.13,128.05,127.3,126.9,126. 8,126.7,115.6,85.1,72.1,59.0,49.9,49.8,35.4,32.5,28.4,26.4,26.3,26.2.HRMS(DART):[M+H] ⊕ calcd for C 27 H 32 N ⊕ 370.2529, found 370.2528. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 10.9min (minor), 12.0min (major).

[0355] Application Example 32: Synthesis of Compound 9ae

[0356]

[0357] Compound 9ae, a yellow liquid, yield 64%, [α] D 25-27.0(c 0.6,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.39–7.33(m,2H),7.33–7.28(m,1H),7.28–7.20(m,5H),7 .20–7.14(m,2H),6.16(t,J=7.2Hz,1H),5.78(dddd,J=17.2,10.2,7.9,4.5Hz,2H),5.19 (dd,J=17.2,1.6Hz,2H),5.10(d,J=10.2Hz,2H),3.68(td,J=7.5,2.2Hz,1H),3.26–3.17 (m,2H),2.87(dd,J=14.2,7.9Hz,2H),2.46(td,J=7.5,1.5Hz,2H),2.24(d,J=2.2Hz,1H). 13 CNMR(101MHz,chloroform-d)δ142.9,142.7,140.0,136.5,129.9,128.2,128.1,1 27.3,127.0,126.9,126.0,117.1,81.8,72.9,53.6,52.5,33.7.HRMS(ESI):[M+H] ⊕ calcd forC 24 H 26 N ⊕ 328.2060, found 328.2054. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 12.8min (minor), 13.5min (major).

[0358] Application Example 33: Synthesis of Compound 9af

[0359]

[0360] Compound 9af, a yellow liquid, 58% yield, [α] D 25 -27.7(c 1.4,CHCl3)for 8:1dr; 1H NMR(400MHz,chloroform-d)δ7.41–7.35(m,2H),7.34–7.29(m,1H),7.29–7.1 5(m,8H),7.00–6.93(m,1H),6.93–6.86(m,1H),6.29(s,1H),6.11(t,J=7.1Hz ,1H),5.17(dd,J=7.5,3.6Hz,1H),3.65(td,J=7.7,2.2Hz,1H),2.77–2.68(m, 2H),2.58–2.43(m,2H),2.30(d,J=2.2Hz,1H),2.18(s,3H),2.02–1.90(m,2H). 13 C NMR(101MHz,chloroform-d)δ149.5,144.1,142.4,139.8,129.8,128.3,128.1,127.4,127.2,127 .1,126.6,124.5,123.8,122.4,80.1,74.2,71.7,57.3,54.2,35.9,34.4,33.5.HRMS(DART):[M+H] ⊕ calcd for C 26 H 28 ONS ⊕ 402.1886, found 402.1880. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40°C; 2% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 16.8min (minor), 19.6min (major).

[0361] Application Example 34: Synthesis of Compound 9ag

[0362]

[0363] Compound 9 ag, white solid, yield 58%, [α] D 25 -139.3(c 1.0,CHCl3)for 15:1dr; 1H NMR(400MHz,chloroform-d)δ7.39–7.17(m,7H),7.13(d,J=7.3Hz,2H),7.03(d,J=7.1Hz ,2H),6.42(d,J=9.0Hz,1H),5.98(d,J=6.8Hz,1H),5.89(t,J=6.9Hz,1H),3.93(d,J=3.8 Hz,2H),3.29–3.21(m,1H),2.97(s,1H),2.87–2.66(m,3H),2.45(d,J=8.9Hz,2H),2.42– 2.32(m,2H),2.28(d,J=2.2Hz,1H),1.87(d,J=12.7Hz,1H),1.78(dt,J=12.7,3.1Hz,1H). 13 C NMR(101MHz,chloroform-d)δ163.4,151.5,143.2,142.1,139.8,138.5,129.8,128.2,128.0,127.2,127.1 ,127.0,124.7,116.8,104.4,80.5,73.9,60.2,56.9,52.5,50.0,35.7,33.0,27.6,25.9.HRMS(DART):[M+H] ⊕ calcd for C 29 H 29 ON2 ⊕ 421.2274, found 421.2269. HPLC analysis: Chiracel OJ-H+OJ-H (the two columns were connected to each other); detected at 254nm, 40°C; 2% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 16.8min (minor), 19.6min (major).

[0364] Application Example 35: Synthesis of Compound 9ah

[0365]

[0366] Compound 9ah, a yellow liquid, 59% yield, [α] D 25 -15.8(c 1.2,CHCl3)for 95:5er; 11H NMR (400 MHz, chloroform-d) δ 7.36–7.14 (m, 16H), 7.08–7.03 (m, 2H), 7.03–6.94 (m, 2H), 6.71 (d, J = 8.9 Hz, 1H), 6.64 (dd, J = 8.9, 2.9 Hz, 1H), 6.13 (t, J = 7.2 Hz, 1H), 5.01 (s, 2H), 4.40 (d, J = 16.4 Hz, 1H), 4.39–4.33 (m, 1H), 4.26 (d, J = 16.4 Hz, 1H), 2.69–2.47 (m, 2H), 2.36 (d, J = 2.2 Hz, 1H). 13 13C NMR (101 MHz, chloroform-d) δ 163.00 (d, J = 246.2 Hz), 148.0, 144.1, 143.7, 142.3, 139.7 (d, J = 7.3 Hz), 139.6, 139.0, 130.0 (d, J = 8.2 Hz), 129.7, 128.4, 128.3, 128.1, 127.31, 127.27, 127.17, 127.15, 126.9, 124.6, 123.9, 122.5 (d, J = 2.9 Hz), 120.4, 117.4, 115.5, 114.7 (d, J = 21.2 Hz), 114.0 (d, J = 22.1 Hz), 82.2, 73.6, 71.0, 53.6, 53.4, 34.0. 19 19F NMR (376 MHz, chloroform-d) δ -112.84. HRMS (DART): [M+H] ⊕ calcd for C 38 H 32 ONClF ⊕ 572.2151, found 572.2142. HPLC analysis: Chiracel AD-H + AD-H (the two columns were connected to each other); detected at 254 nm, 40 °C; 3% i-PrOH in n-hexane; flow = 0.7 mL / min; Retention time: 29.1 min (major), 31.0 min (minor).

[0367] Application Example 36: Synthesis of Compound 9ai

[0368]

[0369] Compound 9ai, a yellow liquid, 69% yield, [α] D 25 -23.8(c 0.9,CHCl3)for 92:8er; 1 H NMR(400MHz,chloroform-d)δ7.26–7.18(m,3H),7.16–7.09(m,4H),7.03(d,J=7.6Hz,1H),6 .99–6.93(m,2H),6.92–6.87(m,2H),6.83–6.71(m,5H),6.10(t,J=7.3Hz,1H),4.60(td,J=7 .6,2.3Hz,1H),4.49(d,J=16.6Hz,1H),4.33(d,J=16.6Hz,1H),3.76(s,3H),2.64(dt,J=14. 7,7.5Hz,1H),2.54(dt,J=14.7,7.5Hz,1H),2.32(d,J=2.3Hz,1H),2.31(s,3H),2.29(s,3H). 13 C NMR(101MHz,chloroform-d)δ158.4,148.4,144.3,142.4,139.7,137.8,137.6,131.5,130.3,128.9,128.1,128.0,127.9,127.8 7,127.86,127.8,126.8,124.5,124.4,118.7,115.9,113.8,82.7,73.0,55.2,52.5,51.7,33.9,21.43,21.41.HRMS(DART):[M+H] ⊕ calcd for C 34 H 34 ON ⊕ 472.2635, found 472.2626. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40℃; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 14.8min (major), 16.0min (minor).

[0370] Application Example 37: Synthesis of Compound 9aj

[0371]

[0372] Compound 9aj, a yellow liquid, 74% yield, [α] D 25 -13.3(c 1.3,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.38(d,J=6.9Hz,4H),7.29(t,J=7.4Hz,4H),7.25–7.15(m,4H ),6.81(dt,J=8.1,2.9Hz,4H),6.62(d,J=7.6Hz,1H),6.58(t,J=2.1Hz,1H),6.20–6.01(m,1 H),3.78(s,3H),3.75(d,J=13.7Hz,2H),3.63(s,3H),3.57(ddd,J=9.0,6.7,2.2Hz,1H),3.3 6(d,J=13.7Hz,2H),2.63–2.52(m,1H),2.45(dt,J=15.2,6.5Hz,1H),2.32(d,J=2.2Hz,1H). 13 C NMR(101MHz,chloroform-d)δ159.50,159.46,143.8,142.5,141.1,139.5,129.2,129.0,128.9,128.3,127.0, 126.3,122.2,119.8,114.8,113.1,113.0,112.3,81.4,73.0,55.2,55.1,54.6,51.8,33.6.HRMS(DART):[M+H] ⊕ calcd for C 34 H 34 O2N ⊕ 488.2584, found 488.2577. HPLC analysis: Chiracel AD-H+AD-H (the two columns were connected to each other); detected at 254nm, 40°C; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 14.9min (minor), 20.8min (major).

[0373] Application Example 38: Synthesis of Compound 9ak

[0374]

[0375] Compound 9ak, yellow liquid, yield 63%, [α] D 25 -11.0 (c 1.1, CHCl3) for 93:7 er; 1 H NMR (400 MHz, chloroform-d) δ 7.36 (d, J = 7.0 Hz, 4H), 7.30 (t, J = 7.3 Hz, 4H), 7.27–7.21 (m, 2H), 7.15–7.08 (m, 2H), 7.01–6.90 (m, 6H), 5.99 (t, J = 7.1 Hz, 1H), 3.74 (d, J = 13.7 Hz, 2H), 3.53 (ddd, J = 8.9, 7.1, 2.2 Hz, 1H), 3.37 (d, J = 13.7 Hz, 2H), 2.51 (dt, J = 14.6, 8.9 Hz, 1H), 2.42 (dt, J = 14.6, 7.1 Hz, 1H), 2.34 (d, J = 2.2 Hz, 1H). 13 C NMR (101 MHz, chloroform-d) δ 162.1 (d, J = 246.5 Hz), 161.9 (d, J = 246.3 Hz), 140.9, 139.4, 138.5 (d, J = 3.1 Hz), 135.4 (d, J = 3.3 Hz), 131.3 (d, J = 7.9 Hz), 128.8, 128.7 (d, J = 7.9 Hz), 128.3, 127.0, 126.2, 115.2 (d, J = 27.8 Hz), 115.0 (d, J = 27.9 Hz), 81.2, 73.2, 54.7, 51.9, 33.7. 19 F NMR (376 MHz, chloroform-d) δ -115.02, -115.64. HRMS (DART): [M+H] ⊕ calcd for C 32 H 28 NF2 ⊕ 464.2184, found 464.2181. HPLC analysis: Chiracel AD-H + AD-H (the two columns were connected to each other); detected at 254 nm, 40 °C; 1% i-PrOH in n-hexane; flow = 0.7 mL / min; Retention time: 14.2 min (major), 15.5 min (minor).

[0376] Application Example 39: Asymmetric ring-opening propargyl alkylation reaction catalyzed by copper catalyst and chiral PPBOX ligand

[0377]

[0378] Under nitrogen protection, Cu(CH3CN)4PF6 (3.7 mg, 0.010 mmol), chiral ligand 7j (14 mg, 0.030 mmol), and PhOMe (0.20 mL) were added to a 4 mL reaction flask, and the reaction was stirred at room temperature for 10 min. Then, substrate 9a (70 mg, 0.20 mmol), carbon nucleophile 12a (0.11 g, 0.60 mmol), pentamethylpiperidine (62 mg, 0.40 mmol), Bi(OTf)3 (13 mg, 0.020 mmol, 10 mol%), and PhOMe (0.80 mL) were added sequentially to the reaction. The reaction was stirred at 50 °C for 72 h. After the reaction was complete, the reaction solution was concentrated, and the target product 13a was obtained by column chromatography.

[0379] Compound 13a, yellow liquid, yield 59%, [α] D 25 -2.4(c 1.7,CHCl3)for 92:8er; 1 H NMR(400MHz,chloroform-d)δ7.82(d,J=7.0Hz,2H),7.47(t,J=7.4Hz,1H),7.35(t,J=7.7Hz,2H),7.29–7.11(m,8H),7.05(d,J =6.2Hz,2H),6.17(t,J=7.4Hz,1H),3.24–3.08(m,2H),2.97(dd,J=16.7,6.2Hz,1H),2.53–2.20(m,2H),2.03(d,J=2.4Hz,1H). 13 C NMR(101MHz,chloroform-d)δ197.28,143.94,142.37,139.81,136.84,133.15,129.85,128.56,128.22, 128.10,128.08,127.29,127.12,127.06,125.88,86.39,69.98,43.14,34.34,27.21.HRMS(DART):[M+H] ⊕ calcd for C 26 H 23 O ⊕351.1743, found 351.1743. HPLC analysis: Chiracel AD-H+AD-H (the two columns were connected to each other); detected at 254nm, 40℃; 5% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 19.6min (minor), 21.1min (major).

[0380] Using the appropriate raw materials, and referring to the reaction conditions and operating methods in Application Example 39, the following compounds 13b-13j were prepared.

[0381] Application Example 40: Synthesis of Compound 13b

[0382]

[0383] Compound 13b, a yellow liquid in 55% yield, [α] D 25 -3.1(c 1.9,CHCl3)for 92:8er; 1 H NMR(400MHz,chloroform-d)δ7.72(d,J=8.3Hz,2H),7.28–7.19(m,3H),7.19–7.11(m,7H),7.05(dd,J=8.0,1.7Hz,2H),6.16(t,J=7.4Hz,1H), 3.17(qd,J=6.8,2.4Hz,1H),3.09(dd,J=16.8,6.8Hz,1H),2.94(dd,J=16.8,6.8Hz,1H),2.39–2.32(m,2H),2.31(s,3H),2.02(d,J=2.4Hz,1H). 13 C NMR(101MHz,chloroform-d)δ196.9,143.9,143.9,142.4,139.8,134.4,129.9,129.2,128. 2,128.1,127.3,127.1,127.0,126.0,86.5,69.9,43.0,34.4,27.3,21.6.HRMS(DART):[M+H] ⊕ calcd for C 27 H 25 O ⊕365.1900, found 365.1899. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40℃; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 19.7min (minor), 20.5min (major).

[0384] Application Example 41: Synthesis of Compound 13c

[0385]

[0386] Compound 13c, a yellow liquid, 55% yield, [α] D 25 -3.7(c 1.6,CHCl3)for 91:9er; 1 H NMR(400MHz,chloroform-d)δ7.81(d,J=8.9Hz,2H),7.28–7.12(m,8H),7.05(dd,J=8.0,1.6Hz,2H),6.83(d,J=8.9Hz,2H),6.16(t,J=7.4Hz,1H) ,3.78(s,3H),3.18(pd,J=6.8,2.4Hz,1H),3.07(dd,J=16.7,6.8Hz,1H),2.91(dd,J=16.7,6.8Hz,1H),2.42–2.25(m,2H),2.02(d,J=2.4Hz,1H). 13 C NMR(101MHz,chloroform-d)δ195.8,163.6,143.8,142.4,139.8,130.4,130.0,129.9,128.2,1 28.1,127.3,127.1,127.0,126.0,113.7,86.6,69.9,55.4,42.8,34.4,27.3.HRMS(DART):[M+H] ⊕ calcd for C 27 H 25 O2 ⊕381.1849, found381.1845. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40℃; 5% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 19.6min (minor), 21.1min (major).

[0387] Application Example 42: Synthesis of Compound 13d

[0388]

[0389] Compound 13d, a yellow liquid, 50% yield, [α] D 25 -2.3(c 2.3,CHCl3)for 92:8er; 1 H NMR(400MHz,chloroform-d)δ7.75(d,J=8.3Hz,2H),7.28–7.11(m,10H),7.08–7.03(m,2H),6.16(t,J=7.4Hz,1H),3.18(ddt,J=8.5,6.5,2.4Hz,1H) ,3.10(dd,J=16.9,6.5Hz,1H),2.95(dd,J=16.9,6.5Hz,1H),2.61(q,J=7. 6Hz,2H),2.43–2.26(m,2H),2.02(d,J=2.4Hz,1H),1.17(t,J=7.6Hz,3H). 13 C NMR(101MHz,chloroform-d)δ197.0,150.2,143.9,142.4,139.8,134.6,129.9,128.3,128.2,128.0 9,128.05,127.3,127.1,127.0,126.0,86.5,69.9,43.0,34.4,28.9,27.2,15.1.HRMS(DART):[M+H] ⊕ calcd for C 28 H 27 O ⊕379.2056, found 379.2054. HPLC analysis: Chiracel AD-H+AD-H (the two columns were connected to each other); detected at 254nm, 40℃; 3% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 28.3min (minor), 29.7min (major).

[0390] Application Example 43: Synthesis of Compound 13e

[0391]

[0392] Compound 13e, a yellow liquid, yield 46%, [α] D 25 -4.0(c 1.5,CHCl3)for 92:8er; 1 H NMR(400MHz,chloroform-d)δ7.88–7.79(m,2H),7.29–7.11(m,8H),7.09–6.97(m,4H),6.16(t,J=7.4Hz,1H),3.16(qd, J=6.5,2.4Hz,1H),3.09(dd,J=16.8,6.5Hz,1H),2.93(dd,J=16.8,6.5Hz,1H),2.41–2.26(m,2H),2.03(d,J=2.4Hz,1H). 13 C NMR(101MHz,chloroform-d)δ195.7,165.8(d,J=255.0Hz),144.0,142.3,139.8,133.3(d,J=3.2Hz),130.7(d,J =9.3Hz),129.8,128.2,128.1,127.3,127.14,127.07,125.7,115.6(d,J=21.9Hz),86.2,70.1,43.0,34.3,27.3. 19 F NMR(376MHz,chloroform-d)δ-105.08.HRMS(DART):[M+H] ⊕ calcd for C 26 H 22 OF ⊕369.1649, found 369.1649. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40℃; 2% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 24.2min (minor), 24.9min (major).

[0393] Application Example 44: Synthesis of Compound 13f

[0394]

[0395] Compound 13f, a yellow liquid, yield 67%, [α] D 25 -5.1(c 2.2,CHCl3)for 91:9er; 1 H NMR(400MHz,chloroform-d)δ7.74(d,J=8.5Hz,2H),7.32(d,J=8.6Hz,2H),7.27–7.10(m,8H),7.04(d,J=6.0Hz,2H),6.15(t,J=7.4Hz,1H ),3.16(qd,J=12.8,6.4,2.3Hz,1H),3.08(dd,J=16.9,6.4Hz,1H),2.91(dd,J=16.9,6.4Hz,1H),2.49–2.23(m,2H),2.03(d,J=2.3Hz,1H). 13 C NMR(101MHz,chloroform-d)δ196.1,144.1,142.3,139.8,139.7,135.1,129.8,129.5,128.9 ,128.2,128.1,127.3,127.2,127.1,125.7,86.2,70.2,43.1,34.3,27.2.HRMS(DART):[M+H] ⊕ calcd for C 26 H 22 OCl ⊕385.1354, found 385.1352. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40℃; 1% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 40.4min (major), 44.4min (minor).

[0396] Application Example 45: Synthesis of Compound 13g

[0397]

[0398] Compound 13g, yellow liquid, yield 60%, [α] D 25 -5.1(c 2.0,CHCl3)for 91:9er; 1 H NMR(400MHz,chloroform-d)δ7.67(d,J=8.6Hz,2H),7.50(d,J=8.6Hz,2H),7.29–7.11(m,8H),7.04(dd,J=7.9,1.5Hz,2H),6.15(t,J=7.4 Hz,1H),3.16(pd,J=6.6,2.4Hz,1H),3.07(dd,J=16.9,6.6Hz,1H),2.91(dd,J=16.9,6.6Hz,1H),2.40–2.26(m,2H),2.03(d,J=2.4Hz,1H). 13 C NMR(101MHz,chloroform-d)δ196.3,144.1,142.3,139.7,135.5,131.9,129.8,129.6,128.4 ,128.2,128.1,127.3,127.2,127.1,125.7,86.1,70.2,43.0,34.3,27.2.HRMS(DART):[M+H] ⊕ calcd for C 26 H 22 OBr ⊕429.0849, found 429.0845. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40°C; 5% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 19.6min (major), 21.1min (minor).

[0399] Application Example 46: Synthesis of Compound 13h

[0400]

[0401] Compound 13h, yellow liquid, yield 65%, [α] D 25 -0.3(c 1.9,CHCl3)for 92:8er; 1 H NMR(400MHz,chloroform-d)δ7.74(td,J=7.6,1.9Hz,1H),7.47–7.37(m,1H),7.29–7.09(m,9H),7.09–6.97( m,3H),6.16(t,J=7.4Hz,1H),3.20–3.07(m,2H),3.06–2.96(m,1H),2.42–2.23(m,2H),2.02(d,J=2.2Hz,1H). 13 CNMR(101MHz,chloroform-d)δ195.6,161.9(d,J=254.4Hz),143.9,142.4,139.8,134.6(d,J=9.0Hz),130.7,130.7,12 9.8,128.2,128.1,127.3,127.1,127.0,125.9,124.5(d,J=3.3Hz),116.6(d,J=23.8Hz),86.3,69.9,48.1,34.3,27.0. 19 F NMR(376MHz,chloroform-d)δ-109.21.HRMS(DART):[M+H] ⊕ calcd forC 26 H 22 OF ⊕369.1649, found 369.1648. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40℃; 5% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 14.8min (minor), 16.2min (major).

[0402] Application Example 47: Synthesis of Compound 13i

[0403]

[0404] Compound 13i, a yellow liquid, 56% yield, [α] D 25 -3.2(c 2.0,CHCl3)for 91:9er; 1 H NMR(400MHz,chloroform-d)δ7.77(t,J=1.9Hz,1H),7.68(dt,J=7.8,1.4Hz,1H),7.48–7.39(m,1H),7.34–7.10(m,9H),7.08–6.99(m,2H),6.15(t ,J=7.4Hz,1H),3.15(qd,J=6.5,2.4Hz,1H),3.08(dd,J=17.0,6.5Hz,1H),2.93(dd,J=17.0,6.5Hz,1H),2.42–2.26(m,2H),2.04(d,J=2.4Hz,1H). 13 C NMR(101MHz,chloroform-d)δ196.0,144.1,142.3,139.7,138.3,135.0,133.1,129.9,129.8,128.3 ,128.2,128.1,127.3,127.2,127.1,126.1,125.6,86.1,70.2,43.2,34.2,27.2.HRMS(DART):[M+H] ⊕ calcd for C 26 H 22 OCl ⊕385.1354, found385.1355. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40°C; 5% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 34.5min (minor), 36.0min (major).

[0405] Application Example 48: Synthesis of Compound 13j

[0406]

[0407] Compound 13j, yellow liquid, yield 49%, [α] D 25 +1.1(c 1.2,CHCl3)for 92:8er; 1 H NMR(400MHz,chloroform-d)δ7.58(dd,J=3.9,1.2Hz,1H),7.54(dd,J=4.9,1.2Hz,1H),7.29–7.11(m,8H),7.08–6.99(m,3H),6.14(t,J=7. 4Hz,1H),3.17(qd,J=6.8,2.4Hz,1H),3.04(dd,J=16.4,6.8Hz,1H),2.90(dd,J=16.4,6.8Hz,1H),2.44–2.26(m,2H),2.03(d,J=2.4Hz,1H). 13 C NMR(101MHz,chloroform-d)δ190.2,144.2,144.0,142.4,139.8,133.8,132.0,129.8,128.2, 128.1,128.0,127.3,127.13,127.08,125.7,86.0,70.2,43.8,34.4,27.5.HRMS(DART):[M+H] ⊕ calcd for C 24 H 21 OS ⊕357.1308, found 357.1306. HPLC analysis: Chiracel OD-H+OD-H (the two columns were connected to each other); detected at 254nm, 40℃; 5% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 23.0min (minor), 24.9min (major).

[0408] Application Example 49: Asymmetric propargyl olefin oxidation reaction catalyzed by copper catalyst and chiral PPBOX ligand

[0409] Preparation of compound 14a

[0410]

[0411] Under nitrogen protection, 24a (0.55 g, 2.2 mmol), K₂CO₃ (2.0 equiv, 0.62 g), anhydrous ethanol (4.5 mL), and 25 (2.0 equiv, 0.7 mL) were sequentially added to a 50 mL reaction flask. The reaction mixture was stirred at room temperature and monitored by TLC until substrate 24a disappeared. The reaction solution was concentrated to remove ethanol, then saturated aqueous solution of NaHCO₃ was added, followed by extraction with ethyl acetate, concentration, and column chromatography (petroleum ether:ethyl acetate = 5:1) to give product 14a (61% yield, 0.33 g). It was a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.96–7.87(m,2H),7.61–7.53(m,1H),7.51–7.41(m,2H),4.17–3.91(m,2H),2.8 3–2.69(m,1H),2.04(dtd,J=9.4,4.7,1.9Hz,1H),1.77(s,1H),1.63–1.59(m,1H),1.02–0.90(m,3H). 13 C NMR(101MHz,chloroform-d)δ192.9,191.8,169.8,167.9,137.0,136.6,133.1,132.9,128.6,128.6,128.4, 128.2,79.8,79.5,69.3,68.6,61.8,61.7,40.9,39.0,22.1,20.6,16.8,14.5,13.8,13.6.HRMS(ESI):[M+H] ⊕ calcd for C 15 H 15O3 ⊕ 243.1016, found 243.1018.

[0412]

[0413] Under nitrogen protection, Cu(CH3CN)4PF6 (1.5 mg, 0.0040 mmol), chiral ligand 7k (6.4 mg, 0.0012 mmol), and dry n-butanol (0.10 mL) were added to a 4 mL reaction flask. The reaction was stirred at room temperature for 10 min. Then, LiOTf (39 mg, 0.25 mmol), dry n-butanol (0.20 mL), substrate 14a (24 mg, 0.10 mmol), and Et2NMe (17 mg, 0.020 mmol) were added sequentially to the reaction. The reaction was stirred at 0 °C for 72 h. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography to obtain the target product 15a.

[0414] Compound 15a, colorless oil, 80% yield, 96:4er. 1 H NMR(400MHz,chloroform-d)δ7.82–7.73(m,2H),7.45–7.34(m,3H),5.30(ddd,J=10.4,7.9,2.2Hz,1H),4.14(q,J=7 .1Hz,2H),3.43(dd,J=15.0,10.6Hz,1H),3.23(dd,J=15.0,7.9Hz,1H),2.62(d,J=2.2Hz,1H),1.21(t,J=7.1Hz,3H). 13 C NMR(101MHz,chloroform-d)δ162.13,161.40,127.98,126.84,125.04,99.55,7 9.14,74.75,74.43,74.12,72.19,67.20,57.39,36.49,11.62.HRMS(ESI):[M+H] ⊕ calcd for C 15 H 14 O3 ⊕ 243.1016,found 243.1013.HPLC analysis:Chiracel AD-ADcolumn; detected at 284nm,40 o C; 10% iPrOH in n-hexane; flow=0.7mL / min; Retentiontime: 13.8min (minor), 15.8min (major).

[0415] Application Example 50 used the same substrate and ligands as in Application Example 49, and prepared under the reaction conditions shown below. The yields and enantioselectivity of the products are shown in the table below:

[0416]

[0417]

[0418]

[0419] Using the appropriate raw materials, and referring to the reaction conditions and operating methods in Application Example 49, the following compounds 15b-15e were prepared.

[0420] Application Example 51: Synthesis of Compound 15b

[0421]

[0422] Compound 15b, white solid, 58% yield. [α] D 16 =-0.4(c=0.59in CHCl3)for 98:2er; 1 H NMR (400MHz, CDCl3) δ7.75 (d, J=3.6Hz, 1H), 7.56–7.47 (m, 1H), 6.52 (ddd, J=3.6, 1.7, 0.8Hz, 1H), 5.41–5.24 (m, 1H), 4.22 (qd, J=7. 2,1.0Hz,2H),3.40(dd,J=15.2,10.5Hz,1H),3.21(dd,J=15.2,8.0Hz,1H),2.61(dd,J=2.2,0.8Hz,1H),1.30(td,J=7.1,0.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ164.1,153.4,144.2,143.8,117.9,111.9,100.9,81.3,75.0,70.2,60.0,38.7,14.4.HRMS(ESI):[M+H] ⊕ calcd for C 13 H 12 O4 ⊕233.0808,found233.0809.HPLC analysis:Chiracel AD-H+AD-H column; detected at 294nm,40 o C; 10% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 15.3min (minor), 17.2min (major).

[0423] Application Example 52: Synthesis of Compound 15c

[0424]

[0425] Compound 15c is a yellow oil, yielding 55%. [α] D 16 =-5.2(c=0.6in CHCl3)for 91:9er; 1 HNMR (400MHz, CDCl3) δ8.05(d,J=8.4Hz,2H),7.85(d,J=8.1Hz,2H),5.34(ddd,J=10.4,7.9,2.2Hz,1H),4.39(q,J=7.0Hz,2H),4.15(q,J=7. 1Hz,2H),3.45(dd,J=15.1,10.6Hz,1H),3.32–3.14(m,1H),2.65(d,J=2.1Hz,1H),1.40(dd,J=8.0,6.0Hz,3H),1.21(td,J=7.2,1.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.0,164.3,162.5,133.5,132.0,131.6,129.4,129.3,128.7,10 3.7,81.5,75.0,70.0,69.8,61.1,60.1,39.2,14.3,14.3,14.2.HRMS(ESI):[M+H]⊕calcd for C 18 H 18 O5⊕315.1240,found 315.1225.HPLC analysis:ChiracelAD-H+AD-H column; detected at 297nm,40 o C; 10% i PrOH in n-hexane; flow=0.7mL / min; Retention time: 21.0min (minor), 28.1min (major).

[0426] Application Example 53: Synthesis of Compound 15d

[0427]

[0428] Compound 15d is a yellow oil with a yield of 63%. [α] D 16 =2.6(c=0.76in CHCl3)for 95:5er; 1 HNMR (400MHz, CDCl3) δ7.79–7.72(m,2H),7.45–7.38(m,2H),5.32(ddd,J=10.4,7.9,2.2Hz,1H),4.09(t,J=6.4Hz,2H),3.49(t,J=6.6Hz,2H),3.4 7–3.38(m,1H),3.23(dd,J=14.9,7.9Hz,1H),2.64(d,J=2.1Hz,1H),1.74 (dq,J=9.3,6.8Hz,2H),1.60(s,2H),1.40(tdd,J=10.1,6.6,5.2Hz,2H). 13 C NMR (101MHz, CDCl3) δ164.6,164.2,130.5,129.5,129.4,128.6,128.5,127.6, 102.1,81.7,74.8,69.9,63.7,44.7,39.0,32.1,27.9,23.4.HRMS(ESI):[M+H] ⊕ calcd for C 18 H 19 O3Cl ⊕ 319.1095,found 319.1094.HPLC analysis:ChiracelAD-H+AD-H column; detected at 284nm,40 o C; 10% i-PrOH in n-hexane; flow=0.7mL / min; Retention time: 17.7min (minor), 20.0min (major).

[0429] Application Example 54: Synthesis of Compound 15e

[0430]

[0431] Compound 15e is a yellow oil, 85% yield. [α] D 16=-3.8(c=0.79in CHCl3)for 96:4er; 1 HNMR(400MHz,CDCl3)δ7.86–7.70(m,2H),7.45–7.35(m,3H),5.32(ddd,J=10.4,8.0,2.2Hz,1H),4.31–4.18(m,2H),3.58–3.52(m,2H),3.46(dd,J=14.9,10.7Hz,1H),3.34(s,3H),3.26(dd,J=14.9,7.9Hz,1H),2.63(d,J=2.1Hz,1H). 13 C NMR(101MHz,CDCl3)δ164.5,164.4,130.5,129.4,129.3,127.6,101.8,81.6,74.8,70.4,69.9,63.1,58.8,39.0.HRMS(ESI):[M+H] ⊕ calcd for C 16 H 16 O4 ⊕ 273.1121,found 273.1125.HPLC analysis:ChiracelAD-H+AD-H column;detected at 284nm,40 o C;10%i-PrOH in n-hexane;flow=0.7mL / min;Retention time:18.4min(minor),20.1min(major).

Claims

1. The use of a compound of formula I as a chiral ligand in a reaction, said reaction being reaction A, reaction B, or reaction C; Reaction A: Asymmetric propargyl amination catalyzed by copper catalyst and driven by strain release involving a long-range leaving group. Reaction B: A copper-catalyzed strain release-driven asymmetric alkylation reaction involving long-range leaving groups. Reaction C: Asymmetric propargyl olefin oxidation catalyzed by a copper catalyst; X is a leaving group; express Configuration; n can be 1, 2, 3, or 4 independently; R1 is independently C 1～6 Alkyl, with one or more R 1a Replacement C 1～6 Alkyl, C 6～10 aryl, or, by one or more R 1b Replacement C 6～10 Aryl; R2 is independently H and C 1～6 Alkyl, C 1～6 Alkoxy, halogen, -CN, -C(=O)-R 2-1 C 6～10 aryl, with one or more R 2a Replacement C 1～6 Alkyl, with one or more R 2b Replacement C 1～6 alkoxy, or, by one or more R 2c Replacement C 6～10 Aryl; R 2-1 Independently for C 1～6 Alkyl or C 6～10 Aryl; R 1a R 1b R 2a R 2b and R 2c Each independently constitutes a halogen, C 1～6 Alkyl, C 1～6 alkoxy- or halogen-substituted C 1～6 Alkyl or C 6～10 Aryl; And / or, two R2 atoms together with the attached C atom form C 6～10 Aryl; Alternatively, the three R2 atoms together with the attached C atoms form C. 13～20 Aryl.

2. The application as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) R1 is independently methyl or phenyl; (2) R2 is independently F, Cl, Br, ethyl, tert-butyl, methoxy, -CN, isopropyl, CF3 or phenyl; (3) The two R2 atoms together with the attached C atoms form (4) The three R2 atoms together with the attached C atoms form 3. The application as described in claim 1 or 2, characterized in that, The compound represented by Formula I is as shown in Formula I-1, I-2, I-3, or I-4: Wherein, n, R1, and R2 are all as described in claim 1 or 2; Preferably, the compound shown in Formula I has any of the following structures: Or its enantiomers.

4. The application as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) Reaction A: Asymmetric propargyl amination catalyzed by the copper catalyst and driven by a long-range leaving group, which includes the following steps: In a solvent, in the presence of a copper catalyst, a compound as shown in Formula I, and a basic reagent, compounds 9-1 and 10-1 are reacted as shown below to give compound 11-1 or compound 11-2. X can be halogen, -OAc, -OBoc, -OBz, -OTs, -OTroc, -OP(O)(OR)2 or -OCO2R independently; R is C 1～6 alkyl; R a1 and R a2 Each is independently a C that is optionally substituted with one or more substituents. 6～10 Aryl; R b1 and R b2 Each is independently H, and C is optionally substituted with one or more substituents. 6～10 aryl, C substituted with one or more substituents 1～6 Alkyl, 3- to 10-membered cycloalkyl optionally substituted with one or more substituents, or C optionally substituted with one or more substituents 2～6 alkenyl; Or R b1 and R b2 Together with the attached N atom, it forms a 5- to 16-membered heterocyclic alkyl group that may be optionally substituted with one or more substituents; the 5- to 16-membered heterocyclic alkyl group contains 1, 2, 3 or 4 N atoms and is a monocyclic, bicyclic or tricyclic saturated or semi-saturated cyclic group. (2) Reaction B: The asymmetric alkylation reaction catalyzed by the copper catalyst and driven by the release of tension, involving a long-range leaving group, includes the following steps: In a solvent, in the presence of a copper catalyst, a compound as shown in Formula I, a Lewis acid of metal salt and a basic reagent, compounds 9-1 and 12-1 are reacted as shown below to give compound 13-1 or compound 13-2. X can be halogen, -OAc, -OBoc, -OBz, -OTs, -OTroc, -OP(O)(OR)2 or -OCO2R independently; R is C 1～6 alkyl; R a1 and R a2 Each is independently a C that is optionally substituted with one or more substituents. 6～10 Aryl; R c1 and R c2 Each is independently H, or C optionally substituted with one or more substituents. 1～6 alkyl; R c3 Independently, C is optionally substituted with one or more substituents. 6～10 Aryl, or, optionally, 5- to 10-membered heteroaryl groups substituted with one or more substituents; (3) Reaction C: The asymmetric propargyl olefin oxylation reaction catalyzed by the copper catalyst includes the following steps: In a solvent, in the presence of a copper catalyst, a compound as shown in Formula I, a metal salt Lewis acid, and a basic reagent, compound 14-1 undergoes the reaction shown below to give compound 15-1 or compound 15-2. R d1 Independently, C is optionally substituted with one or more substituents. 6～10 Aryl, or, optionally, 5- to 10-membered heteroaryl groups substituted with one or more substituents; R d2 -C(=O)OC is optionally substituted with one or more substituents. 1～6 alkyl.

5. The application as described in claim 4, characterized in that, It satisfies one or more of the following conditions: (1)R a1 R a2 R b1 R b2 R c1 R c2 R c3 R d1 and R d2 In the case where the optional substitution is by one or more substituents, the substituents are independently C 1～6 Alkyl, C 1～6 Alkoxy, halogen, C 6～10 Aryl, -OH 3- to 10-membered cycloalkyl groups, -C(=O)OC 1～6 Alkyl, 5-10-membered heteroaryl, 3-16-membered heterocyclic alkyl or -O(CH2)mC 6～10 Aryl; the C 1～6 Alkyl, C 1～6 Alkoxy, C 6～10 Aryl, 3-10 membered cycloalkyl, -C(=O)OC 1～6 Alkyl, 5-10-membered heteroaryl, 3-16-membered heterocyclic alkyl or -O(CH2)mC 6～10 The aryl group may be optionally replaced by one or more R's; The heteroatoms in the 5- to 10-membered heteroaryl groups are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. The heteroatoms in the 3- to 16-membered heterocyclic alkyl groups are independently selected from 1, 2, 3, or 4 of B, N, O, and S, and the number of heteroatoms is independently 1, 2, 3, or 4, and they are monocyclic, bicyclic, or tricyclic saturated or semi-saturated cyclic groups. R a21 R a22 and R a23 Each independently is H or C 1～6 alkyl; m can be 1, 2, or 3 independently; R' is independently of halogen, oxo, and C. 1～6 Alkyl, C 1～6 Alkoxy or optional 3- to 16-membered heterocyclic alkyl groups substituted with one or more R1'; R1' is C 1～6 alkyl; (2) X is independently -OBoc or -OAc; (3) Compound 9-1 is in the E configuration, Z configuration, or a mixture of Z / E; for example, the E configuration; (4) In reaction A, when the compound shown in formula I is When, the compound is obtained (5) In reaction A, when the compound shown in formula I is When, the compound is obtained (6) In reaction B, when the compound shown in formula I is When, the compound is obtained (7) In reaction B, when the compound shown in formula I is When, the compound is obtained (8) In reaction C, when the compound shown in formula I is When, the compound is obtained (9) In reaction C, when the compound shown in formula I is When, the compound is obtained Preferably, it satisfies one or more of the following conditions: (1)R a1 and R a2 Each independently serves as an optional entity to be controlled by one or more Rs. a1-1 Replacement C 6～10 Aryl; R a1-1 Independently for C 1～6 Alkyl, C 1～6 Alkyl or halogen; (2)R b1 and R b2 Each is independently H, arbitrarily controlled by one or more R b1-1 Replacement C 6～10 aryl, optionally with one or more R b1-2 Replacement C 1～6 Alkyl, 3- to 10-membered cycloalkyl, or, optionally with one or more R b1-3 Replacement C 2～6 alkenyl; R b1-1 Independently -OH, halogen, or -O(CH2)mC 6～10 Aryl; wherein, the -O(CH2)mC 6～10 C in aryl 6～10 The aryl group is replaced by one or more halogens; m can be 1 or 2 independently; R b1-2 Independently for optional use by one or more R b1-2-1 Replacement C 6～10 Aryl, -OH C 1～6 Alkoxy, 3- to 10-membered cycloalkyl, -C(=O)OC 1～6 Alkyl, 5- to 10-membered heteroaryl, or, optionally with one or more R b1-2-2 Substituted 3- to 16-membered heterocyclic alkyl groups; R b1-2-1 Independently for C 1～6 Alkoxy, or, optionally, by one or more R b1-2-1-1 Substituted 3- to 16-membered heterocyclic alkyl groups; R a21 R a22 and R a23 Each independently is C 1～6 alkyl; R b1-2-1-1 C 1～6 alkyl; R b1-2-2 Independently for C 1～6 Alkyl or oxo; R b1-3 -C(=O)OC 1～6 alkyl; (3)R b1 and R b2 Together with the attached N atom, it forms an optional structure controlled by one or more R atoms. b1-4 Substituted 5- to 16-membered heterocyclic alkyl groups; R b1-4 For oxygenation; (4)R c1 and R c2 Each independently is C 1～6 Alkoxy; (5)R c3 Independently for optional use by one or more R c3-1 Replacement C 6～10 Aryl, or 5- to 10-membered heteroaryl; R c3-1 Independently for C 1～6 Alkyl, C 1～6 Alkyl or halogen; (6)R d1 For optional use by one or more R d1-1 Replacement C 6～10 Aryl, or 5- to 10-membered heteroaryl; R d1-1 -C(=O)OC 1～6 alkyl; (7)R d2 For optional use by one or more R d2-1 Substituted -C(=O)OC 1～6 alkyl; R d2-1 Independently halogen or C 1～6 Alkyl group.

6. The application as described in claim 5, characterized in that, It satisfies one or more of the following conditions: (1)R a1 and R a2 Each independently (2)R b1 and R b2 Each independently -CH3、 (3)R c1 and R c2 Each is independently -CH2CH3; (4)R c3 for (5)R d1 for (6)R d2 for Preferably, it satisfies one or more of the following conditions: (1) Compound 9-1 is (2) Compound 10-1 is (3) Compound 12-1 is (4) Compound 14-1 is 7. The application as described in claim 4, characterized in that, It satisfies one or more of the following conditions: (1) In reaction A, the solvent is an ether solvent, such as methyl anisole or 1,4-dioxane; (2) In reaction A, the copper catalyst is a monovalent copper salt or a divalent copper salt; preferably copper tetraacetonitrile hexafluorophosphate. (3) Reaction A also includes a metal salt Lewis acid, wherein the metal salt Lewis acid is Bi(OTf)3 or LiOTf, for example Bi(OTf)3; (4) In reaction A, the alkaline reagent is an organic base, preferably a tertiary amine organic base; for example, diisopropylethylamine; (5) In reaction A, the molar ratio of compound 9-1 to the copper catalyst is 1:(0.01 to 0.5); for example, 1:0.05; (6) In reaction A, the molar ratio of compound 9-1 to the compound shown in Formula I is 1:(0.01 to 1); preferably 1:(0.01 to 0.5); for example 1:0.15; (7) In reaction A, the molar ratio of compound 9-1 to compound 10-1 is 1:(0.5-2); for example, 1:1; (8) In reaction A, the molar ratio of compound 9-1 to the Lewis acid of the metal salt is 1:(0.01 to 0.5); for example, 1:0.1; (9) In reaction A, the molar ratio of compound 9-1 to the basic reagent is 1:(0.5-4); for example, 1:2; (10) In reaction A, the temperature of the reaction is 25 to 80°C; for example, 50°C or 60°C; (11) In reaction B, the solvent is an ether solvent, such as methyl anisole; (12) In reaction B, the copper catalyst is a monovalent copper salt or a divalent copper salt; preferably Cu(CH3CN)4PF6; (13) In reaction B, the Lewis acid of the metal salt is Bi(OTf)3 or LiOTf, for example Bi(OTf)3; (14) In reaction B, the basic reagent is an organic base, preferably a piperidine organic base; for example, pentamethylpiperidine; (15) In reaction B, the molar ratio of compound 9-1 to the copper catalyst is 1:(0.01 to 0.5); for example, 1:0.05; (16) In reaction B, the molar ratio of compound 9-1 to the compound shown in Formula I is 1:(0.01 to 1); for example, 1:0.15; (17) In reaction B, the molar ratio of compound 9-1 to compound 12-1 is 1:(1-6); for example, 1:3; (18) In reaction B, the molar ratio of compound 9-1 to the Lewis acid of the metal salt is 1:(0.01 to 0.5); for example, 1:0.1; (19) In reaction B, the molar ratio of compound 9-1 to the basic reagent is 1:(0.5-4); for example, 1:2; (20) In reaction B, the temperature of the reaction is 25–80°C; for example, 50°C; (21) In reaction C, the solvent is an alcohol solvent, such as n-butanol; (22) In reaction C, the copper catalyst is a monovalent copper salt or a divalent copper salt; preferably Cu(CH3CN)4PF6; (23) In reaction C, the Lewis acid of the metal salt is Bi(OTf)3 or LiOTf, for example LiOTf; (24) In reaction C, the basic reagent is an organic base, preferably a tertiary amine organic base; for example, Et2NMe; (25) In reaction C, the molar ratio of compound 14-1 to the copper catalyst is 1:(0.01 to 0.5); for example, 1:0.04; (26) In reaction C, the molar ratio of compound 14-1 to the compound shown in Formula I is 1:(0.01 to 1); preferably 1:(0.06 to 0.5); for example 1:008 or 1:0.12; (27) In reaction C, the molar ratio of compound 14-1 to the Lewis metal salt is 1:(1-6); preferably 1:(1.2-4); for example 1:2.5; (28) In reaction C, the molar ratio of compound 14-1 to the basic reagent is 1:(0.5-4); for example, 1:2; (29) In reaction C, the temperature of the reaction is -15 to 40°C; preferably -10 to 25°C; for example, 0°C.

8. A chiral ligand, which is a compound as shown in formula II, III or IV; n can be 1, 2, 3, or 4 independently; R3 is independently C 1～6 Alkyl, or, by one or more R 3a Replacement C 1～6 alkyl; R4 is independently C 1～6 Alkyl, C 1～6 Alkoxy, halogen, -CN, -C(=O)-R 4-1 , by one or more R 4a Replacement C 1～6 Alkyl, or, by one or more R 4b Replacement C 1～6 Alkoxy; R 4-1 Independently for C 1～6 Alkyl or C 6～10 Aryl; R5 is a halogen; R6 is independently C 6～10 aryl, or, by one or more R 6a Replacement C 6～10 Aryl; R7 is independently C 1～6 Alkyl, C 6～10 aryl, with one or more R 7a Replacement C 1～6 Alkyl, or, by one or more R 7b Replacement C 6～10 Aryl; R 3a R 4a R 4b R 6a R 7a and R 7b Each independently constitutes a halogen, C 1～6 Alkyl, C 1～6 alkoxy- or halogen-substituted C 1～6 Alkyl or C 6～10 Aryl; Or two R7 atoms together with the attached C atom form C 6～10 Aryl; Or three R7 atoms together with the attached C atom form C 13～20 Aryl; express Configuration; The compound shown in Formula II is not...

9. The chiral ligand as described in claim 8, characterized in that, It satisfies one or more of the following conditions: (1) R3 is a methyl group; (2) R4 is independently F, Br, ethyl, tert-butyl, methoxy, -CN, isopropyl, (3) R5 is Br; (4) R6 is a phenyl group; (5) R7 is independently CF3, phenyl or tert-butyl; (6) Two R7 atoms together with the attached C atoms form (7) The three R7 atoms together with the attached C atoms form 10. The chiral ligand as described in claim 9, characterized in that, It can be any of the following structures: Or its enantiomers.

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