Alkyl borane compound with high optical purity as well as preparation method and application of alkyl borane compound

Abstract

The invention relates to a high-optical-purity alkyl borane compound and a preparation method and application thereof, and particularly relates to a method for preparing a high-optical-purity alkyl borane compound by using a monovalent rhodium / chiral diene ligand as a catalyst. The selective preparation of the chiral organic borane compound is realized through asymmetric insertion reaction of monovalent rhodium metal carbene obtained through diazo decomposition on an organic borane adduct. According to the method, the catalyst and the ligand are simple to prepare, the reaction condition is mild, the operation is simple and convenient, the substrate universality is good, and the alpha-alkyl borane-containing compound can be obtained with good yield and excellent enantioselectivity.

Description

Technical Field

[0001] The invention belongs to the field of chemistry, and in particular relates to a method for preparing chiral organic borane compounds by an asymmetric borohydride insertion reaction involving a monovalent rhodium metal carbene. Background Art

[0002] Transition metal-involved carbene transfer reactions are an important means of rapidly constructing multifunctional compounds. In organic synthesis, metal carbene, as a relatively highly reactive intermediate, can undergo various reactions. Among them, chiral organoborane compounds can be prepared by borohydride insertion reactions between metal carbene and borane. In the past few decades, great progress has been made in the preparation of organoborane compounds by asymmetric catalytic methods. Some transition metals, such as Rh(II), Cu(I), Ru(II), Au(I), Fe(II), etc., have been used to catalyze the asymmetric borohydride insertion reactions of diazo compounds, showing good results in the reaction of α-aryl diazo. It is worth noting that for α-alkyl substituted diazo compounds, β-hydrogen migration is very easy to occur, and the reaction often produces mainly olefin byproducts. In addition, the smaller steric hindrance and flexible spatial configuration of the alkyl group also make it difficult to control the enantioselectivity of the reaction. Although there are a few examples of asymmetric borohydride insertion of α-alkyl substituted diazo compounds, the substrates are limited to diazopropionates (α-methyl substituted diazo esters) that are relatively less prone to β-hydrogen migration, α-trifluoromethyl substituted diazo esters, and cyclic diazo esters ((a) Kan, SBJ; Huang, X.; Gumulya, Y.; Chen, K.; Arnold, FH Nature, 2017, 552.132-136; (b) Huang, X.; Garcia-Borràs, M.; Miao, K.; Kan, SBJ; Zutshi, A.; Houk, KN; Arnold, FH ACS Cent. Sci. 2019, 5, 270-276; (c) Chen, K.; Huang, X.; Zhang, S.-Q.; Zhou, AZ; Kan, SBJ; Hong, X.; Arnold, FH Synlett 2019, 30, 378-382; (d) Zhao, X.; Wang, G.; Hashmi, ASK; ChemCatChem 2021, 13, 4299-4312). However, for diazo compounds that are prone to β-hydrogen migration, such as substrates with long-chain alkanes, there is currently no method in the art that can obtain asymmetric borohydride insertion products with high yield and high optical purity.

[0003] Chiral organic boronic acid or organic boronic ester compounds are important building blocks for organic synthesis transformation and chiral fragments of various drugs, such as ProboroPro and ValboroPro for the treatment of type II diabetes, Bortezomib, a global best-selling anticancer drug, β-lactamase inhibitor RPX7009, and anticoagulant Dup-714 ((a) Adams, J.; Behnke, M.; Chen, S.; Bioorg. Med. Chem. Lett., 1998, 8, 333-338; (b) Jin, S.; Zhu, C.; Cheng, Y.; Bioorg. Med. Chem., 2010, 18, 1449-1455; (c) Sandford, C.; Aggarwal, VK Chem. Commun., 2017, 53, 5481-5494). The existing methods for synthesizing chiral boronic acids and chiral boric esters mainly come from the induction and chiral resolution of chiral auxiliary groups, or from the conversion of other chiral molecules. There is no report on a universal method for directly synthesizing α-alkyl-substituted chiral boronic acids and boric esters. Therefore, the field urgently needs to develop new efficient, highly selective and practical methods for preparing chiral organoborane compounds with high optical purity. Summary of the invention

[0004] The purpose of the present invention is to provide an efficient, highly selective and practical method for preparing alkyl-substituted chiral organoborane compounds with high optical purity and its use.

[0005] Another object of the present invention is to provide an alkyl-substituted organic borane compound with high optical purity for use in the synthesis of chiral drugs.

[0006] The first aspect of the present invention provides a method for preparing an organoborane compound with high optical purity, comprising the following steps:

[0007] In an organic solvent, in the presence of a monovalent rhodium catalyst and a chiral diene ligand, an α-alkyl diazo compound as shown in Formula 1 and a borane adduct as shown in Formula 2 are subjected to a borohydride insertion reaction to obtain a compound as shown in Formula 3 or ent-3;

[0008]

[0009] In the formula, R 1 For R 1a or R 1b ;

[0010] n is a positive integer selected from 1-30;

[0011] R 1a Selected from: H, substituted or unsubstituted straight chain or branched chain C 1-30Alkyl, substituted or unsubstituted C 3-30 Cycloalkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 2-10 Alkynyl; wherein said R 1a Substitution refers to having one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, aryl-substituted C 1-6 Alkoxy, aryloxy, NH(C 1-6 Alkyl), N(C 1-6 alkyl) 2 , C 2-10 Ester group, C 2-10 Amide, C 1-6 Alkylformyloxy, arylformyloxy, C 0-6 Alkyl substituted indolyl, arylamine, C 1-6 Alkylsilyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, arylsulfonyl, C 3 -C 8 Cycloalkyl, or a combination thereof; said R 1a In the above, aryl is phenyl or naphthyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, nitro, C 2-10 Ester group, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy;

[0012] R 1b Selected from: substituted or unsubstituted C 6 -C 30 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted (C 6 -C 30 Aryl)-CH=CH-; wherein the R 1b Substitution refers to having one or more substituents selected from the following groups: halogen, oxo (ie, =O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 1-4 Alkylamino, C 1-6 Halogenated alkoxy, C 1-6 Alkyl substituted amino, C 1-6Alkylsilyl, or a combination thereof; the halogen is F, Cl, Br, or I;

[0013] R 2 C 1-6 Alkyl, C 1-6 C substituted with halogenated alkyl or aryl 1-6 Alkyl, C 6 -C 10 Aryl;

[0014] X has a structure selected from the group consisting of:

[0015] Substituted or unsubstituted pyridine; the substitution refers to having one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 phenyl, methoxybenzyl, dimethoxybenzyl, amino; or

[0016] X is Where Z is N; R 11 , R 12 and R 13 Each independently selected from the following group: substituted or unsubstituted straight chain or branched chain C 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl; or said R 11 and R 12 Together they constitute a substituted or unsubstituted 5-9 membered Z-containing heterocycle; wherein the substitution refers to having one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, and the aryl or heteroaryl may be optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0017] The halogen is F, Cl, Br, or I.

[0018] In another preferred embodiment, the X is and

[0019] The R 11 and R 12 Together they constitute a 5-9 membered Z-containing heterocyclic ring which is unsubstituted or substituted by a substituent selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0020] R 13 is a substituted or unsubstituted straight chain or branched chain C 1-10 alkyl;

[0021] Wherein, the substitution refers to having one or more substituents selected from the following group: 6-10 Aryl, 5-10 membered heteroaryl, and the aryl or heteroaryl may be optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy.

[0022] In another preferred embodiment, the reaction is carried out under anhydrous and oxygen-free conditions.

[0023] In another preferred embodiment, n is a positive integer selected from 1-20; R 1a Selected from: H, substituted or unsubstituted straight chain or branched chain C 1-20 Alkyl, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 2-10 Alkynyl.

[0024] In another preferred embodiment, n is a positive integer selected from 1-10; R 1a Selected from: H, substituted or unsubstituted straight chain or branched chain C 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 2-10 Alkynyl.

[0025] In another preferred embodiment, n is a positive integer selected from 1-6, R 1a Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-dodecyl,

[0026] In another preferred embodiment, n is a positive integer selected from 1-20; R 1b Selected from: substituted or unsubstituted C 6 -C 18 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclyl, substituted or unsubstituted (C 6 -C 18 aryl)-CH=CH-.

[0027] In another preferred embodiment, n is a positive integer selected from 1-10; R 1b Selected from: substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclyl, substituted or unsubstituted (C 6 -C10 aryl)-CH=CH-.

[0028] In another preferred embodiment, R 1b Selected from: substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted thiophene, substituted or unsubstituted furan.

[0029] In another preferred embodiment, n is a positive integer selected from 1-6, R 1b Selected from the following group: phenyl, methyl substituted phenyl, methoxy substituted phenyl, fluorophenyl, difluorophenyl, bromophenyl, chlorophenyl, trifluoromethyl substituted phenyl, naphthyl, chloropyridyl, thienyl, Ph-CH=CH-, furanyl.

[0030] In another preferred embodiment, R 2 Select from the following group: C 1-4 Alkyl, C 1-4 C substituted with halogenated alkyl or aryl 1-6 Alkyl, C 6 -C 10 Aryl.

[0031] In another preferred embodiment, R 2 Selected from the group consisting of tert-butyl, phenyl, C 1-4 Halogenated alkyl.

[0032] In another preferred embodiment, X is selected from the following group: N-(3,5-dimethoxybenzyl)-tetrahydropyrrole, N-benzyl-tetrahydropyrrole, N-methyl-tetrahydropyrrole, N-(4-methoxybenzyl)-tetrahydropyrrole, and 3,5-dimethylpyridine.

[0033] In another preferred embodiment, the compound of formula 1 is selected from the following group:

[0034]

[0035]

[0036]

[0037] In another preferred embodiment, the compound of formula 2 is selected from the following group:

[0038]

[0039] In another preferred embodiment, the compound of formula 3 or ent-3 is selected from the following group:

[0040]

[0041]

[0042] In another preferred embodiment, the chiral diene ligand has the following structural formula:

[0043]

[0044] in,

[0045] R 3 , R 4 are each independently substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted metal complexed C 6-30 Aryl, wherein R 3 and R 4 The groups may be the same or different; the substitution means that one or more H is replaced by a group selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, nitro, -CON i Pr 2 .

[0046] In another preferred embodiment, R 3 , R 4 are each independently substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted metal complexed C 6-20 Aryl.

[0047] In another preferred embodiment, R 3 , R 4 are each independently substituted or unsubstituted C 6-14 Aryl.

[0048] In another preferred embodiment, R 3 , R 4 Each is independently a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted anthracenyl, or a substituted or unsubstituted ferrocenyl.

[0049] In another preferred embodiment, R 3 and R 4 Can be the same or different.

[0050] In another preferred embodiment, R 3 is an unsubstituted phenyl group, R 4 is a substituted phenyl group; or R 4 is an unsubstituted phenyl group, R 3 is a substituted phenyl group.

[0051] In another preferred embodiment, R 3 and R 4The same is phenyl.

[0052] In another preferred embodiment, the chiral diene ligand has the following structural formula:

[0053]

[0054] In another preferred embodiment, the monovalent rhodium catalyst is selected from the following group: [Rh(C 2 H 4 ) 2 Cl] 2 , [Rh(C 2 H 4 ) 2 OH] 2 、[Rh(coe) 2 Cl] 2 、[Rh(coe) 2 OH]] 2 , [Rh(C 2 H 4 ) 2 OMe] 2 、[Rh(coe) 2 OMe] 2 , or a combination thereof.

[0055] In another preferred embodiment, the method further comprises one or more features selected from the following group:

[0056] (1) Based on the amount of the compound of formula 2, the amount of the monovalent rhodium catalyst is 0.1 to 20 mol%;

[0057] (2) Based on the amount of the compound of formula 2, the amount of the chiral diene ligand is 0.12 to 22 mol%;

[0058] In another preferred embodiment, in the method, the organic solvent is C 1-4 Halogenated alkane; the C 1-4 The halogenated alkane is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dichloropropane, 1-chlorobutane, or a combination thereof.

[0059] In another preferred embodiment, the method further comprises one or more features selected from the following group:

[0060] (i) the reaction temperature is between -20 and 40°C;

[0061] (ii) The reaction time is 0.148 hours.

[0062] The second aspect of the present invention provides a compound as shown in Formula 3 or Formula ent-3:

[0063]

[0064] In the formula,

[0065] R 1 , R 2 , n, X as defined in claim 1.

[0066] In another preferred embodiment, X is Where Z is N; R 11 , R 12 and R 13 Each independently selected from the following group: substituted or unsubstituted straight chain or branched chain C 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl; or said R 11 and R 12 Together they form a 5-9 membered Z-containing heterocyclic ring; more preferably, the R 11 and R 12 Together they form a 5-9 membered Z-containing heterocyclic ring, and R 13 is a substituted or unsubstituted straight chain or branched chain C 1-10 Alkyl; More preferably, said R 11 and R 12 Together they form a 5-7 membered Z-containing heterocyclic ring, and R 13 is a substituted or unsubstituted straight chain or branched chain C 1-10 alkyl.

[0067] In another preferred embodiment, the compound is selected from the following group:

[0068]

[0069]

[0070] The third aspect of the present invention provides the use of the compound represented by formula 3 or formula ent-3 for preparing a chiral synthetic building block, a pharmaceutical intermediate or an active compound represented by the following formula:

[0071]

[0072] Among them, R 1 , n as defined in claim 1, OMOM is -O-CH 2 -O-CH 3 .

[0073] The fourth aspect of the present invention provides a method for preparing a compound as shown in the following formula 4-1, comprising the steps of:

[0074]

[0075] Using the structure shown in Formula 3-1 and 1,3-dimethylimidazolium iodide to perform ligand exchange, thereby forming a chiral borane compound 4-1;

[0076] Among them, R 1 and R 2 As defined in the first aspect of the present invention, R 5 is a substituted or unsubstituted phenyl group, wherein the substitution is as defined in the first aspect of the present invention.

[0077] In another preferred embodiment, the method is carried out in the presence of NaHMDS.

[0078] In another preferred embodiment, the method is carried out in THF.

[0079] The fifth aspect of the present invention provides a method for preparing a compound as shown in the following formula 5-1, wherein the method comprises the steps of:

[0080] (1) preparing a compound of formula 4-1 by the method according to the fourth aspect of the present invention; and

[0081]

[0082] (2) Reducing the compound 4-1 to obtain compound 5-1.

[0083] In another preferred embodiment, DIBAL-H is used as the reducing agent in step (2).

[0084] In another preferred embodiment, the method in step (2) is carried out in toluene solvent.

[0085] The sixth aspect of the present invention provides a method for preparing a compound as shown in Formula 6, wherein the method comprises the steps of: preparing a compound of Formula 5-1 by the method described in the fifth aspect of the present invention, and

[0086]

[0087] Compound 5-1 is protected with a MOM group to obtain compound 6-1.

[0088] In another preferred embodiment, the protection step is carried out in the presence of DIPEA by reacting with MOMCl.

[0089] In another preferred embodiment, the method is carried out in DCM solvent.

[0090] The seventh aspect of the present invention provides a method for preparing a compound of formula 7-1, wherein the method comprises the steps of: preparing a compound of formula 6-1 by the method of the sixth aspect of the present invention, and

[0091]

[0092] The compound of formula 6-1 is reacted with pinacol to obtain the chiral boron ester of formula 7-1, and these compounds can then be further converted into other important organic synthesis intermediates.

[0093] The eighth aspect of the present invention provides a method for preparing an organic synthesis intermediate, the method comprising the steps of: preparing a compound of formula 7-1 by the method described in the seventh aspect of the present invention, and any step selected from the following groups (a)-(d):

[0094]

[0095] (a) oxidizing the chiral boron ester 7-1 to obtain a chiral alcohol compound 8; preferably, the oxidation is carried out in the presence of NaBO 3 to be carried out in the presence of;

[0096]

[0097] (b) using the compound of formula 7-1 to undergo rearrangement reaction with benzylhydroxylamine, and then protecting with benzoyl to obtain a chiral amine compound 9; preferably, the benzoyl protection step is to react the compound of formula 7-1 with benzoic anhydride in the presence of an organic base (such as triethylamine) to obtain a compound of formula 9;

[0098]

[0099] (c) reacting the compound of formula 7-1 with dibromomethane to obtain compound 10; preferably, the reaction is carried out in the presence of n-butyl lithium, reacting the compound of formula 7-1 with dibromomethane, and then reacting with NaBO 3 The reaction yields a compound of formula 10;

[0100]

[0101] (d) using a compound of formula 7-1 and Reaction to obtain a compound of formula 14, wherein Ar is substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl; the substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, nitro, C 2-10 Ester group, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy;

[0102] M is H or halogen;

[0103] Preferably, the reaction is carried out in the presence of a metal organic reagent selected from the group consisting of n-butyl lithium and tert-butyl lithium.

[0104] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0105] After extensive and in-depth research, the inventors have found that a class of important alkyl-substituted organic borane compounds can be obtained with high yield and enantioselectivity by using a monovalent rhodium catalyst / chiral diene ligand as a catalyst and asymmetric borohydride insertion reaction of a monovalent rhodium metal alkyl carbene obtained by decomposition of alkyl diazo. In addition, by selecting chiral ligands of different configurations, the method of the present invention can obtain various substituted borohydride insertion products of opposite configurations.

[0106] the term

[0107] As used herein, the term "alkyl" refers to a C 1 -C 30 Straight or branched chain or alkyl (such as alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 carbon atoms), in the present invention, alkyl also includes one or more H on the alkyl group is selected from the group consisting of halogen, substituted or unsubstituted phenyl, unsubstituted or substituted by one or more halogen C 1-6 It is to be understood that this term also includes C 3-30 A substituted or unsubstituted cycloalkyl group.

[0108] As used herein, the term "alkoxy" refers to a C 1 -C 10 In the present invention, the alkoxy group also includes a group in which one or more H on the alkyl group is substituted by a substituent selected from the following groups: halogen, substituted or unsubstituted phenyl, unsubstituted or C substituted by one or more halogens 1-6 alkyl.

[0109] As used herein, the term "alkylthio" refers to an RS- group, wherein R is an alkyl group, and the alkyl group is as defined above. When the alkylthio group is preceded by a carbon atom number, such as C 1 -C 8 Alkylthio means that the alkyl group in the alkylthio group has 1 to 8 carbon atoms. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or the like.

[0110] As used herein, the term "aryl" or "Ar" refers to a C 6 -C 30 The representative examples of aryl are phenyl, naphthyl, anthracenyl and phenanthrenyl. In the present invention, aryl also includes a group in which one or more H on the aryl is substituted by a substituent selected from the group consisting of halogen, phenyl, unsubstituted or substituted by one or more halogen C 1-6 Alkyl, unsubstituted or substituted by one or more halogen C 1-6 Alkoxy.

[0111] As used herein, the term "heteroaryl" refers to a 5-10 membered heteroaryl group having one or more heteroatoms, including but not limited to: N, O, S, P and other heteroatoms. Representative examples are pyridyl, thienyl, indolyl, furanyl, or bicyclic fused heteroaryl groups such as quinolyl, quinazolinyl, indolyl, benzofuranyl, etc. In the present invention, heteroaryl also includes a group in which one or more H on the heteroaryl group is substituted by a substituent selected from the group consisting of halogen, phenyl, nitro, unsubstituted or substituted with one or more halogen C 1-6 Alkyl, unsubstituted or substituted by one or more halogen C 1-6 Alkoxy.

[0112] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated ring (but not including an aromatic ring) having one or more heteroatoms in the ring atoms, and the heteroatoms include, but are not limited to, N, O, S, P and the like. In addition to general substituents, the heterocyclic group may also have oxo groups (e.g., CH 2 Substituted to form C(O) structure, or S is substituted to form S(O) 2 Or S(O)), such forms also fall within the scope of the present invention.

[0113] As used herein, the term "ester group" refers to a RC(O)-O- group or a -C(O)-OR group, wherein R is an alkyl group, and the alkyl group is as defined above. For example, a "C2-C4 ester group" refers to a C 1 -C 3 Alkyl-C(O)-O- structure group or -C(O)-OC 1 -C 3 Alkyl structure groups, representative examples of ester groups include but are not limited to: CH 3 COO-, C 2 H 5 COO-, C 3 H 8 COO-, (CH 3 ) 2 CHCOO-、-COOCH3 ,-COOC 2 H 5 ,-COOC 3 H 8 , or a similar group.

[0114] As used herein, the term "acyl" refers to a RC(O)- group, wherein R is an alkyl group, and alkyl is as defined herein above, for example, "C 2 -C 4 "Acyl" refers to C 1 -C 3 Alkyl-C(O)- structure groups, representative examples of ester groups include but are not limited to: CH 3 C(O)-、C 2 H 5 C(O)-、C 3 H 8 C(O)-, (CH 3 ) 2 CHC(O)-, or a similar group.

[0115] As used herein, the term "amide" refers to an R-CO-N- group or a -CO-NR group, wherein R is an alkyl group, and the alkyl group is as defined herein above, for example, "C 2 -C 4 "Amide" refers to C 1 -C 3 Alkyl-CO-N- structure group or -CO-NC 1 -C 3 Alkyl structure groups, representative examples of amide groups include but are not limited to: CH 3 CO-N-, C 2 H 5 CO-N-, C 3 H 8 CO-N-, (CH 3 ) 2 CHCO-N-, -CO-N-CH 3 、-CO-NC 2 H 5 、-CO-NC 3 H 8 , or a similar group.

[0116] As used herein, the term "amino" alone or as part of another substituent means NH 2 .

[0117] As used herein, the term "nitro" alone or as part of another substituent means NO 2 As used herein, the term "carbonyl" by itself or as part of another substituent means C=O.

[0118] As used herein, the term "metal coordination" refers to the coordination of transition metal atoms or ions with the aromatic group herein in whole or in part through coordination bonds, thereby forming a compound or group having aromatic characteristics. 6-20 Representative examples of aryl include, but are not limited to, ferrocenyl.

[0119] As used herein, the term "cyclic alkyl tertiary amine" refers to a compound in which two substituted alkyl groups on the N atom in the tertiary amine form a cyclic structure. Representative examples of cyclic alkyl tertiary amines include, but are not limited to, N-methyl-tetrahydropyrrole, N-ethyl-tetrahydropyrrole, and N-phenyl-tetrahydropyrrole.

[0120] As used herein, the term "halogen" is F, Cl, Br, or I.

[0121] As used herein, the term "one or more" generally refers to 1-6, preferably 1-5, and more preferably 1-3.

[0122] As used herein, the term "Ph" means a phenyl group.

[0123] As used herein, the term "rt" means room temperature, eg, 10-50°C.

[0124] Preparation method

[0125] The synthetic method of the present invention can be represented by the following typical reaction formula:

[0126]

[0127] In the formula,

[0128] R 1 For R 1a or R 1b ;

[0129] n is a positive integer selected from 1-30;

[0130] R 1a Selected from: H, substituted or unsubstituted straight chain or branched chain C 1-30 Alkyl, substituted or unsubstituted C 3-30 Cycloalkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 2-10 Alkynyl; wherein said R 1a Substitution refers to having one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, aryl-substituted C 1-6Alkoxy, aryloxy, NH(C 1-6 Alkyl), N(C 1-6 alkyl) 2 , C 2-10 Ester group, C 2-10 Amide, C 1-6 Alkylformyloxy, arylformyloxy, C 0-6 Alkyl substituted indolyl, arylamine, C 1-6 Alkylsilyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, arylsulfonyl, C 3 -C 8 Cycloalkyl, or a combination thereof; said R 1a In the above, aryl is phenyl or naphthyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, nitro, C 2-10 Ester group, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy;

[0131] R 1b Selected from: substituted or unsubstituted C 6 -C 30 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclyl, substituted or unsubstituted (C 6 -C 30 Aryl)-CH=CH-; wherein the R 1b Substitution refers to having one or more substituents selected from the following groups: halogen, oxo (ie, =O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 1-4 Alkylamino, C 1-6 Halogenated alkoxy, C 1-6 Alkyl substituted amino, C 1-6 Alkylsilyl, or a combination thereof; the halogen is F, Cl, Br, or I;

[0132] R 2 Selected from: C 1-6 Alkyl, C 1-6 C substituted with halogenated alkyl or aryl 1-6 Alkyl, C 6 -C 10 Aryl; X has a structure selected from the group consisting of:

[0133] Substituted or unsubstituted pyridine; the substitution refers to having one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 phenyl, methoxybenzyl, dimethoxybenzyl, amino; or

[0134] X is Where Z is N; R 11 , R 12 and R 13 Each independently selected from the following group: substituted or unsubstituted straight chain or branched chain C 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl; or said R 11 and R 12 Together they constitute a substituted or unsubstituted 5-9 membered Z-containing heterocycle; wherein the substitution refers to having one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, and the aryl or heteroaryl may be optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0135] The halogen is F, Cl, Br, or I.

[0136] In the present invention, the reaction is carried out under anhydrous and oxygen-free conditions.

[0137] [Rh(I)] refers to a monovalent rhodium metal catalyst, representative examples of which include (but are not limited to): [Rh(C 2 H 4 ) 2 Cl] 2 , [Rh(C 2 H 4 ) 2 OH] 2 、[Rh(coe) 2 Cl] 2 、[Rh(coe) 2 OH] 2 , [Rh(C 2 H 4 ) 2 OMe] 2 、[Rh(coe) 2 OMe] 2 or a combination thereof.

[0138] In the present invention, the representative chiral diene ligand has the following structural formula:

[0139]

[0140] Among them, R 3 and R 4 Each is independently a substituted or unsubstituted phenyl, naphthyl or other aryl such as ferrocenyl, wherein the substituent is selected from the following group: halogen, unsubstituted or C substituted by one or more halogens 1-6 Alkyl or unsubstituted or substituted by one or more halogen C 1-6 Alkoxy.

[0141] In the present invention, the R 3 and R 4 Can be the same or different; preferably, the R 3 With R 4 It is an unsubstituted phenyl group.

[0142] In the present invention, the structural formula of typical compounds of chiral diene ligands includes (but is not limited to):

[0143]

[0144]

[0145] In the present invention, the solvent is a conventional organic solvent, which can be C 1-4 The halogenated alkane is dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dichloropropane, 1-chlorobutane or a combination thereof.

[0146] In the above reaction method of the present invention, the reaction temperature is not particularly limited, and is usually -50°C to reflux temperature, preferably -20-40°C, and more preferably 0-30°C.

[0147] In the above reaction method of the present invention, the reaction time is not particularly limited, and is usually 0.1-48 hours, preferably 1-30 hours.

[0148] In a preferred embodiment of the present invention, a representative synthesis method can be described as follows:

[0149] The method of obtaining the chiral alkyl substituted borane with high optical purity according to the present invention can be achieved by dissolving the monovalent rhodium catalyst and the chiral diene complex in an organic solvent, adding the reaction substrate α-alkyl diazonium tert-butyl ester 1 and continuing the reaction for 1-30 hours. In the reaction, the molar ratio of the reaction substrate to the rhodium (I) / chiral diene complex is 60:1 to 1500:1, preferably 100:3; the reaction temperature is -20-40°C, preferably 25°C; and the reaction solvent is preferably dichloromethane.

[0150] Chiral alkyl organoborane compounds with high optical purity

[0151] By using the method of the present invention, alkyl organic borane compounds with high optical purity can be prepared quickly and efficiently.

[0152] In the present invention, the catalyst complex [Rh(R,R-4a)Cl] 2 For example, asymmetric borohydride insertion reaction of α-alkyl diazo esters with different substituents can efficiently produce the desired reaction product with good yield and excellent enantioselectivity (ee), which can reach up to 99%; the absolute configuration of the product is determined by single crystal diffraction.

[0153] Synthetic Applications

[0154] The present invention also provides the application of chiral alkyl substituted organic borane compounds with high optical purity, especially the application in preparing pharmaceutical intermediates or active compounds with high optical purity.

[0155] In a preferred embodiment of the present invention, the first representative use is as follows:

[0156]

[0157] In this application, the chiral alkyl-substituted organoborane compounds of the present invention are subjected to ligand exchange to form nitrogen-containing carbene complexed organoborane compounds 4, which can then be further converted into other useful intermediates.

[0158] In another preferred embodiment of the present invention, the second representative use is as follows:

[0159]

[0160] In this application, the chiral alkyl-substituted organoborane compound 4 of the present invention is reduced to obtain a hydroxyl-containing compound 5, which can then be further converted into other useful intermediates.

[0161] In another preferred embodiment of the present invention, the third representative use is as follows:

[0162]

[0163] In this application, the chiral alkyl-substituted organoborane compounds 5 of the present invention are protected with a MOM group to obtain compounds 6, so that these compounds can be further converted into other useful intermediates.

[0164] In another preferred embodiment of the present invention, the fourth representative use is as follows:

[0165]

[0166] In this application, the chiral alkyl-substituted organoborane compounds of the present invention can be conveniently converted into the corresponding chiral boron esters, and then these compounds can be further converted into other important organic synthesis intermediates.

[0167] In another preferred embodiment of the present invention, the fifth to tenth representative uses are as follows:

[0168]

[0169] In this application, the chiral alkyl substituted organic boron ester compounds of the present invention can be converted into various chiral functional group compounds. Chiral boron ester 7 can be oxidized to obtain chiral alcohol compound 8, which can be rearranged with benzylhydroxylamine and then protected with benzoyl to obtain chiral amine compound 9, which can be reacted with dibromomethane to obtain rearranged carbon chain derivative product 10, which can be reacted with thiophene to obtain rearranged thiophene 2-position coupled compound 11, which can be reacted with 3,5-dimethoxybromobenzene to obtain aromatic coupled chiral compound 12, and which can be rearranged with 4-iodopyridine to obtain pyridyl coupled product 13. These compounds are useful organic synthesis intermediates.

[0170] Compared with the prior art, the main advantages of the present invention include:

[0171] (a) Using monovalent rhodium as a catalyst and easily available multi-substituted α-alkyl diazo esters as reaction precursors; under the action of chiral diene ligands, a monovalent rhodium carbene-mediated asymmetric borohydride insertion reaction is achieved, and various α-alkyl substituted chiral boranes that are difficult to synthesize by conventional methods can be prepared efficiently and highly selectively;

[0172] (b) The catalytic system has good reaction specificity and can effectively inhibit β-hydrogen migration and intramolecular CH insertion side reactions;

[0173] (c) The method of the present invention uses less catalyst and has good substrate universality;

[0174] (d) The method of the present invention has mild reaction conditions and is easy to operate;

[0175] (e) Chiral boranes can be converted into chiral boron esters, which are useful synthetic building blocks, through some simple methods and conditions;

[0176] (f) The reaction of the present invention has good enantioselectivity, the optical purity of the product is high, and has application prospects in organic synthesis and drug development.

[0177] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for which specific conditions are not specified in the following examples are usually based on normal conditions. Unless otherwise stated, percentages and parts are calculated by weight.

[0178] Example 1

[0179] Synthesis of compound 3-1

[0180] Experiment 1: Chiral diene ligand (R,R)-4a and [Rh(C 2 H 4 ) 2 Cl] 2 Dissolve in dry dichloromethane and stir at room temperature for 1 hour to separate [Rh((R,R)-4a)Cl] 2 The obtained [Rh((R,R)-4a)Cl] 2 The complex (0.0015mmol, 1.5mol%) and N-(3,5-dimethoxybenzyl)tetrahydropyrrolidine borane complex (0.1mmol) were put into a reaction bottle, and after anhydrous and oxygen-free treatment, dichloromethane (1mL) was added, and α-alkyl diazo ester 1-1 (0.25mmol) was added to the system at 25°C to continue the reaction. After the N-(3,5-dimethoxybenzyl)tetrahydropyrrolidine borane complex was completely reacted, the reaction solution was dried and separated by silica gel column chromatography to obtain the product 3-1, which was a colorless oily liquid with a yield of 98% and 96% ee.

[0181] Experiment 2: The ligand (R,R)-4a used in Experiment 1 was replaced by (S,S)-4a. The rest of the experimental operations were the same as Experiment 1, and the product ent 3-1 was obtained as a colorless oily liquid with a yield of 98% and 96% ee.

[0182] Experiment 3: The ligand (R,R)-4a used in Experiment 1 was replaced by (R,R)-4c. The rest of the experimental operations were the same as Experiment 1. The product 3-1 was obtained as a colorless oily liquid with 82% yield and 95% ee.

[0183] Experiment 4: The ligand (R,R)-4a used in Experiment 1 was replaced by (R,R)-4f. The rest of the experimental operations were the same as Experiment 1. The product 3-1 was obtained as a colorless oily liquid with a yield of 93% and 93% ee.

[0184] Experiment 5: The ligand (R,R)-4a used in Experiment 1 was replaced by (R,R)-4h. The rest of the experimental operations were the same as Experiment 1, and the product 3-1 was obtained as a colorless oily liquid with a yield of 91% and 93% ee.

[0185] Experiment 6: The ligand (R,R)-4a used in Experiment 1 was replaced by (R,R)-4i. The rest of the experimental operations were the same as Experiment 1. The product 3-1 was obtained as a colorless oily liquid with a yield of 96% and 93% ee.

[0186] Experiment 7: The ligand (R,R)-4a used in Experiment 1 was replaced by (R,R)-4k. The rest of the experimental operations were the same as Experiment 1. The product 3-1 was obtained as a colorless oily liquid with 84% yield and 92% ee.

[0187] Experiments 8-11: The dichloromethane solvent used in Experiment 1 was replaced with other solvents (dichloroethane, chloroform, toluene, tetrahydrofuran) in turn, and the rest of the experimental operations were the same as Experiment 1, to obtain the product 3-1, which was a colorless oily liquid. Dichloroethane: 91% yield, 95% ee; chloroform: 92% yield, 94% ee; toluene: 90% yield, 93% ee; tetrahydrofuran: 82% yield, 90% ee.

[0188] Experiments 12-13: The 25°C in Experiment 1 was replaced with other temperatures (0°C, -20°C) in turn, and the rest of the experimental operations were the same as Experiment 1, to obtain the product 3-1, which was a colorless oily liquid, 0°C: 97% yield, 96% ee; -20°C: 99% yield, 96% ee.

[0189] Experiments 14-15: The amount of catalyst in Experiment 1 was replaced with other amounts (1.0 mol%, 0.5 mol%) in turn, and the rest of the experimental operations were the same as Experiment 1 to obtain product 3-1, which was a colorless oily liquid. 1.0 mol%: 99% yield, 95% ee; 0.5 mol%: 90% yield, 95% ee.

[0190] Experiment 16: N-(3,5-dimethoxybenzyl)tetrahydropyrrolidine borane complex (0.1 mmol), [Rh((R,R)-4a)Cl] 2 The (0.0015mmol, 1.5mol%) complex was put into a reaction bottle, and after anhydrous and oxygen-free treatment, dichloromethane (1mL) was added, and stirred at 0°C for 10min. α-alkyl diazo ester 1-1 (0.2mmol) was added to the system, and the reaction was continued. After the complete reaction of N-(3,5-dimethoxybenzyl)tetrahydropyrrolidine borane complex was monitored by TLC, the reaction solution was dried and separated by silica gel column chromatography to obtain product 3-1, which was a colorless oily liquid with a yield of 85% and 96% ee.

[0191] Experiment 17: Replace 1 mL of dichloromethane in Experiment 17 with 0.5 mL of dichloromethane. The rest of the experimental operation is the same as Experiment 16. The product 3-1 is obtained as a colorless oily liquid with a yield of 98% and 96% ee.

[0192]

[0193] 1 H NMR (400 MHz, CDCl 3)δ7.27(d,J=5.8Hz,1H),7.25-7.18(m,3H),7.18-7.12(m,1H),6.47(t,J=2.2Hz,1H),6.41 (d,J=2.2Hz,2H),4.04(d,J=13.6Hz,1H),3.92(d,J=13.6Hz,1H),3.79(s,6H),3.26-6.17( m,1H),3.11-3.02(m,1H),2.95-3.83(m,2H),2.78-2.68(m,1H),2.59-2.47(m,1H),2.13-1 .87(m,4H),1.84-1.69(br,2H),1.66-1.54(m,3H),1.49(s,9H).ESI-MS(m / z,%)476[M+Na] + .

[0194] In the subsequent experimental operations, unless otherwise specified, other reaction parameters are carried out with reference to Experiment 1 in Example 1.

[0195] Example 2

[0196] Synthesis of compound 3-2

[0197] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-2 in an amount of 0.12 mmol, and the remaining experimental operations were carried out with reference to Experiment 1 of Example 1 to obtain the product 3-2 as a colorless oily liquid; 92% yield, 94% ee.

[0198]

[0199] 1 H NMR (400 MHz, CDCl 3 )δ7.34-7.22(m,2H),7.23-7.10(m,3H),6.50-6.45(m,1H),6.37(d,J=2.2Hz,2H),3.98 (d,J=13.5Hz,1H),3.83(d,J=13.5Hz,1H),3.79(s,6H),3.20-3.12(m,1H),3.05-2.98( m,1H),2.93-2.87(m,2H),2.81-2.70(m,1H),2.54-2.46(m,1H),2.22-2.03(m,2H),2.0 0-1.78(m,4H),1.73(s,3H),1.72(s,3H),1.66-1.49(m,3H).ESI-MS(m / z,%)530[M+Na] + .

[0200] Example 3

[0201] Synthesis of compound 3-3

[0202] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-3, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-3 as a colorless oily liquid; 92% yield, 80% ee.

[0203]

[0204] 1 H NMR (600 MHz, CDCl 3 )δ7.41-7.35(m,2H),7.33-7.26(m,4H),7.23-7.17(m,2H),7.16-7.11(m,2H),6.50-6.48(m,1 H),6.43(d,J=2.3Hz,2H),4.08(d,J=13.5Hz,1H),4.01(d,J=13.5Hz,1H),3.79(s,6H),3.30-3. 23(m,1H),3.18-3.11(m,1H),3.02-2.93(m,2H),2.91-2.84(m,1H),2.73-2.65(m,1H),2.36-2 .26(m,1H),2.11-1.99(m,5H),1.86-1.77(m,1H),1.72-1.63(m,2H).ESI-MS(m / z,%)496[M+Na] + .

[0205] Example 4

[0206] Synthesis of Compound 3-4

[0207] The N-(3,5-dimethoxybenzyl)tetrahydropyrrolidine borane complex used in Example 1 was replaced with N-methyltetrahydropyrrolidine borane complex, and the remaining experimental operations were referred to Experiment 1 of Example 1 to obtain product 3-4 as a colorless oily liquid; 99% yield, 94% ee.

[0208]

[0209] 1 H NMR (400 MHz, CDCl 3)δ7.29-7.22(m,2H),7.22-7.17(m,2H),7.17-7.11(m,1H),3.24-3.12(m,2H),2.87-2.61(m,3H),2.58( s,3H),2.56-2.46(m,1H),2.09-1.87(m,6H),1.67-1.51(m,3H),1.47(s,9H).ESI-MS(m / z,%)340[M+Na] + .

[0210] Example 5

[0211] Synthesis of Compound 3-5

[0212] The N-(3,5-dimethoxybenzyl)tetrahydropyrrolidine borane complex used in Example 1 was replaced with N-benzyltetrahydropyrrolidine borane complex, and the remaining experimental operations were referred to Experiment 1 of Example 1 to obtain product 3-5 as a colorless oily liquid; 92% yield, 96% ee.

[0213]

[0214] 1 H NMR (400 MHz, CDCl 3 )δ7.53-7.49(m,2H),7.43-7.36(m,3H),7.29-7.20(m,3H),7.19-7.15(m,2H),4.57(t,J=1.2Hz,2H),3.76-3.68(m,2H),3.25-3.17(m,2H) ,2.90(t,J=5.6Hz,1H),2.80-2.73(m,1H),2.68-2.59(m,1H),2.49-2.40(m,1H),2.07-1.89(m,5H),1.41(s,9H).ESI-MS(m / z,%)416[M+Na] + .

[0215] Example 6

[0216] Synthesis of Compound 3-6

[0217] The N-(3,5-dimethoxybenzyl)tetrahydropyrrolidine borane complex used in Example 1 was replaced with N-(4-methoxybenzyl)tetrahydropyrrolidine borane complex, and the remaining experimental operations were referred to Experiment 1 of Example 1 to obtain product 3-6 as a colorless oily liquid; 94% yield, 96% ee.

[0218]

[0219] 1H NMR (400 MHz, CDCl 3 )δ7.31-7.13(m,9H),6.87(d,J=8.8Hz,2H),4.03(d,J=13.7Hz,1H),3.93(d,J=13.7Hz,1H),3.82(s,3H),3.22-3.13(m,1H),3.10-3.01(m, 1H),2.89-2.69(m,3H),2.56-2.47(m,2H),2.14-1.86(m,4H),1.80-1.72(m,3H),1.66-1.51(m,1H),1.49(s,9H).ESI-MS(m / z,%)446[M+Na] + .

[0220] Example 7

[0221] Synthesis of Compound 3-7

[0222] The N-(3,5-dimethoxybenzyl)tetrahydropyrrolidine borane complex used in Example 1 was replaced with 3,5-dimethylpyridine borane complex, and the remaining experimental operations were referred to Experiment 1 of Example 1 to obtain product 3-7 as a colorless oily liquid; 96% yield, 93% ee.

[0223]

[0224] 1 H NMR (400 MHz, CDCl 3 )δ9.07(d,J=1.4Hz,2H),8.51(s,1H),7.35-7.21(m,3H),7.19-7.13(m,2H),2.87(t,J=5.7Hz,1H),2.81-2.74(m, 1H),2.68-2.61(m,1H),2.58(s,6H),2.51-2.40(m,1H),2.01-1.90(m,1H),1.41(s,9H).ESI-MS(m / z,%)362[M+Na] + .

[0225] Example 8

[0226] Synthesis of Compound 3-8

[0227] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-4, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain product 3-8 as a colorless oily liquid; 99% yield, 96% ee.

[0228]

[0229] 1 H NMR (600 MHz, CDCl 3 )δ7.14(t,J=7.5Hz,1H),7.03(s,1H),7.01(d,J=7.6Hz,1H),6.96(d,J=7.5Hz,1H),6.48-6.46(m,1H),6.4 3-6.40(m,2H),4.04(d,J=13.6Hz,1H),3.93(d,J=13.6Hz,1H),3.79(s,6H),3.25-3.18(m,1H),3.11-3.04 (m,1H),2.89(ddt,J=14.8,10.9,7.4Hz,2H),2.73-2.65(m,1H),2.54-2.46(m,1H),2.31(s,3H),2.09-2.0 2(m,1H),2.02-1.92(m,2H),1.89-1.67(m,3H),1.65-1.54(m,3H),1.49(s,9H).ESI-MS(m / z,%)490[M+Na] + .

[0230] Example 9

[0231] Synthesis of Compound 3-9

[0232] The α-alkyl tert-butyl diazonium ester used in Example 1 was replaced with 1-1 to 1-5, and the rest of the experimental operations were referred to Experiment 1 of Example 1 to obtain product 3-9 as a colorless oily liquid; 99% yield, 95% ee.

[0233]

[0234] 1 H NMR (600 MHz, CDCl 3 )δ7.27-7.22(m,2H),7.21-7.16(m,2H),7.16-7.10(m,1H),6.53-6.40(m ,3H),4.07(d,J=13.3Hz,1H),3.98(d,J=13.3Hz,1H),3.79(s,6H),3.27-3 .17(m,1H),3.15-3.05(m,1H),2.97-2.84(m,2H),2.68-2.52(m,2H),2.0 4-1.92(m,2H),1.82-1.52(m,9H),1.43(s,9H).ESI-MS(m / z,%)490[M+Na] + .

[0235] Example 10

[0236] Synthesis of Compound 3-10

[0237] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-6, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-10 as a colorless oily liquid; 98% yield, 95% ee.

[0238]

[0239] 1 H NMR (600 MHz, CDCl 3 )δ7.10(d,J=8.3Hz,2H),6.80(d,J=8.3Hz,2H),6.46(d,J=9.7Hz,3H),4.06(d,J=13 .6Hz,1H),3.98(d,J=13.6Hz,1H),3.79(s,6H),3.77(s,3H),3.25-3.18(m,1H),3.13 -3.05(m,1H),2.97-2.85(m,2H),2.61-2.50(m,2H),2.04-1.93(m,2H),1.81-1.69( m,4H),1.66-1.54(m,4H),1.44(s,9H),1.40-1.32(m,1H).ESI-MS(m / z,%)520[M+Na] + .

[0240] Embodiment 11

[0241] Synthesis of compound 3-11

[0242] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-7, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-11 as a colorless oily liquid; 99% yield, 98% ee.

[0243]

[0244] 1 H NMR (600 MHz, CDCl 3)δ7.21(d,J=8.1Hz,2H),7.11(d,J=8.0Hz,2H),6.49-6.43(m,3H),4.10-3. 95(m,2H),3.79(s,6H),3.26-3.18(m,1H),3.13-3.06(m,1H),2.97-2.86(m ,2H),2.64-2.53(m,J=7.2Hz,2H),2.04-1.94(m,2H),1.82-1.68(m,3H),1. 65-1.53(m,5H),1.43(s,9H),1.38-1.30(m,1H).ESI-MS(m / z,%)524[M+Na] + .

[0245] Example 12

[0246] Synthesis of Compound 3-12

[0247] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-8, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-12 as a colorless oily liquid; 99% yield, 95% ee.

[0248]

[0249] 1 H NMR (600 MHz, CDCl 3 )δ7.3-7.21(m,2H),7.20-7.11(m,3H),6.51-6.43(m,3H),4.07(d,J=13.4H z,1H),3.99(d,J=13.4Hz,1H),3.79(s,6H),3.26-3.17(m,1H),3.15-3.04( m,1H),2.97-2.85(m,2H),2.67-2.52(p,J=8.6Hz,2H),2.07-2.18(m,3H),1 .77-1.55(m,8H),1.43(s,9H),1.38-1.29(m,2H).ESI-MS(m / z,%)504[M+Na] + .

[0250] Example 13

[0251] Synthesis of Compound 3-13

[0252] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-9, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-13 as a colorless oily liquid; 99% yield, 97% ee.

[0253]

[0254] 1 H NMR (600 MHz, CDCl 3 )δ7.07(dd,J=5.1,1.0Hz,1H),6.90(dd,J=5.1,3.4Hz,1H),6.79(d,J=2.5Hz,1H),6.47(t,J=2.2Hz ,1H),6.43(d,J=2.2Hz,2H),4.05(d,J=13.6Hz,1H),3.94(d,J=13.6Hz,1H),3.79(s,6H),3.26-3.19 (m,1H),3.12-3.06(m,1H),2.94-2.87(m,3H),2.82-2.75(m,1H),2.18-2.10(m,1H),2.05-1.93(m,3 H),1.86-1.75(m,2H),1.71-1.66(m,1H),1.64-1.56(m,2H),1.48(s,9H).ESI-MS(m / z,%)482[M+Na] + .

[0255] Embodiment 14

[0256] Synthesis of Compound 3-14

[0257] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-10, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1 to obtain the product 3-14 as a colorless oily liquid; 98% yield, 95% ee.

[0258]

[0259] 1 H NMR (600 MHz, CDCl 3)δ7.07(d,J=6.0Hz,1H),6.89(dd,J=5.0,3.4Hz,1H),6.78(d,J=3.2Hz,1H),6.47(dd,J=9 .4,2.1Hz,3H),4.07(d,J=13.6Hz,1H),3.99(d,J=13.6Hz,1H),3.80(s,6H),3.28-3.19(m ,1H),3.16-3.06(m,1H),2.99-2.87(m,2H),2.87-2.78(m,2H),2.04-1.95(m,2H),1.84-1 .72(m,4H),1.71-1.59(m,4H),1.45(s,9H),1.43-1.37(m,1H).ESI-MS(m / z,%)496[M+Na] + .

[0260] Embodiment 15

[0261] Synthesis of Compound 3-15

[0262] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-11, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-15 as a colorless oily liquid; 89% yield, 96% ee.

[0263]

[0264] 1 H NMR (400 MHz, CDCl 3 )δ7.26(s,1H),6.51-6.44(m,3H),6.25(dd,J=3.0,1.9Hz,1H),6.01-5.92(m, 1H),4.11-3.96(m,2H),3.80(s,6H),3.28-3.19(m,1H),3.16-3.07(m,1H),2. 98-2.85(m,2H),2.62(t,J=7.5Hz,2H),2.07-1.95(m,2H),1.85-1.69(m,4H), 1.66-1.52(m,4H),1.45(s,9H),1.40-1.34(m,1H).ESI-MS(m / z,%)480[M+Na] + .

[0265] Example 16

[0266] Synthesis of Compound 3-16

[0267] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-12, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-16 as a colorless oily liquid; 99% yield, 86% ee.

[0268]

[0269] 1 H NMR (600 MHz, CDCl 3 )δ6.49-6.46(m,3H),4.10(d,J=13.6Hz,1H),4.01(d,J=13.6Hz,1H),3.80(s,6H),3.30-3.22(m,1H),3.17-3.10(m,1H),2.99-2. 87(m,2H),2.08-1.97(m,2H),1.87-1.74(m,2H),1.72-1.54(m,3H),1.45(s,9H),1.08(d,J=6.9Hz,3H).ESI-MS(m / z,%)386[M+Na] + .

[0270] Embodiment 17

[0271] Synthesis of Compound 3-17

[0272] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-13, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-17 as a colorless oily liquid; 83% yield, 96% ee.

[0273]

[0274] 1 H NMR (600 MHz, CDCl 3 )δ6.50-6.43(m,3H),4.09(d,J=13.6Hz,1H),4.00(d,J=13.6Hz,1H),3.80(s,6H),3.28-3.20(m,1H),3.16-3.09(m,1H),2.99-2.88(m,2H) ,2.06-1.95(m,2H),1.74-1.67(m,1H),1.65-1.55(m,3H),1.46(s,9H),1.41-1.33(m,1H),0.93(t,J=7.2Hz,3H).ESI-MS(m / z,%)400[M+Na] + .

[0275] Embodiment 18

[0276] Synthesis of Compound 3-18

[0277] The α-alkyl diazonium tert-butyl ester 1-1 used in Example 1 was replaced by 1-14, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-18 as a colorless oily liquid; 99% yield, 96% ee.

[0278]

[0279] 1 H NMR (600 MHz, CDCl 3 )δ6.50-6.44(m,3H),4.12-3.96(m,2H),3.80(s,6H),3.27-3.20(m,1H),3.16-3.08(m,1H),2.97-2.87(m,2H),2.07-1.95(m,2H),1.8 0-1.67(m,3H),1.66-1.54(m,2H),1.45(s,9H),1.42-1.33(m,1H),1.32-1.21(m,2H),0.89(t,J=7.2Hz,3H).ESI-MS(m / z,%)414[M+Na] + .

[0280] Embodiment 19

[0281] Synthesis of Compound 3-19

[0282] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-15, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-19 as a colorless oily liquid; 99% yield, 96% ee.

[0283]

[0284] 1 H NMR (600 MHz, CDCl 3 )δ6.50-6.45(m,3H),4.09(d,J=13.6Hz,1H),4.00(d,J=13.0Hz,1H),3.80(s,6H),3.26-3.20(m,1H),3.15-3.09(m,1H),2.98-2.87(m,2H) ,2.06-1.95(m,2H),1.75-1.68(m,2H),1.66-1.52(m,4H),1.45(s,9H),1.36-1.24(m,5H),0.88(t,J=6.1Hz,3H).ESI-MS(m / z,%)428[M+Na] +

[0285] Embodiment 20

[0286] Synthesis of Compound 3-20

[0287] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-16, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-20 as a colorless oily liquid; 95% yield, 96% ee.

[0288]

[0289] 1 H NMR (400 MHz, CDCl 3 )δ6.47(s,3H),4.13-3.96(m,2H),3.80(s,6H),3.28-3.18(m,1H),3.16-3.08(m,1H),3.00-2.87(m,2H),2.07-1 .94(m,2H),1.88-1.52(m,6H),1.45(s,9H),1.37-1.22(m,7H),0.88(t,J=6.8Hz,3H).ESI-MS(m / z,%)442[M+Na] + .

[0290] Embodiment 21

[0291] Synthesis of compound 3-21

[0292] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-17, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-21 as a colorless oily liquid; 88% yield, 96% ee.

[0293]

[0294] 1 H NMR (400 MHz, CDCl 3 )δ6.47(s,3H),4.09(d,J=13.6Hz,1H),4.00(d,J=13.6Hz,1H),3.80(s,6H),3.28-3.19(m,1H),3.17-3.16(m,1H),2.98-2.85(m,2H), 2.07-1.93(m,2H),1.71(br,2H),1.65-1.54(m,2H),1.45(s,9H),1.33-1.21(m,9H),0.87(t,J=6.0Hz,3H).ESI-MS(m / z,%)456[M+Na] + .

[0295] Embodiment 22

[0296] Synthesis of Compound 3-22

[0297] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-18, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-22 as a colorless oily liquid; 95% yield, 96% ee.

[0298]

[0299] 1 H NMR (400 MHz, CDCl 3 )δ6.47(s,3H),4.13-3.96(m,2H),3.80(s,6H),3.29-3.18(m,1H),3.16-3.06(m,1H),3.00-2.85(m,2H),2.07-1.95(m, 2H),1.70(s,2H),1.65-1.53(m,2H),1.45(s,9H),1.37-1.20(m,23H),0.88(t,J=6.8Hz,3H).ESI-MS(m / z,%)540[M+Na] + .

[0300] Embodiment 23

[0301] Synthesis of Compound 3-23

[0302] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-19, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-23 as a colorless oily liquid; 85% yield, 95% ee.

[0303]

[0304] 1 H NMR (600 MHz, CDCl 3 )δ6.47(s,3H),4.15-3.96(m,2H),3.80(s,6H),3.27-3.20(m,1H),3.1 5-3.07(m,1H),3.00-2.85(m,2H),2.06-1.96(m,2H),1.95-1.81(m,2H) ,1.73-1.79(m,1H),1.68-1.51(m,4H),1.44(s,9H),1.10-1.00(m,1H),0.89(d,J=3.0Hz,3H),0.88(d,J=3.0Hz,3H).ESI-MS(m / z,%)428[M+Na] + .

[0305] Embodiment 24

[0306] Synthesis of Compound 3-24

[0307] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-20, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain product 3-24 as a colorless oily liquid; 89% yield, 94% ee.

[0308]

[0309] 1 H NMR (600 MHz, CDCl 3 )δ6.47(s,3H),4.09(d,J=13.4Hz,1H),4.00(d,J=13.4Hz,1H),3.80(s,6H),3.27-3.19(m,1H),3.16-3.07(m,1H),2.98-2.86(m,2H), 2.08-1.95(m,2H),1.78-1.50(m,7H),1.45(s,9H),1.36-1.27(m,1H),1.24-1.16(m,2H),0.91-0.82(m,6H).ESI-MS(m / z,%)442[M+Na] + .

[0310] Embodiment 25

[0311] Synthesis of Compound 3-25

[0312] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-21, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-25 as a colorless oily liquid; 52% yield, 92% ee.

[0313]

[0314] 1 H NMR (600 MHz, CDCl 3)δ6.47(s,3H),4.13 - 3.97(m,2H),3.80(s,6H),3.22(td,J=10.2,8.8,4.6Hz,1H),3.11(dt,J=11.9,6.5Hz,1H),2.99 - 2.87(m,2H),1.99(tt,J=13.7,6.9Hz,2H),1.88(d,J=8.6Hz,2H),1.76 - 1.60(m,8H),1.45(s,9H),1.32 - 1.06(m,6H),0.95 - 0.85(m,1H),0.84 - 0.75(m,1H).ESI-MS(m / z,%)462[M + Na] + .

[0315] Example 26

[0316] Synthesis of Compound 3 - 26

[0317] Replace the α-alkyl diazo tert-butyl ester 1 - 1 used in Example 1 with 1 - 22, and refer to Experiment 1 of Example 1 for the remaining experimental operations to obtain the product 3 - 26, which is a colorless oily liquid; 95% yield, 96% ee.

[0318]

[0319] 1 H NMR(600MHz,CDCl 3 )δ6.47(s,3H),4.09(d,J=12.6Hz,1H),4.00(d,J=13.1Hz,1H),3.80(s,6H),3.29 - 3.19(m,1H),3.17 - 3.08(m,1H),2.99 - 2.86(m,2H),2.11 - 1.97(m,2H),1.86 - 1.69(m,3H),1.66 - 1.54(m,2H),1.44(s,9H),1.38 - 1.25(m,2H),1.23 - 0.16(m,2H),0.71 - 0.61(m,1H),0.41 - 0.30(m,2H),0.07--0.08(m,2H).ESI-MS(m / z,%)417[M + Na] + .

[0320] Example 27

[0321] Synthesis of Compound 3 - 27

[0322] Replace the α-alkyl diazo tert-butyl ester 1 - 1 used in Example 1 with 1 - 23, and refer to Experiment 1 of Example 1 for the remaining experimental operations to obtain the product 3 - 27, which is a colorless oily liquid; 57% yield, 85% ee.

[0323]

[0324] 1 H NMR(600MHz,CDCl 3 ) δ 7.32 (d, J = 7.2 Hz, 2H), 7.29 - 7.24 (m, 2H), 7.15 (t, J = 7.3 Hz, 1H), 6.47 (s, 3H), 6.42 - 6.37 (m, 1H), 6.35 - 6.29 (m, 1H), 4.07 (dd, J = 13.7 Hz, 1H), 4.03 (d, J = 13.6 Hz, 1H), 3.80 (s, 6H), 3.28 - 3.21 m, 1H), 3.19 - 3.10 (m, 1H), 3.01 - 2.89 (m, 2H), 2.62 - 2.54 (m, 1H), 2.26 - 2.18 (m, 1H), 2.05 - 1.96 (m, 2H), 1.92 - 1.86 (m, 1H), 1.77 - 1.54 (m, 3H), 1.44 (s, 9H). ESI-MS (m / z, %) 488 [M+Na] + .

[0325] Example 28

[0326] Synthesis of Compound 3 - 28

[0327] Replace the α-alkyl diazo tert-butyl ester 1 - 1 used in Example 1 with 1 - 24, and refer to Experiment 1 of Example 1 for the remaining experimental operations to obtain the product 3 - 28, which is a colorless oily liquid; 82% yield, 99% ee.

[0328]

[0329] 1 H NMR(400MHz,CDCl 3 ) δ 6.52 - 6.42 (m, 3H), 4.04 (dd, J = 21.0, 13.6 Hz, 2H), 3.80 (s, 6H), 3.44 - 3.35 (m, 2H), 3.32 (s, 3H), 3.28 - 3.19 (m, 1H), 3.17 - 3.08 (m, 1H), 2.99 - 2.86 (m, 2H), 2.09 - 1.96 (m, 2H), 1.74 - 1.51 (m, 7H), 1.45 (s, 9H). ESI-MS (m / z, %) 444 [M+Na] + .

[0330] Example 29

[0331] Synthesis of Compound 3 - 29

[0332] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-25, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-29 as a colorless oily liquid; 83% yield, 96% ee.

[0333]

[0334] 1 H NMR (400 MHz, CDCl 3 )δ6.51-6.43(m,3H),4.08(d,J=13.5Hz,1H),3.99(d,J=13.5Hz,1H),3. 80(s,6H),3.42-3.35(m,2H),3.32(s,3H),3.28-3.19(m,1H),3.17-2.0 7(m,1H),2.99-2.86(m,2H),2.08-1.96(m,2H),1.76-1.66(m,2H),1.67 -1.51(m,5H),1.45(s,9H),1.37-1.31(m,2H).ESI-MS(m / z,%)458[M+Na] + .

[0335] Embodiment 30

[0336] Synthesis of Compound 3-30

[0337] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-26, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-30 as a colorless oily liquid; 95% yield, 97% ee.

[0338]

[0339] 1 H NMR (600 MHz, CDCl 3 )δ6.85-6.79(m,4H),6.47(t,J=2.2Hz,1H),6.45(d,J=2.2Hz,2H),4.08(d,J= 13.6Hz,1H),3.99(d,J=13.6Hz,1H),3.97-3.87(m,2H),3.79(s,6H),3.76(s,3 H),3.28-3.21(m,1H),3.16-3.08(m,1H),2.98-2.87(m,2H),2.08-1.94(m,2H) ,1.86-1.72(m,5H),1.64-1.50(m,4H),1.45(s,9H).ESI-MS(m / z,%)536[M+Na] + .

[0340] Embodiment 31

[0341] Synthesis of compound 3-31

[0342] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-27, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-31 as a colorless oily liquid; 99% yield, 96% ee.

[0343]

[0344] 1 H NMR (400 MHz, CDCl 3 )δ6.43(s,3H),4.12-3.90(m,2H),3.76(s,6H),3.55(t,J=6.7Hz,2H),3 .25-3.13(m,1H),3.12-3.02(m,1H),2.97-2.82(m,2H),2.03-1.91(m,2H ),1.77-1.62(m,4H),1.62-1.52(m,2H),1.50-1.43(m,2H),1.41(s,9H) ,1.31-1.20(m,5H),0.85(s,9H),0.00(s,6H).ESI-MS(m / z,%)586[M+Na] + .

[0345] Embodiment 32

[0346] Synthesis of Compound 3-32

[0347] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-28, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-32 as a colorless oily liquid; 91% yield, 96% ee.

[0348]

[0349] 1 H NMR (400 MHz, CDCl 3 )δ6.53-6.43(m,3H),4.14-3.96(m,4H),3.81(s,6H),3.32-3.21(m,1H),3.16-3.07(m,1H),3.02-2.87( m,2H),2.10-1.94(m,6H),1.84-1.74(m,2H),1.72-1.52(m,4H),1.45(s,9H).ESI-MS(m / z,%)458[M+Na] + .

[0350] Embodiment 33

[0351] Synthesis of Compound 3-33

[0352] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-29, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1 to obtain the product 3-33 as a colorless oily liquid; 96% yield, 97% ee.

[0353]

[0354] 1 H NMR (600 MHz, CDCl 3 )δ8.04(d,J=7.2Hz,2H),7.53(s,1H),7.42(t,J=7.1Hz,2H),6.46(s,3H),4. 37-4.26(m,2H),4.13-3.96(m,2H),3.80(s,6H),3.31-3.18(m,1H),3.17-3.0 3(m,1H),3.01-2.82(m,2H),2.08-1.95(m,2H),1.84-1.69(m,5H),1.60-1.48 (m,2H),1.44(s,9H),1.38-1.31(d,J=22.9Hz,2H).ESI-MS(m / z,%)548[M+Na] + .

[0355] Embodiment 34

[0356] Synthesis of Compound 3-34

[0357] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-30, and the remaining experimental operations were carried out with reference to Experiment 1 of Example 1 to obtain the product 3-34 as a white solid; 91% yield, 97% ee.

[0358]

[0359] 1 H NMR (600 MHz, CDCl 3)δ7.78(d,J=8.3Hz,2H),7.34(d,J=8.0Hz,2H),6.50-6.44(m,3H),4.07 (d,J=13.6Hz,1H),4.02-3.98(m,3H),3.80(s,6H),3.25-3.18(m,1H),3. 14-3.08(m,1H),2.97-2.88(m,2H),2.45(s,3H),2.05-1.94(m,2H),1.71 -1.60(m,7H),1.44(s,9H),1.33-1.18(m,8H).ESI-MS(m / z,%)626[M+Na] + .

[0360] Embodiment 35

[0361] Synthesis of Compound 3-35

[0362] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-31, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1 to obtain the product 3-35 as a colorless oily liquid; 99% yield, 97% ee.

[0363]

[0364] 1 H NMR (600 MHz, CDCl 3 )δ6.52-6.42(m,3H),4.11(q,J=7.0Hz,2H),4.08(d,J=14.0Hz,1H),3.99(d,J=1 4.0Hz,1H),3.80(s,6H),3.25-3.19(m,1H),3.15-3.08(m,1H),2.97-2.89(m,2H ),2.34-2.24(m,2H),2.04-1.95(m,2H),1.84-1.72(m,2H),1.69-1.53(m,5H),1 .45(s,9H),1.36-1.28(m,2H),1.25(t,J=7.0Hz,3H).ESI-MS(m / z,%)500[M+Na] + .

[0365] Embodiment 36

[0366] Synthesis of Compound 3-36

[0367] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-32, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1 to obtain the product 3-36 as a colorless oily liquid; 98% yield, 98% ee.

[0368]

[0369] 1 H NMR (600 MHz, CDCl 3 )δ7.82(dd,J=5.4,3.0Hz,2H),7.68(dd,J=5.4,3.0Hz,2H),6.47(s,3H),4.06(d, J=13.6Hz,1H),4.00(d,J=13.6Hz,1H),3.80(s,6H),3.76-3.64(m,2H),3.27-3.1 9(m,1H),3.14-3.07(m,1H),2.99-2.87(m,2H),2.04-1.94(m,2H),1.82-1.74(m, 3H),1.69-1.54(m,5H),1.42(s,9H),1.39-1.32(m,1H).ESI-MS(m / z,%)559[M+Na] + .

[0370] Embodiment 37

[0371] Synthesis of Compound 3-37

[0372] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-33, and the remaining experimental operations were carried out with reference to Experiment 1 of Example 1 to obtain the product 3-37 as a colorless liquid; 94% yield, 96% ee.

[0373]

[0374] 1 H NMR (600 MHz, CDCl 3 )δ7.83(dd,J=5.4,3.1Hz,2H),7.70(dd,J=5.5,3.0Hz,2H),6.51-6.43(m,3H),4.08(d,J =13.6Hz,1H),3.99(d,J=13.6Hz,1H),3.80(s,6H),3.67(t,J=7.4Hz,2H),3.27-3.19(m, 1H),3.15-3.06(m,1H),2.97-2.86(m,2H),2.03-1.93(m,2H),1.82-1.70(br,2H),1.70- 1.64(m,4H),1.63-1.53(m,2H),1.44(s,9H),1.38-1.26(m,7H).ESI-MS(m / z,%)601[M+H] + .

[0375] Embodiment 38

[0376] Synthesis of Compound 3-38

[0377] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-34, and the remaining experimental operations were carried out with reference to Experiment 1 of Example 1 to obtain the product 3-38 as a colorless oily liquid; 92% yield, 96% ee.

[0378]

[0379] 1 H NMR (600 MHz, CDCl 3 )δ7.54(d,J=7.8Hz,1H),7.28(d,J=8.2Hz,1H),7.17(t,J=7.6Hz,1H),7.07(t,J=7.8H z,1H),6.86(s,1H),6.51-6.41(m,3H),4.11-3.96(m,4H),3.79(s,6H),3.24-3.18(m, 1H),3.14-3.05(m,1H),2.97-2.85(m,2H),2.31(s,3H),2.05-1.93(m,2H),1.86-1.74 (m,3H),1.72-1.53(m,5H),1.44(s,9H),1.36-1.25(m,7H).ESI-MS(m / z,%)585[M+Na] + .

[0380] Embodiment 39

[0381] Synthesis of Compound 3-39

[0382] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-35, and the remaining experimental operations were carried out with reference to Experiment 1 of Example 1 to obtain the product 3-39 as a white solid; 81% yield, 99% ee.

[0383]

[0384] 1 H NMR (400 MHz, CDCl 3)δ7.93-7.86(m,2H),7.66-7.60(m,1H),7.58-7.51(m,2H),6.48(t,J=2.2Hz,1H),6.44(d, J=2.2Hz,2H),3.99(dd,J=13.5,10.9Hz,2H),3.80(s,6H),3.23-3.13(m,1H),3.12-3.03(m 3H),2.97-2.84(m,2H),2.04-2.91(m,2H),1.77-1.66(m,4H),1.63-1.53(m,3H),1.36(s,9H).ESI-MS(m / z,%)554[M+Na] + .

[0385] Embodiment 40

[0386] Synthesis of Compound 3-40

[0387] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-36, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-40 as a colorless oily liquid; 92% yield, 95% ee.

[0388]

[0389] 1 H NMR (400 MHz, CDCl 3 )δ6.53-6.43(m,3H),4.14-3.96(m,4H),3.81(s,6H),3.32-3.21(m,1H),3.16-3.07(m,1H),3.02-2.87( m,2H),2.10-1.94(m,6H),1.84-1.74(m,2H),1.72-1.52(m,4H),1.45(s,9H).ESI-MS(m / z,%)472[M+Na] + .

[0390] Embodiment 41

[0391] Synthesis of Compound 3-41

[0392] The α-alkyl diazonium tert-butyl ester 1-1 used in Example 1 was replaced with 1-37, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-41 as a colorless oily liquid; 84% yield, 94% ee.

[0393]

[0394] 1 H NMR (400 MHz, CDCl 3)δ6.47(s,3H),5.11(t,J=6.8Hz,1H),4.13-3.96(m,2H),3.80(s,6H),3.27-3.18(m,1H),3.17-3.08(m,1H),2.99-2.85(m,2H),2.05- 1.92(m,4H),1.72-1.55(m,10H),1.45(s,9H),1.40-1.23(m,4H),1.22-1.06(m,2H),0.87(d,J=6.4Hz,3H).ESI-MS(m / z,%)510[M+Na] + .

[0395] Embodiment 42

[0396] Synthesis of Compound 3-42

[0397] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced with 1-38, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-42 as a colorless oily liquid; 93% yield, 95% ee.

[0398]

[0399] 1 H NMR (400 MHz, CDCl 3 )δ6.54-6.42(m,3H),4.14-3.96(m,2H),3.80(s,6H),3.29-3.18(m,1H),3.07-3.17(m,1H),3.02-2.87( m,2H),2.14-1.95(m,4H),1.84-1.50(m,8H),1.45(s,9H),1.41-1.32(m,1H).ESI-MS(m / z,%)482[M+Na] + .

[0400] Embodiment 43

[0401] Synthesis of Compound 3-43

[0402] The α-alkyl tert-butyl diazonium ester 1-1 used in Example 1 was replaced by 1-39, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-43 as a colorless oily liquid; 99% yield, 97% ee.

[0403]

[0404] 1 H NMR (600 MHz, CDCl 3)δ6.47(dd,J=9.4,2.2Hz,3H),4.11-3.97(m,2H),3.81(s,6H),3.61-3.49(m,2H),3.27-3.18(m,1H),3.15-3.09(m,1H) ),2.98-2.89(m,2H),2.07-1.93(m,2H),1.89-1.54(m,8H),1.53-1.47(m,1H),1.45(s,9H).ESI-MS(m / z,%)448[M+Na] + .

[0405] Embodiment 44

[0406] Synthesis of Compound 3-44

[0407] The α-alkyl diazonium tert-butyl ester 1-1 used in Example 1 was replaced by 1-40, and the rest of the experimental operations were carried out with reference to Experiment 1 of Example 1, to obtain the product 3-44 as a colorless oily liquid; 94% yield, 95% ee.

[0408]

[0409] 1 H NMR (400 MHz, CDCl 3 )δ6.53-6.41(m,3H),4.61-4.31(m,2H),4.14-3.96(m,2H),3.81(s,6H),3.32-3.22(m,1H),3.17-3.07( m,1H),3.02-2.90(m,2H),2.19-1.87(m,5H),1.83-1.57(m,4H),1.45(s,9H).ESI-MS(m / z,%)418[M+Na] + .

[0410] Embodiment 45

[0411] Synthesis of compound 4

[0412] Dimethyl imidazole iodide was put into a reaction flask, treated with anhydrous and oxygen-free conditions, and then added with dry tetrahydrofuran (20 mL). NaHMDS (2 mL, 2M in THF, 4 mmol) was slowly added dropwise at -78 °C. After stirring at -78 °C for 1 hour, 3-1 (101.2 mg, 0.5 mmol, 96% ee, dissolved in 2 mL tetrahydrofuran) was added to the system. The temperature was raised to 45 °C and the reaction was continued for 8 hours. After the reaction was completed as monitored by TLC, the reaction was moved to room temperature and saturated ammonium chloride solution was added dropwise to quench the reaction. The reaction was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated to remove the solvent. The residue was separated by silica gel column chromatography to obtain product 4 as a white solid with a yield of 88% and 94% ee.

[0413]

[0414] 1 H NMR (600 MHz, CDCl 3 )δ7.26-7.19(m,4H),7.13(t,J=7.0Hz,1H),6.80(s,2H),3.74(s,6H),2.73-2.65(m,1H),2.58-2.5 2(m,1H),2.11-2.03(m,1H),1.82(s,1H),1.72-1.52(m,3H),1.27(s,9H).ESI-MS(m / z,%)264[M+Na] + .

[0415] Embodiment 46

[0416] Synthesis of compound 6

[0417] Azacarbene borane adduct 4 (101.2 mg, 0.5 mmol, 94% ee) was placed in a reaction flask, treated with anhydrous and oxygen-free conditions, and dry tetrahydrofuran (20 mL) was added. DIBAL-H (2 mL, 1 M in Toluene, 2 mmol) was slowly added dropwise at -78 °C. The mixture was transferred to room temperature and stirred for 6 hours. Celite was added to the system, and water was used for quenching. After stirring for 1 hour, the mixture was filtered. The filtrate was dried to obtain the intermediate alcohol 5, which was directly used for the next step. Intermediate 5 was added to a reaction flask, treated with anhydrous and oxygen-free conditions, and then added with dry dichloromethane (20 mL), DIPEA (3 equivalents) and MOMCl (1.5 equivalents), and reacted for 2 hours. After the reaction was completed as monitored by TLC, a saturated aqueous sodium bicarbonate solution was added to the system for quenching, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and filtering. The organic phase was rotary evaporated to remove the solvent, and the residue was separated by silica gel column chromatography to obtain product 6, a colorless oily liquid with a yield of 68% and 92% ee.

[0418]

[0419] 1 H NMR (600 MHz, CDCl 3 )δ7.24-7.20(m,2H),7.19-7.17(m,2H),7.13-7.09(m,1H),6.79(s,2H),4.61-4.54(m,2H),3.74(s,6H),3.50-3.45(m,1H),3. 41-3.38(m,1H),3.33(s,3H),2.73-2.62(m,2H),1.91-1.81(m,1H),1.55-1.48(m,1H),1.03(s,1H).ESI-MS(m / z,%)325[M+Na] + .

[0420] Embodiment 47

[0421] Synthesis of compound 7

[0422] Intermediate 6 (101.2 mg, 0.5 mmol, 92% ee) and pinacol (2 equivalents) were placed in a reaction flask, 20 mL of acetonitrile was added to dissolve, NCS (1.1 equivalents, dissolved in acetonitrile) was slowly added dropwise, and after stirring at room temperature for 1 hour, saturated sodium bicarbonate aqueous solution was added to the system for quenching, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, filtering, and removing the solvent on a rotary evaporator. The residue was separated by silica gel column chromatography to obtain product 7, a colorless oily liquid with a yield of 96% and 92% ee.

[0423]

[0424] 1 H NMR (600 MHz, CDCl 3 )δ7.28-7.24(m,2H),7.21-7.14(m,3H),4.60(s,2H),3.66-3.58(m,2H),3.35(s,3H),2.70- 2.56(m,2H),1.87-1.70(m,2H),1.47-1.40(m,1H),1.26(s,12H).ESI-MS(m / z,%)343[M+Na] + .

[0425] Examples 48-53

[0426] After obtaining the key chiral boron ester intermediate, a variety of chiral functional group compounds can be further synthesized, such as chiral alcohols, chiral amines, and chiral alkyl and chirality-preserving aromatic coupling products.

[0427]

[0428] Embodiment 48

[0429] Synthesis of compound 8

[0430] Intermediate 7 (32 mg, 0.1 mmol, 92% ee) was placed in a reaction flask, 2 mL of tetrahydrofuran and water were added to dissolve, and NaBO 3 (2 equivalents), after stirring at room temperature for 12 hours, ethyl acetate was added to the system for extraction, dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator. The residue was separated by silica gel column chromatography to obtain product 8, a colorless oily liquid, 92% yield, 92% ee.

[0431] 1 H NMR (400 MHz, CDCl 3 )δ7.32-7.25(m,2H),7.24-7.16(m,3H),4.71-4.61(m,2H),3.79(br,1H),3.62(dd,J=10.3,2.9Hz,1H),3.43(dd,J =10.3,7.5Hz,1H),3.38(s,3H),2.89-2.77(m,1H),2.76-2.65(m,2H),1.87-1.68(m,3H).ESI-MS(m / z,%)211[M+H] + .

[0432] Embodiment 49

[0433] Synthesis of compound 9

[0434] Benzylhydroxylamine (3 equivalents) was placed in a reaction bottle, and after anhydrous and oxygen-free treatment, 2 mL of anhydrous tetrahydrofuran was added to dissolve it. n-Butyl lithium (3 equivalents) was slowly added dropwise at -78°C and stirred for 1 hour. A tetrahydrofuran solution of intermediate 7 (32 mg, 0.1 mmol, 92% ee) was added. After stirring at 60°C for 12 hours, triethylamine and benzoic anhydride were added to the system. After stirring at room temperature for 6 hours, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator. The residue was separated by silica gel column chromatography to obtain product 9 as a white solid with a yield of 76% and 92% ee.

[0435] 1 H NMR (400 MHz, CDCl 3)δ7.78-7.72(m,2H),7.50(dd,J=8.4,6.3Hz,1H),7.43(t,J=7.4Hz,2H),7.29 (d,J=7.4Hz,1H),7.24-7.15(m,3H),6.53(d,J=8.8Hz,1H),4.70-4.61(m,2H) ,4.48-4.33(m,1H),3.78(dd,J=10.2,3.3Hz,1H),3.65(dd,J=10.2,3.6Hz,1H ),3.37(s,3H),2.83-2.68(m,2H),2.08-1.96(m,2H).ESI-MS(m / z,%)314[M+H] + .

[0436] Embodiment 50

[0437] Synthesis of compound 10

[0438] Dibromomethane (3 equivalents) was added to the reaction bottle, and after anhydrous and oxygen-free treatment, 2 mL of anhydrous tetrahydrofuran was added to dissolve it. n-Butyl lithium (3 equivalents) was slowly added dropwise at -78 °C and stirred for 1 hour. A tetrahydrofuran solution of intermediate 7 (32 mg, 0.1 mmol, 92% ee) was added. After stirring at room temperature for two hours, tetrahydrofuran and water (2 mL) were added to dissolve it. NaBO was slowly added. 3 (2 equivalents), after stirring at room temperature for 12 hours, ethyl acetate was added to the system for extraction, dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator. The residue was separated by silica gel column chromatography to obtain the product 10 as a white solid with a yield of 92% and 92% ee.

[0439] 1 H NMR (400 MHz, CDCl 3 )δ7.31-7.25(m,2H),7.22-7.15(m,3H),4.62(s,2H),3.78-3.65(m,3H),3.59(dd,J=9.5,6.9Hz,1H),3.37( s,3H),2.68(t,J=8.0Hz,2H),2.38(br,1H),1.93-1.81(m,1H),1.73-1.58(m,2H).ESI-MS(m / z,%)225[M+H] + .

[0440] Embodiment 51

[0441] Synthesis of compound 11

[0442] Thiophene (3 equivalents) was put into a reaction flask, and after anhydrous and oxygen-free treatment, 2 mL of anhydrous tetrahydrofuran was added to dissolve it, and n-butyl lithium (3 equivalents) was slowly added dropwise at -78°C. The mixture was transferred to room temperature and stirred for 1 hour. A tetrahydrofuran solution of intermediate 7 (32 mg, 0.1 mmol, 92% ee) was added again at -78°C and stirred for 1 hour. NBS (3 equivalents, dissolved in 5 mL of tetrahydrofuran) was slowly added. After stirring at -78°C for 1 hour, an aqueous sodium sulfite solution was added to the system, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator. The residue was separated by silica gel column chromatography to obtain product 11, a colorless oily liquid with a yield of 62% and 92% ee.

[0443] 1 H NMR (400 MHz, CDCl 3 )δ7.30-7.21(m,3H),7.21-7.12(m,3H),7.00(dd,J=5.1,3.4Hz,1H),6.91(dd,J=3.2,0.8Hz,1H),3.81-3.63(m,2H) ,3.18-3.05(m,1H),2.72-2.50(m,2H),2.13-2.00(m,1H),2.00-1.83(m,1H),1.52(br,1H).ESI-MS(m / z,%)233[M+H] + .

[0444] Embodiment 52

[0445] Synthesis of compound 12

[0446] 3,5-Dimethoxybromobenzene (3 equivalents) was put into a reaction bottle, and after anhydrous and oxygen-free treatment, 2 mL of anhydrous tetrahydrofuran was added to dissolve it. Tert-butyl lithium (3 equivalents) was slowly added dropwise at -78°C and stirred for 1 hour. A tetrahydrofuran solution of intermediate 7 (32 mg, 0.1 mmol, 92% ee) was added at -78°C and stirred for 1 hour. NBS (3 equivalents, dissolved in 5 mL of methanol) was slowly added. After stirring at -78°C for 1 hour, an aqueous sodium sulfite solution was added to the system, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator. The residue was separated by silica gel column chromatography to obtain product 12, a colorless oily liquid with a yield of 65% and 92% ee.

[0447] 1 H NMR (600 MHz, CDCl 3)δ7.27-7.23(m,2H),7.18-7.11(m,3H),6.40(d,J=2.2Hz,2H),6.35(t,J=2.1Hz,1H),4.59-4.51(m,2H),3.79(s,6H),3.70-3 .62(m,2H),3.26(s,3H),2.86-2.76(m,1H),2.62-2.45(m,2H),2.17-2.07(m,1H),1.92-1.83(m,1H).ESI-MS(m / z,%)331[M+H] + .

[0448] Embodiment 53

[0449] Synthesis of compound 13

[0450] 4-Iodine-pyridine (3 equivalents) was put into a reaction bottle, and after anhydrous and oxygen-free treatment, 2 mL of anhydrous tetrahydrofuran was added to dissolve it, and n-butyl lithium (3 equivalents) was slowly added dropwise at -78°C and stirred for 2 hours. A tetrahydrofuran solution of intermediate 7 (32 mg, 0.1 mmol, 92% ee) was added at -78°C and stirred for 1 hour, and Troc-Cl was slowly added and stirred at room temperature overnight. Sodium bicarbonate aqueous solution was added to quench, and ethyl acetate was added to extract 3 times, dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator. The residue was quickly separated by short silica gel column chromatography to obtain the intermediate. Added into the reaction bottle, NaOH (1 mL, 2M) was added, and H 2 O 2 (1mL, 30%), stirred at room temperature overnight, added sodium sulfite aqueous solution to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator. The residue was separated by silica gel column chromatography to obtain product 13, a brown oily liquid, with a yield of 67% and 92% ee.

[0451] 1 H NMR (600 MHz, CDCl 3 )δ8.55(d,J=5.7Hz,2H),7.31-7.23(m,2H),7.18(t,J=6.4Hz,3H),7.10(d,J=7.1Hz,2H),4.58-4.49(m,2H),3.74-3.63( m,2H),3.20(s,3H),2.91-2.84(m,1H),2.58-2.44(m,2H),2.15-2.06(m,1H),1.97-1.89(m,1H).ESI-MS(m / z,%)272[M+H] + .

[0452] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing an organoborane compound with high optical purity, It is characterized in that The method comprises the following steps: In an organic solvent, in the presence of a monovalent rhodium catalyst and a chiral diene ligand, an α-alkyl diazo compound as shown in Formula 1 and a borane adduct as shown in Formula 2 are subjected to a borohydride insertion reaction to obtain a compound as shown in Formula 3 or ent-3; In the formula, R 1 For R 1a or R 1b ; n is a positive integer selected from 1-30; R 1a Selected from: H, substituted or unsubstituted straight chain or branched chain C 1-30 Alkyl, substituted or unsubstituted C 3-30 Cycloalkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 2-10 Alkynyl; wherein said R 1a Substitution refers to having one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, aryl-substituted C 1-6 Alkoxy, aryloxy, NH(C 1-6 Alkyl), N(C 1-6 alkyl) 2 , C 2-10 Ester group, C 2-10 Amide, C 1-6 Alkylformyloxy, arylformyloxy, C 0-6 Alkyl substituted indolyl, arylamine, C 1-6 Alkylsilyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, arylsulfonyl, C 3 -C 8 Cycloalkyl, or a combination thereof; said R 1a In the above, aryl is phenyl or naphthyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, nitro, C 2-10 Ester group, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy; R 1b Selected from: substituted or unsubstituted C 6 -C 30 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted (C 6 -C 30 Aryl)-CH=CH-; wherein the R 1b Substitution refers to having one or more substituents selected from the following groups: halogen, oxo (ie, =O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 1-4 Alkylamino, C 1-6 Halogenated alkoxy, C 1-6 Alkyl substituted amino, C 1-6 Alkylsilyl, or a combination thereof; the halogen is F, Cl, Br, or I; R 2 Selected from: C 1-6 Alkyl, C 1-6 C substituted with halogenated alkyl or aryl 1-6 Alkyl, C 6 -C 10 Aryl; X has a structure selected from the group consisting of: Substituted or unsubstituted pyridine; the substitution refers to having one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 phenyl, methoxybenzyl, dimethoxybenzyl, amino; or X is Where Z is N; R 11 , R 12 and R 13 Each independently selected from the following group: substituted or unsubstituted straight chain or branched chain C 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl; or said R 11 and R 12 Together they constitute a substituted or unsubstituted 5-9 membered Z-containing heterocycle; wherein the substitution refers to having one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, and the aryl or heteroaryl may be optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy; The halogen is F, Cl, Br, or I.

2. The method according to claim 1, It is characterized in that n is a positive integer selected from 1-20; preferably a positive integer of 1-10; more preferably a positive integer of 1-6; R 1a Selected from: H, substituted or unsubstituted straight chain or branched chain C 1-20 Alkyl, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 2-10 Alkynyl; Preferably, R 1a Selected from: H, substituted or unsubstituted straight chain or branched chain C 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 2-10 Alkynyl; More preferably, R 1a Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-dodecyl, R 1b Selected from: substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted (C 6 -C 10 Aryl)-CH=CH-; Preferably, R 1b Selected from: substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted thiophene, substituted or unsubstituted furan; More preferably, R 1b Selected from: phenyl, methyl substituted phenyl, methoxy substituted phenyl, fluorophenyl, difluorophenyl, bromophenyl, chlorophenyl, trifluoromethyl substituted phenyl, naphthyl, chloropyridyl, thienyl, Ph-CH=CH-, furanyl.

3. The method according to claim 1, It is characterized in that The chiral diene ligand has the following structural formula: in, R 3 , R 4 are each independently substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted metal complexed C 6-30 Aryl, wherein R 3 and R 4 The groups may be the same or different; the substitution means that one or more H is replaced by a group selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, nitro, -CON i Pr 2 .

4. The method according to claim 1, It is characterized in that The monovalent rhodium catalyst is selected from the group consisting of: [Rh(C 2 H 4 ) 2 Cl] 2 , [Rh(C 2 H 4 ) 2 OH] 2 、[Rh(coe) 2 Cl] 2 、[Rh(coe) 2 OH] 2 , [Rh(C 2 H 4 ) 2 OMe] 2 、[Rh(coe) 2 OMe] 2 , or a combination thereof.

5. The method according to claim 1, It is characterized in that The X is and The R 11 and R 12 Together they constitute a 5-9 membered Z-containing heterocyclic ring which is unsubstituted or substituted by a substituent selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R 13 is a substituted or unsubstituted straight chain or branched chain C 1-10 alkyl; Wherein, the substitution refers to having one or more substituents selected from the following group: 6-10 Aryl, 5-10 membered heteroaryl, and the aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy.

6. The method according to claim 1, It is characterized in that The method further comprises one or more features selected from the group consisting of: (1) Based on the amount of the compound of formula 2, the amount of the monovalent rhodium catalyst is 0.1 to 20 mol%; (2) Based on the amount of the compound of formula 2, the amount of the chiral diene ligand is 0.12 to 22 mol%.

7. The method according to claim 1, It is characterized in that In the method described, the organic solvent is C 1-4 Halogenated alkane; the C 1-4 The halogenated alkane is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dichloropropane, 1-chlorobutane, or a combination thereof; Preferably, the method further comprises one or more features selected from the following group: (i) The reaction temperature of the method is -20-40°C; (ii) The reaction time of the method is 0.1-48 hours.

8. A compound represented by formula 3 or formula ent-3, It is characterized in that In the formula, R 1 , R 2 , n, X as defined in claim 1; Preferably, X is Where Z is N; R 11 , R 12 and R 13 Each independently selected from the following group: substituted or unsubstituted straight chain or branched chain C 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl; or said R 11 and R 12 Together they form a 5-9 membered Z-containing heterocyclic ring; more preferably, the R 11 and R 12 Together they form a 5-9 membered Z-containing heterocyclic ring, and R 13 is a substituted or unsubstituted straight chain or branched chain C 1-10 alkyl.

9. The compound according to claim 8, It is characterized in that The compound is selected from the following group:

10. Use of the compound according to any one of claims 8 to 9 for preparing a chiral synthetic building block, a pharmaceutical intermediate or an active compound selected from the group consisting of: in, R 1 , n as defined in claim 1, OMOM is -O-CH 2 -O-CH 3 .

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