Axially chiral pyridine biaryl compounds and methods for their preparation

Abstract

The application discloses a chiral pyridine biaromatic ring compound and a preparation method thereof. The application provides a preparation method of a compound 1, which comprises the following steps: under the protection of a gas atmosphere, asymmetric coupling reaction of a compound as shown in formula II with a compound as shown in formula III is carried out in an organic solvent in the presence of a rhodium catalyst, an oxidant and a chiral acid, and the compound 1 is a compound as shown in formula I and / or formula I'. The preparation method of the application can synthesize the axially chiral pyridine biaromatic ring compound in one step, does not need to pre-functionally group the raw material, can further make the product have a relatively high yield and enantioselectivity on the basis of simplifying the operation, and has good substrate universality.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to an axially chiral pyridine biaromatic compound and its preparation method. Background Technology

[0002] Compounds with axial chiral skeletons are widely found in natural products and biologically active compounds (Bringmann, G.; Gulder, T.; Gulder, TAM; Breuning, M. Chem. Rev. 2011, 111, 563–639. Brunel, JM; Chem. Rev. 2005, 105, 857–897. Murphy, AR; Fréchet, JMJ Chem. Rev. 2007, 107, 1066–1096.), and play an important role in medicinal chemistry (Glunz, PW, Bioorg. Med. Chem. Lett. 2018, 28, 53–60; Toenjes, ST; Gustafson, JL, Future Med. Chem. 2018, 10, 409–422.). They are also used as organic catalysts or chiral ligands in asymmetric catalysis (Privileged). Chiral Ligands and Catalysts; Zhou, Q.-L.Ed.; Wiley-VCH: Weinheim, Germany, 2011). The development of catalytic asymmetric methods for the synthesis of axially chiral compounds has attracted widespread interest from researchers and has yielded significant progress.

[0003] Direct asymmetric functionalization reactions of C-H bonds are a very concise method for synthesizing axially chiral compounds (Liao, G.; Zhou, T.; Yao, QJ; Shi, B.-F., Chem. Commun. 2019, 55, 8514-8523; Wang, Q., Gu, Q., You, S.-L., Acta Chim. Sinica 2019, 77, 690-704.). However, reported methods often require the use of pre-functionalized aryl reagents, such as aryl halides, aryl metal reagents, and diazo compounds. Directly using simple aromatic hydrocarbons as the source of arylating reagents would undoubtedly improve the efficiency of synthesizing axially chiral compounds.

[0004] Given the wide range of applications of axially chiral pyridine biaromatic compounds and their derivatives in chiral ligands and catalysts (Rokade, BV; Guiry, PJACS Catal. 2018, 8, 624-643; Francos, J.; Grande-Carmona, F.; Faustino, H.; Iglesias-Sigüenza, J.; Díez, E.; Alonso, I.; Fernández, R.; Lassaletta, JM; López, F.; JLJAm.Chem.Soc.2012,134,14322-14325.Malkov,AV;Ramírez-López,P.;Biedermannová,L.; L.; Dufková, L.; Kotora, M.; Zhu, F.; (PJAm.Chem.Soc.2008,130,5341-5348.). Furthermore, previous reports on the use of aryl halides as arylation reagents have limited applicability to electron-rich heterocyclic substrates, and the enantioselectivity of the reaction is insufficiently controlled (Wang,Q.;Cai,Z.-J.;Liu,C.-X.;Gu,Q.;You,S.-L.,J.Am.Chem.Soc.2019,141,9504.). Therefore, developing efficient asymmetric C-H / C-H oxidative coupling reactions to synthesize these compounds is of great significance. Summary of the Invention

[0005] The technical problem this invention aims to solve is to overcome the shortcomings of existing methods for preparing axially chiral pyridine biaromatic compounds, which are relatively simple, require the use of pre-functionalized reagents, and have low yields and enantioselectivity. This invention provides an axially chiral pyridine biaromatic compound and its preparation method. The preparation method of this invention can synthesize axially chiral pyridine biaromatic compounds in one step without the need for pre-functionalization of the starting materials. While simplifying the operation, it also allows for a comparable or higher yield and enantioselectivity, and exhibits good substrate universality.

[0006] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0007] The present invention provides a method for preparing compound 1, which includes the following steps: under a protective gas atmosphere, in an organic solvent, in the presence of a rhodium catalyst, an oxidant and a chiral acid, the compound shown in formula II and the compound shown in formula III are subjected to the following asymmetric coupling reaction to obtain compound 1.

[0008] Compound 1 is a compound as shown in Formula I and / or Formula I':

[0009]

[0010] Among them, X 1 For CR 1 Or N;

[0011] R 1 R 2 R 5 and R 6 Independently hydrogen, halogen, C 1-10 alkyl, C 1-10 alkyl-O-, C 6-10 aryl or aryl group or one or more R 1-1 Replacement C 6-10 aryl;

[0012] R 1-1 Independently cyano, halogen, or C substituted with one or more halogens 1-6 Alkyl, C 1-10 alkyl or C 1-10 Alkyl-O-;

[0013] R 3 and R 4 Independently for C 1-10 alkyl, C 1-10 alkyl-O- or C 2-10 oxane alkyl;

[0014] Or, R 2 and R 3 Together with the carbon atoms or R 2 and R 1 Together with the carbon atoms therein, and / or, R 4 and R 5 Together with the carbon atoms or R 5 and R 6 It forms independently along with the carbon atoms in between: C 6-10 aryl, with one or more R 2 -1 Replacement C 6-10 aryl, 5-10 aryl, surrounded by one or more R 2-2 Replacement of 5-10 methyl aryl groups, C 3-7 Cycloalkenyl groups or those with one or more R groups 2-3 Replacement C 3-7 Cycloalkenyl; when multiple substituents are present, they may be the same or different; the 5-10 member heteroaryl and the one or more R 2-2In the substituted 5-10-membered heteroaryl group, the heteroatom is selected from N, O, and S, and the number of heteroatoms is 1-3; when the 5-10-membered heteroaryl group contains NH, the H in the NH is replaced by R. 2-4 replace;

[0015] R 2-1 R 2-2 and R 2-3 Independently for C 1-10 alkyl, C 1-10 alkyl-O-, C 2-10 oxane or phenyl;

[0016] Or, R 1 R 2 and R 3 Together with the carbon atoms therein, and / or, R 4 R 5 and R 6 It forms independently along with the carbon atoms in between: C 10-20 aryl, or, C 6-10 aryl and C 3-7 Cycloalkenyl groups;

[0017] R 7 A 5-membered heteroaryl group, surrounded by one or more R 7-1 Substituted 5-membered heteroaryl or The 5-membered heteroaryl group and one or more R 7-1 In the substituted 5-membered heteroaryl group, the heteroatom is selected from N, O, and S, and the number of heteroatoms is 1-3; when the 5-membered heteroaryl group contains NH, the H in the NH is replaced by R. 7-4 Substitution; when multiple substituents are present, they may be the same or different;

[0018] R 7-1 Independently cyano, halogen, C 1-6 Alkyl-C(=O)-O-, with one or more R 7-a Replacement C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-OC(=O)-, with one or more R 7-b Replacement C 1-6 Alkyl-OC(=O)-, C 1-10 alkyl, by one or more R 7-c Replacement C 1-10 alkyl, C 1-10 alkyl-O-, by one or more R 7-d Replacement C 1-10 alkyl-O-, C 6-10 aryl, with one or more R7-e Replacement C 6-10 aryl, 6-10 aryl, or aryl with one or more R 7-f Substituted 6-10-membered heteroaryl groups; when multiple substituents are present, they may be identical or different; the 6-10-membered heteroaryl group and the group with one or more R... 7-f In the substituted 6-10-membered heteroaryl group, the heteroatom is selected from N, O and S, and the number of heteroatoms is 1-3;

[0019] When R 7-1 Independently for C 6-10 aryl, with one or more R 7-e Replacement C 6-10 aryl, 6-10 aryl, or aryl with one or more R 7-f When 6-10 heteroaryl groups are substituted, R 7-1 It is linked to the adjacent 5-membered heteroaryl group via cyclic fusion or single bond;

[0020] R 7-2 It can be cyano, H or R independently 7-3 -L-;

[0021] L represents a connecting key (single key), -O-, -OC(=O)-, -C(=O)-O-, -OC(=O)-O-, -C(=O)-, -C(=O)-N(R 7b - or -N(R) 7c )-C(=O)-;

[0022] R 7-3 R 7a R 7a’ R 7b and R 7c Independently for C 1-10 alkyl, by one or more R 7-g Replacement C 1-10 Alkyl, 3-10 membered cycloalkyl, with one or more R 7-h Substituted 3-10 membered cycloalkyl, C 6-10 aryl or aryl group or one or more R 7-i Replacement C 6-10 The aryl group; when multiple substituents are present, they may be the same or different;

[0023] connection key in This indicates that the double bond is in Z configuration, E configuration, or a mixture of Z and E configurations;

[0024] R 2-4 and R 7-4 Independently for C 1-10Alkyl or N-protecting group;

[0025] R 7-a R 7-b R 7-c R 7-d R 7-e R 7-f R 7-g R 7-h and R 7-i Independently cyano, halogen, or C substituted with one or more halogens 1-6 Alkyl, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-OC(=O)-, C 1-10 alkyl or C 1-10 Alkyl-O-.

[0026] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0027] When R 1 R 2 R 5 and R 6 When it is a halogen on its own, the halogen can be fluorine, chlorine, bromine or iodine, such as fluorine.

[0028] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0029] When R 1 R 2 R 5 and R 6 Independently for C 1-10 alkyl or C 1-10 When alkyl-O-, the C 1-10 alkyl and C 1-10 C in alkyl-O- 1-10 The alkyl group can be C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl.

[0030] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0031] When R 1 R 2 R 5 and R 6 Independently for C 6-10aryl or aryl group or one or more R 1-1 Replacement C 6-10 When the aryl group is present, the C 6-10 aryl and one or more R 1-1 Replacement C 6-10 C in aryl 6-10 The aryl group can be phenyl or naphthyl.

[0032] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0033] When R 1-1 C that is independently a halogen, or a C substituted with one or more halogens. 1-6 When alkyl, the halogen and C substituted with one or more halogens. 1-6 The halogen in the alkyl group can be fluorine, chlorine, bromine, or iodine, for example, fluorine, chlorine, or bromine.

[0034] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0035] When R 1-1 Independently for C substituted with one or more halogens 1-6 When alkyl, the C 1-6 Alkyl groups can be C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl.

[0036] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0037] When R 1-1 Independently for C substituted with one or more halogens 1-6 When alkyl is used, the number of halogens can be 1, 2 or 3;

[0038] For example, trifluoromethyl.

[0039] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0040] When R 1-1 Independently for C 1-10 alkyl or C 1-10 When alkyl-O-, the C 1-10 alkyl and C 1-10 C in alkyl-O- 1-10 The alkyl group can be C1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl.

[0041] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0042] When R 3 and R 4 Independently for C 1-10 alkyl or C 1-10 When alkyl-O-, the C 1-10 alkyl and C 1-10 C in alkyl-O- 1-10 The alkyl group can be C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl.

[0043] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0044] When R 3 and R 4 Independently for C 2-10 When the oxane is alkyl, the C 2-10 The oxane group can be C 2-4 Oxyalkyl groups, such as Me-O-CH2-CH2- or Me-O-CH2-.

[0045] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0046] When R 2 and R 3 Together with the carbon atoms or R 2 and R 1 Together with the carbon atoms therein, and / or, R 4 and R 5 Together with the carbon atoms or R 5 and R 6 It independently forms C along with the carbon atoms in between. 6-10 aryl, or by one or more R 2-1 Replacement C 6-10 When the aryl group is present, the C 6-10 aryl and one or more R 2-1 Replacement C 6-10 C in aryl 6-10 The aryl group can be phenyl or naphthyl; for example (Indicates the location of the parallel-loop connection, the same below); preferably, The central ring A is located on the side of the chiral axis in compound 1.

[0047] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0048] When R 2 and R 3 Together with the carbon atoms or R 2 and R 1 Together with the carbon atoms therein, and / or, R 4 and R 5 Together with the carbon atoms or R 5 and R 6 Together with the carbon atoms therein, it independently forms a 5-10 membered heteroaryl group, or is bound by one or more R groups. 2-2 When the 5-10 membered heteroaryl group is substituted, the 5-10 membered heteroaryl group and the group substituted with one or more R 2-2 The 5-10 substituted heteroaryl group can be a 5-6 substituted heteroaryl group, such as furanyl, pyrrolithyl, thiophenyl, pyranyl or pyridyl.

[0049] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0050] When R 2 and R 3 Together with the carbon atoms or R 2 and R 1 Together with the carbon atoms therein, and / or, R 4 and R 5 Together with the carbon atoms or R 5 and R 6 It independently forms C along with the carbon atoms in between. 3-7 Cycloalkenyl groups or those with one or more R groups 2-3 Replacement C 3-7 When the cycloalkenyl group is present, the C 3-7 cycloalkenyl and one or more R 2-3 Replacement C 3-7 C in the cycloalkenyl group 3-7 The cycloalkenyl group can be cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.

[0051] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0052] When R2-1 R 2-2 and R 2-3 Independently for C 1-10 alkyl or C 1-10 When alkyl-O-, the C 1-10 alkyl and C 1-10 C in alkyl-O- 1-10 The alkyl group can be C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl.

[0053] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0054] When R 2-1 R 2-2 and R 2-3 Independently for C 2-10 When the oxane is alkyl, the C 2-10 The oxane group can be C 2-4 Oxyalkyl groups, such as Me-O-CH2-CH2- or Me-O-CH2-.

[0055] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0056] When R 2-1 R 2-2 and R 2-3 When independently of one or more, preferably, one of the one or more R 2-1 R 2-2 and R 2-3 It is independently located at the meta position of the chiral axis in compound 1.

[0057] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0058] When R 1 R 2 and R 3 Together with the carbon atoms therein, and / or, R 4 R 5 and R 6 It independently forms C along with the carbon atoms in between. 10-20 When the aryl group is present, the C 10-20 The aryl group can be C 10-14 Aryl groups, for example

[0059] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0060] When R 1 R 2 and R 3 Together with the carbon atoms therein, and / or, R 4 R 5 and R 6 It independently forms C along with the carbon atoms in between. 6-10 aryl and C 3-7 When the cycloalkenyl group is present, the C 6-10 aryl and C 3-7 The cycloalkenyl group can be C 6-10 aryl and C 5-6 The cycloalkenyl group can be 1H-finalenyl or benzocyclopentenyl, or, for example...

[0061] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0062] When R 7 For one or more R 7-1 When the 5-membered heteroaryl group is substituted, the R 7-1 The number of elements can be 1, 2, or 3.

[0063] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0064] When R 7 It is a 5-membered heteroaryl group or is composed of one or more R groups. 7-1 When the 5-membered heteroaryl group is substituted, the 5-membered heteroaryl group and one or more R 7-1 The 5-membered heteroaryl group in the substituted 5-membered heteroaryl group can be furanyl, pyrrolithyl, thiopheneyl, pyranyl, or pyridyl, and can also be furanyl, thiopheneyl, or pyrrolithyl, for example...

[0065] Those skilled in the art will anticipate that, in the aforementioned asymmetric coupling reaction, the compound represented by Formula II preferentially connects to the electron-rich carbon atom of the compound represented by Formula III; for example, at the 2-position of the furanyl and thiophene groups, and at the 3-position of the pyrrole group.

[0066] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0067] When R 7-1When it is a halogen on its own, the halogen can be fluorine, chlorine, bromine or iodine, for example fluorine, chlorine or bromine.

[0068] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0069] When R 7-1 Independently for C 1-6 Alkyl-C(=O)-O-, with one or more R 7-a Replacement C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-OC (=O)-, or with one or more R 7-b Replacement C 1-6 When alkyl-OC (=O)-, the C 1-6 Alkyl-C(=O)-O-, with one or more R 7-a Replacement C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-OC (=O)- and alkyl groups with one or more R groups 7-b Replacement C 1-6 The C in alkyl-OC(=O)- 1-6 Alkyl groups can be independently C10. 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl or ethyl.

[0070] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0071] When R 7-1 Independently for C 1-10 alkyl, by one or more R 7-c Replacement C 1-10 alkyl, C 1-10 alkyl-O-, or with one or more R 7-d Replacement C 1-10 When alkyl-O-, the C 1-10 alkyl, by one or more R 7-c Replacement C 1-10 alkyl, C 1-10 alkyl-O- and by one or more R 7-d Replacement C 1-10 C in alkyl-O- 1-10 The alkyl group can be C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl or n-butyl.

[0072] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0073] When R 7-1 Independently for C 6-10 aryl or aryl group or one or more R 7-e Replacement C 6-10 When the aryl group is present, the C 6-10 aryl and one or more R 7-e Replacement C 6-10 C in aryl 6-10 The aryl group can be phenyl or naphthyl.

[0074] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0075] When R 7-1 Independently a 6-10 aryl group or surrounded by one or more R groups 7-f When the 6-10-membered heteroaryl group is substituted, the 6-10-membered heteroaryl group and the group substituted with one or more R 7-f The 6-10 member of the substituted heteroaryl group can be furanophenyl, for example...

[0076] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0077] When R 7-3 R 7a R 7a’ R 7b and R 7c Independently for C 1-10 alkyl or by one or more R 7-g Replacement C 1-10 When alkyl, the C 1-10 alkyl groups and those containing one or more R 7-g Replacement C 1-10 C in alkyl 1-10 The alkyl group can be C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl, ethyl or tert-butyl.

[0078] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0079] When R 7-3 R 7a R 7a’ R 7b and R 7c Independently 3-10 membered cycloalkyl or surrounded by one or more R 7-h When the 3-10 membered cycloalkyl group is substituted, the 3-10 membered cycloalkyl group and the R group are substituted with one or more R groups. 7-h The 3-10 membered cycloalkyl group in the substituted 3-10 membered cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.

[0080] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0081] When R 7-3 R 7a R 7a’ R 7b and R 7c Independently for C 6-10 aryl or aryl group or one or more R 7-i Replacement C 6-10 When the aryl group is present, the C 6-10 aryl and one or more R 7-i Replacement C 6-10 C in aryl 6-10 The aryl group can be phenyl or naphthyl; for example

[0082] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0083] When R 2-4 and R 7-4 Independently for C 1-10 When alkyl, the C 1-10 The alkyl group can be C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl or n-butyl.

[0084] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0085] When R 2-4 and R 7-4 When the N protecting group is independent, the N protecting group may be p-toluenesulfonyl (Ts).

[0086] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0087] When R 7-a R 7-b R 7-c R 7-d R 7-e R 7-f R 7-g R 7-h and R 7-i C that is independently a halogen or is substituted by one or more halogens 1-6 When alkyl, the halogen can be fluorine, chlorine, bromine or iodine, such as fluorine.

[0088] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0089] When R 7-a R 7-b R 7-c R 7-d R 7-e R 7-f R 7-g R 7-h and R 7-i Independently for C substituted with one or more halogens 1-6 Alkyl, C 1-6 Alkyl-C(=O)-O- or C 1-6 When alkyl-OC (=O)-, the C substituted with one or more halogens 1-6 Alkyl, C 1-6 Alkyl-C(=O)-O- and C 1-6 The C in alkyl-OC(=O)- 1-6 The alkyl group can be C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl.

[0090] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0091] When R 7-a R 7-b R 7-c R 7-d R 7-e R 7-f R 7-g R 7-h and R 7-iIndependently for C substituted with one or more halogens 1-6 When alkyl is used, the number of halogens can be 1, 2 or 3;

[0092] For example, trifluoromethyl.

[0093] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0094] When R 7-a R 7-b R 7-c R 7-d R 7-e R 7-f R 7-g R 7-h and R 7-i Independently for C 1-10 alkyl or C 1-10 When alkyl-O-, the C 1-10 alkyl and C 1-10 C in alkyl-O- 1-10 The alkyl group can be C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl or tert-butyl), such as methyl.

[0095] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0096] R 1 R 2 R 5 and R 6 Independently hydrogen, halogen, C 1-10 alkyl or C 1-10 Alkyl-O-;

[0097] For example, R 1 R 2 and R 5 Independently hydrogen;

[0098] R 6 For hydrogen, halogen, C 1-10 alkyl or C 1-10 Alkyl-O-.

[0099] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0100] R 2 and R 3 Together with the carbon atoms or R2 and R 1 Together with the carbon atoms therein, and / or, R 4 and R 5 Together with the carbon atoms or R 5 and R 6 It forms independently along with the carbon atoms in between: C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 Aryl groups.

[0101] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0102] R 2 and R 3 Together with the carbon atoms therein, and / or, R 4 and R 5 It forms independently along with the carbon atoms in between: C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 Aryl groups.

[0103] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0104] R 4 R 5 and R 6 It forms independently along with the carbon atoms in between: C 10-20 aryl, or, C 6-10 aryl and C 3-7 Cycloalkenyl groups.

[0105] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0106] R 7-1 Independently for C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-OC(=O)-, C 1-10 alkyl, by one or more R 7-c Replacement C 1-10 alkyl, C 1-10 alkyl-O-, by one or more R 7-d Replacement C 1-10 alkyl-O-, C 6-10 aryl, with one or more R 7-e Replacement C 6-10aryl, 6-10 aryl, or aryl with one or more R 7-f Replacement of 6-10 aryl compounds.

[0107] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0108] R 7 It is a 5-membered heteroaryl group or is composed of one or more R groups. 7-1 The substituted 5-membered heteroaryl group.

[0109] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0110] R 7 for For example,

[0111] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0112] R 7-2 Independently for H or R 7-3 -L-; for example, R 7-3 -L-;

[0113] For example, L is the connection key, and / or R 7-3 C 6-10 aryl or aryl group or one or more R 7-i Replacement C 6-10 aryl groups; for example, C 6-10 Aryl groups.

[0114] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0115] R 1 R 2 R 5 and R 6 Independently hydrogen, halogen, C 1-10 alkyl or C 1-10 Alkyl-O-;

[0116] R 3 and R 4 Independently for C 1-10 alkyl, C 1-10 alkyl-O- or C 2-10 oxane alkyl;

[0117] Or, R2 and R 3 Together with the carbon atoms therein, and / or, R 4 and R 5 It forms independently along with the carbon atoms in between: C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 aryl;

[0118] Or, R 4 R 5 and R 6 It forms independently along with the carbon atoms in between: C 10-20 aryl, or, C 6-10 aryl and C 3-7 Cycloalkenyl groups;

[0119] R 7 A 5-membered heteroaryl group, surrounded by one or more R 7-1 Substituted 5-membered heteroaryl or

[0120] R 7-1 Independently for C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-OC(=O)-, C 1-10 alkyl, by one or more R 7-c Replacement C 1-10 alkyl, C 1-10 alkyl-O-, by one or more R 7-d Replacement C 1-10 alkyl-O-, C 6-10 aryl, with one or more R 7-e Replacement C 6-10 aryl, 6-10 aryl, or aryl with one or more R 7-f Substituted 6-10 nucleotide heteroaryl groups;

[0121] R 7-2 Independently for H or R 7-3 -L-;

[0122] For example, R 1 R 2 and R 5 Independently hydrogen;

[0123] And / or, R 6 For hydrogen, halogen, C 1-10 alkyl or C 1-10 Alkyl-O-.

[0124] And / or, R 3 and R 4 Independently for C1-10 alkyl, C 1-10 alkyl-O- or C 2-10 oxane alkyl;

[0125] And / or, R 2-1 R 2-2 and R 2-3 Independently for C 1-10 alkyl, C 1-10 alkyl-O-, C 2-10 oxane or phenyl;

[0126] And / or, L is the connector key;

[0127] And / or, R 7-3 C 6-10 aryl or aryl group or one or more R 7-i Replacement C 6-10 aryl;

[0128] And / or, R 2-4 and R 7-4 Independently for C 1-10 Alkyl or N-protecting group;

[0129] And / or, R 7-c R 7-d R 7-e and R 7-f Independently halogen or C 1-6 Alkyl-OC(=O)-.

[0130] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0131] X 1 It can be CH or N.

[0132] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0133] R 2 and R 3 It can be hydrogen or methyl independently; for example, R 2 It is hydrogen; R 3 It is methyl.

[0134] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0135] R 2 and R 3 Together with the carbon atoms therein, they form phenyl and naphthyl groups.

[0136] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0137] for

[0138] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0139] R 4 It can be methyl, methyl-O- or Me-O-CH2- independently.

[0140] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0141] R 5 and R 6 Independently hydrogen, F, methyl, or methyl-O-; for example, R 5 It is hydrogen; R 6 Independently hydrogen, F, methyl or methyl-O-.

[0142] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0143] R 4 R 5 It forms together with the carbon atoms in between:

[0144] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0145] R 4 R 5 and R 6 It forms together with the carbon atoms in between:

[0146] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0147] for

[0148] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0149] R 7-1 Independently, it is methyl, n-butyl, Me-O-CH2-CH2-, phenyl, p-methoxyphenyl, p-fluorophenyl, Ac(CH3-C(=O)-O-), CH3-OC(=O)-or

[0150] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0151] When R 7 It is a 5-membered heteroaryl group or is composed of one or more R groups. 7-1 When the 5-membered heteroaryl group is substituted, for example

[0152] In certain preferred embodiments of the present invention, certain groups in compound 1 are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0153] When R 7 for At times, such as vinyl,

[0154] In certain preferred embodiments of the present invention, compound 1 may have any of the following structures:

[0155]

[0156]

[0157]

[0158] In this invention, the protective gas can be a conventional protective gas in the art, such as one or more of helium, neon, nitrogen and argon, for example, argon.

[0159] In this invention, the organic solvent can be a conventional organic solvent in the art, preferably an amide solvent {e.g., dimethylformamide (DMF) and / or dimethylacetamide (DMA)} and / or an ether solvent {e.g., tetrahydrofuran (THF)}.

[0160] In this invention, the molar concentration of the compound as shown in Formula II in the organic solvent can be a conventional molar concentration in the art, preferably 0.01-0.8 mol / L, more preferably 0.05-0.5 mol / L (e.g. 0.05-0.1 mol / L).

[0161] In this invention, the molar ratio of the compound shown in Formula III to the compound shown in Formula II can be a conventional molar ratio in the art, preferably 1:1-8:1, more preferably 2:1-4:1 (e.g. 3:1).

[0162] In this invention, the molar ratio of the rhodium catalyst to the compound shown in Formula II can be a conventional molar ratio in the art, preferably 0.02:1-0.2:1, more preferably 0.025:1-0.07:1 (e.g. 0.05:1).

[0163] In this invention, the molar ratio of the chiral acid to the rhodium catalyst can be a conventional molar ratio in the art, preferably 1:1-10:1 (e.g., 4:1).

[0164] In this invention, the rhodium catalyst can be a conventional rhodium catalyst in the art, such as a monovalent rhodium catalyst and / or a trivalent rhodium catalyst; preferably, it is a monovalent rhodium catalyst.

[0165] In this invention, the trivalent rhodium catalyst can be a chiral cyclopentadiene rhodium(III) complex conventional in the art; for example, a chiral cyclopentadiene rhodium(III) complex derived from binaphthol (BINOL) and / or a cyclopentadiene rhodium(III) complex derived from a spirocyclic skeleton.

[0166] The preferred location is: or its enantiomers, or its enantiomer; wherein, R 1a and R 1a‘ Independently selected from H, C1~C 16 Alkyl, C1-C 16 Perfluoroalkyl, C1-C 16 Alkyl-O-, C6-C 20 Aryl or benzyloxy; R 1b Independently selected from H, C1~C 16 Alkyl, C3-C7 cycloalkyl; R 1c and R 1c’ Independently selected from H, C1~C 16 Alkyl, C1-C 16 Perfluoroalkyl, C1-C 16 Alkyl-O-, C6-C 20 Aryl or benzyloxy.

[0167] In one embodiment of the present invention, the trivalent rhodium catalyst may be:

[0168] Or its enantiomer, or, Or its enantiomers.

[0169] In this invention, the monovalent rhodium catalyst can be a chiral cyclopentadiene rhodium(I) complex conventional in the art, such as a binatol-derived chiral cyclopentadiene rhodium(I) complex and / or a spirocyclic skeleton-derived cyclopentadiene rhodium(I) complex; preferably: or its enantiomers, or its enantiomers Among them, R 1d and R 1d‘ Independently selected from H, C1~C 16 Alkyl, C1-C 16 Perfluoroalkyl, C1-C 16 Alkyl-O-, C6-C 20 Aryl or benzyloxy; R 1e and R 1e’ Selected from H, C1~C 16 Alkyl, C1-C 16 Perfluoroalkyl, C1-C 16 Alkyl-O-, C6-C 20 Aryl or benzyloxy.

[0170] In one embodiment of the present invention, the monovalent rhodium catalyst may be: or its enantiomers, or its enantiomers or its enantiomers, Or its enantiomers.

[0171] In this invention, the oxidant can be a conventional oxidant in the art, preferably one or more of silver oxide, silver fluoride, silver acetate and silver benzoate, and more preferably silver fluoride.

[0172] In this invention, the molar ratio of the oxidant to the rhodium catalyst can be a conventional molar ratio in the art, preferably 100:1-20:1, and more preferably 40:1-70:1 (e.g., 60:1).

[0173] In this invention, the molar ratio of the oxidant to the compound shown in Formula II can be a conventional molar ratio in the art, preferably 1:1-5:1, more preferably 2:1-4:1 (e.g., 3:1).

[0174] In this invention, the chiral acid can be a conventional chiral acid in the art, such as a chiral acid containing a carboxyl group, a sulfonic acid group, or a phosphate group; preferably, it is a chiral acid containing a carboxyl group or a sulfonic acid group; more preferably, it is a chiral acid containing a carboxyl group.

[0175] The chiral acid may be or its enantiomer; wherein, R 8 and R 8’ Independently H, unsubstituted or by one or more R 8-1 Replacement C6-C 10 aryl, R 9 and R 9’ Independently H or halogen; R 10 and R 10’ Independently for not replaced or by one or more R 10-1 Replacement C6-C 10 aryl, unsubstituted or with one or more R 10-2 Replacement C1-C 16 Alkyl group; R 11a and R 11b R 11a’ and R 11b′ Together they form C6-C 10 The aryl group; when there are multiple substituents, they may be the same or different; R 8-1 Independently a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more halogens; R 10-1 Independently a halogen or a C1-C6 alkyl group; R 10-2 Independently for C6-C 10 Aryl groups.

[0176] In this invention, the chiral acid may be any of the following structures or its enantiomers:

[0177]

[0178] In this invention, the chiral acid is preferably... or its enantiomer, or or its enantiomers

[0179] In this invention, the temperature of the asymmetric coupling reaction can be a conventional temperature in the art, preferably 0-100°C, and more preferably 40-80°C (e.g., 40°C, 50°C, 60°C or 80°C).

[0180] In this invention, the progress of the asymmetric coupling reaction can be monitored using conventional testing methods in the art (such as TLC, HPLC, GC, or NMR), and the reaction endpoint is generally defined as when the compound shown in Formula II no longer reacts. The duration of the asymmetric coupling reaction is preferably 1-48 hours (e.g., 12 hours, 24 hours, or 48 hours).

[0181] In one embodiment of the present invention (undefined groups are as described in any preceding embodiment), under a protective gas atmosphere, in an organic solvent, and in the presence of a rhodium catalyst, a chiral acid, and an oxidant, a compound of formula II is subjected to an asymmetric coupling reaction with a compound of formula III; the organic solvent is an amide solvent; the oxidant is one or more of silver oxide, silver fluoride, silver acetate, and silver benzoate; for example, silver fluoride; the rhodium catalyst is... or its enantiomers, or its enantiomers, or its enantiomers, or its enantiomers The chiral acid is For example

[0182] The molar concentration of the compound of Formula II in the organic solvent is 0.05-0.3 mol / L; the molar ratio of the compound of Formula III to the compound of Formula II is 2:1-4:1; the molar ratio of the rhodium catalyst to the compound of Formula II is 0.025:1-0.07:1 (e.g., 0.05:1); the molar ratio of the chiral acid to the rhodium catalyst is 1:1-10:1 (e.g., 4:1); and the molar ratio of the oxidant to the monovalent rhodium catalyst is 40:1-70:1 (e.g., 60:1).

[0183] In one embodiment of the present invention (undefined groups are as described in any embodiment of this application), when the rhodium catalyst is In the case of compound 1, the dominant configuration is the compound shown in Formula I (e.g., ee value greater than 40%, preferably greater than 80%, more preferably greater than 90%, most preferably 95%); the chiral acid is preferably [missing information].

[0184] In one embodiment of the present invention (undefined groups are as described in any embodiment of this application), when the rhodium catalyst is In the case of compound 1, the compound shown in formula I' is the dominant configuration, and the chiral acid is preferably [missing information].

[0185] In one embodiment of the present invention, the preparation method of compound 1 includes the following steps: adding a rhodium catalyst, a chiral acid, adding compounds as shown in Formula II and Formula III, an oxidant and an organic solvent, and carrying out the asymmetric coupling reaction at 40-80°C.

[0186] After the asymmetric coupling reaction is completed, preferably, it may further include post-processing operations. The post-processing operations and conditions are conventional post-processing operations and conditions for this type of reaction in the art, and preferably include the following steps: diluting the reaction solution, concentrating, and separating and purifying. The dilution operations and conditions are conventional operations and conditions in the art, and the solvent used for dilution is preferably an ester solvent (e.g., ethyl acetate). The concentration operations and conditions are conventional operations and conditions in the art, preferably concentration under reduced pressure. The separation and purification operations and conditions are conventional operations and conditions in the art, preferably column chromatography separation; the developing solvent system for column chromatography separation is a conventional developing solvent system for this type of reaction in the art, preferably an ester solvent / aromatic solvent (e.g., ethyl acetate / toluene), more preferably an ester solvent / aromatic solvent ratio of 1 / 50.

[0187] The present invention provides a catalyst composition comprising the rhodium catalyst, the oxidant, and the chiral acid as described above.

[0188] In this invention, the molar ratio of the oxidant to the monovalent rhodium catalyst can be a conventional molar ratio in the art, preferably 100:1-20:1, more preferably 40:1-70:1 (e.g. 60:1).

[0189] In this invention, the molar ratio of the chiral acid to the rhodium catalyst can be a conventional molar ratio in the art, preferably 1:1-10:1 (e.g., 4:1).

[0190] The present invention also provides the application of the catalyst composition described above in asymmetric catalytic reactions.

[0191] In one embodiment, the application is for the preparation of axially chiral pyridine biaromatic compounds; for example, the reaction conditions and procedures described above for the preparation of compound 1 in the application.

[0192] The present invention also provides a compound as shown in Formula I or Formula I', the structure of which is shown below.

[0193]

[0194] Among them, R 7 It is a 5-membered heteroaryl group or is composed of one or more R groups. 7-1 The substituted 5-membered heteroaryl group; said 5-membered heteroaryl group or substituted with one or more R7-1 Replaced 5-membered heteroaryl, X 1 R 2 -R 6 The definition is as described in any of the previous schemes;

[0195] Furthermore, the compound shown in Formula I does not have any of the following structures:

[0196] or its enantiomers, Or its enantiomers.

[0197] In one embodiment of the present invention, the compound of formula I may have any of the following structures:

[0198]

[0199]

[0200]

[0201]

[0202] In one embodiment of the present invention, the compound shown in Formula I' can be...

[0203] Unless otherwise specified, the terms used in this invention have the following meanings:

[0204] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0205] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group having a total of 1, 2, 3, 4, 5, or 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0206] In this paper, the numerical ranges defined in the substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicate the integers within that range, such as 1-6 being 1, 2, 3, 4, 5, 6.

[0207] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0208] The terms “one or more” or “one or more kinds” refer to 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0209] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0210] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable.

[0211] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0212] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, this invention includes every independent secondary combination of the respective members of these group types and scopes. The term "C" x -C y "Alkyl" refers to a straight-chain or branched saturated hydrocarbon containing x to y carbon atoms. For example, the terms "C1-C6 alkyl" or "C 1-6 "alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl; "C" 1-4 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl (i.e. propyl, including n-propyl and isopropyl), and C4 alkyl (i.e. butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

[0213] The term "halogen" is selected from F, Cl, Br or I, especially F or Cl.

[0214] The term "alkoxy group" refers to the group -OR X , where R X It is an alkyl group as defined above.

[0215] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups within a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0216] When a listed substituent does not specify which atom it is attached to in a compound included but not specifically mentioned in the general chemical formula, such a substituent may be bonded to any of its atoms. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0217] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C1-C4 alkyl" is not preceded by the qualifier "substituted or unsubstituted", it refers only to "C1-C4 alkyl" itself or "unsubstituted C1-C4 alkyl".

[0218] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", then it should be understood that "alkyl" represents a linked alkylene group.

[0219] In some specific structures, when an alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group. For example, the C1-C6 alkyl in the group “halogenated-C1-C6 alkyl” should be understood as C1-C6 alkylene.

[0220] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, and so on.

[0221] In this application, as a group or part of other groups (e.g., in halogen-substituted alkyl groups), the term "alkyl" means a saturated aliphatic hydrocarbon group comprising a branched or straight chain having a specified number of carbon atoms; for example, a straight-chain or branched saturated hydrocarbon chain containing 1 to 16 carbon atoms; or, for example, a C1-C6 alkyl group. As defined in "C1-C6 alkyl," it includes groups comprising 1, 2, 3, 4, 5, or 6 carbon atoms in a straight-chain or branched structure. Wherein, propyl is a C3 alkyl group (including isomers, such as n-propyl or isopropyl); butyl is a C4 alkyl group (including isomers, such as n-butyl, sec-butyl, isobutyl or tert-butyl); pentyl is a C5 alkyl group (including isomers, such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); and hexyl is a C6 alkyl group (including isomers, such as n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl).

[0222] The term “halogenated alkyl” refers to an alkyl group that has been substituted with one or more halogens, such as trifluoromethyl, wherein “multiple”, “halogen” and “alkyl” are as defined above.

[0223] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic carbocyclic substituent consisting only of carbon and hydrogen atoms, which can be connected to the rest of the molecule via a single bond through any suitable carbon atom; when polycyclic, it can be a fused ring system, a bridged ring system, or a spiro ring system (i.e., the two geminal hydrogens on the carbon atom are replaced by alkylene groups). In one embodiment, a monovalent saturated cycloalkyl group having 3-10 ring carbon atoms, more preferably 3-7 carbon atoms, is preferred. Typical monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0224] In this application, the term "cycloalkenyl" refers, either alone or as part of another substituent, to an unsaturated, non-aromatic group containing a double bond. It is a monocyclic, polycyclic, or bridged carbocyclic substituent containing a partially unsaturated double bond, and can be connected to the rest of the molecule via a single bond through any suitable carbon atom; when polycyclic, it can be a fused or spirocyclic system (i.e., two union hydrogens on the carbon atom are replaced by alkylene groups) of either a bridged or spirocyclic system. In some embodiments, "cycloalkenyl" is preferably a non-aromatic group containing a single double bond and having 3-7 ring carbon atoms, more preferably 3-6 carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl. In some embodiments, "cycloalkenyl" is a monocyclic, unsaturated carbocyclic alkenyl group ("5-6 membered cycloalkenyl") having 5 to 6 ring atoms.

[0225] The term "heterocyclic alkyl" refers to a saturated monocyclic group having a heteroatom, preferably a 3- to 7-membered saturated monocyclic group containing one, two, or three cyclic heteroatoms independently selected from N, O, and S. Examples of heterocyclic alkyl groups include: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolidinyl, azaheptanyl, thiazolyl, azoleyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, azaheptanyl, diazaheptanyl, oxonitroheptanyl, dioxopentyl, dioxohexyl, etc. Preferred heterocyclic groups are 1,3-dioxopentyl and 1,4-dioxohexyl.

[0226] In this application, the term "heterocyclic alkenyl" refers, either alone or as part of another substituent, unless otherwise specified, to an unsaturated, non-aromatic group having a heteroatom and containing a double bond. It can be a cyclic alkenyl group linked by heteroatoms or heteroatomic groups. Thus, "heterocyclic alkenyl" encompasses the above definitions of "hetero" and cyclic alkenyl. In some embodiments, in one particular embodiment, the "heterocyclic alkenyl" is a group consisting of 2-9 carbon atoms and 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(=O), or S(=O)2 heteroatoms or heteroatom-containing groups, forming a stable 3-10 member heterocyclic system containing an unsaturated double bond. Unless otherwise specifically indicated in this specification, heterocyclic rarefaction groups may be monocyclic (“monocyclic heterocyclic rarefaction”) or bicyclic, tricyclic, or more cyclic systems, which may include fused, bridged, or spirocyclic systems (e.g., bicyclic systems (“bicyclic heterocyclic rarefaction”). A bicyclic heterocyclic rarefaction system may include one or more heteroatoms in one or both rings) and contain unsaturated double bonds. The heterocyclic rarefaction group may be linked to the rest of the molecule via a carbon atom and through a single bond; in heterocyclic rarefaction groups containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom; or, it may be cyclically linked to the rest of the molecule, provided the valence permits. In some embodiments, it is preferred to contain one, two, or three 3- to 7-membered, more preferably 3- to 6-membered, unsaturated, non-aromatic groups, independently selected from N, O, and S.

[0227] The term "aryl" refers to a fully carbon-based aromatic group having a fully conjugated π-electron system with a specified number of carbon atoms (e.g., when it is bicyclic or tricyclic, each ring satisfies Hückel's rule). It can be monocyclic or fused, typically having 6-20 carbon atoms, preferably 6-14 carbon atoms, and most preferably 6 carbon atoms. Examples of aryl groups include, but are not limited to: monocyclic aryl groups such as C6 aryl (phenyl), bicyclic aryl groups such as C6 aryl... 10 Aryl (naphthyl), tricyclic aryl, such as C 14 Aryl (phenanthryl and anthracene).

[0228] The term "arylcycloalkenyl" refers to a group formed by the fusion of an aryl and a cycloalkenyl group, where "aryl" and "cycloalkenyl" are as described above, and examples of "arylcycloalkenyl" are...

[0229] The term "heteroaryl" refers to an aromatic group containing a heteroatom, which can be monocyclic or fused ring, preferably containing 1-4 5-12 membered heteroaryl groups independently selected from N, O, and S, including but not limited to pyrrole, furanyl, thiophene, indolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, (benzo)oxazolyl, (benzo)furanyl, (benzo)thiophene, (benzo)thiazolyl, and triazolyl. In one embodiment, it typically contains one or more 5-6 membered monocyclic heteroaryl groups independently selected from N, O, and S. In another embodiment, "heteroaryl" is a 5-6 membered heteroaryl group, wherein the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0230] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0231] The reagents and raw materials used in this invention are all commercially available.

[0232] The positive and progressive effects of this invention are as follows: the preparation method of this invention can synthesize axially chiral isoquinoline compounds in one step without the need for pretreatment of raw materials. On the basis of simplifying the operation, it can further enable the product to have a comparable or higher yield and enantioselectivity, and the substrate versatility is good. Attached Figure Description

[0233] Figure 1 The structure diagram of compound I obtained by single-crystal X-ray diffraction is shown. Detailed Implementation

[0234] 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.

[0235] Example 1: Synthesis of Compound I

[0236]

[0237] Under an argon atmosphere, [SCpRh] (2.6 mg, 0.005 mmol), A11 (6.8 mg, 0.02 mmol), AgF (38.0 mg, 0.30 mmol), compound II (0.10 mmol), the corresponding aromatic hydrocarbon III (0.30 mmol, 3.0 equiv.), and DMF (2.0 mL) were added to a Schlenk reaction flask, and the mixture was heated to 60 °C. After the reaction was complete, the mixture was diluted with ethyl acetate, and saturated carbonic acid solution (10.0 mL) was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulfate, and the solvent residue was removed under reduced pressure. The target product I (ethyl acetate / toluene = 1 / 50) was obtained by column chromatography.

[0238] The compounds in Examples 2-34 below were prepared according to Example 1.

[0239] Example 2

[0240] I-1:

[0241] (36.1 mg, 85% yield, 93% ee). Analytical data: (c=0.5, CHCl3, 93% ee). 1 HNMR (400MHz, CDCl3) δ8.87(d,J=4.5Hz,1H),8.04(d,J=8.3Hz,1H),7.98-7.89(m,2H),7.89-7.82(m,2H),7.80-7.76(m,2H),7.60( d,J=8.4Hz,1H),7.43-7.38(m,2H),7.25-7.14(m,1H),7.14-6.94(m,2H),6.39(d,J=3.6Hz,1H),6.28(d,J=3.8Hz,1H),2.17(s,3H). 13 CNMR (101MHz, CDCl3) δ 156.9, 144.0, 140.5, 140.3, 138.0, 137.7, 133.2, 133.1, 132.4, 132.1, 130.7, 129.3, 128.8, 128.8, 128.0, 128.0, 127.5, 127.0, 126.9, 126.8, 126.5, 126.1, 126.0, 126.0, 125.7, 125.1, 121.8, 15.1. Chiralpak IG column (25cm), n-hexane / isopropanol = 90:10, 1mL / min, detection wavelength = 254nm, t R(minor) = 30.81 min,t R (major) = 45.02 min.

[0242] Example 3

[0243] I-2:

[0244] (36.7 mg, 83% yield, 91% ee). Analytical data: (c=0.5, CHCl3, 91%ee)). 1 HNMR (400MHz, CDCl3) δ8.85(d,J=5.2Hz,1H),8.04(d,J=8.7Hz,1H),7.97-7.90(m,1H),7.88(d,J=8.8Hz,1H),7.83(d,J =7.7Hz,1H),7.81(d,J=4.3Hz,1H),7.77(dd,J=7.9,1.5Hz,1H),7.74(d,J=8.8Hz,1H),7.61-7.53(m,1H),7.43(ddd,J= 8.1,4.5,3.3Hz,1H),7.39(ddd,J=8.0,7.0,1.1Hz,1H),7.26-7.19(m,2H),7.03(ddd,J=8.6,7.0,1.5Hz,1H),6.27(d,J =3.6Hz,1H),6.25(d,J=3.6Hz,1H),2.48(t,J=7.5Hz,2H),1.41-1.33(m,2H),1.17-1.08(m,2H),0.81(t,J=7.3Hz,3H). 13 C NMR (101MHz, CDCl3) δ 157.0, 146.4, 144.0, 139.9, 138.0, 138.0, 133.3, 133.1, 132.2, 132.1, 130.8, 129.3, 128.7, 128.7, 128.1, 128.0, 127.3, 126.9, 126.8, 126.2, 126.1, 126.1, 125.6, 123.8, 121.5, 33.4, 29.4, 21.9, 13.8. Chiralpak IG column (25cm), n-hexane / isopropanol = 90:10, 1mL / min, detection wavelength = 254nm, t R (minor) = 18.92min,t R (major) = 36.60 min.

[0245] Example 4

[0246] I-3:

[0247] (38.0 mg, 85% yield, 90% ee). Analytical data: (c=0.5, CHCl3, 90% ee). 1 HNMR(400MHz, CDCl3)δ8.86(d,J=5.2Hz,1H),8.04(d,J=8.6Hz,1H),7.93(d,J=8.2Hz, 1H),7.89(d,J=8.8Hz,1H),7.84(d,J=8.6Hz,1H),7.82(d,J=5.3Hz,1H),7.80-7.72(m ,2H),7.57(d,J=8.7Hz,1H),7.46-7.35(m,2H),7.25-7.14(m,2H),7.03(ddd,J=8.7,7 .0,1.5Hz,1H),6.34(s,2H),3.35(t,J=6.8Hz,2H),3.21(s,3H),2.76(t,J=6.8Hz,2H). 13 CNMR (101MHz, CDCl3) δ 157.0, 144.1, 141.9, 140.8, 138.1, 138.0, 133.3, 133.1, 132.2, 132.1, 130.6, 129.3, 128.8, 128.1, 128.0, 127.4, 127.0, 126.8, 126.8, 126.3, 126.1, 126.1, 126.1, 125.6, 124.9, 121.6, 73.0, 58.6, 30.3. Chiralpak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 18.88min,t R (major) = 30.31 min.

[0248] Example 5

[0249] I-4:

[0250] (36.5 mg, 79% yield, 94% ee). Analytical data: (c=0.5, CHCl3, 94% ee). 1HNMR (400MHz, CDCl3) δ8.92(d,J=5.2Hz,1H),8.11(d,J=8.7Hz,1H),7.98(d,J=8.2Hz,1H),7.93(d ,J=6.5Hz,1H),7.91(d,J=6.9Hz,1H),7.88(d,J=5.2Hz,1H),7.81-7.77(m,2H),7.62(d,J=8.7Hz,1 H),7.48(ddd,J=8.1,6.5,1.4Hz,1H),7.42(t,J=7.4Hz,1H),7.34-7.30(m,2H),7.30-7.22(m,4H), 7.22-7.15(m,1H),7.08(ddd,J=8.5,6.9,1.4Hz,1H),6.84(d,J=3.8Hz,1H),6.51(d,J=3.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ 156.8, 144.4, 144.1, 142.1, 138.3, 138.1, 134.1, 133.5, 133.2, 132.4, 132.1, 130.3, 129.2, 128.9, 128.9, 128.7, 128.1, 128.0, 127.6, 127.4, 127.3, 127.1, 126.9, 126.7, 126.4, 126.2, 126.0, 125.6, 125.5, 122.9, 121.8. Chiralpak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 18.66min,t R (major) = 38.46 min.

[0251] Example 6

[0252] I-5:

[0253] (44.0 mg, 89% yield, 93% ee). Analytical data: (c=0.5, CHCl3, 93% ee). 1HNMR (400MHz, CDCl3) δ8.86(d,J=5.2Hz,1H),8.05(d,J=8.6Hz,1H),7.92(d,J=8.2Hz,1H),7.87(dd,J=8.8 ,7.6Hz,2H),7.82(d,J=5.3Hz,1H),7.78-7.70(m,2H),7.58(d,J=8.7Hz,1H),7.42(ddd,J=8.1,6.5,1.5Hz, 1H),7.37(ddd,J=8.0,7.0,1.1Hz,1H),7.23-7.15(m,3H),7.19(d,J=8.0Hz,1H)7.03(ddd,J=8.6,7.0,1.5 Hz,1H),6.76-6.73(m,1H),6.75(d,J=8.0Hz,1H)6.67(d,J=3.8Hz,1H),6.44(d,J=3.8Hz,1H),3.72(s,3H). 13 C NMR (101MHz, CDCl3) δ 159.0, 156.9, 144.4, 144.2, 141.1, 138.2, 138.1, 133.4, 133.2, 132.4, 132.2, 130.4, 129.2, 128.9, 128.1, 127.9, 127.5, 127.4, 127.1, 127.0, 126.9, 126.7, 126.3, 126.2, 126.0, 125.6, 122.0, 121.7, 114.1, 55.3. Chiral Pak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 28.42min,t R (major) = 58.00 min.

[0254] Example 7

[0255] I-6:

[0256] (47.0 mg, 98% yield, 95% ee). Analytical data: (c=0.5, CHCl3, 95% ee). 1HNMR(400MHz, CDCl3) δ8.86(d,J=5.2Hz,1H),8.06(d,J=8.6Hz,1H),7.93(d,J=8.2Hz, 1H),7.90-7.84(m,2H),7.82(d,J=5.2Hz,1H),7.78-7.68(m,2H),7.56(d,J=8.7Hz,1H) ,7.43(ddd,J=8.1,6.5,1.5Hz,1H),7.41-7.33(m,1H),7.26-7.13(m,4H),7.03(ddd,J =8.6,7.0,1.5Hz,1H),6.95-6.84(m,2H),6.69(d,J=3.8Hz,1H),6.45(d,J=3.8Hz,1H). 13 CNMR (101MHz, CDCl3) δ162.12 (d, J = 247.0Hz), 156.76, 144.17, 143.29, 142.11, 138.41, 13 8.07,133.49,133.17,132.39,132.14,130.42(d,J=3.4Hz),130.11,129.21,128.94(d,J=4 0.5Hz), 128.09, 127.89, 127.57, 127.46, 127.15, 127.14, 127.06, 126.89, 126.73, 126.41, 126.19, 125.99, 125.63, 122.90 (d, J = 1.2Hz), 121.77, 115.62 (d, J = 21.8Hz). Chiralpak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 15.93min,t R (major) = 44.06 min.

[0257] Example 8

[0258] I-7:

[0259] (21.1 mg, 45% yield, 87% ee). Analytical data: (c=0.5, CHCl3, 87% ee). 1HNMR (400MHz, CDCl3) δ8.88(d,J=5.2Hz,1H),8.07(d,J=8.6Hz,1H),7.95(d,J=8.2Hz,1H),7. 90(d,J=8.8Hz,1H),7.89-7.82(m,2H),7.81-7.74(m,2H),7.55(d,J=8.7Hz,1H),7.45(ddd,J= 8.1, 6.5, 1.4Hz, 1H), 7.40 (ddd, J=8.0, 6.9, 1.1Hz, 1H), 7.23 (dd, J=6.6, 1.4Hz, 1H), 7.21-7. 16(m,1H),7.11-6.99(m,2H),6.94-6.80(m,2H),6.67(d,J=3.8Hz,1H),6.41(d,J=3.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ 156.6, 144.1, 141.6, 138.3, 138.1, 137.6, 137.2, 133.5, 133.2, 132.4, 132.1, 130.0, 129.2, 129.0, 128.9, 128.1, 127.8, 127.6, 127.5, 127.3, 127.1, 126.9, 126.7, 126.4, 126.2, 126.0, 125.6, 124.1, 123.5, 123.3, 121.8. Chiralpak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 20.08min,t R (major) = 32.87 min.

[0260] Example 9

[0261] I-8:

[0262] (34.0 mg, 73% yield, 91% ee). Analytical data: (c=0.5, CHCl3, 91%ee). 1HNMR (400MHz, CDCl3) δ8.93(d,J=5.2Hz,1H),8.12(d,J=8.6Hz,1H),8.01(d,J=8.2Hz,1H),7. 93-7.88(m,2H),7.87(d,J=5.2Hz,1H),7.80(d,J=8.0Hz,1H),7.76(d,J=8.8Hz,1H),7.60(d,J =8.7Hz,1H),7.54-7.48(m,1H),7.45-7.40(m,1H),7.39-7.31(m,2H),7.31-7.26(m,2H),7.25 -7.18(m,3H),7.09(ddd,J=8.6,7.0,1.5Hz,1H),7.03(d,J=1.5Hz,1H),6.82(d,J=1.6Hz,1H). 13 C NMR (101MHz, CDCl3) δ 156.8, 144.1, 143.1, 141.4, 138.6, 138.1, 135.7, 133.6, 133.1, 132.4, 132.1, 130.3, 129.2, 129.0, 128.9, 128.6, 128.1, 128.0, 127.4, 127.2, 126.9, 126.9, 126.8, 126.5, 126.3, 126.1, 126.0, 125.8, 125.5, 121.7, 121.0. Chiralpak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 19.12 min,t R (major) = 43.20 min.

[0263] Example 10

[0264] I-9:

[0265] (31.0 mg, 70% yield, 82% ee). Analytical data: (c=0.5, CHCl3, 82% ee). 1HNMR(400MHz, CDCl3)δ8.87(d,J=5.2Hz,1H),8.08(d,J=8.6Hz,1H),8.01-7.95(m,1H) ,7.90(d,J=8.8Hz,1H),7.85(d,J=5.2Hz,1H),7.81(d,J=8.6Hz,1H),7.80-7.77(m,1H ),7.76(d,J=8.8Hz,1H),7.50(ddd,J=8.1,5.1,2.9Hz,1H),7.46-7.37(m,2H),7.32-7 .27(m,2H),7.03(ddd,J=8.6,7.0,1.5Hz,1H),6.29(s,1H),2.20(s,3H),2.16(s,3H). 13 C NMR (101MHz, CDCl3) δ 190.9, 156.2, 146.7, 144.3, 144.0, 139.4, 138.1, 136.0, 133.9, 133.2, 132.5, 132.2, 132.0, 129.2, 129.1, 129.0, 128.9, 128.1, 127.5, 127.4, 127.4, 126.9, 126.9, 126.7, 126.5, 125.8, 125.5, 121.8, 29.4, 16.6. Chiralpak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 30.90 min, t R (major) = 44.63 min.

[0266] Example 11

[0267] I-10:

[0268] (27.0 mg, 59% yield, 87% ee). Analytical data: (c=0.5, CHCl3, 87% ee). 1HNMR(400MHz, CDCl3)δ8.89(d,J=5.2Hz,1H),8.10(d,J=8.6Hz,1H),7.98(d, J=8.2Hz,1H),7.92(d,J=8.8Hz,1H),7.87(d,J=5.2Hz,1H),7.85-7.79(m,2H) ,7.78(d,J=8.8Hz,1H),7.53-7.46(m,2H),7.44-7.39(m,1H),7.31-7.24(m,2 H),7.05(ddd,J=8.6,7.0,1.5Hz,1H),6.28(s,1H),3.70(s,3H),2.19(s,3H). 13 C NMR (101MHz, CDCl3) δ 163.1, 156.2, 146.9, 145.6, 144.0, 139.2, 138.1, 133.8, 133.2, 132.5, 132.0, 131.2, 129.4, 129.1, 129.0, 128.9, 128.1, 127.7, 127.4, 127.3, 126.9, 126.8, 126.6, 126.4, 126.3, 125.8, 125.6, 121.8, 51.5, 15.7. Chiralpak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 19.94 min,t R (major) = 34.05 min.

[0269] Example 12

[0270] I-11:

[0271] (36.4 mg, 88% yield, 95% ee). Analytical data: (c=0.5, CHCl3, 95% ee) 1HNMR (400MHz, CDCl3) δ8.87(d,J=5.2Hz,1H),8.02(d,J=8.7Hz,1H),7.91(dd,J=8.5,3.3Hz,2H),7.86(d,J=6.9Hz,1H),7.84(d,J=3.6Hz,1H),7.80- 7.76(m,2H),7.59(d,J=8.8Hz,1H),7.41-7.37(m,2H),7.17(ddd,J=8.2,6 .7,1.3Hz,1H),7.08-7.00(m,2H),6.37(s,1H),2.01(s,3H),1.81(s,3H). 13 C NMR (101MHz, CDCl3) δ 156.0, 143.1, 136.9, 136.5, 136.4, 133.0, 132.1, 131.7, 131.2, 131.1, 129.5, 128.6, 128.3, 127.7, 127.6, 126.9, 126.7, 126.4, 125.8, 125.8, 125.7, 125.0, 124.9, 124.6, 120.6, 12.3, 11.7. Chiralpak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 21.33min,t R (major) = 29.96 min.

[0272] Example 13

[0273] I-12:

[0274] (24.4 mg, 55% yield, 90% ee). Analytical data: (c=0.5, CHCl3, 90% ee). 1HNMR(400MHz, CDCl3)δ8.89(d,J=5.2Hz,1H),8.14(d,J=8.6Hz,1H),8.01-7.97(m ,2H),7.89(d,J=8.8Hz,1H),7.85(d,J=5.2Hz,1H),7.80(dd,J=7.9,1.5Hz,1H),7 .75(d,J=8.8Hz,1H),7.64(d,J=8.7Hz,1H),7.55-7.50(m,2H),7.48-7.39(m,2H) ,7.31-7.25(m,1H),7.22(dd,J=8.6,1.2Hz,1H),7.19-7.05(m,3H),6.89(s,1H). 13 C NMR (101MHz, CDCl3) δ 156.5, 144.1, 143.0, 140.4, 139.6, 139.4, 138.0, 133.7, 133.2, 132.4, 132.0, 130.4, 129.2, 129.0, 128.9, 128.4, 128.1, 127.4, 127.2, 126.9, 126.8, 126.7, 126.3, 126.0, 125.6, 123.9, 123.8, 123.4, 123.4, 121.9, 121.7. Chiral Pak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 16.40 min, t R (major) = 31.92 min.

[0275] Example 14

[0276] I-13:

[0277] (44.0 mg, 97% yield, 94% ee). Analytical data: (c=0.5, CHCl3, 94% ee). 1HNMR(400MHz, CDCl3)δ8.89(d,J=5.2Hz,1H),8.14(d,J=8.6Hz,1H),8.01-7.97(m, 2H),7.91-7.83(m,2H),7.83-7.73(m,2H),7.65(d,J=8.7Hz,1H),7.50(ddd,J=8.2 ,6.7,1.3Hz,1H),7.45-7.37(m,2H),7.30-7.24(m,2H),7.23-7.18(m,1H),7.10(d dd,J=8.7,7.0,1.5Hz,1H),6.96(dd,J=8.2,1.7Hz,1H),6.82(s,1H),2.33(s,3H). 13 C NMR (101MHz, CDCl3) δ 156.5, 144.0, 143.1, 140.0, 139.3, 138.0, 137.6, 133.7, 133.6, 133.2, 132.4, 132.0, 130.5, 129.2, 129.0, 128.9, 128.4, 128.1, 127.4, 127.2, 126.9, 126.8, 126.6, 126.3, 126.0, 125.7, 125.6, 123.3, 123.1, 121.9, 121.4, 21.3. Chiral column (Chiralpak) IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 25.07min,t R (major) = 38.71 min.

[0278] Example 15

[0279] I-14:

[0280] (42.0 mg, 93% yield, 95% ee). Analytical data: (c=0.5, CHCl3, 95% ee). 1HNMR (400MHz, CDCl3) δ8.79(d,J=5.2Hz,1H),8.10(d,J=8.5Hz,1H),8.03(d,J=8.2Hz,1H),7.83-7.71(m,2H),7.65(d,J=5.2Hz,1H),7.62(d,J= 8.5Hz,1H),7.58(d,J=8.4Hz,1H),7.57-7.47(m,3H),7.48-7.41(m,2H) ,7.41-7.33(m,2H),7.21-7.16(m,1H),7.16-7.03(m,2H),1.98(s,3H). 13 C NMR (101MHz, CDCl3) δ 156.2, 143.5, 141.5, 139.7, 139.7, 137.7, 136.7, 133.9, 133.0, 131.9, 131.9, 130.6, 129.8, 129.4, 129.3, 128.8, 128.2, 128.2, 127.1, 126.9, 126.7, 126.7, 126.5, 126.4, 126.2, 125.4, 123.6, 123.3, 121.6, 121.5, 121.4, 12.3. Chiral column Chiralpak IG column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 8.93min,t R (major) = 15.58 min.

[0281] Example 16

[0282] I-15:

[0283] (33.0 mg, 86% yield, 88% ee). Analytical data: (c=0.5, CHCl3, 88% ee). 1HNMR (400MHz, CDCl3) δ8.89 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8. 8Hz,1H),7.95(d,J=8.8Hz,1H),7.91(d,J=8.2Hz,1H),7.88(d,J=5.2Hz,1H),7.84 -7.78(m,2H),7.62(d,J=8.7Hz,1H),7.42-7.36(m,2H),7.17(ddd,J=8.2,6.7,1.3 Hz,1H),7.08-6.99(m,2H),5.66-5.52(m,1H),5.06(d,J=3.3Hz,1H),2.04(s,3H). 13 C NMR (101MHz, CDCl3) δ 157.6, 151.7, 150.7, 144.7, 138.1, 135.6, 133.1, 133.0, 132.4, 132.2, 129.3, 128.8, 128.6, 128.0, 127.6, 126.9, 126.8, 126.6, 126.2, 126.1, 125.9, 125.8, 125.7, 124.4, 121.6, 110.0, 107.8, 13.4. Chiral column: Phenomenex Lux 5u Cellulose-4 column (25cm), n-hexane / isopropanol = 95:5, 1mL / min, detection wavelength = 254nm, t R (minor) = 25.04min,t R (major) = 34.48 min.

[0284] Example 17

[0285] I-16:

[0286] (31.0 mg, 61% yield, 85% ee). Analytical data: (c=0.5, CHCl3, 85% ee). 1HNMR (400MHz, CDCl3) δ8.86(d,J=5.2Hz,1H),8.15(d,J=8.8Hz,1H),8.10(d,J=8.8H z,1H),8.02(d,J=8.8Hz,1H),7.94(d,J=8.2Hz,1H),7.92-7.86(m,2H),7.85-7.80( m,3H),7.72(d,J=8.7Hz,1H),7.45-7.38(m,2H),7.19(t,J=7.6Hz,1H),7.10-7.02( m,2H),7.02-7.01(m,2H),6.49(d,J=3.6Hz,1H),5.86(d,J=3.6Hz,1H),3.89(s,3H). 13 C NMR (101MHz, CDCl3) δ 166.7, 157.4, 153.6, 152.2, 144.6, 138.0, 136.8, 134.1, 133.4, 133.1, 132.5, 132.1, 129.7, 129.2, 129.0, 128.9, 128.1, 128.0, 127.6, 127.1, 126.9, 126.4, 126.3, 126.0, 125.9, 125.7, 125.6, 124.7, 122.9, 121.6, 111.2, 109.3, 52.0. Chiral column IG column (25cm), n-hexane / isopropanol = 70:30, 1mL / min, detection wavelength = 254nm, t R (minor) = 22.14min,t R (major) = 31.19 min.

[0287] Example 18

[0288] I-17:

[0289] (25.0 mg, 61% yield, 90% ee). Analytical data: (c=0.5, CHCl3, 90% ee). 1HNMR (400MHz, CDCl3) δ8.77(d,J=5.2Hz,1H),8.12(d,J=8.5Hz,1H),8.02(d ,J=8.2Hz,1H),7.80-7.70(m,3H),7.67(d,J=5.2Hz,1H),7.61-7.57(m,3H), 7.56-7.49(m,1H),7.40-7.34(m,2H),7.19(dd,J=7.4,1.7Hz,1H),7.04(ddd ,J=8.8,7.1,1.6Hz,1H),7.02-6.95(m,2H),6.68-6.60(m,1H),1.93(s,3H). 13 C NMR (101MHz, CDCl3) δ 156.8, 153.6, 150.8, 143.6, 140.9, 137.5, 134.0, 132.9, 132.0, 131.7, 129.8, 129.3, 128.5, 128.4, 128.1, 127.6, 127.2, 127.1, 126.8, 126.6, 126.6, 126.6, 126.5, 126.2, 125.2, 123.6, 121.6, 120.7, 118.8, 113.1, 110.3, 8.4. Chiral column AD-H column (25cm), n-hexane / isopropanol = 90:10, 1mL / min, detection wavelength = 254nm, t R (minor) = 11.62min,t R (major) = 33.84 min.

[0290] Example 19

[0291] I-18:

[0292] (43.0 mg, 85% yield, 91% ee). Analytical data: (c=0.5, CHCl3, 91%ee). 1HNMR (400MHz, CDCl3) δ8.90(d,J=5.2Hz,1H),8.09(d,J=8.6Hz,1H),7.96(d,J=8.1Hz,1H),7.92(d,J=8.6Hz,1H), 7.89(d,J=8.9Hz,1H),7.85(d,J=5.2Hz,1H),7.78-7.75(m,2H),7.61(d,J=8.7Hz,1H),7.56(d,J=2.0Hz,1H),7.5 0(d,J=1.6Hz,1H),7.45(ddd,J=8.1,6.6,1.3Hz,1H),7.41(d,J=7.2Hz,1H),7.35(d,J=8.6Hz,1H),7.25-7.18(m, 3H), 7.06 (ddd, J=8.5, 7.1, 1.4Hz, 1H), 6.78 (d, J=3.8Hz, 1H), 6.68 (dd, J=2.2, 1.1Hz, 1H), 6.49 (d, J=3.8Hz, 1H). 13 C NMR (101MHz, CDCl3) δ 156.8, 154.4, 145.7, 144.9, 144.2, 141.6, 138.3, 138.1, 133.4, 133.2, 132.4, 132.2, 130.3, 129.4, 129.2, 128.9, 128.9, 128.1, 128.0, 127.8, 127.6, 127.5, 127.1, 126.9, 126.7, 126.3, 126.2, 126.0, 125.6, 122.7, 122.6, 121.8, 118.1, 111.5, 106.7. Chiral column IG column (25cm), n-hexane / isopropanol = 70:30, 1mL / min, detection wavelength = 254nm, t R (minor) = 15.73min,t R (major) = 64.21 min.

[0293] Example 20

[0294] I-19:

[0295] (48.8 mg, 85% yield, 81% ee). Analytical data: (c=0.5, CHCl3, 81%ee). 1HNMR (400MHz, CDCl3) δ8.82(d,J=5.2Hz,1H),8.12(d,J=8.5Hz,1H),8.01(d,J=8.2Hz,1H),7.80(d,J=8.8Hz,1H),7.77–7.72(m,2H),7.72–7.63(m,3H ),7.58–7.48(m,2H),7.40(d,J=7.9Hz,1H),7.36-7.29(m,3H),7.23-7.21( m,2H),7.10(t,J=7.7Hz,1H),7.04-7.00(m,4H),6.74(s,1H),2.31(s,3H). 13 C NMR (101MHz, CDCl3) δ 157.0, 144.5, 143.5, 140.1, 137.7, 135.0, 134.1, 133.5, 133.0, 132.2, 132.2, 130.1, 129.7, 129.0, 128.9, 128.7, 128.6, 128.4, 128.2, 127.1, 127.0, 126.9, 126.5, 126.4, 126.2, 126.1, 126.1, 125.3, 124.7, 124.3, 123.0, 121.6, 121.3, 120.4, 113.0, 21.6. Chiral column IC column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 17.79min,t R (major) = 34.95 min.

[0296] Example 21

[0297] I-20:

[0298] (13.0 mg, 25% yield, 89% ee). Analytical data: (c=0.5, CHCl3, 89%ee). 1 HNMR (400MHz, CD2Cl2) δ8.73(d,J=5.2Hz,1H),8.00(d,J=8.6Hz,1H),7.89(d,J=8.2Hz,1H),7.84(d,J=8 .8Hz,1H),7.78(d,J=5.2Hz,1H),7.76–7.70(m,2H),7.66(d,J=8.6Hz,1H),7.42–7.29(m,3H),7.19(AB,J AB=8.1Hz,2H),7.14(ddd,J=8.2,6.8,1.2Hz,1H),7.05(BA,J BA =8.1Hz,2H),7.01(d,J=8.5Hz,1H),6.91(ddd,J=8.6,7.1,1.4Hz,1H),6.65(dd,J =3.2, 2.3Hz, 1H), 6.30 (t, J = 1.9Hz, 1H), 5.83 (dd, J = 3.3, 1.7Hz, 1H), 2.31 (s, 3H). 13 CNMR (101MHz, CDCl3) δ 157.3, 144.5, 143.9, 138.3, 137.9, 135.8, 133.3, 133.0, 132.2, 132.0, 129.7, 129.7, 129.1, 128.8, 128.8, 128.4, 128.0, 127.5, 127.3, 126.9, 126.8, 126.4, 126.2, 126.0, 125.9, 125.5, 121.5, 120.1, 118.7, 114.2, 21.6. Chiral column IC column (25cm), n-hexane / isopropanol = 70:30, 1mL / min, detection wavelength = 254nm, t R (minor) = 25.37min,t R (major) = 30.91 min.

[0299] Example 22

[0300] I-21:

[0301] (48.5 mg, 97% yield, 97% ee). Analytical data: (c=0.5, CHCl3, 97% ee). 1 HNMR (400MHz, CDCl3) δ8.88(d,J=5.2Hz,1H),8.23(d,J=8.3Hz,1H),7.90(d,J=8.8Hz,1 H),7.86(d,J=5.2Hz,1H),7.80-7.75(m,2H),7.61(d,J=7.2Hz,1H),7.58(d,J=4.4Hz,1H ),7.52(t,J=7.6Hz,1H),7.42(t,J=7.4Hz,1H),7.30(t,J=7.7Hz,1H),7.23-7.18(m,3H) ,7.10(t,J=7.9Hz,1H),6.94-6.90(m,2H),6.73(d,J=3.8Hz,1H),6.50(d,J=3.8Hz,1H).13 C NMR (101MHz, CDCl3) δ162.2 (d, J = 247.4Hz), 158.8 (d, J = 253.0Hz), 156.0, 144.2, 143.8, 141.0 (d, J = 1Hz), 138.2 ,134.5(d,J=4.3Hz),133.6(d,J=5.4Hz),133.2,132.5,130.4(d,J=8.6Hz),130.2(d,J=3.4Hz),129.1,129.0,12 8.2, 127.9, 127.5, 127.2 (d, J = 7.9 Hz), 127.0, 126.9, 126.7 (d, J = 1.8 Hz), 126.2 (d, J = 2.9 Hz), 125.8, 125.6, 123.8 (d, J = 16.6 Hz), 122.9 (d, J = 1.3 Hz), 122.0, 120.7 (d, J = 5.0 Hz), 115.7 (d, J = 21.8 Hz), 111.3 (d, J = 21.4 Hz). Chiral column IG column (25 cm), n-hexane / isopropanol = 70:30, 1 mL / min, detection wavelength = 254 nm, t R (minor) = 9.57min,t R (major) = 30.67 min.

[0302] Example 23

[0303] I-22:

[0304] (45.8 mg, 92% yield, 92% ee). Analytical data: (c=0.5, CHCl3, 92% ee). 1 HNMR (400MHz, CDCl3) δ8.85(d,J=5.2Hz,1H),8.09(d,J=8.4Hz,1H),7.87(d,J=8. 8Hz,1H),7.82(d,J=5.2Hz,1H),7.79-7.69(m,3H),7.65(d,J=8.7Hz,1H),7.48(dd d,J=8.3,6.2,1.8Hz,1H),7.38(t,J=7.5Hz,1H),7.25-7.17(m,4H),7.08-7.02(m, 1H),6.93-6.88(m,2H),6.70(d,J=3.8Hz,1H),6.43(d,J=3.8Hz,1H),2.88(s,3H). 13C NMR (101MHz, CDCl3) δ162.1 (d, J = 247.0Hz), 157.0, 144.2, 143.1, 142.3, 138. 0,136.8,135.3,133.2,132.8,132.3,132.3,130.5(d,J=3.4Hz),129.6,129. 3, 128.9, 128.5, 127.4, 127.4, 127.1 (d, J = 8.0 Hz), 126.8, 126.8, 126.7, 126.2, 126.1, 125.6, 124.3, 122.9, 122.8, 121.6, 115.6 (d, J = 21.8 Hz), 19.8. Chiral column IG column (25 cm), n-hexane / isopropanol = 70:30, 1 mL / min, detection wavelength = 254 nm, t R (minor) = 9.38min,t R (major) = 45.41 min.

[0305] Example 24

[0306] I-23:

[0307] (46.3 mg, 90% yield, 97% ee). Analytical data: (c=0.5,CHCl3). 1 H NMR (400MHz, DMSO-D6) δ8.88(d,J=5.2Hz,1H),8.32(d,J=8.4Hz,1H),8.12(d,J=5.2Hz,1 H),8.08(d,J=8.9Hz,1H),7.99(d,J=8.8Hz,1H),7.94(d,J=7.8Hz,1H),7.57(d,J=8.7Hz, 1H),7.53-7.47(m,1H),7.45(t,J=7.5Hz,1H),7.40(s,1H),7.36-7.30(m,2H),7.27(d,J= 7.7Hz,1H),7.16-7.06(m,4H),6.91(d,J=8.5Hz,1H),6.86(d,J=3.9Hz,1H),4.21(s,3H). 13C NMR (101MHz, DMSO-D6) δ 162.0 (d, J = 245.3Hz), 156.4, 155.4, 144.8, 143.0, 142.1, 138.2, 133.4, 133.1, 132.6, 131.3, 130.3 (d, J = 3.3Hz), 130.0, 129.7, 129.0, 128.6, 128.2, 127.8, 127.5, 127.3 (d, J = 8.3Hz), 126.5, 126.4, 126.0, 125.5, 125.3, 124.1, 122.5, 122.2, 116.4 (d, J = 21.8Hz), 105.9, 56.5. Chiral column IG column (25cm), n-hexane / isopropanol = 70:30, 1mL / min, detection wavelength = 254nm, t R (minor) = 9.88min,t R (major) = 40.34 min.

[0308] Example 25

[0309] I-24:

[0310] (45.6 mg, 90% yield, 93% ee). Analytical data: (c=0.5, CHCl3, 93% ee). 1 HNMR (400MHz, CDCl3) δ8.82(d,J=5.2Hz,1H),7.86(d,J=8.8Hz,1H),7.78-7.77(m,2H),7.76-7.69(m,2H),7.65(s,1H),7.39(ddd,J=8.1,7.1,1.1 Hz,1H),7.28-7.19(m,4H),7.07(ddd,J=8.5,6.9,1.5Hz,1H),6.94-6.88 (m,3H),6.68(d,J=3.8Hz,1H),6.41(d,J=3.8Hz,1H),3.65-3.42(m,4H). 13C NMR (101MHz, CDCl3) δ162.1 (d, J = 246.9Hz), 156.8, 146.9, 145.8, 144.1, 143.2, 14 2.9,139.4,137.9,134.7,133.1,132.2,131.8,130.5(d,J=3.4Hz),130.2,129.4, 129.0, 128.8, 127.5, 127.3, 127.1 (d, J = 7.9 Hz) 126.8, 126.6, 126.1, 125.6, 122.8 (d, J = 1.2 Hz), 121.5, 121.4, 121.3, 120.1, 115.6 (d, J = 21.8 Hz), 30.6, 30.4. Chiral column IG column (25 cm), n-hexane / isopropanol = 70:30, 1 mL / min, detection wavelength = 254 nm, t R (minor) = 9.99min,t R (major) = 51.96 min.

[0311] Example 26

[0312] I-25:

[0313] (48.0 mg, 86% yield, 90% ee). Analytical data: (c=0.5, CHCl3, 90% ee) 1 H NMR (400MHz, CDCl3) δ8.93(d,J=5.2Hz,1H),8.56(s,1H),8.24(d,J=7.8Hz,1H),8.20(d,J=3 .6Hz,2H),8.11(d,J=7.4Hz,1H),8.01(t,J=7.6Hz,1H),7.93-7.87(m,2H),7.86(d,J=9.3Hz ,1H),7.79-7.76(m,2H),7.50(d,J=9.2Hz,1H),7.39-7.31(m,2H),7.29-7.26(m,2H),6.98- 6.92(m,2H),6.87(ddd,J=8.7,7.0,1.5Hz,1H),6.74(d,J=3.7Hz,1H),6.49(d,J=3.8Hz,1H). 13C NMR (101MHz, CDCl3) δ162.1 (d, J = 247.1Hz), 157.1, 144.1, 143.5, 142.3, 142.3, 138.0, 13 6.8,133.2,132.4,131.5,131.4,131.0,130.9,130.5(d,J=3.3Hz),129.6,129.3,128.9,1 28.6, 128.4, 127.9, 127.5, 127.4, 127.1 (d, J = 8.0 Hz), 126.9, 126.8, 126.4, 126.0, 125.6, 125.6, 125.5, 125.2, 124.9, 124.6, 123.0 (d, J = 1.0 Hz), 121.7, 115.7 (d, J = 21.7 Hz). Chiral column IG column (25 cm), n-hexane / isopropanol = 70:30, 1 mL / min, detection wavelength = 254 nm, t R (minor) = 16.85min,t R (major) = 66.03 min.

[0314] Example 27

[0315] I-26:

[0316] (36.5 mg, 82% yield, 82% ee). Analytical data: (c=0.5, CHCl3, 82% ee). 1 HNMR (400MHz, CDCl3) δ8.79(d,J=5.2Hz,1H),7.87(d,J=8.8Hz,1H),7.82(d,J=7.8Hz ,1H),7.79(d,J=8.7Hz,1H),7.73(d,J=5.2Hz,1H),7.69(d,J=8.8Hz,1H),7.60(d,J= 7.7Hz,1H),7.52-7.47(m,2H),7.39(d,J=7.5Hz,1H),7.31-7.26(m,1H),7.24-7.16( m,2H),6.97-6.85(m,2H),6.65(d,J=3.8Hz,1H),6.31(d,J=3.8Hz,1H),1.92(s,3H). 13C NMR (101MHz, CDCl3) δ 161.0 (d, J = 246.8Hz), 156.6, 142.9, 141.6, 141.1, 140.7, 136.8, 135.3, 132.1, 131.8, 131.1, 129.6, 129.4 (d, J = 3.3Hz), 128.6, 127.9, 127.5, 127.2, 126.5, 126.0, 126.0, 125.9 (d, J = 6.0Hz), 124.6, 124.6, 124.4, 121.7 (d, J = 1.0Hz), 120.3, 114.5 (d, J = 21.8Hz), 19.1. Chiral column AD-H column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 5.30 min, t R (major) = 15.39 min.

[0317] Example 28

[0318] I-27:

[0319] (33.1 mg, 70% yield, 79% ee). Analytical data: (c=0.5, CHCl3, 79% ee). 1 HNMR (400MHz, CDCl3) δ8.79(d,J=5.2Hz,1H),7.85(d,J=8.8Hz,1H),7.80(d,J=7.8Hz,1H),7.77-7.69(m,3H),7.69-7.64(m,2H),7.61(t,J=7.6 Hz,1H),7.49(t,J=7.4Hz,1H),7.30-7.23(m,1H),7.23-7.13(m,2H),6. 93-6.88(m,2H),6.61(d,J=3.8Hz,1H),6.23(d,J=3.8Hz,1H),4.22(AB,J AB =13.2Hz, 1H), 4.04(BA, J BA =13.2Hz, 1H), 3.06(s, 3H). 13C NMR (101MHz, CDCl3) δ 161.0 (d, J = 246.9Hz), 155.3, 142.6, 141.7, 140.6, 139.2, 136.8, 136.0, 132.0 (d, J = 11.0Hz), 131.2, 129.4 (d, J = 3.4Hz), 128.6, 127.9, 127.8, 126.6, 126.4, 126.1, 126.0, 126.0, 125.9, 124.8, 124.8, 124.5, 121.7, 121.6, 120.5, 114.5 (d, J = 21.8Hz), 71.1, 57.3. Chiral column AD-H column (25cm), n-hexane / isopropanol = 80:20, 1mL / min, detection wavelength = 254nm, t R (minor) = 6.08min,t R (major) = 19.83 min.

[0320] Example 29

[0321] I-28:

[0322] (42.0 mg, 91% yield, 92% ee). Analytical data: (c=0.5, CHCl3, 92% ee). 1 HNMR (400MHz, CDCl3) δ8.79(d,J=5.4Hz,1H),7.96(d,J=8.7Hz,1H),7.84(d,J=8.8Hz,1H),7. 81(d,J=7.9Hz,1H),7.74-7.69(m,1H),7.68(d,J=8.7Hz,1H),7.55(t,J=8.1Hz,1H),7.49(t, J=7.4Hz,1H),7.41(d,J=7.8Hz,1H),7.29(dd,J=15.1,7.7Hz,1H),7.25-7.16(m,2H),7.07(d ,J=8.3Hz,1H),6.92-6.87(m,2H),6.66(d,J=3.5Hz,1H),6.36(d,J=3.7Hz,1H),3.57(s,3H). 13C NMR (101MHz, CDCl3) δ 162.1 (d, J = 246.9Hz), 157.3, 155.3, 143.9, 142.9, 141.5, 137.8, 134.1, 133.1, 131.9, 131.5, 130.4 (d, J = 3.4Hz), 129.9, 129.7, 129.0, 127.3, 127.3, 127.1 (d, J = 7.9Hz), 126.8, 126.4, 125.8, 125.5, 122.9 (d, J = 1.2Hz), 122.8, 121.5, 115.6 (d, J = 21.7Hz), 111.2, 56.1. Chiral column IG column (25cm), n-hexane / isopropanol = 70:30, 1mL / min, detection wavelength = 254nm, t R (minor) = 9.04min,t R (major) = 29.03 min.

[0323] Example 30

[0324] I-29:

[0325] (44.0 mg, 87% yield, 47% ee). Analytical data: (c=0.5, CHCl3, 47%ee). 1 HNMR(400MHz, CDCl3)δ8.79(d,J=5.5Hz,1H),7.95-7.84(m,2H),7.65(d,J=8.0Hz,1 H),7.63-7.56(m,1H),7.48(d,J=8.7Hz,1H),7.41-7.27(m,6H),7.15(dd,J=7.0,1. 0Hz,1H),7.04-6.97(m,2H),6.97-6.88(m,2H),6.86(d,J=3.8Hz,1H),6.73(tt,J=7 .3,1.5Hz,1H),6.38(d,J=3.8Hz,1H),6.29(d,J=7.7Hz,1H),6.19(t,J=7.5Hz,1H). 13C NMR (101MHz, CDCl3) δ162.2 (d, J = 247.1Hz), 158.8, 143.0, 141.8, 141.0, 140.5, 138.0,136.4,133.3,132.8,131.4,130.6(d,J=3.4Hz),130.5,129.3,128.5,12 8.4, 127.7 (d, J = 6.8 Hz), 127.7, 127.6, 127.1, 127.1, 126.9, 126.8, 126.4, 126.3, 126.3, 125.5, 125.2, 122.9 (d, J = 1.2 Hz), 121.4, 115.7 (d, J = 21.8 Hz). Chiral AD-H column (25 cm), n-hexane / isopropanol = 80:20, 1 mL / min, detection wavelength = 254 nm, t R (minor) = 13.59min,t R (major) = 26.50 min.

[0326] Example 31

[0327] I-30:

[0328] (36.8 mg, 86% yield, 91% ee). Analytical data: (c=0.5, CHCl3, 91%ee). 1 HNMR (400MHz, CDCl3) δ8.69(d,J=5.5Hz,1H),7.97(d,J=8.6Hz,1H),7.89(d,J=8.2Hz,1H),7 .83(d,J=8.7Hz,1H),7.77(d,J=5.7Hz,1H),7.75(d,J=7.8Hz,1H),7.48(t,J=7.6Hz,1H),7. 43(ddd,J=8.1,6.8,1.2Hz,1H),7.38–7.32(m,2H),7.31–7.25(m,2H),7.23(s,1H),7.20–7. 14(m,2H),7.06(d,J=8.4Hz,1H),6.92(d,J=3.9Hz,1H),6.58(d,J=3.8Hz,1H),1.80(s,3H). 13C NMR (101 MHz, CDCl3) δ 158.3, 144.6, 142.5, 141.6, 138.1, 138.0, 136.0, 134.1, 133.5, 132.7, 130.8, 130.6, 129.9, 129.0, 128.8, 128.8, 128.0, 127.7, 127.4, 127.1, 127.0, 126.4, 126.2, 126.1, 125.5, 123.2, 121.8, 22.9. Chiral column IG column (25 cm), n-hexane / isopropanol = 70:30, 1 mL / min, detection wavelength = 254 nm, t R (minor) = 13.70 min, t R (major) = 24.13 min.

[0329] Example 32

[0330] I-31:

[0331] (33.7 mg, 76% yield, 60% ee). Analytical data: (c=0.5, CHCl3, 60% ee). 1 HNMR (400MHz, CDCl3) δ8.55(d,J=5.8Hz,1H),7.97(d,J=8.6Hz,1H),7.80(dd,J=8.4, 2.5Hz,2H),7.64(d,J=5.8Hz,1H),7.61–7.50(m,2H),7.46(d,J=8.4Hz,1H),7.39(t,J =7.9Hz,1H),7.36–7.32(m,2H),7.32–7.28(m,1H),7.27-7.23(m,2H),7.20–7.13(m, 1H), 6.85 (d, J = 3.8Hz, 1H), 6.68 (d, J = 7.6Hz, 1H), 6.52 (d, J = 3.8Hz, 1H), 3.03 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.9, 156.5, 144.3, 142.2, 140.8, 135.4, 134.8, 134.2, 132.2, 129.8, 129.2, 129.0, 128.7, 128.5, 128.4, 127.2, 127.0, 126.8, 126.7, 126.5, 125.4, 124.9, 122.7, 121.1, 119.6, 107.5, 56.0. Chiral column IG column (25 cm), n-hexane / isopropanol = 80:20, 1 mL / min, detection wavelength = 254 nm, t R (minor) = 24.20 min, t R (major) = 55.88 min.

[0332] Example 33

[0333] I-32:

[0334] (36.0 mg, 87% yield, 97% ee). Analytical data: (c=0.5,CHCl3). 1 H NMR (400MHz, CDCl3) δ8.55(d,J=5.7Hz,1H),7.94(d,J=8.5Hz,1H),7.74(d,J=8.1 Hz,1H),7.67(dd,J=12.5,8.4Hz,2H),7.61(d,J=5.7Hz,1H),7.46(t,J=7.5Hz,1H ),7.38(d,J=8.4Hz,1H),7.29(t,J=7.6Hz,1H),7.27–7.19(m,3H),7.19–7.14(m, 2H),7.13–7.06(m,2H),6.72(d,J=3.7Hz,1H),6.35(d,J=3.7Hz,1H),1.46(s,3H). 13 C NMR (101MHz, CDCl3) δ 161.2, 143.2, 141.5, 140.2, 134.6, 134.3, 133.4, 133.4, 133.1, 132.2, 130.8, 129.8, 129.1, 129.0, 128.9, 127.7, 127.4, 126.7, 126.6, 126.3, 126.2, 126.0, 125.7, 125.0, 124.3, 121.4, 119.7, 22.8. Chiral column IG column (25cm), n-hexane / isopropanol = 90:10, 1mL / min, detection wavelength = 254nm, t R(minor) = 19.56 min,t R (major) = 30.06 min.

[0335] Example 34

[0336] I-33:

[0337] (40.7 mg, 88% yield, 99% ee). Analytical data: (c=0.5, CHCl3, 99% ee). 1 HNMR (400MHz, CDCl3) δ8.68(d,J=5.7Hz,1H),8.07(d,J=8.3Hz,1H),7.89(d,J=8.2Hz,1H),7.85–7.80(m,2H),7.79–7.74(m,3H),7.57– 7.47(m,2H),7.39–7.28(m,3H),7.28–7.22(m,3H),7.20–7.14(m,1H),6.86–6.78(m,2H),6.72(d,J=8.7Hz,1H),6.39(d,J=3.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ 162.49, 144.37, 142.54, 142.42, 136.36, 135.15, 134.30, 134.18, 133.94, 133.27, 130.46, 130.12, 129.79, 129.72, 129.11, 128.87, 128.75, 128.52, 128.49, 127.54, 127.27, 127.26, 127.02, 126.87, 126.52, 126.06, 125.66, 125.41, 122.52, 120.90. Chiral column IG column (25cm), n-hexane / isopropanol = 70:30, 1mL / min, detection wavelength = 254nm, t R (minor) = 16.39min,t R (major) = 41.99 min.

[0338] Example 35

[0339]

[0340] (86% yield, 96% ee). HRMS(ESI) calcd for C 22 H 20 NS[M+H] +:330.1311;Found:330.1310.

[0341] Example 36

[0342]

[0343] (84% yield, 97% ee). HRMS(ESI) calcd for C 25 H 20 NS[M+H] + :366.1311;Found:366.1310。

[0344] Example 37

[0345]

[0346] (82% yield, 99% ee). HRMS(ESI) calcd for C 21 H 19 N2S[M+H] + :331.1263; Found:331.1260.

[0347] Example 38

[0348]

[0349] (85% yield, 95% ee). HRMS(ESI) calcd for C 24 H 19 N2S[M+H] + :367.1263; Found:367.1260.

[0350] Example 39

[0351]

[0352] (81% yield, 96% ee). HRMS(ESI) calcd for C 25 H 20 NS[M+H] + :366.1311;Found:366.1310。

[0353] Example 40

[0354]

[0355] (81% yield, 95% ee). HRMS(ESI) calcd for C 28 H 20 NS[M+H]+ Found: 402.1311; Found: 402.1310.

[0356] Example 41

[0357]

[0358] (83% yield, 93% ee). HRMS(ESI) calcd for C 24 H 19 N2S[M+H] + :367.1263; Found:367.1260.

[0359] Example 42

[0360]

[0361] (87% yield, 96% ee). HRMS(ESI) calcd for C 27 H 19 N2S[M+H] + Found: 403.1263; Found: 403.1260.

[0362] Example 43

[0363]

[0364] Except for the rhodium catalyst and the chiral acid, the other conditions and operations were the same as in Example 1.

[0365] (36.0 mg, 85% yield, 93% ee). Analytical data: [α]2 D 3=-229.1 (c=0.5, CHCl3, 93%ee). 1 H NMR (400MHz, CDCl3) δ8.87(d,J=4.5Hz,1H),8.04(d,J=8.3Hz,1H),7.98-7.89(m,2H),7.89-7.82(m,2H),7.80-7.76(m,2H),7.60(d ,J=8.4Hz,1H),7.43-7.38(m,2H),7.25-7.14(m,1H),7.14-6.94(m,2H),6.39(d,J=3.6Hz,1H),6.28(d,J=3.8Hz,1H),2.17(s,3H). 13C NMR (101MHz, CDCl3) δ 156.9, 144.0, 140.5, 140.3, 138.0, 137.7, 133.2, 133.1, 132.4, 132.1, 130.7, 129.3, 128.8, 128.8, 128.0, 128.0, 127.5, 127.0, 126.9, 126.8, 126.5, 126.1, 126.0, 126.0, 125.7, 125.1, 121.8, 15.1. Chiralpak IG column (25cm), n-hexane / isopropanol = 90:10, 1mL / min, detection wavelength = 254nm, t R (major) = 30.81 min, t R (minor) = 45.02 min.

[0366] Example 44

[0367] Except for the conditions specifically specified in Table 1 below, all other conditions and operations are the same as in Example 1.

[0368]

[0369] Table 1

[0370]

[0371]

[0372] Note: a pass 1 The crude reaction mixture was analyzed by 1H NMR (using 1,3,5-trimethoxybenzene as an internal standard); b Chiral HPLC analysis was used to determine this. c The fraction within parentheses represents the separation yield.

[0373] Example 45 Single-crystal diffraction experiment of compound I-1

[0374] 1. Single crystal culture: The main component compound I-1 (30 mg) obtained in Example 2 was dissolved in a mixed solvent of anhydrous dichloromethane and petroleum ether and allowed to stand at 4°C for 3 days. Single crystals were precipitated and collected for single crystal diffraction test.

[0375] 2. The test parameters are shown in the table below:

[0376]

[0377]

[0378] 3. Measurement results: The configuration of compound I-1 was determined to be Ra configuration by single-crystal diffraction (α indicates axial chirality). Therefore, compounds I-1 to I-41 of this invention are all Ra configurations.

[0379] Example 46 Different Rhodium Catalysts

[0380] Except for the conditions specifically specified below, all other conditions and operations are the same as in Example 1.

[0381]

[0382]

[0383] Example 47 Different chiral acids

[0384] Except for the conditions specifically specified below, all other conditions and operations are the same as in Example 1.

[0385]

[0386]

[0387] Example 48

[0388] Except for the conditions specifically specified below, all other conditions and operations are the same as in Example 1.

[0389]

[0390] When compound III is an alkene, the reaction can occur and better enantioselectivity control can be achieved compared with existing techniques (Lit: Zheng, J.; Cui, WJ; Zheng, C.; You, SL, J. Am. Chem. Soc. 2016, 138, 5242.).

[0391] Experimental Example 1

[0392]

[0393] Following the method of Example 1, under an argon atmosphere, [SCpRh] (2.6 mg, 0.005 mmol), Al1 (6.8 mg, 0.02 mmol), AgF (38.0 mg, 0.30 mmol), compound II (0.10 mmol), benzene (0.30 mmol, 3.0 equiv.), and DMF (2.0 mL) were added to a Schlenk reaction flask, and the mixture was then heated to 60 °C. No corresponding product was obtained.

[0394] Experimental Example 2

[0395] Existing catalytic systems:

[0396]

[0397] The catalytic system of this invention:

[0398]

[0399] Using existing catalytic systems (J.Am.Chem.Soc.2019,141,9504), the yield and enantioselectivity of the product were low.

[0400] Experimental Example 3

[0401]

[0402] Existing catalytic systems are incompatible with heteroaryl substrates.

[0403] Test Example 4

[0404]

[0405] Following the method of Example 1, under an argon atmosphere, [SCpRh] (2.6 mg, 0.005 mmol), A11 (6.8 mg, 0.02 mmol), compounds II (0.10 mmol) and III (0.30 mmol, 3.0 equiv.), and DMF (2.0 mL) were added to a Schlenk reaction flask, and the reaction was then heated to 60 °C. No corresponding product was obtained.

Claims

1. A method for preparing compound 1, characterized in that, It includes the following steps: Under a protective gas atmosphere, in an organic solvent, and in the presence of a rhodium catalyst, an oxidant, and a chiral acid, the compound shown in Formula II and the compound shown in Formula III are subjected to the following asymmetric coupling reaction to obtain compound 1. Compound 1 is a compound as shown in Formula I and / or Formula I': ； Among them, X 1 For CR 1 Or N; R 1 R 2 R 5 and R 6 Independently hydrogen, halogen, C 1-4 alkyl or C 1-4 Alkyl-O-; R 3 and R 4 Independently for C 1-4 alkyl, C 1-4 alkyl-O- or C 2-4 oxane alkyl; Or, R 2 and R 3 Together with the carbon atoms therein, and / or, R 4 and R 5 It forms independently along with the carbon atoms in between: C 6-10 aryl, or by one or more R 2-1 Replacement C 6-10 aryl; R 2-1 Independently for C 1-4 alkyl, C 1-4 alkyl-O-, C 2-4 oxane or phenyl; Or, R 4 R 5 and R 6 It forms independently along with the carbon atoms in between: C 10-14 aryl, or, C 6-10 aryl and C 3-7 Cycloalkenyl groups; R 7 for , , , , , , , , , , , , , , , , , , , or ; R 7-2 For R 7-3 -L-; L stands for connection key; R 7-3 C 6-10 aryl; connection key in This indicates that the double bond is in Z configuration, E configuration, or a mixture of Z and E configurations; The rhodium catalyst is a monovalent rhodium catalyst and / or a trivalent rhodium catalyst; When the rhodium catalyst is a trivalent rhodium catalyst, the trivalent rhodium catalyst is: or its enantiomer, or or its enantiomers; When the rhodium catalyst is a monovalent rhodium catalyst, the monovalent rhodium catalyst is or its enantiomers, or its enantiomers , or its enantiomers, or its enantiomers; The chiral acid is any of the following structures or its enantiomers: ； When the rhodium catalyst is or its enantiomers, When the chiral acid is an enantiomer of the chiral acid or an enantiomer thereof, the chiral acid is any of the following structures or enantiomers thereof: , , , , , , , , , , or ; The oxidizing agent is silver fluoride; The organic solvent is an amide solvent.

2. The preparation method according to claim 1, characterized in that, When R 1 R 2 R 5 and R 6 When it is a halogen on its own, the halogen is fluorine, chlorine, bromine or iodine; And / or, when R 1 R 2 R 5 and R 6 Independently for C 1-4 alkyl or C 1-4 When alkyl-O-, the C 1-4 alkyl and C 1-4 C in alkyl-O- 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R 3 and R 4 Independently for C 1-4 alkyl or C 1-4 When alkyl-O-, the C 1-4 alkyl and C 1-4 C in alkyl-O- 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R 3 and R 4 Independently for C 2-4 When the oxane is alkyl, the C 2-4 The oxane group is Me-O-CH2-CH2- or Me-O-CH2-; And / or, when R 2 and R 3 Together with the carbon atoms therein, and / or, R 4 and R 5 It independently forms C along with the carbon atoms in between. 6-10 aryl, or by one or more R 2-1 Replacement C 6-10 When the aryl group is present, the C 6-10 aryl and one or more R 2-1 Replacement C 6-10 C in aryl 6-10 The aryl group is phenyl or naphthyl; And / or, when R 2-1 Independently for C 1-4 alkyl or C 1-4 When alkyl-O-, the C 1-4 alkyl and C 1-4 C in alkyl-O- 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R 2-1 Independently for C 2-4 When the oxane is alkyl, the C 2-4 The oxane group is Me-O-CH2-CH2- or Me-O-CH2-; And / or, when R 2-1 When independently of one or more, one of the one or more R 2-1 It is independently located in the meta position of the chiral axis in compound 1; And / or, R 4 R 5 and R 6 It independently forms C along with the carbon atoms in between. 10-14 When the aryl group is present, the C 10-14 The aryl group is or ; And / or, R 4 R 5 and R 6 It independently forms C along with the carbon atoms in between. 6-10 aryl and C 3-7 When the cycloalkenyl group is present, the C 6-10 aryl and C 3-7 The cycloalkenyl group is C 6-10 aryl and C 5-6 Cycloalkenyl groups; And / or, when R 7-3 C 6-10 When the aryl group is present, the C 6-10 The aryl group is phenyl or naphthyl; And / or, when R 7 for hour; for ; And / or, the protective gas is one or more of helium, neon, nitrogen and argon; And / or, the molar concentration of the compound of formula II in the organic solvent is 0.01-0.8 mol / L; And / or, the molar ratio of the compound of formula III to the compound of formula II is 1:1 to 8:1; And / or, the molar ratio of the rhodium catalyst to the compound shown in Formula II is 0.02:1 to 0.2:1; And / or, the molar ratio of the chiral acid to the rhodium catalyst is 1:1 to 10:1; And / or, the molar ratio of the oxidant to the rhodium catalyst is 100:1-20:1; And / or, the molar ratio of the oxidant to the compound shown in Formula II is 1:1 to 5:

1.

3. The preparation method according to claim 1, characterized in that, R 1 R 2 and R 5 It is hydrogen independently.

4. The preparation method according to claim 2, characterized in that, When R 1 R 2 R 5 and R 6 When it is a halogen on its own, the halogen is fluorine; And / or, when R 1 R 2 R 5 and R 6 Independently for C 1-4 alkyl or C 1-4 When alkyl-O-, the C 1-4 alkyl and C 1-4 C in alkyl-O- 1-4 The alkyl group is methyl; And / or, when R 3 and R 4 Independently for C 1-4 alkyl or C 1-4 When alkyl-O-, the C 1-4 alkyl and C 1-4 C in alkyl-O- 1-4 The alkyl group is methyl; And / or, when R 2 and R 3 Together with the carbon atoms therein, and / or, R 4 and R 5 It independently forms C along with the carbon atoms in between. 6-10 aryl, or by one or more R 2-1 Replacement C 6-10 When the aryl group is present, the C 6-10 aryl and one or more R 2-1 Replacement C 6-10 C in aryl 6-10 The aryl group is or ; And / or, when R 2-1 Independently for C 1-4 alkyl or C 1-4 When alkyl-O-, the C 1-4 alkyl and C 1-4 C in alkyl-O- 1-4 The alkyl group is methyl; And / or, when R 2-1 When independently of one or more, one of the one or more R 2-1 It is independently located in the meta position of the chiral axis in compound 1; And / or, R 4 R 5 and R 6 It independently forms C along with the carbon atoms in between. 6-10 aryl and C 3-7 When the cycloalkenyl group is present, the C 6-10 aryl and C 3-7 The cycloalkenyl group is or ; And / or, when R 7-3 C 6-10 When the aryl group is present, the C 6-10 The aryl group is ; And / or, the protective gas is argon; And / or, the amide solvent is dimethylformamide and / or dimethylacetamide; And / or, the molar concentration of the compound of formula II in the organic solvent is 0.05-0.5 mol / L; And / or, the molar ratio of the compound of formula III to the compound of formula II is 2:1 to 4:1; And / or, the molar ratio of the rhodium catalyst to the compound shown in Formula II is 0.025:1 to 0.07:1; And / or, the molar ratio of the chiral acid to the rhodium catalyst is 4:1; And / or, the molar ratio of the oxidant to the rhodium catalyst is 40:1-70:1; And / or, the molar ratio of the oxidant to the compound shown in Formula II is 2:1 to 4:

1.

5. The preparation method according to claim 4, characterized in that, When R 2 and R 3 Together with the carbon atoms therein, and / or, R 4 and R 5 It independently forms C along with the carbon atoms in between. 6-10 aryl, or by one or more R 2-1 Replacement C 6-10 When the aryl group is present, the C 6-10 aryl and one or more R 2-1 Replacement C 6-10 C in aryl 6-10 The aryl group is or ; The central ring A is located on the side of the chiral axis in compound 1.

6. The preparation method according to claim 1, characterized in that, X 1 For CH or N; And / or, R 2 Independently hydrogen or methyl; R 3 Methyl; or, R 2 and R 3 Together with the carbon atoms in between, they form phenyl groups. , or ; And / or, R 4 Independently methyl, methyl-O-, or Me-O-CH2-; R 5 and R 6 Independently hydrogen, F, methyl, or methyl-O-; or, R 4 R 5 It forms together with the carbon atoms in between: , , or Or, R 4 R 5 and R 6 It forms together with the carbon atoms in between: or .

7. The preparation method according to claim 6, characterized in that, for , , , , , or ; And / or, for , , , , , , , , , , or ; And / or, when R 7 for At that time, R 7 for , or .

8. The preparation method according to claim 7, characterized in that, Compound 1 has any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; And / or, the chiral acid is or its enantiomer, or or its enantiomers ; And / or, when the rhodium catalyst is , , , , or In the case of compound 1, the compound shown in formula I is the dominant configuration; And / or, when the rhodium catalyst is , or In the case of compound 1, the compound shown in formula I' is the dominant configuration.

9. The preparation method according to any one of claims 1-8, characterized in that, In a protective gas atmosphere, in an organic solvent, and in the presence of a rhodium catalyst, a chiral acid, and an oxidant, the compound shown in Formula II is subjected to an asymmetric coupling reaction with the compound shown in Formula III; the organic solvent is an amide solvent; the oxidant is silver fluoride; and the rhodium catalyst is... or its enantiomers, or its enantiomers, or its enantiomers, or its enantiomers , or its enantiomers , or its enantiomers The chiral acid mentioned is Or its enantiomers.

10. The preparation method according to claim 9, characterized in that, In a protective gas atmosphere, in an organic solvent, and in the presence of a rhodium catalyst, a chiral acid, and an oxidant, the compound shown in Formula II is subjected to an asymmetric coupling reaction with the compound shown in Formula III; the organic solvent is an amide solvent; the oxidant is silver fluoride; and the rhodium catalyst is... , or The chiral acid mentioned is or ; Alternatively, the rhodium catalyst is , or ; The chiral acid mentioned is: or .

11. A catalyst composition, characterized in that, It is a rhodium catalyst, oxidant, and chiral acid; The rhodium catalyst, the oxidant, and the chiral acid are defined as described in any one of claims 1-10.

12. The use of the catalyst composition as described in claim 11 in asymmetric catalytic reactions; The application described is for the preparation of axially chiral pyridine biaromatic compounds; The reaction conditions and operations described in the application are as described in any one of claims 1-10.

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