Selective synthesis of axially chiral 1,3-diene derivatives by organocatalytic olefin c-h functionalization

Abstract

The application belongs to the field of chemical synthesis and provides a method for constructing an axially chiral 1,3-diene-3-bromide skeleton of a compound containing or having the axially chiral 1,3-diene-3-bromide skeleton, wherein the method is to react a compound containing or having a non-chiral 1,3-diene skeleton with a chiral phosphate, an alkali metal carbonate and a bromination reagent. The obtained compound containing or having the axially chiral 1,3-diene-3-bromide skeleton has a good yield and ee value, and provides a new method for constructing the compound with the axially chiral skeleton.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to an organocatalytic method for the selective synthesis of axially chiral 1,3-diene derivatives through CH functionalization of olefins. Background Technology

[0002] The design and synthesis of novel chiral structures is a key focus in the development of chemical science and asymmetric catalysis. The unique structural features of axially chiral compounds have led to their increasing use in pharmaceutical and materials chemistry settings. For 1,3-butadiene-like structures, cyclic structures are often used to provide axial stability. Ligands and organocatalysts based on axially chiral 1,3-butadiene can be traced back to the flexible diene-based bisphosphine (NUPHOS) used by Doherty and Knight. The conformation of these dienes is locked on the metal coordination (Doherty, S. et al. Zirconium-mediated synthesis of a new class of 1,4-bis(diphenylphosphino)-1,3-butadiene-bridged diphosphine, NUPHOS: highly efficient catalysts for palladium-mediated crosscouplings. J. Am. Chem. Soc. 123, 5110-5111 (2001); Doherty, S., et al. Lewis acidplatinum complexes of conformationally flexible NUPHOS diphosphines: highly efficient catalysts for the carbonyl-ene reaction. Organometallics 24, 5945-5955 (2005)).Enantiopure CATPHOS ligands can be obtained by resolution through complex substitutions. These ligands play a role in asymmetric hydrogenation, carbonylene, and Friedel-Crafts reactions (Doherty, S., Smyth, CH, Harriman, A., Harrington, RW & Clegg, W. Can a butadiene-based architecture compete with its biaryl counterpart in asymmetric catalysis? Enantiopure Me-CATPHOS, a markably efficient ligand for asymmetric hydrogenation. Organometallics 28, 888-895 (2009); Doherty, S., Knight, JG & Mehdi-Zodeh, H. Asymmetric carbonylene and Friedel-Crafts reactions catalyzed by Lewis acid platinum group metal complexes of the enantiopure atropisomeric biaryl-like diphosphine(S)-Me2-CATPHOS: a comparison with BINAP. Tetrahedron: Asymmetry). 23, 209-216 (2012)). Nakajima et al. demonstrated the ability of tetrahydronaphthalene-fused dienyl diphosphine dioxide as a Lewis base organocatalyst (Ogasawara, M., et al. Atropisomeric chiral dienes in asymmetric catalysis: C2-symmetric(Z,Z)-2,3-bis[1-(diphenylphosphinyl)ethylidene]tetralin as a highly active Lewis base organocatalyst. Angew. Chem. Int. Ed. 52, 13798-13802 (2013)). These advances illustrate the potential uses of axially chiral dienes, but also highlight the lack of catalytic asymmetric methods for obtaining enantiomeric pure materials. Summary of the Invention

[0003] To address the aforementioned technical problems, this invention provides a method for constructing the axially chiral 1,3-diene-3-bromide skeleton of a compound comprising or having an axially chiral 1,3-diene-3-bromide skeleton. The method involves reacting a chiral phosphate or alkali metal carbonate with a brominating reagent to obtain the bromide. This bromide provides a novel method for constructing this type of axially chiral skeleton compound. Specifically, the desired functional group can be converted from bromine. This bromide can also be used to obtain functionalized compounds comprising or having an axially chiral 1,3-diene skeleton via a one-pot process.

[0004] On one hand, the present invention provides a method for constructing the axially chiral 1,3-diene-3-bromide skeleton of a compound comprising or having an axially chiral 1,3-diene-3-bromide skeleton, wherein the method comprises reacting a compound comprising or having an achiral 1,3-diene skeleton with a bromide reagent in the presence of a chiral phosphate or an alkali metal carbonate.

[0005] The axially chiral 1,3-diene skeleton is shown in Formula I:

[0006]

[0007] The achiral 1,3-diene skeleton is shown in Formula II:

[0008]

[0009] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R is selected from: substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted heterocyclic groups; Indicates the position where Formula I or Formula II is connected to the remainder of a compound that contains or has Formula I or Formula II;

[0010] The brominizing agent has the structure shown in Formula III:

[0011]

[0012] X is selected from: Br and Cl;

[0013] Ar 1 Selected from: 3,5-(CF3)2-C6H3-, C6F5-, 4-tBu-C6H4- and C6H5.

[0014] In some embodiments, the achiral 1,3-diene skeleton is as shown in Formula II-1:

[0015]

[0016] In some embodiments, the compound comprising or having an axially chiral 1,3-diene-3-bromide skeleton has the structure shown in Formula I':

[0017]

[0018] The compounds containing or having a non-chiral 1,3-diene skeleton have the structure shown in Formula II':

[0019]

[0020] Among them, R 1 and R 2 Each is independently selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl; or R 1 R 2 Together with the nitrogen atoms attached to them, they form substituted or unsubstituted heterocyclic groups;

[0021] R 3 and R 4 Each is independently selected from: substituted or unsubstituted alkyl groups.

[0022] In some embodiments, the compound comprising or having a non-chiral 1,3-diene skeleton has the structure shown in Formula II'-1:

[0023]

[0024] On the other hand, the present invention also provides a method for constructing a compound comprising or having an axially chiral 1,3-diene-3-bromide skeleton, wherein the method comprises reacting a compound comprising or having an achiral 1,3-diene skeleton with a bromide reagent under the action of a chiral phosphate or an alkali metal carbonate.

[0025] The axially chiral 1,3-diene skeleton is shown in Formula I':

[0026]

[0027] The compounds containing or having a non-chiral 1,3-diene skeleton have the structure shown in Formula II':

[0028]

[0029] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R is selected from: substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted heterocyclic groups; Indicates the position where Formula I or Formula II is connected to the remainder of a compound that contains or has Formula I or Formula II;

[0030] The brominizing agent has the structure shown in Formula III:

[0031]

[0032] X is selected from: Br and Cl;

[0033] Ar 1 Selected from: 3,5-(CF3)2-C6H3-, C6F5-, 4-tBu-C6H4- and C6H5; preferably, Ar is substituted or unsubstituted C. 6-10 5-10 heteroaryl groups, aryl or substituted or unsubstituted; R is selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl groups and substituted or unsubstituted 5-10 membered heterocyclic groups;

[0034] R 1 and R 2 Each is independently selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl; or R 1 R 2 Together with the nitrogen atoms attached to them, they form substituted or unsubstituted heterocyclic groups;

[0035] R 3 and R 4 Each is independently selected from: substituted or unsubstituted alkyl groups.

[0036] In some embodiments, the compound comprising or having a non-chiral 1,3-diene skeleton has the structure shown in Formula II'-1:

[0037]

[0038] In some embodiments of the present invention, Ar is substituted or unsubstituted C. 6-10 5-10 heteroaryl groups, aryl or substituted or unsubstituted; R is selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl and substituted or unsubstituted 5-10 membered heterocyclic groups.

[0039] In some embodiments of the present invention, Ar is substituted or unsubstituted C. 6-105-10 heteroaryl groups, aryl or substituted or unsubstituted; R is selected from: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted heteroalkyl containing 1-6 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl and substituted or unsubstituted 5-10 membered heterocyclic groups.

[0040] In some embodiments of the present invention, R 1 and R 2 Each is independently selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-10 Alkyne, substituted or unsubstituted C 6-10 Fragrance C 1-10 Alkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryl C 1-10 Alkyl groups and substituted or unsubstituted heteroalkyl groups containing 1-10 carbon atoms and 1-3 heteroatoms; or R 1 R 2 Together with the nitrogen atoms attached to them, they form substituted or unsubstituted 5-10 membered heterocyclic groups; R 3 and R 4 Each is independently selected from: substituted or unsubstituted C 1-10 alkyl.

[0041] In some embodiments of the present invention, R 1 and R 2 Each is independently selected from: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 6-10 Fragrance C 1-6 Alkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryl C 1-6 Alkyl groups and substituted or unsubstituted heteroalkyl groups containing 1-6 carbons and 1-3 heteroatoms; or R 1 R 2 Together with the nitrogen atoms attached to them, they form substituted or unsubstituted 5-10 membered heterocyclic groups; R 3 and R 4 Each is independently selected from: substituted or unsubstituted C 1-6 alkyl.

[0042] In some embodiments of the present invention, the chiral phosphate has any of the C1-C6 structures:

[0043]

[0044] In some embodiments of the present invention, the alkali metal carbonate is selected from sodium carbonate, potassium carbonate and cesium carbonate.

[0045] In some embodiments of the present invention, the molar amount of the compound containing or having a non-chiral 1,3-diene skeleton is used as unit 1, the amount of the chiral phosphate is 1 to 20% molar monomass, the amount of the alkali metal carbonate is 3 to 6 molar equivalents, and the amount of the brominating agent is 1.05 to 3 molar equivalents.

[0046] In some embodiments of the present invention, the molar amount of the compound comprising or having a non-chiral 1,3-diene skeleton is used as unit 1, the amount of the chiral phosphate is 1 to 10% molar monomass, the amount of the alkali metal carbonate is 4 to 5 molar equivalents, and the amount of the brominating agent is 1.1 to 2 molar equivalents.

[0047] In some embodiments of the invention, the molar amount of a compound comprising or having a non-chiral 1,3-diene skeleton is used as unit 1, and the amount of the chiral phosphate is 1 to 5% molar unit.

[0048] In some embodiments of the present invention, the molar amount of the compound comprising or having a non-chiral 1,3-diene skeleton is used as unit 1, the amount of the chiral phosphate is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% molar monomass, the amount of the alkali metal carbonate is 3, 4, or 5 molar equivalents, and the brominating agent is 1.1, 1.3, 1.5, 1.8, or 2 molar equivalents.

[0049] In some embodiments of the present invention, the reaction temperature is 0–40°C; the reaction time is 0.5–10 hours.

[0050] In some embodiments of the present invention, the reaction temperature is 25–35°C; the reaction time is 0.5–5 hours.

[0051] In some embodiments of the present invention, the reaction solvent is a solvent that is inert to the reaction.

[0052] In some embodiments of the present invention, the reaction solvent is an aprotic organic solvent.

[0053] In some embodiments of the present invention, the reaction solvent is one or more combinations of dichloromethane, trichloromethane, carbon tetrachloride, benzene, toluene, xylene, n-hexane, tetrahydrofuran, and diethyl ether.

[0054] In some embodiments of the present invention, the reaction solvent is selected from one or more combinations of toluene, n-hexane, tetrahydrofuran, trifluorotoluene, ethyl acetate, and diethyl ether.

[0055] In some embodiments of the present invention, the reaction solvent is toluene or diethyl ether.

[0056] On the other hand, the present invention provides a one-pot method for synthesizing compounds containing or having an axially chiral 1,3-diene-3-functional skeleton, comprising: 1) synthesizing compounds containing or having an axially chiral 1,3-diene-3-bromide skeleton from compounds containing or having an achiral 1,3-diene skeleton using the construction method described in the present invention; 2) adding an electrophilic reagent after adding a Grignard reagent or a lithium reagent at low temperature;

[0057] In some embodiments, the low temperature is -30°C to -70°C.

[0058] In some embodiments, the low temperature is -30°C to -50°C, preferably -40°C.

[0059] In some embodiments, the reaction time is 1.5 to 5 hours.

[0060] In this invention, Grignard reagents can all play the same role. Examples include PhMgCl, MeMgBr, PhMgBr, iPrMgBr, etc. Lithium reagents can also be used, such as nBuLi, PhLi, sBuLi, etc. The principle is that a substitution reaction occurs between the metal and the bromine atom, the axially chiral diene debrominates to generate the corresponding metal reagent intermediate, and the metal reagent is brominated to generate the corresponding bromide.

[0061] In some embodiments, the Grignard reagent or lithium reagent is selected from: PhMgCl, MeMgBr, PhMgBr, iPrMgBr, nBuLi, PhLi, and sBuLi. In some embodiments, the Grignard reagent is selected from: PhMgCl, MeMgBr, PhMgBr, and iPrMgBr.

[0062] In some embodiments, the lithium reagent is selected from nBuLi, PhLi, and sBuLi.

[0063] In some embodiments, the electrophilic reagent is selected from: phenylsulfonyl chloride, phenyl selenium chloride, phenyl phosphine dichloride, cyclohexylphosphine dichloride 1,3-dichloro-5,5-dimethylhydantoin, toluenesulfonyl azide, aryldiazagenium salt, molecular iodine, and imine salt.

[0064] In some embodiments, the molar amount of the compound comprising or having a non-chiral 1,3-diene skeleton is used as unit 1, the amount of the Grignard reagent is 2-3 molar equivalents, and the amount of the electrophilic reagent is 1.1-6 molar equivalents.

[0065] In some embodiments, the molar amount of the compound comprising or having a non-chiral 1,3-diene skeleton is used as unit 1, the amount of the Grignard reagent is 2, 2.2, 2.5, 2.8 or 3 molar equivalents, and the electrophilic reagent is 1.1, 1.2, 1.4, 1.5, 1.8, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 molar equivalents.

[0066] Terminology Explanation

[0067] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0068] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0069] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0070] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0071] In the following content, all figures disclosed herein, whether or not the words "approximately" or "about" are used, are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%, etc. Whenever a figure with a value of N is disclosed, any figure with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% will be explicitly disclosed, where "+ / -" indicates addition or subtraction.

[0072] Unless otherwise expressly indicated, the descriptive terms “each…independently”, “…each…independently”, and “…independently” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0073] The terms “optional,” “optionally,” or “arbitrarily” mean that the event or situation described below may, but is not necessarily, occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, “optionally replaced by…” means that the replacement may or may not occur.

[0074] When the terms “independent” and “arbitrarily” are used together, for example, “independently and arbitrarily replaced by…”, it means that specific options are replaced by or not replaced by each other without affecting each other.

[0075] The term "unsaturated" or "unsaturated" means that a portion contains one or more degrees of unsaturation.

[0076] "A compound comprising or having a chiral 1,3-diene-3-bromide skeleton" means that part or all of the structure of the compound is a chiral 1,3-diene-3-bromide. Similarly, "a compound comprising or having a non-chiral 1,3-diene skeleton" means that part or all of the structure of the compound is a non-chiral 1,3-diene.

[0077] When used as a prefix to a functional group, the term "substituted or unsubstituted" in this invention refers to both cases where the group is substituted by the substituents described in this invention and cases where it is not substituted by the substituents described in this invention. The substituents involved in "substituted" are conventional substituents in the art, such as, but not limited to, hydroxyl, cyano, nitro, amino, mercapto, halogen, oxo, ester, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocyclic, etc., and these conventional substituents can be further substituted. The substituents involved in "substituted" can also be unconventional substituents in the art, which can be substituent fragments formed by a reasonable combination of conventional substituents. The common feature of these substituents is that they do not affect the process of the method described in this invention.

[0078] The term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position, i.e., the various substitutions are independent of each other. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0079] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of S, N, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrrolidinyl), or NRT (like NRT in N-substituted pyrrolidinyl, where RT is a substituent on N). In the compounds of this invention, when containing multiple heteroatoms, the resulting compounds conform to the covalent and compositional rules of organic compounds; that is, compounds containing multiple heteroatoms should exclude those that do not conform to the covalent and compositional rules of organic compounds.

[0080] The term "substituted or unsubstituted aryl" refers to an aryl group that is substituted by or not substituted by the substituents described in this invention. "Aryl" or "aromatic ring" refers to aromatic carbocyclic systems that are monocyclic, bicyclic, or tricyclic. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". A 6-10 membered aryl group refers to an aryl group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl groups.

[0081] The term "substituted or unsubstituted heteroaryl" refers to a heteroaryl group that is substituted by or not substituted by the substituents described in this invention. "Hyperaryl" or "heteroaryl ring" refers to a monocyclic, bicyclic, or tricyclic aromatic system containing a heteroatom. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring" or "heteroaryl compound." The heteroatom has the definition described in this invention. In some embodiments, a heteroaryl is a heteroaryl consisting of 5-10 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-10-membered heteroaryl; a heteroaryl is a heteroaryl consisting of 5-8 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-8-membered heteroaryl; in some embodiments, a heteroaryl is a heteroaryl consisting of 5-7 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-7-membered heteroaryl. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-6 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 6 membered heteroaryl group.Examples of heteroaryl groups include, but are not limited to, furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrroleyl (e.g., N-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), and pyrimidinyl (e.g., 2-pyrimidinyl). ,4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5H-tetrazolel, 2H-tetrazolel), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1,2,3-triazolyl), thiophene (e.g., 2-thiophene, 3-thiophene), pyrazolyl (e.g., 2-pyrazolyl, 3-pyrazolyl), isothiazolyl, oxadiazolyl (e.g., 1,2... ,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiodiazolyl (e.g., 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl), pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic or tricyclic groups, but is by no means limited to the following groups: benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl), 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, indololinyl, 1,2,3,4-tetrahydroisoquinolinyl, etc.

[0082] The term "substituted or unsubstituted alkyl" refers to an alkyl group that is either substituted by or not substituted by the substituents described in this invention. "alkyl" or "alkyl group" indicates a carbon-containing, saturated straight-chain or branched hydrocarbon group. In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., C64-C ... 1-6 Alkyl group; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C64-C44-C6 ... 1-4 Alkyl group; in another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., C64-C ... 1-3 Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and similar alkyl groups.

[0083] The term "substituted or unsubstituted heteroalkyl" refers to a heteroalkyl group that includes those substituted by the substituents described in this invention or those not substituted by the substituents described in this invention. A "heteroalkyl" is a group formed by adding one or more heteroatoms to an alkyl group. The alkyl group and heteroatoms are as defined in this invention. In some embodiments, the heteroalkyl group contains 1-8 carbon atoms and 1-3 heteroatoms; in some embodiments, the heteroalkyl group contains 1-6 carbon atoms and 1-2 heteroatoms. The heteroalkyl group can be attached to the remainder of the molecule via carbon atoms or heteroatoms. In some embodiments of this invention, the heteroalkyl group is attached to the remainder of the molecule via carbon atoms.

[0084] The term "substituted unsubstituted cycloalkyl" refers to a cycloalkyl group that includes those substituted by the substituents described in this invention or those not substituted by the substituents described in this invention. "Cycloalkyl" means a monocyclic, bicyclic, or tricyclic system containing a carbon atom, either monocyclic or polycyclic (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl), or bicyclic, including spirocyclic, fused, or bridged systems (e.g., bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), which may be fully saturated or contain one or more unsaturations, but may not contain any aromatic rings. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, such as C 3-6 Saturated or partially unsaturated cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc. In one embodiment, the saturated or partially unsaturated cycloalkyl group is selected from: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, and partially unsaturated tricyclic cycloalkyl. C 4-7 Cycloalkyl refers to cycloalkyl groups with 4-7 ring atoms. C 3-6 Cycloalkyl refers to cycloalkyl groups with 3 to 6 ring atoms.

[0085] The term "substituted or unsubstituted heterocyclic group" refers to a heterocyclic group that includes cases where it is substituted by the substituents described in this invention or cases where it is not substituted by the substituents described in this invention. "Heterocyclic group" refers to a saturated (i.e., "heterocyclic alkyl") or partially unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2, and NR', wherein R' represents a hydrogen atom or C 1-6 Alkyl or halogenated -C 1-6Alkyl group. The heterocyclic group may be attached to the remainder of the molecule via any one of the carbon atoms or a nitrogen atom (if present). In particular, 3-10 membered heterocyclic groups are groups having 3-10 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in the ring, such as, but not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolyl, pyrrolidone, imidazoalkyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0086] The term "substituted or unsubstituted alkenyl" refers to an alkenyl group that is either substituted by or not substituted by the substituents described in this invention. "Alkenyl" represents a straight-chain or branched monovalent hydrocarbon group containing carbon atoms, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, including "cis" and "tans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-6 carbon atoms, i.e., C 2-6 Alkenyl group; in another embodiment, the alkenyl group comprises 2-4 carbon atoms, i.e., C 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0087] The term "substituted or unsubstituted alkynyl" refers to an alkynyl group that is either substituted by or not substituted by the substituents described in this invention. "Alynyl" represents a straight-chain or branched monovalent hydrocarbon group containing a carbon atom, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond. In one embodiment, the alkynyl group contains 2-6 carbon atoms, i.e., C1... 2-6 Alkyne group; in another embodiment, the alkynyl group comprises 2-4 carbon atoms, i.e., C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0088] The term "substituted or unsubstituted aralkyl" refers to an aralkyl group that is substituted by or not substituted by the substituents described in this invention. "Aralkyl" means aryl-alkyl-, wherein aryl and alkyl have the definitions described in this invention.

[0089] The term "substituted or unsubstituted heteroarylalkyl" refers to heteroarylalkyl that includes cases substituted by the substituents described in the present invention or cases not substituted by the substituents described in the present invention. "Heteroarylalkyl" refers to heteroaryl-alkyl-, where heteroaryl and alkyl have the definitions described in the present invention.

[0090] The term "hydrogen" refers to 1 H; "deuterium" refers to 2 H.

[0091] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0092] The term "amino" refers to -NH2.

[0093] The term "hydroxy" refers to -OH.

[0094] The term "mercapto" refers to -SH.

[0095] The term "cyano" refers to -CN.

[0096] The term "nitro" refers to -NO2.

[0097] The term "carboxy" refers to HO(C=O)-.

[0098] The term "oxo" is used interchangeably with "O=", i.e., when the substituent is O=, O is connected to the substituted group by a double bond.

[0099] The term "thioxo" is used interchangeably with "S=", i.e., when the substituent is S=, S is connected to the substituted group by a double bond.

[0100] The terms "comprising", "including", "containing", or "characterized by" are synonymous and are inclusive or open-ended, and do not exclude additional unmentioned elements or components from the drug (or in the case of a method, the steps). The phrase "consisting of" does not include any element, step, or component not specified in the drug (or in the case of a method, the steps). The phrase "consisting essentially of" means the specified materials and those materials that do not substantially affect the basic and novel properties of the drug (or in the case of a method, the steps).

[0101] The axially chiral compounds described in the present invention are of the Z and S types. Brief Description of the Drawings

[0102] Figure 1 It is a single crystal structure diagram of compound 2w. Detailed Description of the Embodiments

[0103] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and techniques have also been described in many publications.

[0104] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0105] Raw material preparation

[0106] Based on the raw material structure required by this invention, compound 1 (e.g., 1a, wherein R) can be prepared by the following method. 1 R 2 R 3 (where R is methyl and R is tert-butyl; select the relevant raw materials according to this rule).

[0107]

[0108] Preparation of S1 and compound (Z)-Ma

[0109] Diethyl (cyanomethyl)phosphonate (1.18 mL, 13 mmol) was added fractionally to a mixture of NaH (60% mineral oil dispersion, 560 mg, 14.0 mmol) and anhydrous THF (40.0 mL) at 0 °C. After stirring at room temperature for 1 hour, benzophenone derivative (10.0 mmol) was slowly added to the solution, and the reaction mixture was stirred at 75 °C for 5–15 hours. The reaction was monitored by TLC on silica gel. After the benzophenone derivative was completely consumed, the reaction mixture was cooled to room temperature, quenched with water, and extracted with 3 × 100 mL EA. The organic layers were combined, washed with water and brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel to give product (Z)-Ma.

[0110] Preparation of S2 and compound Mb

[0111] Under argon atmosphere, compound (Z)-Ma (6 mmol), malonate (18 mmol), DCE (7 mL), and SnCl4 (2.8 mL, 24 mmol) were added sequentially to a 100 mL Schlenk tube equipped with a magnetic stir bar. After sealing the vial, the reaction mixture was stirred at 90–110 °C for 2–30 hours, and the reaction was monitored by TLC on silica gel. The reaction mixture was cooled to room temperature and then slowly poured into 100 mL of saturated NaHCO3 aqueous solution. After stirring at room temperature for 5 minutes, the mixture was diluted with 200 mL H2O and extracted with 3 × 100 mL EA. The organic layers were combined, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel to give compound Mb.

[0112] S3, Preparation of compound Mc

[0113] R was added dropwise to a mixture of compound Mb (2.0 mmol), TBAB (3.2 g, 10 mmol), Cs₂CO₃ (3.3 g, 10 mmol), and THF (24 mL). 1 -X (where X is a halogen, such as bromine). The reaction mixture was vigorously stirred at room temperature and monitored by TLC on silica gel. After 0.5–7.0 days, the mixture was diluted with 20 mL H2O and extracted with 3 × 20 mL EA. The organic layers were combined, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel to give compound Mc.

[0114] S4, Preparation of compound Md

[0115] R was added dropwise to a mixture of compound Mc (2.0 mmol), TBAB (3.2 g, 10 mmol), Cs₂CO₃ (3.3 g, 10 mmol), and THF (24 mL). 2 -X (where X is a halogen, such as bromine). The reaction mixture was vigorously stirred at room temperature for 0.5–7.0 days, and monitored by TLC on silica gel. After complete consumption of compound Mc, the mixture was diluted with 20 mL H₂O and extracted with 3 × 20 mL EA. The organic layers were combined, washed with water and brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel to give compound Md.

[0116] S5, Preparation of intermediate compound 1

[0117] At 0 °C, NBS (231 mg, 1.3 mmol) was added to a MeCN (3 mL) solution of compound Md (1.0 mmol). After stirring for 3 minutes at room temperature, the reaction mixture was diluted with 30 mL of EA and washed with 10 mL of saturated NaHCO3 aqueous solution and 10 mL of H2O. The combined aqueous phases were then extracted with 2 × 10 mL of EA. The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in EA (3 mL), and then PPh3 (341 mg, 1.3 mmol) and H2O (24 μL, 1.3 mmol) were added to the solution. After stirring for 3 minutes at room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel to give intermediate compound 1.

[0118] Preparation 1: Synthesis of compounds containing or having an axially chiral 1,3-diene-3-bromide skeleton

[0119] Preparation 1:

[0120]

[0121] Compound 1a (0.10 mmol), a bromide reagent (1.1 equiv), a chiral phosphate (10 mol%), an alkali metal carbonate (4.0 equiv), and a solvent (1.0 mL) were stirred at room temperature to obtain axially chiral compound 2a. The ee value was determined by HPLC using a chiral stationary phase. (This reaction can also be performed using intermediate compound Md to obtain axially chiral compound 2a.)

[0122] 1 H NMR (600MHz, DMSO-d6) δ7.41-7.36(m,2H),7.30(t,J=7.4Hz,1H),7.09(d,J=7.7H z, 1H), 7.07 (d, J = 7.7Hz, 1H), 3.68 (s, 3H), 3.63 (s, 3H), 2.99 (s, 6H), 1.08 (s, 9H).

[0123] 13 C NMR (151MHz, DMSO-d6) δ166.84,166.29,161.06,151.68,143.18,128.34,127. 63,127.50,127.37,126.68,115.18,95.05,51.26,50.60,41.87,38.50,29.44.

[0124] HRMS(ESI)calcd for C 20 H 27 BrNO4 +([M+H)) + ),m / z:424.1118,found:424.1113.

[0125] HPLC analysis: HPLC DAICEL CHIRALPAK ID, hexane / isopropanol = 80 / 20, flow rate = 1.0 mL / min, λ = 335 nm), t R (minor) = 7.9min,t R (major) = 9.4 min, ee = 96% (serial number 20) b ).

[0126] Based on single-crystal data, its axial chiral configuration is determined to be Z-type and S-type.

[0127] The specific raw materials and reaction conditions are shown in Table 1, where the following are marked: a Different reaction conditions, reaction temperature -78; (Note) b The different reaction conditions were compound 1a (0.20 mmol) and chiral phosphate (1 mol%).

[0128] Table 1

[0129]

[0130]

[0131] The structure of the catalyst (C1-C6) is as follows:

[0132]

[0133] The structures of the brominating reagents DBC, B1-B6 are as follows:

[0134]

[0135] The above study shows that the choice of brominating reagent can affect the bromination of CH on the alkenyl group. When B1 is chosen, the enantiomeric ee value of the product is significantly improved, and when C2 is chosen, it can increase to 88%. Compound 2a was identified as a configurationally stable trans-isomer (ΔG≠enantiomer = 35.5 kcal / mol). This part of the research lays the foundation for diversified starting materials.

[0136] Preparation 2:

[0137]

[0138] Compound 1 (0.20 mmol), B3 (1.1 equiv), C2 (1 mol%), K2CO3 (4.0 equiv), and Et2O (1.0 mL) were stirred at room temperature for 0.5–8.0 h to obtain the compounds listed in Table 2. The ee values ​​were determined by HPLC using a chiral stationary phase. Specific product structures and results are shown in Table 2, where the following are indicated: a Different reaction conditions were applied to C2 (5 mol%). B3 and C2 were prepared as described in Preparation 1.

[0139] Table 2

[0140]

[0141] The above study shows that the structure of compound 1 can be diversified, with R linked to the ester group. 3 R 4 Adjustments to the N-substituted compounds do not affect the bromination yield or the ee value of the products. Significant changes in the N-substituted compounds also have little impact on the bromination yield and ee value. Other straight-chain amines containing aryl (2f), trifluoromethyl (2g), olefin (2h, 2i), or alkyne (2j) components exhibit good tolerance and minimal impact on the enantiomeric purity (90-98% ee) of the corresponding dienes. Morpholine (2m) or piperazines with different N-substituted aryl groups (2n-2q) also show good yields (77-94%) and excellent enantioselectivity (86-96% ee). Reactive terminal alkynes (2j) and aromatics, especially electron-rich aromatics (2s, 2t, 2x), have no effect on the reaction. Complete Z / E selectivity (>20:1) was observed in all products studied.

[0142] The configuration is determined by the single crystal structure to be Z and S type, for example, the 2w single crystal structure diagram is as follows. Figure 1 As shown.

[0143] Preparation 2: One-pot synthesis of compounds containing or having an axially chiral 1,3-diene-3-functional skeleton.

[0144]

[0145] Preparation method: Compound 1 (0.10 mmol), B3 (1.1 equiv), C2 (5 mol%), K2CO3 (4.0 equiv), and Et2O (1.0 mL) were stirred at room temperature for 0.5 hours; wherein, the following are the labelings: a The reaction was carried out at -40°C by adding PhMgCl (2.2 equiv) and stirring for 10 minutes, followed by adding an electrophilic reagent (EI, 1.3-2.6 equiv) at the same temperature and stirring for 5 minutes. bThe reaction was carried out as follows: PhMgCl (2.2 equiv) was added at -40°C and stirred for 10 minutes, followed by the addition of I2 (2.0 equiv) at the same temperature and stirring for 1 hour. c The reaction was carried out as follows: PhMgCl (2.2 equiv) was added at -40°C and stirred for 10 minutes, followed by CyPCl2 (2.6 equiv) at the same temperature. The reaction mixture was then stirred at room temperature for 2 hours. d The reaction: Compound 2a (0.10 mmol) was reacted with nBuLi (1.3 equiv) and an imine salt (5.0 equiv) at -40 °C. The reaction mixture was then stirred at room temperature for 4.0 h. The ee value was determined by HPLC using a chiral stationary phase. The reaction product was DCDMH, 1,3-dichloro-5,5-dimethylhydantoin. The EI and the structure and results of the reaction products are shown in Table 3.

[0146] Table 3

[0147]

[0148] As the above study shows, this 1,3-diene bromide can be converted into a reactive nucleophilic intermediate with a stereochemical monoform using Grignard reagents such as PhMgCl. To simplify the reaction, this invention provides the aforementioned one-pot reaction. Functionalized 1,3-dienes are obtained by reacting with phenylsulfinyl chloride (3a), phenylselenoyl chloride (3b), dichlorophosphine (3c-d), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) (3e), toluenesulfonyl azide (3f), aryldiazagenium salt (3g), molecular iodine (3h), and imine salt (3p-u). The acquisition of these functionalized 1,3-dienes provides a foundation for subsequent applications.

[0149] Preparation 3: Applications of compounds containing or having an axially chiral 1,3-diene-3-functional skeleton

[0150] Application A:

[0151]

[0152] By reducing the azide group in structure 3f, an amino-substituted diene structure 4 is obtained. This structure is not very stable, but it can react with isocyanates / isothiocyanates to obtain stable chiral diene-derived urea / thiourea 5a-b, while still retaining a high ee value.

[0153] Application B:

[0154]

[0155] For structures where the alkenyl group is methyl and the nitrogen atom is methyl-substituted, such as 3p, cyclization can be performed using diisopropyllithium (LDA) or potassium hexamethyldiazid (KHMDS) to form a substituted pyrrole ring, thus retaining a high ee value.

[0156] Application C:

[0157]

[0158] Similarly, 3q was obtained in a one-pot manner from N,N-dimethyl-substituted, sterically hindered 3q-r derivatives with LDA and trifluorosulfonating agent PhNTf2 to yield further hydroxyl-protected polyolefin pyrroles 7a-b, which also retained a high ee value.

[0159] Application D:

[0160]

[0161] Under similar conditions (LDA in THF), N,N-methyl-substituted dienes with tert-butyl groups tend to form another type of central chiral pyrrole 8a-8c, with all transformations occurring under conditions of almost no steric chemistry integrity erosion.

[0162] Application E:

[0163]

[0164] 3c can serve as an effective ligand for the enantioselective allylic alkylation and amination of racemate 9 catalyzed by palladium. Racemate 9 reacts in the presence of a palladium catalyst (2 mol%) and 3c (10 mol%) to give products 10a-d in good yield and stereoselectivity (80-84% ee).

[0165] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for constructing the axially chiral 1,3-diene-3-bromide skeleton of a compound comprising or having an axially chiral 1,3-diene-3-bromide skeleton, wherein, The method of construction involves reacting a compound containing or having a non-chiral 1,3-diene skeleton with a bromide reagent in the presence of a chiral phosphoric acid compound, an alkali metal carbonate, and a reaction solvent. The chiral phosphoric acid compound has any of the structures shown in C1-C6: or ; The axially chiral 1,3-diene-3-bromide skeleton is shown in Formula I: （I）； The achiral 1,3-diene skeleton is shown in Formula II: (II); Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R is selected from: substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted heterocyclic groups; Indicates the position where Formula I or Formula II is connected to the remainder of a compound that contains or has Formula I or Formula II; The brominizing agent has the structure shown in Formula III: (III); X is selected from: Br and Cl; Ar 1 Selected from: 3,5-(CF3)2-C6H3-, C6F5-, 4- t Bu-C6H4- and C6H5.

2. The construction method according to claim 1, characterized in that, The achiral 1,3-diene skeleton is shown in Formula II-1: (II-1); Wherein, Ar and R are as described in claim 1.

3. The construction method according to claim 1, characterized in that, The Ar is substituted or unsubstituted C. 6-10 5-10 heteroaryl groups, aryl or substituted or unsubstituted; R is selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl and substituted or unsubstituted 5-10 membered heterocyclic groups.

4. The construction method according to claim 1, characterized in that, The compound comprising or having an axially chiral 1,3-diene-3-bromide skeleton has the structure shown in Formula I': （I’）； The compounds containing or having a non-chiral 1,3-diene skeleton have the structure shown in Formula II': (II’); Among them, R 1 and R 2 Each is independently selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl; or R 1 R 2 Together with the nitrogen atoms attached to them, they form substituted or unsubstituted heterocyclic groups; R 3 and R 4 Each is independently selected from: substituted or unsubstituted alkyl groups; The Ar and R are as described in claim 1.

5. The construction method according to claim 4, characterized in that, The compounds containing or having a non-chiral 1,3-diene skeleton have the structure shown in Formula II'-1: (II’-1); Wherein, Ar and R are as described in claim 4.

6. The construction method according to claim 4, characterized in that, R 1 and R 2 Each is independently selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-10 Alkyne, substituted or unsubstituted C 6-10 Fragrance C 1-10 Alkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryl C 1-10 Alkyl groups and substituted or unsubstituted heteroalkyl groups containing 1-10 carbon atoms and 1-3 heteroatoms; or R 1 R 2 Together with the nitrogen atoms attached to them, they form substituted or unsubstituted 5-10 membered heterocyclic groups; R 3 and R 4 Each is independently selected from: substituted or unsubstituted C 1-10 alkyl.

7. A method for constructing a compound comprising or having an axially chiral 1,3-diene-3-bromide skeleton, wherein, The method of construction involves reacting a compound containing or having a non-chiral 1,3-diene skeleton with a bromide reagent in the presence of a chiral phosphoric acid compound, an alkali metal carbonate, and a reaction solvent. The chiral phosphoric acid compound has any of the structures shown in C1-C6: or ; The axially chiral 1,3-diene-3-bromide skeleton is shown in Formula I': （I’）； The compounds containing or having a non-chiral 1,3-diene skeleton have the structure shown in Formula II': (II’); Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R is selected from: substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted heterocyclic groups; Indicates the position where Formula I or Formula II is connected to the remainder of a compound that contains or has Formula I or Formula II; The brominizing agent has the structure shown in Formula III: (III); X is selected from: Br and Cl; Ar 1 Selected from: 3,5-(CF3)2-C6H3-, C6F5-, 4- t Bu-C6H4- and C6H5; R 1 and R 2 Each is independently selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl; or R 1 R 2 Together with the nitrogen atoms attached to them, they form substituted or unsubstituted heterocyclic groups; R 3 and R 4 Each is independently selected from: substituted or unsubstituted alkyl groups.

8. The construction method according to claim 7, characterized in that, in, Ar represents substituted or unsubstituted C. 6-10 5-10 heteroaryl groups, aryl or substituted or unsubstituted; R is selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl and substituted or unsubstituted 5-10 membered heterocyclic groups.

9. The construction method according to claim 7, wherein the compound comprising or having a non-chiral 1,3-diene skeleton has the structure shown in Formula II'-1: (II’-1); in, The Ar, R, R 1 R 2 R 3 R 4 As described in claim 7.

10. The construction method according to claim 7, R 1 and R 2 Each is independently selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-10 Alkyne, substituted or unsubstituted C 6-10 Fragrance C 1-10 Alkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryl C 1-10 Alkyl groups and substituted or unsubstituted heteroalkyl groups containing 1-10 carbon atoms and 1-3 heteroatoms; or R 1 R 2 Together with the nitrogen atoms attached to them, they form substituted or unsubstituted 5-10 membered heterocyclic groups; R 3 and R 4 Each is independently selected from: substituted or unsubstituted C 1-10 alkyl.

11. The construction method according to any one of claims 1-10, characterized in that, The alkali metal carbonate is selected from sodium carbonate, potassium carbonate, and cesium carbonate.

12. The construction method according to any one of claims 1-10, characterized in that, The molar amount of the compound containing or having a non-chiral 1,3-diene skeleton is used as the unit 1, wherein the amount of the chiral phosphate is 1 to 20% molar monomass, the amount of the alkali metal carbonate is 3 to 6 molar equivalents, and the amount of the brominating agent is 1.05 to 3 molar equivalents.

13. The construction method according to any one of claims 1-10, characterized in that, The molar amount of the compound containing or having a non-chiral 1,3-diene skeleton is used as unit 1, the amount of the chiral phosphate is 1 to 10% molar monomass, the amount of the alkali metal carbonate is 4 to 5 molar equivalents, and the amount of the brominating agent is 1.1 to 2 molar equivalents.

14. The construction method according to any one of claims 1-10, characterized in that, The reaction temperature is 0~40℃; the reaction time is 0.5~10 hours; and the reaction solvent is an inert solvent.

15. The construction method according to any one of claims 1-10, characterized in that, The reaction temperature is 25~35℃; the reaction time is 0.5~5 hours.

16. The construction method according to any one of claims 1-10, characterized in that, The reaction solvent is an aprotic organic solvent.

17. The construction method according to any one of claims 1-10, characterized in that, The reaction solvent is one or a combination of dichloromethane, trichloromethane, carbon tetrachloride, benzene, toluene, xylene, n-hexane, tetrahydrofuran, and diethyl ether.

18. The construction method according to any one of claims 1-10, characterized in that, The reaction solvent is selected from one or more combinations of toluene, n-hexane, tetrahydrofuran, trifluorotoluene, ethyl acetate, and diethyl ether.

19. A one-pot method for synthesizing compounds containing or having an axially chiral 1,3-diene-3-functional skeleton, comprising: 1) To synthesize a compound containing or having an axially chiral 1,3-diene-3-bromide skeleton from a compound containing or having an achiral 1,3-diene skeleton using the construction method described in any one of claims 1-16; 2) To react with an electrophilic reagent after adding a Grignard reagent or a lithium reagent at low temperature.

20. The method according to claim 19, characterized in that, The low temperature ranges from -30°C to -70°C.

21. The method according to claim 19, characterized in that, The specified reagent or lithium reagent is selected from: PhMgCl, MeMgBr, PhMgBr, i PrMgBr, n BuLi, PhLi and s BuLi; and / or the electrophilic reagent is selected from: phenylsulfonyl chloride, phenyl selenium chloride, phenyl phosphine dichloride, cyclohexylphosphine dichloride 1,3-dichloro-5,5-dimethylhydantoin, toluenesulfonyl azide, aryldiazagenium salt, molecular iodide and imine salt.

22. The method according to any one of claims 19 to 21, characterized in that, The molar amount of the compound containing or having a non-chiral 1,3-diene skeleton is used as unit 1, the amount of the Grignard reagent is 2 to 3 molar equivalents, and the amount of the electrophilic reagent is 1.1 to 6 molar equivalents.

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