CN112457219A - Beta-carbonyl chiral amino compound and preparation method thereof - Google Patents

Beta-carbonyl chiral amino compound and preparation method thereof Download PDF

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CN112457219A
CN112457219A CN202011292283.3A CN202011292283A CN112457219A CN 112457219 A CN112457219 A CN 112457219A CN 202011292283 A CN202011292283 A CN 202011292283A CN 112457219 A CN112457219 A CN 112457219A
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黄湧
陈杰安
郭芳芳
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Shenzhen Bay Laboratory Pingshan Biomedical R & D And Transformation Center
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Abstract

The application relates to the technical field of organic synthetic chemistry, in particular to a beta-carbonyl chiral amino compound and a preparation method thereof, wherein the molecular structure general formula of the beta-carbonyl chiral amino compound is shown as formula I in the specification, and R is para-substituted in the formula I1、R2、FG1And FG2Introducing different kinds of functional group substituent groups to have various kinds of beta-carbonyl chiral amino compounds, and the carbonyl in the formula I can be reduced into hydroxyl or carboxylThe functional group on the nitrogen can be removed to become a naked amino group; thus providing a research basis for screening useful molecules.

Description

Beta-carbonyl chiral amino compound and preparation method thereof
Technical Field
The application belongs to the technical field of organic synthetic chemistry, and particularly relates to a beta-carbonyl chiral amino compound and a preparation method thereof.
Background
The term "chiral" means that an object cannot coincide with its mirror image, as in our hands, where the left hand does not coincide with the right hand, which is a mirror image of each other. The term chirality is more commonly used in the chemical and pharmaceutical arts, where chirality of a molecule is usually caused by asymmetric carbons, i.e., four groups on a carbon are different from each other. A pair of molecules cannot coincide with each other like the two hands of a human being, and are called chiral compounds (chiral compounds), which refer to compounds having the same molecular weight and molecular structure but arranged in opposite directions (e.g., an enantiomer in a mirror thereof).
Beta-carbonyl chiral amino compounds are an important class of chiral compounds. The beta-carbonyl chiral amino compound is an important construction unit for the synthesis of a drug intermediate, particularly a compound containing a chiral structure and the preparation of a functional material. The general method for synthesizing the chiral amino compound is mainly asymmetric aza Michael addition reaction catalyzed by cinchona alkaloid or derivatives of cinchona alkaloid, and the method has relatively limited variety for constructing beta-carbonyl chiral amino compounds because the Bronsted alkali of cinchona alkaloid is weaker, the catalyzed substrate is limited, and the substrate is limited to chalcone compounds.
Disclosure of Invention
The application aims to provide a beta-carbonyl chiral amino compound and a preparation method thereof, and aims to solve the technical problem of how to provide more beta-carbonyl chiral amino compounds.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the present application provides a beta-carbonyl chiral amino compound, wherein the molecular structure of the beta-carbonyl chiral amino compound is represented by formula i:
Figure BDA0002784143980000021
wherein, R is1And R2Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl radical, C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy radical, C1-C20Alkyloxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, aryl (C)1-C20) Alkyl, aryl (C)1-C20) Alkoxy, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and halo (C)1-C20) Any one of alkyl groups; the FG1And FG2Are identical or different C1-C20Alkyl radical, C1-C20Alkoxy radical, C1-C20Alkyloxycarbonyl, aryl, aryloxy, aryloxycarbonyl, aryl (C)1-C20) Alkyl, aryl (C)1-C20) Alkoxy and aryl radicals (C)1-C20) Any one of alkoxycarbonyl groups.
The beta-carbonyl chiral amino compound shown in the formula I provided by the application has a typical multi-functional group structure formed by the reaction of R1、R2、FG1And FG2Introducing different functional group substituents, so that the beta-carbonyl chiral amino compound has various beta-carbonyl chiral amino compounds, the carbonyl in the formula I can be reduced into hydroxyl or carboxyl, and the functional group on nitrogen can be removed to form naked amino; such a wide variety of beta-carbonyl chiral amino compounds may provide a potential research basis for screening molecules that may be used as pharmaceutical intermediates or functional materials.
In a second aspect, the present application provides a process for the preparation of a beta-carbonyl chiral amino compound, comprising the steps of:
providing a nucleophile compound A and a conjugated ketene compound B represented by the following structural general formulas:
A：
Figure BDA0002784143980000022
B：
Figure BDA0002784143980000023
and adding the nucleophilic reagent compound A and the conjugated ketene compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst and an alkali reagent to carry out asymmetric Michael addition reaction to obtain the beta-carbonyl chiral amino compound with the structural general formula shown as the formula I.
According to the preparation method, the activated azacyclo-carbene, a Michael acceptor (conjugated ketene compound B) and a nucleophilic reagent compound A form a rigid transition state through non-covalent interaction, the nucleophilicity of the nucleophilic reagent is enhanced, a double bond is selectively attacked from one side of the Michael acceptor, and an asymmetric aza-Michael addition reaction is carried out to generate the beta-carbonyl chiral amino compound. The reaction has high enantioselectivity, can obtain a beta-carbonyl chiral amino compound with potential application value by a simple chemical conversion means, greatly expands the designability and application prospect of the compound, adopts a simple organic micromolecular asymmetric catalytic system, is safe and controllable in reaction process, avoids heating or high-pressure conditions, simplifies the operation in the preparation production process, has high utilization rate of substrate atoms, is easy to obtain raw materials, does not need other additives in the reaction, simplifies the operation steps, shortens the reaction route, and has high forward reaction rate, thereby obviously improving the production efficiency and reducing the production cost.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
The compounds and derivatives thereof referred to in the examples of the present invention are named according to the IUPAC (International Union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, Ohio) naming system. Accordingly, the groups of compounds specifically referred to in the examples of the present invention are illustrated and described as follows:
"alkoxy" refers to a straight or branched chain saturated aliphatic chain bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. (C)a-Cb) Alkoxy means any straight or branched, monovalent, saturated aliphatic chain in which an alkyl group containing "a" to "b" carbon atoms is bonded to an oxygen atom.
"alkyl" refers to a straight or branched chain saturated aliphatic chain, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like.
"heteroalkyl" means a saturated aliphatic chain, straight or branched, containing at least one heteroatom linkage, such as, but not limited to, methylaminoethyl, methyloxypropyl, or other similar groups.
"alkenyl" refers to straight or branched chain hydrocarbons having one or more double bonds, including but not limited to, groups such as ethenyl, propenyl, and the like.
"Heteroalkenyl" means a straight or branched chain hydrocarbon with one or more double bonds containing at least one heteroatom linkage, including but not limited to, for example, vinylaminoethyl or other similar groups.
"alkynyl" refers to a straight or branched chain hydrocarbon with one or more triple bonds, including but not limited to, for example, ethynyl, propynyl, and the like.
"Heteroalkynyl" refers to a straight or branched chain hydrocarbon with one or more triple bonds containing at least one heteroatom linkage.
"aryl" refers to a cyclic aromatic hydrocarbon, which may be a monocyclic or polycyclic or fused ring aromatic hydrocarbon, including but not limited to, for example, phenyl, naphthyl, anthryl, phenanthryl, and the like.
"heteroaryl" means a monocyclic or polycyclic or fused ring aromatic hydrocarbon in which one or more carbon atoms have been replaced with a heteroatom such as nitrogen, oxygen, or sulfur. If the heteroaryl group contains more than one heteroatom, these heteroatoms may be the same or different. Heteroaryl groups include, but are not limited to, groups such as benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine [3,4-b ] indolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiatriazolyl, thiazolyl, thienyl, triazinyl, triazolyl, xanthenyl, and the like.
"cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group. Cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, tetrahydronaphthyl, and the like.
"Heterocycloalkyl" means a saturated monocyclic or polycyclic alkyl group in which at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen or sulfur, possibly fused to an aromatic hydrocarbon group. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different. Heterocycloalkyl groups include, but are not limited to, groups such as azepanyl, azetidinyl, indolinyl, morpholinyl, pyrazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydroquinolinyl, tetrahydroindazolyl, tetrahydroindolyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinoxalinyl, tetrahydrothiopyranyl, thiazolidinyl, thiomorpholinyl, thioxanthyl, and the like.
"cycloalkenyl" refers to an unsaturated monocyclic or polycyclic alkenyl group with one or more double bonds, possibly fused to an aromatic hydrocarbon group, including but not limited to, cyclic ethenyl, cyclopropenyl, or other similar groups.
"Heterocycloalkenyl" means an unsaturated monocyclic or polycyclic alkenyl group with one or more double bonds, wherein at least one carbon atom is replaced by a heteroatom such as nitrogen, oxygen or sulfur, possibly fused to an aromatic hydrocarbon group. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
"cycloalkynyl" refers to an unsaturated monocyclic or polycyclic alkynyl group with one or more triple bonds, possibly fused to an aromatic hydrocarbon group, including, but not limited to, cycloalkynyl, cyclopropynyl, or other like groups.
"Heterocycloalkynyl" means an unsaturated monocyclic or polycyclic alkynyl group having one or more triple bonds in which at least one carbon atom is replaced by a heteroatom such as nitrogen, oxygen or sulfur, possibly fused to an aromatic hydrocarbon group. If a heterocyclic alkynyl group contains more than one heteroatom, these heteroatoms may be the same or different.
The hetero atom may be an oxygen atom, a nitrogen atom, a sulfur atom or the like.
In one aspect, the embodiment of the present invention provides a β -carbonyl chiral amino compound, wherein the molecular structural general formula of the β -carbonyl chiral amino compound is shown in formula i:
Figure BDA0002784143980000051
wherein, R is1And R2Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl radical, C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy radical, C1-C20Alkyloxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, aryloxycarbonylHeteroaryloxy group, heteroaryloxycarbonyl group, aryl group (C)1-C20) Alkyl, aryl (C)1-C20) Alkoxy, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and halo (C)1-C20) Any one of alkyl groups; the FG1And FG2Are identical or different C1-C20Alkyl radical, C1-C20Alkoxy radical, C1-C20Alkyloxycarbonyl, aryl, aryloxy, aryloxycarbonyl, aryl (C)1-C20) Alkyl, aryl (C)1-C20) Alkoxy and aryl radicals (C)1-C20) Any one of alkoxycarbonyl groups.
R1And R2Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl radical, C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy radical, C1-C20Alkyloxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, aryl (C)1-C20) Alkyl, aryl (C)1-C20) Alkoxy, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and halo (C)1-C20) Any one of the alkyl radicals is R1And R2Are respectively and independently selectedFrom the above groups, the same or different; FG (fringe field switching)1And FG2Are identical or different C1-C20Alkyl radical, C1-C20Alkoxy radical, C1-C20Alkyloxycarbonyl, aryl, aryloxy, aryloxycarbonyl, aryl (C)1-C20) Alkyl, aryl (C)1-C20) Alkoxy and aryl radicals (C)1-C20) Any one of alkoxycarbonyl, denotes FG1And FG2Each independently selected from the above groups, and may be the same or different.
When R is1Or R2Is selected from C1-C20When it is an alkyl group, in one embodiment, the group (C)1-C20) The alkyl group may be (C)1-C10) Alkyl, (C)1-C5) Alkyl, (C)1-C4) Alkyl, (C)1-C3) Alkyl, (C)1-C2) Alkyl groups, and the like. In certain embodiments, (C)1-C20) The alkyl group may be methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, and the like.
When R is1Or R2Is selected from (C)1-C20) When it is heteroalkyl, in one embodiment, (C) is1-C20) The heteroalkyl group may be (C)1-C10) Heteroalkyl group, (C)2-C5) Heteroalkyl group, (C)3-C4) Heteroalkyl groups and the like. In certain embodiments, the heteroatom may be an atom, a nitrogen atom, a sulfur atom, and the like.
When R is1Or R2Is selected from (C)3-C20) Cycloalkyl, in one embodiment, the (C)3-C20) The cycloalkyl group may be (C)3-C10) Cycloalkyl group, (C)3-C5) Cycloalkyl group, (C)3-C4) Cycloalkyl groups, and the like. In certain embodiments, (C)3-C20) Cycloalkyl groups may be cyclopropyl, cyclobutyl, cyclopentyl, and the like.
When R is1Or R2Is selected from (C)3-C20) When it is heterocycloalkyl, in one embodiment, (C) is3-C20) The heterocycloalkyl group may be (C)3-C10) Heterocycloalkyl group, (C)3-C10) Heterocycloalkyl group, (C)3-C5) Heterocycloalkyl group, (C)3-C4) Heterocycloalkyl, and the like. In certain embodiments, the heteroatom may be an oxygen atom, a nitrogen atom, a sulfur atom, and the like.
When R is1Or R2Is selected from (C)2-C20) Alkenyl, in one embodiment, the (C)2-C20) The alkenyl group may be (C)3-C10) Alkenyl, (C)3-C5) Alkenyl, (C)3-C4) Alkenyl, (C)2-C3) Alkenyl groups, and the like. In certain embodiments, (C)2-C20) The alkenyl group may be ethenyl, propenyl, butenyl, pentenyl, etc.
When R is1Or R2Is selected from (C)2-C20) (iii) when heteroalkenyl, in one embodiment, the (C)2-C20) The heteroalkenyl group can be (C)2-C10) Heteroalkenyl, (C)3-C10) Heteroalkenyl, (C)3-C5) Heteroalkenyl and the like. In certain embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1Or R2Is selected from (C)3-C20) Cycloalkenyl group, in one embodiment, the (C)3-C20) Cycloalkenyl can be (C)3-C10) Cycloalkenyl group, (C)3-C5) Cycloalkenyl group, (C)3-C4) Cycloalkenyl groups, and the like. In certain embodiments, (C)3-C20) Cycloalkenyl can be cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.
When R is1Or R2Is selected from (C)3-C20) When heterocycloalkenyl is present, in one embodiment, (C) is3-C20) The heterocycloalkenyl group may be (C)3-C10) Heterocycloalkenyl, (C)3-C5) Heterocycloalkenyl, (C)3-C4) Heterocycloalkenyl, and the like. In certain embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1Or R2Is selected from (C)2-C20) Alkynyl, in one embodiment, (C)2-C20) Alkynyl may be (C)2-C10) Alkynyl, (C)3-C10) Alkynyl, (C)3-C5) Alkynyl, (C)3-C4) Alkynyl, (C)2-C3) Alkynyl and the like. In certain embodiments, (C)2-C20) The alkynyl group may be an ethynyl group, propynyl group, butynyl group, pentynyl group or the like.
When R is1Or R2Is selected from (C)2-C20) When heteroalkynyl is present, in one embodiment, (C) is2-C20) The heteroalkynyl can be (C)2-C10) Heteroalkynyl, (C)3-C10) Heteroalkynyl, (C)3-C5) Heteroalkynyl, (C)3-C4) Heteroalkynyl, and the like. In certain embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1Or R2Is selected from (C)3-C20) When cycloalkynyl is present, in one embodiment, (C) is3-C20) The cycloalkynyl group can be (C)3-C10) Cycloalkynyl, (C)3-C5) Cycloalkynyl, (C)3-C4) Cycloalkynyl, and the like. In certain embodiments, (C)2-C20) The cycloalkynyl group may be cyclopropynyl, cyclobutynyl, cyclopentynyl, or the like.
When R is1Or R2Is selected from (C)3-C20) When heterocycloalkynyl is present, in one embodiment, (C) is3-C20) The heterocycloalkynyl can be (C)3-C10) Heterocycloalkynyl, (C)3-C5) Heterocycloalkynyl, (C)3-C4) Heterocycloalkynyl, and the like. In certain embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1Or R2Is selected from (C)1-C20) Alkoxy, in one embodiment, the (C)1-C20) The alkoxy group may be (C)1-C10) Alkoxy group, (C)1-C8) Alkoxy group, (C)1-C6) Alkoxy group, (C)1-C4) Alkoxy group, (C)1-C3) Alkoxy group, (C)1-C2) An alkoxy group. In certain embodiments, this (C)1-C20) Alkoxy groups may be, but are not limited to, methyloxy, ethyloxy, propyloxy, and the like.
When R is1Or R2Is selected from (C)1-C20) In the case of an alkyloxycarbonyl group (i.e., an ester group), in one embodiment, the group (C)1-C20) The alkyloxycarbonyl group may be (C)1-C10) Alkyl oxycarbonyl radical, (C)1-C8) Alkyl oxycarbonyl radical, (C)1-C6) Alkyl oxycarbonyl radical, (C)1-C4) Alkoxy group, (C)1-C3) An alkyloxycarbonyl group, and the like. In certain embodiments, this (C)1-C20) The alkyloxycarbonyl group can be, but is not limited to, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, and the like.
When R is1Or R2When selected from aryl, the aryl group can be, but is not limited to, monocyclic aryl, polycyclic aryl, fused ring aryl. In one embodiment, the aryl group is a monocyclic aryl group. In certain embodiments, the aryl group may be C4-C14Aryl groups such as phenyl, naphthyl, fluorenyl, anthracenyl, phenanthrenyl, and the like.
When R is1Or R2When selected from substituted aryl groups, the substituted aryl groups may be, but are not limited to, phenyl groups substituted singly or multiply in the ortho, meta, or para positions. Substituents include, but are not limited to, alkyl, substituted alkyl, aryl, substituted aryl, acyl, halo, alkoxy, nitro, -NR9R10、-NR9-CO-NR10、-OCONR9、-PR9R10、-SOR9、-SO2-R9、-SiR9R10R11、-BR9R10Wherein R is9、R10、R11R as defined above, which may be the same or different1、R2The groups shown. Where the substituent is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, ethyl, propyl, isobutyl, substituted or unsubstituted,An isobutyl group; when the substituent is a substituted alkyl group, such as, but not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl; when the substituent is halogen, such as, but not limited to, fluorine, chlorine, bromine, iodine; when the substituent is an alkoxy group, the alkoxy group is, for example, but not limited to, methyloxy, ethyloxy, propyloxy. In one embodiment, the substituted aryl group may be substituted (C)4-C14) Aryl, e.g. being cyano (C)1-C10) Alkyl radical (C)4-C8) Aryl, substituted (C)4-C8) And (4) an aryl group.
When R is1Or R2When selected from heteroaryl, in one embodiment, the heteroaryl may be (C)4-C14) Heteroaryl groups such as thienyl, thiazolyl, pyrrolyl, pyrazinyl, pyridyl, benzothiophene, and the like.
When R is1Or R2When selected from substituted heteroaryl, in one embodiment, the substituted heteroaryl may be substituted (C)4-C14) Heteroaryl, e.g. alkoxy-substituted furans, (C)3-C8) Heteroaryl substituted furans, aliphatic chain substituted thiophenes, and the like.
When R is1Or R2When selected from aryloxy, in one embodiment, the aryloxy may be C4-C14Aryloxy groups such as phenoxy, naphthoxy, anthracenoxy, phenanthrenoxy and the like.
When R is1Or R2When selected from aryloxycarbonyl, in one embodiment, the aryloxycarbonyl group may be C4-C14Aryloxycarbonyl groups such as phenoxycarbonyl, naphthyloxycarbonyl, and the like.
When R is1Or R2When selected from heteroaryloxy, in one embodiment, the heteroaryloxy group may be C4-C14A heteroaryloxy group.
When R is1Or R2When selected from heteroaryloxycarbonyl, in one embodiment, the heteroaryloxycarbonyl group can be C4-C14A heteroaryloxycarbonyl group.
When R is1Or R2Selected from aryl (C)1-C20) When it is an alkyl group, in one embodiment, the aryl group (C)1-C20) The alkyl group may be C4-C14Aryl radical (C)1-C10) Alkyl radicals, e.g. phenyl (C)1-C10) Alkyl, phenyl (C)1-C5) Alkyl, phenyl (C)1-C4) Alkyl, phenyl (C)1-C3) Alkyl, phenyl (C)1-C2) Alkyl groups, and the like. In certain embodiments, aryl (C)1-C20) The alkyl group may be phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylisobutyl, phenylpentyl, phenylisopentyl, phenylneopentyl, and the like.
When R is1Or R2Selected from aryl (C)1-C20) Alkoxy, in one embodiment, the aryl (C)1-C20) The alkoxy group may be C4-C14Aryl radical (C)1-C10) Alkoxy radicals, e.g. phenyl (C)1-C10) Alkoxy, phenyl (C)1-C5) Alkoxy, and the like. In certain embodiments, aryl (C)1-C20) The alkoxy group may be phenylmethoxy, phenylethoxy, and the like.
When R is1Or R2Is selected from heteroaryl (C)1-C20) When alkyl, in one embodiment, the heteroaryl (C)1-C20) The alkyl group may be C4-C14Heteroaryl (C)1-C10) Alkyl radicals, e.g. heteroaryl (C)1-C10) Alkyl, heteroaryl (C)1-C5) Alkyl, heteroaryl (C)1-C4) Alkyl, heteroaryl (C)1-C3) Alkyl, heteroaryl (C)1-C2) Alkyl groups, and the like.
When R is1Or R2Is selected from (C)2-C20) Alkenyl (C)1-C20) When it is an alkyl group, in one embodiment, the group (C)2-C20) Alkenyl (C)1-C20) The alkyl group may be (C)2-C10) Alkenyl (C)1-C10) Alkyl, (C)2-C5) Alkenyl (C)1-C3) Alkyl groups, and the like.
When R is1Or R2Is selected from (C)2-C20) Alkynyl (C)1-C20) When it is an alkyl group, in one embodiment, the group (C)2-C20) Alkynyl (C)1-C20) The alkyl group may be (C)2-C10) Alkynyl (C)1-C10) Alkyl, (C)2-C5) Alkynyl (C)1-C3) Alkyl groups, and the like.
When R is1Or R2Is selected from cyano (C)1-C20) Alkyl, in one embodiment, the cyano (C)1-C20) The alkyl group may be cyano (C)1-C10) Alkyl, cyano (C)1-C5) Alkyl, cyano (C)1-C4) Alkyl, cyano (C)1-C3) Alkyl, cyano (C)1-C2) Alkyl groups, and the like. In certain embodiments, cyano (C)1-C20) The alkyl group may be cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, cyanopentyl, or the like.
When R is1Or R2Selected from halo (C)1-C20) When alkyl, in one embodiment, the halo (C)1-C20) The alkyl group may be halo (C)1-C10) Alkyl radicals, e.g. monohalogenated C1-C3Alkyl, dihalo C1-C3Alkyl, trihalo C1-C3The alkyl group, wherein the halogen may be fluorine substituted, chlorine substituted, bromine substituted or iodine substituted, etc. For example, perfluoroalkyl groups such as trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, and the like may be mentioned.
When R is1Or R2Is selected from C1-C20Alkyl oxycarbonyl (C)1-C20) When it is alkyl, in one embodiment, the C1-C20Alkyl oxycarbonyl (C)1-C20) The alkyl group may be (C)1-C10) Alkyl oxycarbonyl (C)1-C10) Alkyl, (C)1-C5) Alkyl oxycarbonyl (C)1-C5) Alkyl, (C)1-C4) Alkyl oxycarbonyl (C)1-C4) Alkyl groups, and the like.
Further, when FG1Or FG2Is selected from C1-C20When it is an alkyl group, in one embodiment, the group (C)1-C20) The alkyl group may be (C)1-C10) Alkyl, (C)1-C5) Alkyl, (C)1-C4) Alkyl, (C)1-C3) Alkyl, (C)1-C2) Alkyl groups, and the like. When FG1Or FG2Is selected from C1-C20Alkoxy, in one embodiment, the (C)1-C20) The alkoxy group may be (C)1-C10) Alkoxy group, (C)1-C8) Alkoxy group, (C)1-C6) Alkoxy group, (C)1-C4) Alkoxy, and the like. When FG1Or FG2Is selected from C1-C20An alkyloxycarbonyl group, the compound of (C)1-C20) The alkyloxycarbonyl group may be (C)1-C10) Alkyl oxycarbonyl radical, (C)1-C8) Alkyl oxycarbonyl radical, (C)1-C6) Alkyl oxycarbonyl radical, (C)1-C4) Alkoxy group, (C)1-C3) An alkyloxycarbonyl group, and the like. When FG1Or FG2When selected from aryl, in one embodiment, the aryl group can be, but is not limited to, monocyclic aryl, polycyclic aryl, fused ring aryl, and can be, for example, C4-C14And (4) an aryl group. When FG1Or FG2When selected from aryloxy, in one embodiment, the aryloxy may be C4-C14An aryloxy group. When FG1Or FG2When selected from the group consisting of aryloxycarbonyl, in one embodiment, the aryloxycarbonyl group may be C4-C14An aryloxycarbonyl group. When FG1Or FG2Selected from aryl (C)1-C20) When it is an alkyl group, in one embodiment, the aryl group (C)1-C20) The alkyl group may be C4-C14Aryl radical (C)1-C10) Alkyl radicals, e.g. phenyl (C)1-C10) An alkyl group. When FG1Or FG2Selected from aryl (C)1-C20) Alkoxy, in one embodiment, the aryl (C)1-C20) The alkoxy radical may beTo be C4-C14Aryl radical (C)1-C10) Alkoxy radicals, e.g. phenyl (C)1-C10) Alkoxy, phenyl (C)1-C5) Alkoxy, and the like. When FG1Or FG2Selected from aryl (C)1-C20) Alkoxycarbonyl, in one embodiment, the aryl (C)1-C20) Alkoxycarbonyl may be C4-C14Aryl radical (C)1-C10) Alkoxycarbonyl, e.g. phenyl (C)1-C10) Alkoxycarbonyl, phenyl (C)1-C5) Alkoxycarbonyl groups, and the like.
In a preferred embodiment, R in the beta-carbonyl chiral amino compound1Is C4-C14Aryl, substituted C4-C14Aryl radical, C4-C14Heteroaryl and substituted C4-C14Any one of heteroaryl, R2Is C1-C10Alkyl, halo (C)1-C10) Alkyl radical, C1-C10Alkyl oxycarbonyl radical, C4-C14Aryloxycarbonyl and C4-C14Any one of heteroaryloxycarbonyl groups. Further, R1Is any one of phenyl, naphthyl, fluorenyl, thienyl, thiazolyl, pyrrolyl, pyrazinyl, pyridyl and benzothienyl, R2Is C1-C3Alkyl, monohalo C1-C3Alkyl, dihalo C1-C3Alkyl, trihalo C1-C3Alkyl and C1-C3Any one of alkyl oxycarbonyl groups.
In a more preferred embodiment, FG in the beta-carbonyl chiral amino compound1Is C1-C10Alkoxy radical, C1-C10Alkyl oxycarbonyl radical, C4-C14Aryloxy radical, C4-C14Aryloxycarbonyl group, C4-C14Aryl radical (C)1-C10) Alkyl radical, C4-C14Aryl radical (C)1-C10) Alkoxy and aryl radicals (C)1-C20) Any one of alkoxycarbonyl, FG2Is C1-C10Alkoxy radical, C1-C10Alkyl oxycarbonyl radical, C4-C14Aryloxy radical, C4-C14Aryloxycarbonyl group, C4-C14Aryl radical (C)1-C10) Alkyl radical, C4-C14Aryl radical (C)1-C10) Alkoxy and aryl radicals (C)1-C20) Any one of alkoxycarbonyl groups. Further, FG1Is any one of methoxyl, ethoxyl, propoxyl, tert-butyloxycarbonyl, benzyl, benzyloxy, benzyloxycarbonyl and fluorenylmethoxycarbonyl, FG2Is any one of methoxyl, ethoxyl, propoxyl, tert-butyloxycarbonyl, benzyl, benzyloxy, benzyloxycarbonyl and fluorenylmethyloxycarbonyl. Further, FG1And FG2Different.
The beta-carbonyl chiral amino compound shown in the formula I has a typical multi-functional group structure, and R is represented by1、R2、FG1And FG2Introducing different functional group substituents, so that the beta-carbonyl chiral amino compound has various beta-carbonyl chiral amino compounds, the carbonyl in the formula I can be reduced into hydroxyl or carboxyl, and the functional group on nitrogen can be removed to form naked amino; such a wide variety of beta-carbonyl chiral amino compounds may provide a potential research basis for screening molecules that may be used as pharmaceutical intermediates or functional materials.
On the other hand, on the basis of the beta-carbonyl chiral amino compound, the embodiment of the application also provides a preparation method of the beta-carbonyl chiral amino compound with the molecular structure general formula I, which comprises the following steps:
s01: providing a nucleophile compound A and a conjugated ketene compound B represented by the following structural general formulas:
A：
Figure BDA0002784143980000121
B：
Figure BDA0002784143980000122
s02: and adding the nucleophilic reagent compound A and the conjugated ketene compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst and an alkali reagent to carry out asymmetric Michael addition reaction to obtain the beta-carbonyl chiral amino compound with the structural general formula shown as the formula I.
FG in the above molecular Structure of nucleophile Compound A1And FG2Groups represented, with FG in the beta-carbonyl chiral amino compounds of formula I above1And FG2The groups represented are the same. R in molecular structural formula of B conjugated ketene compound1And R2The group represented by the formula (I) and R in the beta-carbonyl chiral amino compound shown in the formula (I)1And R2The groups represented are the same. For economy of disclosure, further description is omitted here.
According to the preparation method, activated azacyclo-carbene, a Michael acceptor (conjugated ketene compound B) and a nucleophilic reagent compound A form a rigid transition state through non-covalent interaction, the nucleophilicity of the nucleophilic reagent is enhanced, a double bond is selectively attacked from one side of the Michael acceptor, and an asymmetric Michael addition reaction is carried out to generate the beta-carbonyl chiral amino compound. The reaction has high enantioselectivity, can obtain a beta-carbonyl chiral amino compound with potential application value by a simple chemical conversion means, greatly expands the designability and application prospect of the compound, adopts a simple organic micromolecular asymmetric catalytic system, is safe and controllable in reaction process, avoids heating or high-pressure conditions, simplifies the operation in the preparation production process, has high utilization rate of substrate atoms, is easy to obtain raw materials, does not need other additives in the reaction, simplifies the operation steps, shortens the reaction route, and has high forward reaction rate, thereby obviously improving the production efficiency and reducing the production cost.
In step S01, the nucleophile compound a and the conjugated ketene compound B may be prepared according to a conventional method in the art, or may be directly obtained commercially.
In step S02, as can be seen from the structural formula shown in the reactant conjugated ketene compound B, which has a β -unsaturated conjugated structure, the carbonyl group is activated by the carbene catalyst, so that the LUMO (lowest unoccupied molecular orbital) of the michael acceptor is reduced. In addition, carbene catalysts also raise the HOMO (highest occupied orbital) of nucleophiles through non-covalent interactions with nucleophiles. Thus, the activation energy of the reaction of the two substrates is reduced, the reaction activity is increased, the target product precursor with high enantioselectivity and extremely wide range can be efficiently and greenly prepared through chiral control, and the beta-carbonyl chiral amino compound with potential application value can be obtained through simple chemical conversion reaction.
The nitrogen heterocyclic carbene catalyst and the alkali reagent have synergistic effect, so that the catalytic system has low toxicity, the atom utilization rate and the reaction efficiency are improved, and the byproducts are few. Meanwhile, the reaction process is safe and controllable, and the operation in the preparation production process is simplified. Wherein the base reagent deprotonates the azacyclocarbene reagent to form a protic base catalyst.
In order to enable the synergistic catalytic system to play a more effective catalytic role, the molar ratio of the N-heterocyclic carbene catalyst, the alkali reagent, the nucleophilic reagent compound A and the conjugated ketene compound B is (0.1-20): 1-100): 1-150. In one embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the basic agent is (0.1-20): 0.1-20, preferably (0.1-20): 20. In one embodiment, the molar ratio of azacyclocarbene catalyst to base reagent is 1: 1.
In one embodiment, the base reagent may be selected from at least one of the following compounds: lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, 1-azabicyclo [2.2.2] octane, DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene), TBD (1,5, 7-triazabicyclo (4.4.0) dec-5-ene), triethylamine, diisopropylethylamine, bistrimethylsilyl lithium, bistrimethylsilyl sodium, bistrimethylsilyl potassium, diisopropylamino lithium, n-butyllithium, tert-butyllithium, methyllithium, sodium methoxide, sodium ethoxide, and ethyl mercaptan sodium. The preferred alkali reagent, particularly, the inorganic alkali potassium phosphate can realize the complete non-metallization of a catalytic system, and obtain a target product with higher medical application value.
Under the action of the N-heterocyclic carbene catalytic system, the asymmetric Michael addition reaction can be smoothly carried out at different temperatures, the applicable reaction temperature range is-90-35 ℃, and the time is 6-48 hours. . In order to further improve the reaction efficiency and the enantioselectivity of the reaction product, in an embodiment, the reaction temperature of the reaction system is-90 ℃ to 0 ℃. In another embodiment, the reaction temperature of the reaction system is from-50 ℃ to-40 ℃. The reaction time in the environment of the temperature of each preferred reaction should be such that the above reactants are sufficiently reacted, for example, the reaction time may be 6 to 48 hours, or longer.
In the above reaction system, a certain amount of solvent is optionally added. Such solvents include, but are not limited to, toluene, diethyl ether, tetrahydrofuran, dichloromethane. Alternative solvents will be readily selected by those of ordinary skill in the art based on the reactions and disclosures set forth herein. In one embodiment, the solvent is added in a molar ratio of solvent to catalyst such that (1000- > 1000000): 1.
further, the N-heterocyclic carbene catalyst is selected from nitrogen-containing heterocyclic compounds with the following molecular structural general formula:
Figure BDA0002784143980000141
wherein Q is boron tetrafluoride anion or chloride ion, R3Is C1-C20Alkyl radical, C1-C20Heteroalkyl, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Any one of an alkyl group, an aryl group and a substituted aryl group.
The preparation method of the beta-carbonyl chiral amino compound has the synergistic effect of the N-heterocyclic carbene catalyst and the alkali reagent, so that the catalytic system has low toxicity, high atom utilization rate and production efficiency, safe and controllable reaction process, and simplified operation in the preparation production process. Meanwhile, the toxicity of the reaction residues is reduced to the minimum, the pollution to the environment in the production process is reduced, and the steps and the operation for removing the residues after the reaction are simplified. In addition, reactant raw materials are very easy to obtain, and the reactants can be directly used for preparation production without additional modification before reaction, so that the operation steps are simplified, and the reaction route is shortened; obviously reduces the production cost. Secondly, the method can also flexibly adjust the proportion and the addition amount among the azacyclo-catalyst, the alkali reagent and the reactant, further improves the utilization rate and the production efficiency of the atoms, reduces the production of byproducts, and simultaneously efficiently ensures the enantioselectivity of the products, and the introduction of the asymmetric catalysis concept of the small organic molecules ensures that the environmental pollution pressure of the methodology is small. In conclusion, the method can obtain a large amount of chiral compounds (such as amino alcohol, amino acid, amino ketone, lactam derivative and the like) with special functional groups through simple chemical conversion, and has good application prospect.
The following description will be given with reference to specific examples.
Example 1
This example provides a chiral (S) - (1,1, 1-trifluoro-4-oxo-4-phenylbutan-2-yl) (benzyloxy) carbamic acid tert-butyl ester, the structural formula of which is shown in molecular formula I1 below, and a method for preparing the same:
Figure BDA0002784143980000151
the preparation method comprises the following steps:
a dry 10mL test tube is added with mesitylene substituted indanol derived triazole carbene catalyst (0.02mmol,0.2equiv.), 0.6mL anhydrous toluene, replaced by argon for three times, added with alkali (0.02mmol,0.2eq) to react, sealed and stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol,1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 h. The corresponding β -trifluoromethylenone (0.1mmol,1.0equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is finished, the reaction solution is filtered by a glass dropper containing silica gel, after ether washing, the filtrate is dried by spinning, and column chromatography separation is carried out, so as to obtain a target product precursor, namely colorless oily liquid, wherein the yield is 95 percent, and the ee is 92 percent.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,Chloroform-d)δ7.93–7.84(m,2H),7.56(t,J＝7.4Hz,1H),7.42(t,J＝7.7Hz,2H),7.37–7.27(m,5H),5.48–5.32(m,1H),4.89(dd,J＝27.1,9.7Hz,2H),3.74(dd,J＝17.7,9.7Hz,1H),3.17(dd,J＝17.7,3.4Hz,1H),1.57(s,9H).13C NMR(101MHz,CDCl3)δ194.57,156.17,136.15,135.15,133.62,129.40,128.74,128.65,128.53,128.28,125.24(q,J＝282.1Hz),83.07,78.15,56.47(q,J＝31.1Hz),33.68,28.26.19F NMR(376MHz,CDCl3)δ-73.22.HRMS(ESI-TOF)[M+Na]calculated for[C22H24F3NO4Na]+446.1550,observed 446.1547.HPLC(Chiralpak-OJ column,98:2hexane/ethanol,flow rate:1.0mL/min):tmajor＝10.433min；tminor＝7.081min.[α]D 25＝-19.9(c＝0.80in CHCl3) (ii) a This result further confirmed the molecular structure of the product as described above for molecular structure I1.
Example 2
This example provides a chiral (S) - (4- (9H-fluoren-2-yl) -1,1, 1-trifluoro-4-oxobutan-2-yl) (benzyloxy) carbamic acid tert-butyl ester and its preparation, the structural formula of which is shown in molecular structural formula I2:
Figure BDA0002784143980000161
the preparation method comprises the following steps:
a dry 10mL test tube is added with mesitylene substituted indanol derived triazole carbene catalyst (0.02mmol,0.2equiv.), 0.6mL anhydrous toluene, replaced by argon for three times, added with alkali (0.02mmol,0.2eq) to react, sealed and stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol,1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 h. The corresponding β -trifluoromethylenone (0.1mmol,1.0equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is finished, the reaction solution is filtered by a glass dropper containing silica gel, after ether washing, the filtrate is dried by spinning, and column chromatography separation is carried out, so as to obtain the target product precursor, colorless oily liquid, the yield is 86%, and 88% ee is obtained.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,Chloroform-d)δ8.09–8.01(m,1H),7.93(dd,J＝8.0,1.6Hz,1H),7.87–7.81(m,1H),7.78(d,J＝8.0Hz,1H),7.65–7.56(m,1H),7.50–7.35(m,4H),7.34–7.28(m,3H),5.49–5.40(m,1H),4.89(dd,J＝45.9,9.7Hz,2H),3.89(s,2H),3.81(dd,J＝17.6,9.7Hz,1H),3.22(dd,J＝17.6,3.5Hz,1H),1.59(s,9H).13C NMR(101MHz,Chloroform-d)δ194.21,156.10,146.86,144.56,143.32,140.36,135.11,134.46,129.33,128.55,128.44,128.20,127.56,127.12,125.29,125.23(q,J＝282.2Hz),124.90,120.98,119.72,82.96,78.06,56.49(q,J＝30.9Hz),36.86,33.66,28.20.19F NMR(376MHz,Chloroform-d)δ-73.10.HRMS(ESI-TOF)[M+Na]calculated for[C29H28F3NO4Na]+534.1863,observed 534.1860.HPLC(Chiralpak-OD-H column,99.2:0.8hexane/ethanol,flow rate:1.0mL/min):tmajor＝14.973min；tminor＝10.511min.[α]D 25＝+19.2(c＝0.80in CHCl3) (ii) a This result further confirmed the molecular structure of the product as described above for molecular structure I2.
Example 3
This example provides a chiral (S) - (benzyloxy) (1,1, 1-trifluoro-4-oxo-4- (thiazol-2-yl) butandin-2-yl) carbamic acid tert-butyl ester and its preparation method, which has the following molecular formula I3:
Figure BDA0002784143980000171
the preparation method comprises the following steps:
a dry 10mL test tube is added with mesitylene substituted indanol derived triazole carbene catalyst (0.02mmol,0.2equiv.), 0.6mL anhydrous toluene, replaced by argon for three times, added with alkali (0.02mmol,0.2eq) to react, sealed and stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol,1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 h. The corresponding β -trifluoromethylenone (0.1mmol,1.0equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is finished, the reaction solution is filtered by a glass dropper containing silica gel, after ether washing, the filtrate is dried by spinning, and column chromatography separation is carried out, so as to obtain the target product precursor, colorless oily liquid, the yield of 93 percent and 98 percent ee.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,Chloroform-d)δ7.97(d,J＝3.0Hz,1H),7.68(d,J＝3.0Hz,1H),7.43–7.21(m,5H),5.23–5.14(m,1H),4.88(dd,J＝26.6,9.5Hz,2H),3.98(dd,J＝18.0,10.3Hz,1H),3.45(dd,J＝18.0,3.5Hz,1H),1.55(s,9H).13C NMR(101MHz,Chloroform-d)δ188.39,165.62,156.07,144.77,134.86,129.43,128.50,128.37,126.75,124.83(q,J＝282.3Hz),83.03,78.13,56.10(q,J＝31.2Hz),33.82,28.14.19F NMR(376MHz,Chloroform-d)δ-73.25.HRMS(ESI-TOF)[M+Na]calculated for[C19H21F3N2O4SNa]+453.1066,observed 453.1065.HPLC(Chiralpak-OD-H column,99:1hexane/ethanol,flow rate:1.0mL/min):tmajor＝7.391min；tminor＝6.722min.[α]D 25＝-35.3(c＝0.80in CHCl3) (ii) a This result further confirmed the molecular structure of the product as described above for molecular structure I3.
Example 4
This example provides a chiral (S) - (benzyloxy) (1,1, 1-trifluoro-4-oxo-4- (pyrazin-2-yl) butan-2-yl) carbamic acid tert-butyl ester and a method for its preparation, which has the following molecular structural formula I4:
Figure BDA0002784143980000181
the preparation method comprises the following steps:
a dry 10mL test tube is added with mesitylene substituted indanol derived triazole carbene catalyst (0.02mmol,0.2equiv.), 0.6mL anhydrous toluene, replaced by argon for three times, added with alkali (0.02mmol,0.2eq) to react, sealed and stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol,1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 h. The corresponding β -trifluoromethylenone (0.1mmol,1.0equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is finished, the reaction solution is filtered by a glass dropper containing silica gel, after ether washing, the filtrate is dried by spinning, and column chromatography separation is carried out, so as to obtain a target product precursor, namely a white solid, wherein the yield is 92 percent, and the ee is 94 percent.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,Chloroform-d)δ9.17(d,J＝1.5Hz,1H),8.72(d,J＝2.5Hz,1H),8.56(dd,J＝2.5,1.5Hz,1H),7.50–7.10(m,5H),5,39–5.29(m,1H),4.86(dd,J＝35.8,9.6Hz,2H),4.02(dd,J＝18.3,10.5Hz,1H),3.40(dd,J＝18.3,3.4Hz,1H),1.57(s,9H).13C NMR(101MHz,Chloroform-d)δ195.84,156.26,148.15,146.61,143.75,143.44,134.86,129.43,128.48,128.33,124.97(q,J＝281.9Hz),83.04,78.07,56.18(q,J＝31.0Hz),32.96,28.15.19F NMR(376MHz,Chloroform-d)δ-73.46.HRMS(ESI-TOF)[M+Na]calculated for[C20H22F3N3O4Na]+448.1455,observed 448.1451.HPLC(Chiralpak-OD-H column,99:1hexane/ethanol,flow rate:1.0mL/min):tmajor＝11.972min；tminor＝9.124min.[α]D 25＝-27.4(c＝0.80in CHCl3) (ii) a This result further confirmed the molecular structure of the product as described above for molecular structure I4.
Example 5
This example provides a chiral (S) - (benzyloxy) (1,1,1,2, 2-pentafluoro-5-oxo-5-phenylpentyl-3-yl) carbamic acid tert-butyl ester, the structural formula of which is shown in molecular formula I5 below, and a method for preparing the same:
Figure BDA0002784143980000191
a dry 10mL test tube is added with mesitylene substituted indanol derived triazole carbene catalyst (0.02mmol,0.2equiv.), 0.6mL anhydrous toluene, replaced by argon for three times, added with alkali (0.02mmol,0.2eq) to react, sealed and stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol,1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 h. The corresponding β -pentafluoroethyl ketene (0.1mmol,1.0equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is finished, the reaction solution is filtered by a glass dropper containing silica gel, after ether washing, the filtrate is dried by spinning, and column chromatography separation is carried out, so as to obtain a target product precursor, namely colorless oily liquid, the yield is 91 percent, and the ee is 95 percent.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,CDCl3)δ7.90–7.83(m,2H),7.54(d,J＝7.4Hz,1H),7.41(dd,J＝8.3,7.2Hz,2H),7.34(dd,J＝4.6,1.6Hz,2H),7.32–7.27(m,3H),5.61–5.50(m,1H),4.89(dd,J＝37.7,9.6Hz,2H),3.84(dd,J＝17.9,9.6Hz,1H),3.18(ddd,J＝17.9,3.5,1.2Hz,1H),1.58(s,9H).13C NMR(101MHz,Chloroform-d)δ194.60,155.80,136.08,135.09,133.48,129.16,128.60,128.47,128.40,128.17,118.97(qt,J＝286.8,35.8Hz),112.75(tq,J＝259.0,36.1Hz),83.04,77.61,54.73(dd,J＝26.7,20.2Hz),32.62,28.09.19F NMR(376MHz,Chloroform-d)δ-81.95(s,3F),-118.34(d,J＝275.1Hz,1F),-124.36(d,J＝277.3Hz,1F).HRMS(ESI-TOF)[M+Na]calculated for[C23H24F5NO4Na]+496.1518,observed 496.1518.HPLC(Chiralpak-OJ column,98:2hexane/ethanol,flow rate:1.0mL/min):tmajor＝6.696min；tminor＝4.901min.[α]D 25＝-46.4(c＝0.80in CHCl3) (ii) a This result further confirmed the molecular structure of the product as described above for molecular structure I5.
Example 6
This example provides a chiral (S) - (benzyloxy) (1, 1-difluoro-4-oxo-4-phenylbutan-2-yl) carbamic acid tert-butyl ester and its preparation, which has the following molecular formula I6:
Figure BDA0002784143980000201
the preparation method comprises the following steps:
a dry 10mL test tube is added with mesitylene substituted indanol derived triazole carbene catalyst (0.02mmol,0.2equiv.), 0.6mL anhydrous toluene, replaced by argon for three times, added with alkali (0.02mmol,0.2eq) to react, sealed and stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol,1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 h. The corresponding β -difluoromethylenone (0.1mmol,1.0equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is finished, the reaction solution is filtered by a glass dropper containing silica gel, after ether washing, the filtrate is dried by spinning, and column chromatography separation is carried out, so as to obtain a target product precursor, namely colorless oily liquid, wherein the yield is 92 percent, and the ee is 95 percent.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,CDCl3)δ7.97–7.83(m,2H),7.66–7.51(m,1H),7.44(t,J＝7.7Hz,2H),7.34(m,5H),6.00(td,J＝56.0,4.1Hz,1H),5.08–4.84(m,1H),4.87(dd,J＝14.0,9.8Hz,2H),3.50(dd,J＝17.6,8.4Hz,1H),3.24(dd,J＝17.6,4.8Hz,1H),1.54(s,9H).13C NMR(101MHz,CDCl3)δ195.74,156.50,136.31,135.19,133.43,129.50,128.64,128.62,128.47,128.18,115.01(t,J＝245.8Hz),82.65,78.03,57.38(t,J＝24.0Hz),34.05,28.19.19F NMR(376MHz,CDCl3)δ-123.62(d,J＝284.0Hz,1F),-127.51(d,J＝284.2Hz,1F).HRMS(ESI-TOF)[M+Na]calculated for[C22H25F2NO4Na]+428.1644,observed 428.1643.HPLC(Chiralpak-AD-H column,99:1hexane/ethanol,flow rate:1.0mL/min):tmajor＝9.301min；tminor＝10.891min.[α]D 25＝-30.4(c＝0.80in CHCl3) (ii) a This result further confirmed the molecular structure of the product as described above for molecular structure I6.
Example 7
This example provides a chiral (S) -methyl 4- (benzo [ b ] thiophen-2-yl) -2- ((benzyloxy) (tert-butoxycarbonyl) amino) -4-oxobutanoate and a process for its preparation, having the following molecular structure I7:
Figure BDA0002784143980000211
the preparation method comprises the following steps:
a dry 10mL test tube is added with mesitylene substituted indanol derived triazole carbene catalyst (0.02mmol,0.2equiv.), 0.6mL anhydrous toluene, replaced by argon for three times, added with alkali (0.02mmol,0.2eq) to react, sealed and stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol,1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 h. The corresponding beta-methyl formate enone (0.1mmol,1.0equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is finished, the reaction solution is filtered by a glass dropper containing silica gel, after ether washing, the filtrate is dried by spinning, and column chromatography separation is carried out, so as to obtain a target product precursor, colorless oily liquid, the yield of which is 96 percent and the ee of which is 90 percent.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,Chloroform-d)δ7.97–7.80(m,3H),7.53–7.35(m,4H),7.34–7.26(m,3H),5.28(t,J＝6.6Hz,1H),4.90(dd,J＝40.3Hz,10.5Hz,2H),3.75(s,3H),3.71(dd,J＝17.2Hz,6.9Hz,1H),3.25(dd,J＝17.3,6.3Hz,1H),1.53(s,9H).13C NMR(101MHz,Chloroform-d)δ190.87,170.25,156.86,142.93,142.62,139.03,135.53,129.72,129.66,128.59,128.46,127.58,126.03,125.06,122.99,82.66,77.88,59.47,52.67,38.71,28.20.HRMS(ESI-TOF)[M+Na]calculated for[C25H27NO6SNa]+492.1451,observed 492.1451.HPLC(Chiralpak-AD-H column,96:6hexane/ethanol,flow rate:1.0mL/min):tmajor＝20.679min；t minor＝23.634min.[α]D 25＝-21.6(c＝0.80in CHCl3) (ii) a This result further confirmed the molecular structure of the product as described above for molecular structure I7.
Example 8
This example provides a chiral ((8S,9S,10R,13R,14S,17R) -10, 13-dimethyl-17- ((R-6-6-methylheptyl-2-yl) -2,3,4,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (2S) -4- (benzo [ b ] thiophen-2-yl) -2- ((benzyloxy) (tert-butoxycarbonyl) amino) -4-oxobutanoate, having the following molecular structure I8:
Figure BDA0002784143980000221
the preparation method comprises the following steps:
a dry 10mL test tube is added with mesitylene substituted indanol derived triazole carbene catalyst (0.02mmol,0.2equiv.), 0.6mL anhydrous toluene, replaced by argon for three times, added with alkali (0.02mmol,0.2eq) to react, sealed and stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol,1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 h. The corresponding β -ethyl formate enone (0.1mmol,1.0equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is finished, the reaction solution is filtered by a glass dropper containing silica gel, after ether washing, the filtrate is dried by spinning, and column chromatography separation is carried out, so as to obtain a target product precursor, namely a white solid, wherein the yield is 87 percent, and 92 percent ee is obtained.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,Chloroform-d)δ7.86(d,J＝7.7Hz,3H),7.48–7.35(m,4H),7.35–7.28(m,3H),5.34(s,1H),5.26–5.21(m,1H),4.91(dd,J＝47.0,10.5Hz,2H),4.71–4.63(m,1H),3.71(ddd,J＝16.8,7.3,2.7Hz,1H),3.18(dd,J＝16.4,4.8Hz,1H),2.40–2.24(m,2H),2.03–1.91(m,2H),1.89–1.78(m,3H),1.59(d,J＝34.8Hz,5H),1.53(s,9H),1.49–1.39(m,4H),1.37–1.22(m,5H),1.18–1.04(m,7H),0.95(s,3H),0.91(d,J＝6.5Hz,3H),0.87(d,J＝1.8Hz,3H),0.85(d,J＝1.8Hz,3H),0.66(s,3H).13C NMR(101MHz,Chloroform-d)δ191.08(d,J＝2.6Hz),168.95(d,J＝2.8Hz),156.74,143.15,142.63,139.41,139.05,135.73,129.59(d,J＝3.8Hz),128.48,128.41,127.50,126.00,125.02,122.98,122.83(d,J＝2.4Hz),82.43,77.68(d,J＝2.0Hz),75.77,59.69(d,J＝4.6Hz),56.67,56.14,49.98,42.31,39.72,39.52,38.56(d,J＝3.7Hz),37.96,37.88,36.90(d,J＝2.0Hz),36.55,36.19,35.79,31.86(d,J＝5.1Hz),28.26,28.23,28.09,28.02,27.68,27.59,24.28,23.84,22.83,22.57,21.02,19.24,18.72,11.85.HRMS(ESI-TOF)[M+Na]calculated for[C51H69NO6SNa]+846.4738observed 846.4740.HPLC(Chiralpak-IA column,97.5:2.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝11.946min；tminor＝10.781min.[α]D 25＝-21.1(c＝0.80in CHCl3) (ii) a This result further confirmed the molecular structure of the product as described above for molecular structure I8.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims (10)

1. A beta-carbonyl chiral amino compound is characterized in that the molecular structure general formula of the beta-carbonyl chiral amino compound is shown as formula I:
Figure FDA0002784143970000011
wherein R is1And R2Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl radical, C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy radical, C1-C20Alkyl oxycarbonyl radical, C1-C20Alkyl oxycarbonyl (C)1-C20) Alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, aryl (C)1-C20) Alkyl, aryl (C)1-C20) Alkoxy, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and halo (C)1-C20) Any one of alkyl groups; FG (fringe field switching)1And FG2Are identical or different C1-C20Alkyl radical, C1-C20Alkoxy radical, C1-C20Alkyloxycarbonyl, aryl, aryloxy, aryloxycarbonyl, aryl (C)1-C20) Alkyl, aryl (C)1-C20) Alkoxy and aryl radicals (C)1-C20) Any one of alkoxycarbonyl groups.
2. The beta-carbonyl chiral amino compound of claim 1, wherein: the R is1And R2Are identical or different C1-C10Alkyl radical, C1-C10Heteroalkyl group, C3-C10Cycloalkyl radical, C3-C10Heterocycloalkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C3-C10Cycloalkenyl radical, C3-C10Heterocycloalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C10Cycloalkynyl group, C3-C10Heterocycloalkynyl, C1-C10Alkoxy radical, C1-C10Alkyl oxycarbonyl radical, C1-C10Alkyl oxycarbonyl (C)1-C10) Alkyl radical, C4-C14Aryl, substituted (C)4-C14) Aryl radical, C4-C14Heteroaryl, substituted (C)4-C14) Heteroaryl group, C4-C14Aryloxy radical, C4-C14Aryloxycarbonyl group, C4-C14Heteroaryloxy radical, C4-C14Heteroaryloxycarbonyl radical, C4-C14Aryl radical (C)1-C10) Alkyl radical, C4-C14Aryl radical (C)1-C10) Alkoxy radical,C4-C14Heteroaryl (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Alkyl, cyano (C)1-C10) Alkyl and halo (C)1-C10) Any one of alkyl groups.
3. The beta-carbonyl chiral amino compound of claim 2, wherein: the R is1Is C4-C14Aryl, substituted C4-C14Aryl radical, C4-C14Heteroaryl and substituted C4-C14Any one of heteroaryl; and/or the presence of a gas in the gas,
the R is2Is C1-C10Alkyl, halo (C)1-C10) Alkyl radical, C1-C10Alkyl oxycarbonyl radical, C4-C14Aryloxycarbonyl and C4-C14Any one of heteroaryloxycarbonyl groups.
4. Beta-carbonyl chiral amino compound according to claim 3, characterized in that: the R is1Is any one of phenyl, naphthyl, fluorenyl, thienyl, thiazolyl, pyrrolyl, pyrazinyl, pyridyl and benzothienyl; and/or the presence of a gas in the gas,
the R is2Is C1-C3Alkyl, monohalo C1-C3Alkyl, dihalo C1-C3Alkyl, trihalo C1-C3Alkyl and C1-C3Any one of alkyl oxycarbonyl groups.
5. Beta-carbonyl chiral amino compound according to any one of claims 1 to 4, characterized in that: the FG1And FG2Are identical or different C1-C10Alkoxy radical, C1-C10Alkyl oxycarbonyl radical, C4-C14Aryloxy radical, C4-C14Aryloxycarbonyl group, C4-C14Aryl radical (C)1-C10) Alkyl radical, C4-C14Aryl radical (C)1-C10) Alkoxy and aryl radicals (C)1-C20) Any one of alkoxycarbonyl groups.
6. Beta-carbonyl chiral amino compound according to claim 5, characterized in that: the FG1Is any one of methoxyl, ethoxyl, propoxyl, tert-butyloxycarbonyl, benzyl, benzyloxy, benzyloxycarbonyl and fluorenylmethoxycarbonyl; and/or the presence of a gas in the gas,
the FG2Is any one of methoxyl, ethoxyl, propoxyl, tert-butyloxycarbonyl, benzyl, benzyloxy, benzyloxycarbonyl and fluorenylmethyloxycarbonyl.
7. A process for the preparation of a chiral amino compound, as claimed in any one of claims 1 to 6, comprising the steps of:
providing a nucleophile compound A and a conjugated ketene compound B represented by the following structural general formulas:
A：
Figure FDA0002784143970000021
B：
Figure FDA0002784143970000022
and adding the nucleophilic reagent compound A and the conjugated ketene compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst and an alkali reagent to carry out asymmetric Michael addition reaction to obtain the beta-carbonyl chiral amino compound with the structural general formula shown as the formula I.
8. The method for producing a β -carbonyl chiral amino compound according to claim 7, wherein: the molar ratio of the N-heterocyclic carbene catalyst, the alkali reagent, the nucleophilic reagent compound A and the conjugated ketene compound B is (0.1-20): 1-100): 1-150; and/or the presence of a gas in the gas,
the temperature of the asymmetric Michael addition reaction is-90-35 ℃ and the time is 6-48 hours.
9. The preparation method of the beta-carbonyl chiral amino compound according to claim 7, wherein the N-heterocyclic carbene catalyst is selected from nitrogen-containing heterocyclic compounds having the following molecular structural formula:
Figure FDA0002784143970000031
wherein Q is boron tetrafluoride anion or chloride ion, R3Is C1-C20Alkyl radical, C1-C20Heteroalkyl, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Any one of an alkyl group, an aryl group and a substituted aryl group.
10. The method for producing a β -carbonyl chiral amino compound according to claim 7, wherein the base reagent is at least one of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, 1-azabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1,5, 7-triazabicyclo (4.4.0) dec-5-ene, triethylamine, diisopropylethylamine, bistrimethylsilylaminolithium, bistrimethylsilylaminosodium, bistrimethylsilylaminopotassium, diisopropylaminolithium, n-butyllithium, t-butyllithium, methyllithium, sodium methoxide, sodium ethoxide, and sodium ethylmercaptide.
CN202011292283.3A 2020-11-18 2020-11-18 Beta-carbonyl chiral amino compound and preparation method thereof Pending CN112457219A (en)

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FANGFANG GUO ET AL.: "A bifunctional N-heterocyclic carbene as a noncovalent organocatalyst for enantioselective aza-michael addition reactions", 《ACS CATAL.》 *
HIROAKL HAMANO ET AL.: "Studies on dimethoxyphenylaminoalcohols.1) III. The enantiomers of 1-(2,5-dimethoxyphenyl)-3-diethylamino-n-butanol", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 *
JIHOON LEE ET AL.: "Phase-transfer catalytic aza-Michael addition of tert-butyl benzyloxycarbamate to electron-deficient olefins", 《CHEM.COMMUN.》 *
KATHERINE NORA FANNING: "New approaches for the synthesis of unusual amino acids", 《UNIVERSITY OF GLASGOW PHD THESIS》 *

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