CN112321544B - Chiral quaternary carbon cyanide and preparation method thereof - Google Patents

Chiral quaternary carbon cyanide and preparation method thereof Download PDF

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CN112321544B
CN112321544B CN202011269887.6A CN202011269887A CN112321544B CN 112321544 B CN112321544 B CN 112321544B CN 202011269887 A CN202011269887 A CN 202011269887A CN 112321544 B CN112321544 B CN 112321544B
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黄湧
陈杰安
张林瑞
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Shenzhen Bay Laboratory Pingshan Biomedical R & D And Transformation Center
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
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Abstract

The application relates to the technical field of organic synthetic chemistry, in particular to chiral quaternary carbon cyanide and preparation thereofThe method. The molecular structural general formula of the chiral quaternary carbon cyanide is shown as a formula I in the specification, and is prepared by reacting R 1 、R 2 And R is 3 Different kinds of functional group substituents are introduced so as to have a plurality of kinds of chiral quaternary carbon cyanides, thus providing a potential basis for screening molecules which can be used for preparing pharmaceutical intermediates or functional materials.

Description

Chiral quaternary carbon cyanide and preparation method thereof
Technical Field
The application belongs to the technical field of organic synthetic chemistry, and particularly relates to chiral quaternary carbon cyanide and a preparation method thereof.
Background
The term "chiral" refers to an object that cannot be overlapped with its mirror image, e.g., our hands, left hand, and right hand that are mirror images of each other. The term chiral is more commonly used in the chemical medicine field, a chiral molecule is not coincident with its mirror image, and the chirality of the molecule is usually caused by asymmetric carbons, i.e. four groups on one carbon are different from each other. A pair of molecules, which are not coincident with each other like two human hands, are referred to as chiral compounds (chiral compounds), which refer to compounds that have the same molecular weight and structure but are arranged in opposite sides (e.g., as the solid and the mirror enantiomer).
Chiral quaternary carbon compounds are an important one of chiral compounds, and are an important building block for synthesizing drug intermediates, especially chiral structure-containing compounds and preparing functional materials. Classical methods for synthesizing chiral quaternary carbon compounds mainly comprise Diels-Alder reaction, [3+2] cycloaddition reaction, cyclopropanation reaction, nazarov cyclization reaction, alkylation reaction, dearomatization reaction and the like. However, these reaction types and catalytic methods are still limited and some reported stereoselectivity is not high for the synthesis of large numbers of complex natural products and bioactive molecules. The difficulty in synthesizing quaternary carbon chiral centers is not only in thermodynamic and kinetic disadvantages, but also in the formation of very sterically crowded quaternary carbon centers that need to span a high energy barrier, steric hindrance around the reaction center results in the difficulty in approaching the two reactive sites, increasing the difficulty in carbon-carbon bond formation. In addition, steric hindrance of the chiral center substituent before the reaction is large and the variability is small, resulting in difficulty in achieving chiral control with high efficiency. Many natural products and pharmaceutically active intermediates contain centers of continuous quaternary carbons, which are more challenging to build with high diastereoselectivity and high enantioselectivity than single quaternary carbons. Currently, methods for catalytic asymmetric construction of continuous quaternary carbon structures are relatively limited.
Disclosure of Invention
The invention aims to provide chiral quaternary carbon cyanide and a preparation method thereof, and aims to solve the technical problem of how to provide more chiral quaternary carbon cyano compounds.
In order to achieve the purposes of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the present application provides a chiral quaternary carbon cyanide compound having the general molecular structural formula of formula i:
Figure BDA0002777375860000021
wherein R in the formula I 1 、R 2 And R is 3 C being identical or different 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C) 1 -C 20 ) Alkyl, heteroaryl (C) 1 -C 20 ) Alkyl, C 2 -C 20 Alkenyl (C) 1 -C 20 ) Alkyl, C 2 -C 20 Alkynyl (C) 1 -C 20 ) Alkyl, cyano (C) 1 -C 20 ) Alkyl and (C) 1 -C 20 ) Any one of the alkyl oxycarbonyl groups; and X is any one of O, S and NH.
The chiral quaternary carbon cyanide shown in the formula I has a typical quaternary carbon chiral center structure, and is prepared by reacting R 1 、R 2 And R is 3 Different kinds of functional group substituents are introduced so as to have a plurality of kinds of chiral quaternary carbon cyanides, thus providing a potential basis for screening molecules which can be used for preparing pharmaceutical intermediates or functional materials.
In a second aspect, the present application provides a method for preparing a chiral quaternary carbon cyanide, comprising the steps of:
providing a conjugated olefine aldehyde compound A and a cyano compound B which are represented by the following structural formulas:
A：
Figure BDA0002777375860000022
B：/>
Figure BDA0002777375860000023
and adding the conjugated olefine aldehyde compound A and the cyano compound B into a reaction system containing an aza-carbene catalyst and an alkali reagent to perform beta-asymmetric functionalization reaction, so as to obtain the chiral quaternary carbon cyanide with the structural general formula shown in the formula I.
According to the preparation method, based on a high enol type intermediate formed by an aza-carbene catalyst and an enal substrate, beta-site reacts with a cyanide compound B with an electrophilic reagent function to form a ketone intermediate so as to receive simple nucleophilic attack, and the catalyst is circulated, so that a target product with high enantioselectivity and extremely wide range is efficiently and greenly prepared, chiral quaternary carbon cyanide with potential application value is obtained through a simple chemical conversion means, and the designability of the compound is greatly expanded. The preparation method adopts an organic micromolecule asymmetric catalytic system, can realize strict non-metallization of an integral reaction system, has safe and controllable reaction process, avoids heating or high-pressure conditions, simplifies operation in the preparation production process, has high substrate atom utilization rate, is very easy to obtain raw materials, does not need to carry out extra modification protection before reaction, can be directly used for preparation production, simplifies operation steps, shortens a reaction route, has high forward reaction rate, and obviously improves production efficiency and reduces production cost.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved by the present application more clear, 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 for purposes of illustration only 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 abstract service Co., ltd., columbus, ohio) naming system. Thus, the compound groups specifically referred to in the examples of the present invention are described and illustrated as follows:
"alkoxy" refers to a straight or branched, monovalent, saturated aliphatic chain having an oxygen atom attached thereto and includes, but is not limited to, e.g., methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. (C) a -C b ) Alkoxy refers to any straight or branched, monovalent, saturated aliphatic chain having an alkyl group of "a" to "b" carbon atoms bonded to an oxygen atom.
"alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like.
"heteroalkyl" refers to a straight or branched, monovalent, saturated fatty chain attached to at least one heteroatom, such as, but not limited to, methylaminoethyl or other similar group.
"alkenyl" refers to straight or branched chain hydrocarbons with one or more double bonds, including but not limited to, e.g., ethenyl, propenyl, and the like.
"heteroalkenyl" refers to a straight or branched chain hydrocarbon attached to at least one heteroatom with one or more double bonds, including but not limited to, e.g., vinylaminoethyl or other similar groups.
"alkynyl" refers to a straight or branched hydrocarbon bearing one or more triple bonds, including but not limited to, e.g., ethynyl, propynyl, and the like.
"heteroalkynyl" refers to a straight or branched hydrocarbon attached to at least one heteroatom with one or more triple bonds.
"aryl" refers to a cyclic aromatic hydrocarbon including, but not limited to, groups such as phenyl, naphthyl, anthryl, phenanthryl, and the like.
"heteroaryl" refers to a monocyclic or polycyclic or fused ring aromatic hydrocarbon in which one or more carbon atoms have been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heteroaryl group contains more than one heteroatom, these heteroatoms may be the same or may be 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, pyridin [3,4-b ] indolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolizinyl, quinolinyl, 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, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, tetrahydronaphthyl, and the like.
"Heterocyclyl" refers to a saturated mono-or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group, wherein at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different. Heterocyclylalkyl groups include, but are not limited to, for example, azabicycloheptyl, azetidinyl, indolinyl, morpholinyl, pyrazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroindazolyl, tetrahydroindolyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinoxalinyl, tetrahydrothiopyranyl, thiazolidinyl, thiomorpholinyl, thioxanthyl, thiooxalkyl, and the like.
"cycloalkenyl" refers to an unsaturated, mono-or polycyclic alkenyl group with one or more double bonds, possibly fused to an aromatic hydrocarbon group, including but not limited to a cycloethenyl group, a cyclopropenyl group, or other similar groups.
"heterocycloalkenyl" refers to an unsaturated, monocyclic or polycyclic alkenyl group having one or more double bonds, possibly fused to an aromatic hydrocarbon group, in which at least one carbon atom is replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
"cycloalkynyl" refers to an unsaturated, mono-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" refers to an unsaturated, mono-or polycyclic alkynyl group with one or more triple bonds, possibly fused to an aromatic hydrocarbon group, in which at least one carbon atom is replaced with a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkynyl contains more than one heteroatom, these heteroatoms may be the same or may be different.
In one aspect, an embodiment of the present invention provides a chiral quaternary carbon cyanide compound having a molecular structural formula of formula i:
Figure BDA0002777375860000051
wherein R in the formula I 1 、R 2 And R is 3 C being identical or different 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocyclenyl group,C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C) 1 -C 20 ) Alkyl, heteroaryl (C) 1 -C 20 ) Alkyl, C 2 -C 20 Alkenyl (C) 1 -C 20 ) Alkyl, C 2 -C 20 Alkynyl (C) 1 -C 20 ) Alkyl, cyano (C) 1 -C 20 ) Alkyl and (C) 1 -C 20 ) Any one of the alkyl oxycarbonyl groups; and X is any one of O, S and NH.
When R is 1 、R 2 、R 3 Is the same or different (C 1 -C 20 ) In the case of alkyl groups, in one embodiment, the (C 1 -C 20 ) The alkyl group may be (C 1 -C 10 ) Alkyl, (C) 1 -C 5 ) Alkyl, (C) 1 -C 4 ) Alkyl, (C) 1 -C 3 ) Alkyl, (C) 1 -C 2 ) Alkyl groups, and the like. In certain embodiments, (C) 1 -C 20 ) The alkyl group may be methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, etc.
When R is 1 、R 2 、R 3 Is the same or different (C 1 -C 20 ) In the case of heteroalkyl, in one embodiment, the (C 1 -C 20 ) The heteroalkyl group may be (C) 1 -C 10 ) Heteroalkyl (C) 1 -C 5 ) Heteroalkyl (C) 1 -C 4 ) Heteroalkyl (C) 1 -C 3 ) Heteroalkyl (C) 1 -C 2 ) Heteroalkyl groups, and the like. In certain embodiments, the heteroatom may be an atom, a nitrogen atom, a sulfur atom, or the like.
When R is 1 、R 2 、R 3 Is the same or different (C 3 -C 20 ) In the case of cycloalkyl, in one embodiment, the (C 3 -C 20 ) Cycloalkyl groups may be (C) 3 -C 10 ) Cycloalkyl, (C) 3 -C 5 ) Ring(s)Alkyl, (C) 3 -C 4 ) Cycloalkyl groups, and the like. In certain embodiments, (C) 3 -C 20 ) Cycloalkyl groups may be cyclopropyl, cyclobutyl, cyclopentyl, and the like.
When R is 1 、R 2 、R 3 Is the same or different (C 3 -C 20 ) In the case of heterocycloalkyl, in one embodiment, the (C 3 -C 20 ) Heterocyclylalkyl can be (C) 3 -C 10 ) Heterocycloalkyl, (C) 3 -C 10 ) Heterocycloalkyl, (C) 3 -C 5 ) Heterocycloalkyl, (C) 3 -C 4 ) Heterocycloalkyl, and the like. In certain embodiments, the heteroatom may be an oxygen atom, a nitrogen atom, a sulfur atom, or the like.
When R is 1 、R 2 、R 3 Is the same or different (C 2 -C 20 ) In the case of alkenyl groups, in one embodiment, the (C 2 -C 20 ) Alkenyl groups may be (C) 3 -C 10 ) Alkenyl group (C) 3 -C 5 ) Alkenyl group (C) 3 -C 4 ) Alkenyl group (C) 2 -C 3 ) Alkenyl groups, and the like. In certain embodiments, (C) 2 -C 20 ) Alkenyl groups may be ethenyl, propenyl, butenyl, pentenyl, and the like.
When R is 1 、R 2 、R 3 Is the same or different (C 2 -C 20 ) In the case of heteroalkenyl, in one embodiment, the (C 2 -C 20 ) The heteroalkenyl group may be (C) 2 -C 10 ) Heteroalkenyl, (C) 3 -C 10 ) Heteroalkenyl, (C) 3 -C 5 ) Heteroalkenyl, (C) 3 -C 4 ) Heteroalkenyl, (C) 2 -C 3 ) Heteroalkenyl groups, and the like. In certain embodiments, the heteroatom may be halogen, nitrogen atom, sulfur atom, or the like.
When R is 1 、R 2 、R 3 Is the same or different (C 3 -C 20 ) In the case of cycloalkenyl, in one embodiment, the (C 3 -C 20 ) Cycloalkenyl groups may be (C 3 -C 10 ) Cycloalkenyl, (C) 3 -C 5 ) Cycloalkenyl, (C) 3 -C 4 ) Cycloalkenyl groups, and the like. In some embodiments, the following steps are performed C 3 -C 20 ) The cycloalkenyl group may be cyclopropenyl, cyclobutenyl, cyclopentenyl, and the like.
When R is 1 、R 2 、R 3 Is the same or different (C 3 -C 20 ) In the case of heterocycloalkenyl, in one embodiment, the (C 3 -C 20 ) The heterocycloalkenyl group may be (C 3 -C 10 ) Heterocycloalkenyl, (C) 3 -C 5 ) Heterocycloalkenyl, (C) 3 -C 4 ) Heterocycloalkenyl, and the like. In certain embodiments, the heteroatom may be halogen, nitrogen atom, sulfur atom, or the like.
When R is 1 、R 2 、R 3 Is the same or different (C 2 -C 20 ) In the case of alkynyl groups, in one embodiment, the (C 2 -C 20 ) Alkynyl groups may be (C) 2 -C 10 ) Alkynyl, (C) 3 -C 10 ) Alkynyl, (C) 3 -C 5 ) Alkynyl, (C) 3 -C 4 ) Alkynyl, (C) 2 -C 3 ) Alkynyl groups, and the like. In certain embodiments, (C) 2 -C 20 ) Alkynyl groups may be ethynyl, propynyl, butynyl, pentynyl, and the like.
When R is 1 、R 2 、R 3 Is the same or different (C 2 -C 20 ) In the case of heteroalkynyl groups, in one embodiment, the (C 2 -C 20 ) The heteroalkynyl group may be (C) 2 -C 10 ) Heteroalkynyl, (C) 3 -C 10 ) Heteroalkynyl, (C) 3 -C 5 ) Heteroalkynyl, (C) 3 -C 4 ) Heteroalkynyl, (C) 2 -C 3 ) Heteroalkynyl, and the like. In certain embodiments, the heteroatom may be halogen, nitrogen atom, sulfur atom, or the like.
When R is 1 、R 2 、R 3 Is the same or different (C 3 -C 20 ) In the case of cycloalkynyl groups, in one embodiment, the (C 3 -C 20 ) The cycloalkynyl group may be (C) 3 -C 10 ) Cycloalkynyl, (C) 3 -C 5 ) Cycloalkynyl, (C) 3 -C 4 ) Cycloalkynyl, and the like. In certain embodiments, (C) 2 -C 20 ) The cycloalkynyl group may be cyclopropynyl group, cyclobutynyl group, or a ring Pentynyl, and the like.
When R is 1 、R 2 、R 3 Is the same or different (C 3 -C 20 ) In the case of heterocyclylalkynyl, in one embodiment, the (C 3 -C 20 ) The heterocycloalkynyl group may be (C) 3 -C 10 ) Heterocycloalkynyl, (C) 3 -C 5 ) Heterocycloalkynyl, (C) 3 -C 4 ) Heterocycloalkynyl, and the like. In certain embodiments, the heteroatom may be halogen, nitrogen atom, sulfur atom, or the like.
When R is 1 、R 2 、R 3 Is the same or different (C 1 -C 20 ) In the case of alkoxy groups, in one embodiment, the (C 1 -C 20 ) Alkoxy groups may be (C) 1 -C 10 ) Alkoxy, (C) 1 -C 8 ) Alkoxy, (C) 1 -C 6 ) Alkoxy, (C) 1 -C 4 ) Alkoxy, (C) 1 -C 3 ) Alkoxy, (C) 1 -C 2 ) An alkoxy group. In certain embodiments, the (C 1 -C 20 ) Alkoxy groups may be, but are not limited to, methyl, ethyl, propyl, etc.
When R is 1 、R 2 、R 3 Where the aryl groups are the same or different, the aryl groups may be, but are not limited to, monocyclic aryl groups, polycyclic aryl groups, fused ring aryl groups. In one embodiment, the aryl is a monocyclic aryl. In certain embodiments, aryl groups can be phenyl, naphthyl, fluorenyl, anthracenyl, phenanthrenyl, and the like.
When R is 1 、R 2 、R 3 Where the substituted aryl groups are the same or different, the substituted aryl groups may be, but are not limited to, ortho, meta, para single or multiple substituted phenyl groups. Substituents include, but are not limited to, alkyl, substituted alkyl, aryl, substituted aryl, acyl, halogen, alkoxy, nitro, -NR 9 R 10 、-NR 9 -CO-NR 10 、-OCONR 9 、-PR 9 R 10 、-SOR 9 、-SO 2 -R 9 、-SiR 9 R 10 R 11 、-BR 9 R 10 Wherein R is 9 、R 10 、R 11 R as described above, which may be identical or different 1 、R 2 The radicals shown. Wherein, when the substituent is an alkyl group, the alkyl group is for example but not limited to methyl, ethyl, propyl, butyl, isobutyl; 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, a methyloxy group, an ethyloxy group, a propyloxy group. In one embodiment, the substituted aryl group may also be cyano (C 1 -C 10 ) Alkyl (C) 3 -C 8 ) Aryl, substituted (C) 3 -C 8 ) Aryl groups.
When R is 1 、R 2 、R 3 When the heteroaryl groups are the same or different, in one embodiment, the heteroaryl groups may be (C 3 -C 8 ) Heteroaryl, furan, thiophene.
When R is 1 、R 2 、R 3 In the case of identical or different substituted heteroaryl groups, in one embodiment, the substituted heteroaryl groups may be substituted (C 3 -C 8 ) Heteroaryl, alkoxy substituted furans, (C) 3 -C 8 ) Heteroaryl substituted furans, fatty chain substituted thiophenes.
When R is 1 、R 2 、R 3 When the aryloxy groups are the same or different, in one embodiment, the aryloxy groups may be phenoxy, naphthoxy, anthracenoxy, phenanthroxy.
When R is 1 、R 2 、R 3 Is the same or different aryl (C) 1 -C 20 ) In the case of alkyl, in one embodiment, the aryl group (C 1 -C 20 ) The alkyl group may be aryl (C) 1 -C 10 ) Alkyl, phenyl (C) 1 -C 10 ) Alkyl, phenyl (C) 1 -C 5 ) Alkyl, phenyl (C) 1 -C 4 ) Alkyl, phenyl (C) 1 -C 3 ) Alkyl, phenyl (C) 1 -C 2 ) Alkyl groups, and the like. In certain embodiments, aryl (C 1 -C 20 ) The alkyl group may be benzeneAminomethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylisobutyl, phenylpentyl, phenylisopentyl, phenylneopentyl.
When R is 1 、R 2 、R 3 Heteroaryl groups (C) which are identical or different 1 -C 20 ) In the case of alkyl, in one embodiment, the heteroaryl (C 1 -C 20 ) The alkyl group may be heteroaryl (C) 1 -C 10 ) Alkyl, heteroaryl (C) 1 -C 10 ) Alkyl, heteroaryl (C) 1 -C 5 ) Alkyl, heteroaryl (C) 1 -C 4 ) Alkyl, heteroaryl (C) 1 -C 3 ) Alkyl, heteroaryl (C) 1 -C 2 ) Alkyl groups, and the like. Wherein the heteroaryl group may be (C 3 -C 8 ) Heteroaryl, furan, pyridine, pyrazine, thiazole, indole, quinoline, and the like.
When R is 1 、R 2 、R 3 Is the same or different (C 2 -C 20 ) Alkenyl (C) 1 -C 20 ) In the case of alkyl groups, in one embodiment, the (C 2 -C 20 ) Alkenyl (C) 1 -C 20 ) The alkyl group may be (C 2 -C 10 ) Alkenyl (C) 1 -C 10 ) Alkyl, (C) 2 -C 5 ) Alkenyl (C) 1 -C 3 ) An alkyl group.
When R is 1 、R 2 、R 3 Is the same or different (C 2 -C 20 ) Alkynyl (C) 1 -C 20 ) In the case of alkyl groups, in one embodiment, the (C 2 -C 20 ) Alkynyl (C) 1 -C 20 ) The alkyl group may be (C 2 -C 10 ) Alkynyl (C) 1 -C 10 ) Alkyl, (C) 2 -C 5 ) Alkynyl (C) 1 -C 3 ) An alkyl group.
When R is 1 、R 2 、R 3 Cyano groups (C) 1 -C 20 ) In the case of alkyl groups, in one embodiment, the cyano group (C 1 -C 20 ) The alkyl group may be cyano (C 1 -C 10 ) Alkyl, cyano (C) 1 -C 5 ) Alkyl, cyano (C) 1 -C 4 ) Alkyl, cyano (C) 1 -C 3 ) Alkyl, cyano (C) 1 -C 2 ) Alkyl groups, and the like. In certain embodiments, cyano (C 1 -C 20 ) The alkyl group may be cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, cyanopentyl, and the like.
When R is 1 、R 2 、R 3 When the alkyl groups are the same or different, in one embodiment, the alkyl-oxy-carbonyl-alkyl group may be (C 1 -C 10 ) Alkyloxycarbonyl (C) 1 -C 10 ) Alkyl, (C) 1 -C 5 ) Alkyloxycarbonyl (C) 1 -C 5 ) Alkyl, (C) 1 -C 4 ) Alkyloxycarbonyl (C) 1 -C 4 ) Alkyl, (C) 1 -C 3 ) Alkyloxycarbonyl (C) 1 -C 3 ) Alkyl, (C) 1 -C 2 ) Alkyloxycarbonyl (C) 1 -C 2 ) Alkyl groups, and the like.
In some embodiments, R 1 And R is 2 Are different groups. The chiral quaternary carbon cyanide of formula I thus has a continuous quaternary carbon structure, thereby providing for more highly diastereoselective and highly enantioselective construction of continuous quaternary carbons.
In some embodiments, the X is O.
In some embodiments, the chiral quaternary carbon cyanide represented by formula I: the R is 1 Is aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl (C 1 -C 20 ) Alkyl and heteroaryl (C) 1 -C 20 ) Any one of alkyl groups; the R is 2 Is C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocycloalkynyl and C 1 -C 20 Any one of alkoxy groups; the R is 3 Is aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl (C 1 -C 20 ) Alkyl and heteroaryl (C) 1 -C 20 ) Any one of alkyl groups.
Further, in the chiral quaternary carbon cyanide of formula I: the R is 1 Is aryl or substituted aryl; the R is 2 Is C 1 -C 20 An alkyl group; the R is 3 Is aryl or substituted aryl.
Further, in the chiral quaternary carbon cyanide of formula I: the R is 1 Is one of phenyl, naphthyl, fluorenyl, substituted phenyl, substituted naphthyl and substituted fluorenyl, wherein the substituents in the substituted phenyl, substituted naphthyl and substituted fluorenyl are respectively and independently selected from halogen atoms, (C) 1 -C 5 ) Alkyl, (C) 1 -C 5 ) At least one of an alkoxy group, a phenyl group, a phenoxy group, and an acyl group (e.g., formyl group, acetyl group, propionyl group, etc.); the R is 2 Is C 1 -C 5 An alkyl group; the R is 3 Is one of phenyl, naphthyl, fluorenyl, substituted phenyl, substituted naphthyl and substituted fluorenyl, wherein the substituents in the substituted phenyl, substituted naphthyl and substituted fluorenyl are respectively and independently selected from halogen atoms, (C) 1 -C 5 ) Alkyl, (C) 1 -C 5 ) At least one of an alkoxy group, a phenyl group, a phenoxy group, and an acyl group (e.g., formyl group, acetyl group, propionyl group, etc.).
The chiral quaternary carbon cyanide of the general formula I has various functional structures through R 1 、R 2 And R is 3 Different kinds of functional group substituents are introduced so as to have a plurality of kinds of chiral quaternary carbon cyanides, in particular, chiral quaternary carbon cyanides with continuous quaternary carbon chiral centers, including gamma-cyano chiral centers, which provides a potential basis for screening molecules useful for the preparation of pharmaceutical intermediates or functional materials.
On the other hand, on the basis of the chiral quaternary carbon cyanide, the embodiment of the application also provides a preparation method of the chiral quaternary carbon cyanide with the molecular structural general formula I, which comprises the following steps:
s01: providing a conjugated olefine aldehyde compound A and a cyano compound B which are represented by the following structural formulas:
A：
Figure BDA0002777375860000101
B：/>
Figure BDA0002777375860000102
s02: and adding the conjugated olefine aldehyde compound A and the cyano compound B into a reaction system containing an aza-carbene catalyst and an alkali reagent to perform beta-asymmetric functionalization reaction, so as to obtain the chiral quaternary carbon cyanide with the structural general formula shown in the formula I.
In the above step, R in the conjugated enal compound A 1 And R is 2 Namely R in the chiral quaternary carbon cyanide shown in the formula I 1 And R is 2 The cyanogen compound B is R in the chiral quaternary carbon cyanide shown in the formula I 3 . On one hand, the preparation method adopts an organic micromolecule asymmetric catalytic system, can realize strict non-metallization of the whole reaction system, and has safe and controllable reaction process, and avoids heating or high-pressure conditions, thereby simplifying the operation in the preparation production process. On the other hand, the preparation method is based on a classical high enol type intermediate formed by an aza-carbene catalyst and an enal substrate, and beta-site is reacted with a cyanide compound B to form a ketone type intermediate so as to receive simple nucleophilic attack, so that the catalyst is circulated, and a target product precursor with high enantioselectivity and extremely wide range is efficiently and greenly prepared, namely chiral quaternary carbon cyanide with potential application value is obtained by a simple chemical conversion means, and the designability and application prospect of the compound are greatly expanded. Finally, the preparation method has high substrate atomic utilization rate, accords with atomic economy, adopts the simple and easily obtained olefine aldehyde compound converted from the commercial carbonyl compound as a reaction substrate as a reactant, has very easy acquisition of raw materials, does not need to carry out extra modification protection, can be directly used for preparation and production, simplifies the operation steps and shortens the reaction A route; and the forward reaction rate is high, the production efficiency is obviously improved, and the production cost is reduced.
In the above step S01, R in the molecular structural formula of the conjugated enal compound A 1 And R is 2 The representative group is R in the general formula I of chiral quaternary carbon cyanide molecular structure 1 The groups represented are the same. R in molecular structural formula of cyanogen compound B 3 The represented group is R in the structural general formula I of chiral quaternary carbon cyanide 3 The groups represented are the same and are not described in detail herein for the sake of brevity. In addition, the conjugated enal compound a and the cyano compound B in the step S01 can be prepared and obtained according to a conventional method in the art, and of course, can also be directly obtained in a commercially available manner.
In the above step S02, as is known from the structural formula shown in the reactant conjugated enal compound a, it has a β -position polyfunctional substituent, and forms an electronegative β -position with the carbene catalyst, so that the carbonyl cyanide compound B acts as an electrophile and can attack the β -position of the enal compound a to construct a chiral center; in addition, the carbonyl cyanide compound B is converted into a nucleophilic reagent, and can nucleophilic attack the protoaldehyde carbonyl site to form a new carbon-heteroatom bond. Therefore, the atomic utilization rate of reactants is effectively improved, the characteristics of the two reactants and the reaction of the two reactants, such as the 'polar inversion' action of an aza-carbene catalyst on an enal substrate, are utilized to form a multi-active-site intermediate, so that the introduction of a metal catalyst and the limitation of the substrate or a product are avoided, and the beta-chiral carbonyl compound with potential application value is obtained through a simple chemical conversion reaction.
In the step S02, the aza-carbene catalyst and the alkali reagent act synergistically, so that the catalytic system has low toxicity, the atomic 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 and production processes is simplified. Wherein the base reagent deprotonates the aza-carbene reagent to form a proton base catalyst. In addition, in order to make the reaction system anhydrous, a water removal additive can be added, and the water removal additive is an auxiliary agent for regulating and controlling enantioselectivity when the reaction system is dehydrated, and at a certain loadThe catalyst can synergistically promote the catalytic circulation of the reaction in a range, and under the condition of a certain range of proportion, the reaction has high catalytic efficiency, so that the target product which is close to a single absolute configuration is obtained. The water removing additive is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate and preactivation
Figure BDA0002777375860000121
Molecular sieves, & gt>
Figure BDA0002777375860000122
Molecular sieves, & gt>
Figure BDA0002777375860000123
The molecular sieves incorporate at least one of the 13X molecular sieves. Because the existence of water molecules is easier to disturb the highly ordered transition state intermediate through hydrogen bond interaction, the introduction of the water removal additive can basically and effectively improve the enantioselectivity of the target product. Since the water removal additive is mainly used for controlling the anhydrous requirement of the reaction system, the water removal additive can be added according to the time-solvent characteristic of the specific reaction system, for example, to realize the anhydrous reaction system. As in one embodiment, the ratio of the water scavenging additive, such as the one listed above, to the solvent of the reactants is controlled to be 100mg/mL.
In order to enable the synergistic catalytic system to exert more effective catalytic action, the mole ratio of the aza-carbene catalyst, the alkali reagent, the conjugated olefine aldehyde compound A and the cyano compound B is (0.1-20): 1-20): 0.1-20): 1-100. In an embodiment, the molar ratio of the aza-carbene catalyst to the base reagent is (0.1-20): 0.1-20, preferably (0.1-20): 10. In one embodiment, the molar ratio of the aza-carbene catalyst to the base reagent is 1:10.
In one embodiment, the aza-carbene catalyst is at least one of imidazole aza-carbene, thiazole aza-carbene and triazole aza-carbene. In particular experiments, it was found that the preferred aza-carbene catalysts listed can catalyze the above reaction more efficiently, but different carbene catalysts result in products with different enantioselectivities. As in the specific embodiment, the aza-carbene catalyst is a nitrogen-containing heterocyclic compound of C, D or E:
C：
Figure BDA0002777375860000124
D：/>
Figure BDA0002777375860000125
E：/>
Figure BDA0002777375860000126
p in the structural general formula D is a carbon atom or an oxygen atom, and n is 0 or 1; structural formula C, D and E: q is boron tetrafluoride anion or chloride, R 6 Is C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 ) Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C) 1 -C 20 ) Alkyl, heteroaryl (C) 1 -C 20 ) Alkyl, (C) 2 -C 20 ) Alkenyl (C) 1 -C 20 ) Alkyl, (C) 2 -C 20 ) Alkynyl (C) 1 -C 20 ) Alkyl, cyano (C) 1 -C 20 ) Any one of alkyl groups; r is R 7 R is R 8 Is C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, aryl (C) 1 -C 20 ) Alkyl, heteroaryl (C) 1 -C 20 ) Any one of alkyl, aryl, substituted aryl.
In one embodiment, the alkaline agent may be selected from at least one of the following compounds: lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, 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, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium diisopropylamide, n-butyllithium, t-butyllithium, methyllithium, sodium methoxide, sodium ethoxide, sodium ethylthiolate. Preferred organic base reagents such as 1-azabicyclo [2.2.2] octane, DBU, TBD can achieve complete non-metallization of the catalytic system and yield a target product with more potential medical application value.
Under the action of the aza-carbene catalytic system, the reaction system can be smoothly carried out at different temperatures, and specifically, the temperature of the beta-asymmetric functional group reaction is between-80 and 35 ℃ and the time is between 6 and 48 hours. In order to further increase the reaction efficiency and increase the enantioselectivity of the reaction product, in one embodiment, the reaction temperature of the reaction system is-40 ℃ to 0 ℃. In another embodiment, the reaction temperature of the reaction system is-10 ℃ to 10 ℃. In another embodiment, the reaction temperature of the reaction system is-20 ℃ to 0 ℃. In another embodiment, the reaction temperature of the reaction system is 0℃to 10 ℃. In another embodiment, the reaction temperature of the reaction system is 20℃to 35 ℃. The reaction time in the environment of each preferred reaction temperature should be such that the above reactants react sufficiently, e.g., the reaction time may be 6 to 48 hours, or longer.
In the above reaction system, a certain amount of solvent may be optionally added. Such solvents include, but are not limited to, toluene, diethyl ether, methylene chloride, dichloroethane, 1, 4-dioxane, tetrahydrofuran, tetrahydropyran. Other alternative solvents may be readily selected by one of ordinary skill in the art in view of the reactions and disclosure herein. In one embodiment, the solvent may be added in a molar ratio of solvent to catalyst such that (1000-1000000): 1.
The chiral quaternary carbon cyanide preparation method uses the synergistic effect of the aza-carbene, the alkali reagent and the water removal additive, 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. Simultaneously, the toxicity of the residues in the reaction 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, the reactant raw materials are very easy to obtain, and the reactants do not need to be subjected to additional modification before reaction, so that the reactants can be directly used for preparation and production, the operation steps are simplified, and the reaction route is shortened; the production cost is obviously reduced. And secondly, the proportion and the addition amount of the aza-carbene catalyst, the alkali reagent, the water removal additive and the reactant can be flexibly regulated by the method, so that the high atom utilization rate and the production efficiency are further provided, the production of byproducts is reduced, the enantioselectivity of the products is effectively ensured, and the introduction of the asymmetric catalysis concept of small organic molecules enables the environmental pollution pressure of the methodology to be small. In summary, the process allows a large number of chiral quaternary carbocyanides with specific functionalized centers to be obtained by simple chemical transformations.
The following description is made with reference to specific embodiments.
Example 1
This example provides a chiral (2 s,3 s) -2- (4-methoxyphenyl) -3-methyl-5-oxo-3- (p-tolyl) tetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -2- (4-methoxyphenyl) -3-methyl-5-oxo-3- (p-tolyl) tetrahydrofuran-2-nitrile is shown as the following molecular structural formula I1:
Figure BDA0002777375860000141
the preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000142
molecular sieves (100 mg) were then added to dry 1, 4-dioxane 1.0mL, stirred at room temperature for 1h, added (E) -3- (4-methylphenyl) but-2-enal (0.15 mmol,1.5 equiv.) and stirred for 10min, added 4-methoxybenzoyl cyanide (0.1 mmol,1.0 equiv.) and then stirred at 25 ℃ for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. White solid, 88% yield, 92:8, dr:15:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.29(t,J＝4.0Hz,3H),7.26–7.12(m,3H),7.00–6.94(m,2H),3.89(s,3H),3.81(d,J＝16.0Hz,1H),2.78(d,J＝16.0Hz,1H),2.41(s,3H),1.25–1.19(m,3H). 13 C NMR(101MHz,CDCl3)δ172.69,160.87,138.72,133.73,129.46,128.01,126.91,122.68,117.17,113.73,87.49,77.34,77.23,77.03,76.71,55.43,52.14,41.14,22.81,21.03.HRMS(ESI-TOF)[M+Na] + calculated for[C 20 H 19 NNaO 3 ] + 344.1263,observed 344.1258.HPLC(Chiralpak-AD column,95:5 hexane/ethanol,flow rate:1.0mL/min):t major ＝18.550min；t minor = 11.698min. This result further confirms that the molecular structure of the product is just like the molecular structure I1 described above.
Example 2
This example provides a chiral (2 s,3 s) -2- (4-methoxyphenyl) -3-methyl-5-oxo-3-phenyltetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -2- (4-methoxyphenyl) -3-methyl-5-oxo-3-phenyl tetrahydrofuran-2-nitrile is shown as the following molecular structural formula I2:
Figure BDA0002777375860000151
the preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a s-tribromobenzene-substituted indenol-derived triazole carbene catalyst (0.02 mmol,0.2 equiv.) and tripotassium phosphate (0.02 mmol,0.2e were sequentially weighedquiv.)，
Figure BDA0002777375860000152
Molecular sieves (100 mg) were then added to dry 1, 4-dioxane 1.0mL, stirred at room temperature for 1h, added (E) -3-phenyl-but-2-enal (0.15 mmol,1.5 equiv.) and stirred for 10min, added 4-methoxybenzoyl cyanide (0.1 mmol,1.0 equiv.) and then stirred at 25 ℃ for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. White solid, 82% yield, er 91:9, dr 14:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.47–7.41(m,3H),7.30(d,J＝12.0Hz,2H),7.28–7.24(m,2H),7.02–6.94(m,2H),3.89(s,3H),3.87–3.79(m,1H),2.81(d,J＝16.0Hz,1H),1.27(d,J＝1.0Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ172.55,160.94,136.84,128.80,128.09,127.01,126.66,122.57,117.07,113.77,113.49,87.39,77.35,77.23,77.03,76.71,55.45,52.44,41.08,22.89.HRMS(ESI-TOF)[M+Na] + calculated for[C 19 H 17 NNaO 3 ] + 330.1106,observed 330.1101.HPLC(Chiralpak-AD column,95:5hexane/ethanol,flow rate:1.0mL/min):t major ＝20.488min；t minor = 13.343min. This result further confirms that the molecular structure of the product is as described above for molecular structure I2.
Example 3
This example provides a chiral (2 s,3 s) -2- (4-methoxyphenyl) -3-methyl-5-oxo-3- (m-tolyl) tetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -2- (4-methoxyphenyl) -3-methyl-5-oxo-3- (m-tolyl) tetrahydrofuran-2-nitrile is shown as the following molecular structural formula I3:
Figure BDA0002777375860000161
The preparation method comprises the following steps:
taking a 10mL reaction tube, and sequentially weighing the tribromobenzene to replace in a glove boxIs prepared from an indenol derivative triazole carbene catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000162
molecular sieves (100 mg) were then added to dry 1, 4-dioxane 1.0mL, stirred at room temperature for 1h, added (E) -3- (3-methylphenyl) but-2-enal (0.15 mmol,1.5 equiv.) and stirred for 10min, added 4-methoxybenzoyl cyanide (0.1 mmol,1.0 equiv.) and then stirred at 25 ℃ for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. White solid, 89% yield, 92:8, dr 20:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.29(t,J＝4.0Hz,3H),7.26–7.12(m,3H),7.00–6.94(m,2H),3.89(s,3H),3.81(d,J＝16.0Hz,1H),2.78(d,J＝16.0Hz,1H),2.41(s,3H),1.25–1.19(m,3H). 13 C NMR(101MHz,CDCl3)δ172.69,160.87,138.72,133.73,129.46,128.01,126.91,122.68,117.17,113.73,87.49,77.34,77.23,77.03,76.71,55.43,52.14,41.14,22.81,21.03.HRMS(ESI-TOF)[M+Na] + calculated for[C 20 H 19 NNaO 3 ] + 344.1263,observed 344.1258.HPLC(Chiralpak-AD column,95:5hexane/ethanol,flow rate:1.0mL/min):t major ＝18.550min；t minor = 11.698min. This result further confirms that the molecular structure of the product is as described above for molecular structure I3.
Example 4
This example provides a chiral (2 s,3 s) -3- (4-ethylphenyl) -3-methyl-5-oxo-2- (4-phenoxyphenyl) tetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -3- (4-ethylphenyl) -3-methyl-5-oxo-2- (4-phenoxyphenyl) tetrahydrofuran-2-nitrile is shown as the following molecular structural formula I4:
Figure BDA0002777375860000171
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000172
molecular sieves (100 mg) were then added to dry 1, 4-dioxane 1.0mL, stirred at room temperature for 1h, added (E) -3- (4-ethylphenyl) but-2-enal (0.15 mmol,1.5 equiv.) and stirred for 10min, added 4-phenoxybenzoyl cyanide (0.1 mmol,1.0 equiv.) and then stirred at 25 ℃ for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. Yellow solid, 90% yield, 91:9, dr:20:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.47–7.39(m,2H),7.33–7.29(m,2H),7.29–7.26(m,2H),7.25–7.19(m,3H),7.13–7.08(m,2H),7.08–7.03(m,2H),3.83(d,J＝16.0Hz,1H),2.79(d,J＝16.0Hz,1H),2.71(q,J＝8.0Hz,2H),1.29(t,J＝8.0Hz,3H),1.26(d,J＝1.0Hz,3H). 13 C NMR(101MHz,CDCl3)δ172.51,159.27,155.84,145.01,133.69,130.05,129.85,128.29,128.17,127.88,127.02,126.81,126.63,125.00,124.39,119.87,118.98,118.16,117.64,117.10,87.28,77.36,77.04,76.72,52.09,41.20,28.34,22.76,15.20.HRMS(ESI-TOF)[M+Na] + calculated for[C 26 H 23 NNaO 3 ] + 420.1576,observed 420.1571.HPLC(Chiralpak-OD column,97:3hexane/ethanol,flow rate:1.0mL/min):t major ＝12.946min；t minor = 24.425min. This result further confirms that the molecular structure of the product is as described above for molecular structure I4.
Example 5
This example provides a chiral (2 s,3 s) -3- (4-isopropylphenyl) -2- (4-methoxyphenyl) -3-methyl-5-oxotetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -3- (4-isopropylphenyl) -2- (4-methoxyphenyl) -3-methyl-5-oxo-tetrahydrofuran-2-carbonitrile is shown as the following molecular structural formula I5:
Figure BDA0002777375860000181
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000182
molecular sieves (100 mg) were then added to dry 1, 4-dioxane 1.0mL, stirred at room temperature for 1h, added (E) -3- (4-isopropylphenyl) but-2-enal (0.15 mmol,1.5 equiv.) and stirred for 10min, added 4-methoxybenzoyl cyanide (0.1 mmol,1.0 equiv.) and then stirred at 25 ℃ for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. White solid, 88% yield, er 90:10, dr 13:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.33–7.25(m,4H),7.22–7.13(m,2H),7.01–6.94(m,2H),3.89(s,3H),3.85–3.78(m,1H),2.97(dq,J＝13.8,6.5Hz,1H),2.78(d,J＝16.7Hz,1H),1.30(d,J＝7.0Hz,6H),1.25–1.22(m,3H). 13 C NMR(101MHz,CDCl3)δ172.70,160.86,149.46,133.99,127.99,127.02,126.81,122.76,117.19,113.74,87.44,77.35,77.24,77.03,76.72,55.44,52.13,41.23,33.66,29.71,23.85,23.82,22.84.HRMS(ESI-TOF)[M+Na] + calculated for[C 22 H 23 NNaO 3 ] + 372.1576,observed 372.1571.HPLC(Chiralpak-OD column,95:5hexane/ethanol,flow rate:1.0mL/min):t major ＝9.335min；t minor = 12.464min. This result further confirms that the molecular structure of the product is as described above for molecular structure I5.
Example 6
This example provides a chiral (2 s,3 s) -3- (4- (tert-butyl) phenyl) -3-methyl-2- (naphthalen-2-yl) -5-oxotetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -3- (4- (tert-butyl) phenyl) -3-methyl-2- (naphthalene-2-yl) -5-oxo-tetrahydrofuran-2-carbonitrile is shown as the following molecular structural formula I6:
Figure BDA0002777375860000191
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000192
molecular sieves (100 mg) were then added to dry 1, 4-dioxane 1.0mL, stirred at room temperature for 1h, added (E) -3- (4-tert-butylphenyl) but-2-enal (0.15 mmol,1.5 equiv.) and stirred for 10min, added naphthoyl cyanide (0.1 mmol,1.0 equiv.) and then stirred at 25 ℃ for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. White solid, yield 74%, er 91:9, dr 10:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.97–7.87(m,4H),7.62(m,2H),7.49–7.43(m,2H),7.39(dd,J＝16.0,4.0Hz,1H),7.28–7.21(m,2H),3.90(d,J＝16.0Hz,1H),2.84(d,J＝16.0Hz,1H),1.39(s,9H),1.27(s,3H). 13 C NMR(101MHz,CDCl3)δ172.63,151.97,133.72,133.42,132.37,128.55,128.44,128.32,127.75,127.55,127.09,126.98,126.41,126.30,125.71,125.19,123.20,117.19,87.55,77.35,77.03,76.72,52.17,41.42,34.63,31.27,31.03,22.85.HRMS(ESI-TOF)[M+Na] + calculated for[C 26 H 25 NNaO 2 ] + 406.1783,observed 406.1779.HPLC(Chiralpak-AD column,95:5hexane/ethanol,flow rate:1.0mL/min):t major ＝8.423min；t minor = 7.613min. This result further confirms that the molecular structure of the product is as described above for molecular structure I6.
Example 7
This example provides a chiral (2 s,3 s) -3- (3-fluoro-4-methylphenyl) -2- (4-methoxyphenyl) -3-methyl-5-oxotetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -3- (3-fluoro-4-methylphenyl) -2- (4-methoxyphenyl) -3-methyl-5-oxo-tetrahydrofuran-2-carbonitrile is shown in the following molecular structural formula I7:
Figure BDA0002777375860000201
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000202
molecular sieves (100 mg) were then added to dry 1, 4-dioxane 1.0mL, stirred at room temperature for 1h, added (E) -3- (3-fluoro-4-methylphenyl) but-2-enal (0.15 mmol,1.5 equiv.) and stirred for 10min, added 4-methoxybenzoyl cyanide (0.1 mmol,1.0 equiv.) and then stirred at 25℃for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. White solid, 89% yield, 92:8, dr 10:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.33–7.28(m,3H),7.02–6.95(m,3H),6.85(dd,J＝11.3,2.1Hz,1H),3.89(s,3H),3.77–3.71(m,1H),2.79(d,J＝16.0Hz,1H),2.33(d,J＝4.0Hz,3H),1.22(d,J＝1.0Hz,3H). 13 C NMR(101MHz,CDCl3)δ172.19,162.36,161.02,159.92,136.63,131.81,131.76,128.03,126.63,125.77,125.60,122.35,122.33,116.97,114.21,113.97,113.85,113.64,87.21,77.34,77.23,77.02,76.71,55.46,52.06,52.05,41.11,22.92,14.29,14.26.HRMS(ESI-TOF)[M+Na] + calculated for[C 20 H 18 FNNaO 3 ] + 362.1168,observed 362.1162.HPLC(Chiralpak-AD column,95:5hexane/ethanol,flow rate:1.0mL/min):t major ＝19.971min；t minor = 11.976min. The result isThe molecular structure of the product was further confirmed to be just as the molecular structure I7 described above.
Example 8
This example provides a chiral (2 s,3 s) -3- (4-methoxyphenyl) -3-methyl-5-oxo-2- (3, 4, 5-trimethoxyphenyl) tetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of ((2S, 3S) -3- (4-methoxyphenyl) -3-methyl-5-oxo-2- (3, 4, 5-trimethoxyphenyl) tetrahydrofuran-2-carbonitrile is shown in the following molecular structural formula I8:
Figure BDA0002777375860000211
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000212
molecular sieves (100 mg) were then added to dry 1, 4-dioxane 1.0mL, stirred at room temperature for 1h, added (E) -3- (4-methoxyphenyl) but-2-enal (0.15 mmol,1.5 equiv.) and stirred for 10min, added 3,4, 5-trimethoxybenzoyl cyanide (0.1 mmol,1.0 equiv.) and then stirred at 25℃for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. Yellow solid, yield 87%, er 90:10, dr 20:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(500MHz,Chloroform-d)δ7.34–7.28(m,2H),6.99–6.91(m,2H),6.45(s,2H),3.86(d,J＝21.0Hz,6H),3.80(s,6H),2.75(d,J＝16.8Hz,1H),1.21(s,3H). 13 C NMR(126MHz,CDCl3)δ172.35,160.00,153.13,139.32,128.86,127.96,126.23,117.16,113.85,103.67,87.36,77.31,77.06,76.80,60.95,56.35,56.18,55.36,51.86,41.42,29.69,22.44.HRMS(ESI-TOF)[M+Na] + calculated for[C 22 H 23 NNaO 6 ] + 420.1423,observed 420.1418.HPLC(Chiralpak-IA column,90:10hexane/ethanol,flow rate:1.0mL/min):t major ＝15.785min；t minor = 13.703min. This result further confirms that the molecular structure of the product is as described above for molecular structure I8.
Example 9
This example provides a chiral (2 s,3 s) -2- (3-bromo-4-methoxyphenyl) -3-methyl-5-oxo-3- (4-phenoxyphenyl) tetrahydrofuran-2-carbonitrile and a process for its preparation. The structural formula of the (2S, 3S) -2- (3-bromo-4-methoxyphenyl) -3-methyl-5-oxo-3- (4-phenoxyphenyl) tetrahydrofuran-2-nitrile is shown as the following molecular structural formula I9:
Figure BDA0002777375860000221
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000222
molecular sieves (100 mg), then 1.0mL of dried 1, 4-dioxane, stirring at room temperature for 1h, adding (E) -3- (4-phenoxyphenyl) but-2-ene (0.15 mmol,1.5 equiv.) and stirring for 10min, adding 0.1mmol of 3-chloro-4-methoxybenzoyl cyanide, 1.0 equiv.) and then stirring at 25℃for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. Yellow solid, 96% yield, er 90.5:9.5, dr 20:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.46–7.37(m,3H),7.22(ddd,J＝9.3,4.9,2.5Hz,4H),7.13–7.07(m,2H),7.08–7.02(m,2H),6.99(d,J＝8.7Hz,1H),3.98(s,3H),3.85–3.74(m,1H),2.80(d,J＝16.7Hz,1H),1.27–1.23(m,3H). 13 C NMR(101MHz,CDCl3)δ172.02,158.19,156.40,156.06,130.50,129.98,128.55,128.23,126.25,124.16,123.58,122.92,119.75,118.15,116.79,111.54,86.65,77.39,77.07,76.76,56.35,52.00,41.14,22.79.HRMS(ESI-TOF)[M+Na] + calculated for[C 25 H 20 ClNNaO 4 ]+ 456.0979,observed 456.0974.HPLC(Chiralpak-IA column,95:5hexane/ethanol,flow rate:1.0mL/min):t major ＝19.030min；t minor = 22.399min. This result further confirms that the molecular structure of the product is as described above for molecular structure I9.
Example 10
This example provides a chiral (2 s,3 s) -3- (3-acetylphenyl) -3-methyl-5-oxo-2- (m-tolyl) tetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -3- (3-acetylphenyl) -3-methyl-5-oxo-2- (m-tolyl) tetrahydrofuran-2-carbonitrile is shown in the following molecular structural formula I10:
Figure BDA0002777375860000231
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000232
molecular sieves (100 mg) were then added to dry 1, 4-dioxane 1.0mL, stirred at room temperature for 1h, added (E) -3- (3-acetylphenyl) but-2-ene (0.15 mmol,1.5 equiv.) and stirred for 10min, added 3-methylbenzoyl cyanide 0.1mmol,1.0 equiv.) and then stirred at 25℃for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. Yellow solid, 96% yield, er 89:11, dr 11:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ8.01(dt,J＝7.5,1.5Hz,1H),7.85(t,J＝1.9Hz,1H),7.61–7.49(m,2H),7.41–7.30(m,2H),7.17–7.13(m,2H),3.93–3.80(m,1H),2.86(d,J＝16.6Hz,1H),2.61(s,3H),2.41(d,J＝1.0Hz,1H),1.33–1.23(m,3H). 13 C NMR(101MHz,CDCl3)δ197.27,172.06,138.63,137.72,137.34,131.41,131.24,130.94,130.40,129.17,128.93,128.67,128.47,128.25,127.84,127.06,126.95,126.72,125.76,123.62,122.22,116.93,87.10,77.40,77.08,76.76,52.39,41.01,26.66,26.43,24.39,23.04,21.50.HRMS(ESI-TOF)[M+Na] + calculated for[C 21 H 19 NNaO 3 ] + 356.1263,observed 356.1257.HPLC(Chiralpak-OD column,90:10hexane/ethanol,flow rate:1.0mL/min):t major ＝19.314min；t minor = 22.236min. This result further confirms that the molecular structure of the product is just like the molecular structure I10 described above.
Example 11
This example provides a chiral (2 s,3 s) -3- ([ [1,1' -biphenyl ] -4-yl) -2- (3-chloro-4-methoxyphenyl) -3-methyl-5-oxotetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -3- ([ [1,1' -biphenyl ] -4-yl) -2- (3-chloro-4-methoxyphenyl) -3-methyl-5-oxotetrahydrofuran-2-carbonitrile is shown as the following molecular structural formula I11:
Figure BDA0002777375860000241
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000242
molecular sieves (100 mg), then 1.0mL of dried 1, 4-dioxane, stirring at room temperature for 1h, adding (E) -3- (4-phenylphenyl) but-2-ene (0.15 mmol,1.5 equiv.) and stirring for 10min, adding 0.1mmol,1.0 equiv.) of 3-bromo-4-methoxybenzoyl cyanide, and then stirring at 25℃for 22-26h. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. Yellow solid, 90% yield, 91:9, dr:19:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.72–7.67(m,2H),7.67–7.62(m,2H),7.61(d,J＝2.4Hz,1H),7.53–7.47(m,2H),7.44–7.40(m,1H),7.38–7.32(m,2H),7.31–7.25(m,1H),6.97(d,J＝8.7Hz,1H),3.99(s,3H),3.90–3.81(m,1H),2.85(d,J＝16.7Hz,1H),1.30(d,J＝1.0Hz,3H). 13 C NMR(101MHz,CDCl3)δ172.08,157.33,141.79,139.79,135.18,131.33,128.93,127.87,127.51,127.44,127.12,127.08,124.01,116.79,111.90,111.30,86.44,77.36,77.24,77.04,76.72,56.46,52.31,41.08,22.72.HRMS(ESI-TOF)[M+Na] + calculated for[C 25 H 20 BrNNaO 3 ] + 484.0524,observed 484.0521.HPLC(Chiralpak-AD column,92:8 hexane/ethanol,flow rate:1.0mL/min):t major ＝16.396min；t minor = 20.473min. This result further confirms that the molecular structure of the product is as described above for molecular structure I11.
Example 12
This example provides a chiral (2 s,3 s) -2- (4-methoxyphenyl) -3-methyl-3- (naphthalen-2-yl) -5-oxotetrahydrofuran-2-carbonitrile and a process for its preparation. The structural formula of the (2S, 3S) -2- (4-methoxyphenyl) -3-methyl-3- (naphthalene-2-yl) -5-oxo-tetrahydrofuran-2-nitrile is shown as the following molecular structural formula I12:
Figure BDA0002777375860000251
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000252
molecular sieves (100 mg) then dried 1, 4-dioxane 1.0mL was added and stirred at room temperature for 1h, (E) -3- (naphthalen-2-yl) but-2-ene (0.15 mmol,1.5 equiv.) was added and stirred for 10min, 4-methoxybenzoyl cyanide (0.1 mmol,1.0 equiv.) was added and then stirred at 25 ℃ for 22-26h. After the reaction is finished, filtering by using short silica gel, concentrating, and performing column chromatography separation to obtain a purified targetThe product was then subjected to enantioselectivity using HPLC. White solid, 91% yield, 91:9, dr:7:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.95–7.82(m,3H),7.76(d,J＝2.1Hz,1H),7.62–7.53(m,2H),7.39–7.29(m,3H),7.04–6.95(m,2H),3.99(d,J＝16.7Hz,1H),3.91(s,3H),2.91(d,J＝16.6Hz,1H),1.37(s,3H). 13 C NMR(101MHz,CDCl3)δ172.53,161.01,134.30,132.96,132.94,128.52,128.36,128.20,127.95,127.53,127.03,126.77,126.67,125.93,124.21,122.65,117.13,113.80,113.57,87.44,77.36,77.24,77.04,76.72,55.47,55.30,52.65,41.28,23.06.HRMS(ESI-TOF)[M+Na] + calculated for[C 23 H 19 NNaO 3 ] + 380.1263,observed 380.1258.HPLC(Chiralpak-OD column,95:5hexane/ethanol,flow rate:1.0mL/min):t major ＝20.201min；t minor = 25.058min. This result further confirms that the molecular structure of the product is as described above for molecular structure I12.
Example 13
This example provides a chiral (2 s,3 s) -3- (9, 9-dimethyl-9H-fluoren-3-yl) -3-methyl-5-oxo-2- (m-tolyl) tetrahydrofuran-2-carbonitrile and a process for preparing the same. The structural formula of the (2S, 3S) -3- (9, 9-dimethyl-9H-fluoren-3-yl) -3-methyl-5-oxo-2- (m-tolyl) tetrahydrofuran-2-carbonitrile is shown in the following molecular structural formula I13:
Figure BDA0002777375860000261
The preparation method comprises the following steps:
10mL of a reaction tube was taken, and in a glove box, a homotribromobenzene-substituted indenol-derived triazolecabine catalyst (0.02 mmol,0.2 equiv.), tripotassium phosphate (0.02 mmol,0.2 equiv.),
Figure BDA0002777375860000262
molecular sieves (100 mg) then dried 1.0mL of 1, 4-dioxane was added and stirred at room temperature for 1H, and (E) -3- (9, 9-dimethyl-9H-fluoren-3-yl) but-2-ene (0.15 mmol,1.5 equiv.) was added, stirredStirring for 10min, adding 3-methylbenzoyl cyanide 0.1mmol,1.0 equiv.), and stirring at 25deg.C for 22-26 hr. After the reaction, the reaction mixture was filtered through short silica gel, concentrated, and subjected to column chromatography to obtain a purified target product, and the enantioselectivity of the product was measured by HPLC. Yellow solid, 95% yield, 90:10, dr 12:1.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.83–7.76(m,2H),7.51–7.47(m,1H),7.42–7.38(m,2H),7.38–7.33(m,3H),7.26(d,J＝1.9Hz,1H),7.20–7.13(m,2H),3.94(dd,J＝16.8,1.1Hz,1H),2.87(d,J＝16.6Hz,1H),2.41(s,3H),1.51(d,J＝19.1Hz,6H),1.33(d,J＝1.1Hz,3H). 13 C NMR(101MHz,CDCl3)δ172.65,153.87,140.02,138.31,138.16,135.05,130.98,130.83,128.24,127.92,127.21,127.00,125.94,123.79,122.72,122.62,122.23,121.70,120.43,120.08,117.19,87.67,77.38,77.06,76.74,52.62,47.02,41.45,29.72,27.06,26.92,22.79,21.52.HRMS(ESI-TOF)[M+Na] + calculated for[C 28 H 25 NNaO 2 ] + 430.1783,observed 430.1780.HPLC(Chiralpak-AD column,97:3hexane/ethanol,flow rate:1.0mL/min):t major ＝8.662min；t minor =7.205 min. This result further confirms that the molecular structure of the product is as described above for molecular structure I13.
The foregoing description of the preferred embodiments of the present application is not intended to be limiting, but is intended to cover any and all modifications, equivalents, and alternatives falling within the spirit and principles of the present application.

Claims (5)

1. The preparation method of the chiral quaternary carbon cyanide is characterized by comprising the following steps of:
Providing a conjugated olefine aldehyde compound A and a cyano compound B which are represented by the following structural formulas:
A：
Figure FDA0004131832120000011
B：/>
Figure FDA0004131832120000012
adding the conjugated olefine aldehyde compound A and the cyano compound B into a reaction system containing an aza-carbene catalyst and an alkali reagent to perform beta-asymmetric functionalization reaction to obtain chiral quaternary carbon cyanide with a structural general formula shown in formula I;
Figure FDA0004131832120000013
wherein R in the formula I 1 、R 2 And R is 3 C being identical or different 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, phenyl, naphthyl, fluorenyl, substituted phenyl, substituted naphthyl, substituted fluorenyl, C 3 -C 8 Heteroaryl, phenoxy, naphthoxy, anthracenoxy, phenanthrenoxy, C 3 -C 8 Heteroaryl (C) 1 -C 20 ) Alkyl, C 2 -C 20 Alkenyl (C) 1 -C 20 ) Alkyl, C 2 -C 20 Alkynyl (C) 1 -C 20 ) Alkyl, cyano (C) 1 -C 20 ) Alkyl and C 1 -C 20 Any one of the alkyl oxycarbonyl groups; x is any one of O, S and NH;
the substituents in the substituted phenyl, the substituted naphthyl and the substituted fluorenyl are each independently selected from the group consisting of a halogen atom, C 1 -C 5 Alkyl, C 1 -C 5 At least one of an alkoxy group, a phenyl group, a phenoxy group, a nitro group, and an acyl group;
The aza-carbene catalyst is selected from tribromobenzene substituted indenol derivative triazole carbene catalyst, and the chemical structural formula of the aza-carbene catalyst is shown as follows:
Figure FDA0004131832120000021
q is boron tetrafluoride anion or chloride, R 8 Is tribromophenyl;
the alkali agent is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, 1-azabicyclo [ 2.2.2.2 ]]Octane, 1, 8-diazabicyclo [5.4.0]At least one of undec-7-ene, 1,5, 7-triazido bicyclo (4.4.0) dec-5-ene, triethylamine, diisopropylethylamine, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium diisopropylamide, n-butyllithium, tert-butyllithium, methyllithium, sodium methoxide, sodium ethoxide and sodium ethyl mercaptide, and a water removal additive selected from anhydrous sodium sulfate, anhydrous magnesium sulfate and pre-activated
Figure FDA0004131832120000022
Molecular sieves, & gt>
Figure FDA0004131832120000023
Molecular sieve,
Figure FDA0004131832120000024
The molecular sieves incorporate at least one of the 13X molecular sieves.
2. The method for preparing chiral quaternary carbon cyanide according to claim 1, wherein: the R is 1 Said R is 2 And said R 3 C being identical or different 1 -C 10 Alkyl, C 1 -C 10 Heteroalkyl, C 3 -C 10 Cycloalkyl, C 3 -C 10 Heterocycloalkyl, C 2 -C 10 Alkenyl groups、C 2 -C 10 Heteroalkenyl, C 3 -C 10 Cycloalkenyl, C 3 -C 10 Heterocycloalkenyl, C 2 -C 10 Alkynyl, C 2 -C 10 Heteroalkynyl, C 3 -C 10 Cycloalkynyl radicals, C 3 -C 10 Heterocyclic alkynyl, C 1 -C 10 Alkoxy, phenyl, naphthyl, fluorenyl, substituted phenyl, substituted naphthyl, substituted fluorenyl, C 3 -C 8 Heteroaryl, C 3 -C 8 Heteroaryl (C) 1 -C 20 ) Alkyl, C 2 -C 10 Alkenyl (C) 1 -C 10 ) Alkyl, C 2 -C 10 Alkynyl (C) 1 -C 10 ) Alkyl, cyano (C) 1 -C 10 ) Alkyl and C 1 -C 10 Any one of the alkyl oxycarbonyl groups.
3. The method for preparing chiral quaternary carbon cyanide according to claim 1, wherein: the R is 1 Is phenyl, naphthyl, fluorenyl, substituted phenyl, substituted naphthyl, substituted fluorenyl, C 3 -C 8 Heteroaryl and C 3 -C 8 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups; and/or the number of the groups of groups,
the R is 2 Is C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocycloalkynyl and C 1 -C 20 Any one of alkoxy groups; and/or the number of the groups of groups,
the R is 3 Is phenyl, naphthyl, fluorenyl, substituted phenyl, substituted naphthyl, substituted fluorenyl, C 3 -C 8 Heteroaryl and C 3 -C 8 Heteroaryl (C) 1 -C 20 ) In alkyl groupsAny one of the following.
4. A process for the preparation of chiral quaternary carbon cyanides according to claim 3, characterised in that: the R is 1 Is one of phenyl, naphthyl, fluorenyl, substituted phenyl, substituted naphthyl and substituted fluorenyl, wherein the substituents in the substituted phenyl, substituted naphthyl and substituted fluorenyl are respectively and independently selected from halogen atoms and C 1 -C 5 Alkyl, C 1 -C 5 At least one of an alkoxy group, a phenyl group, a phenoxy group, and an acyl group; and/or the number of the groups of groups,
the R is 2 Is C 1 -C 5 An alkyl group; and/or the number of the groups of groups,
the R is 3 Is one of phenyl, naphthyl, fluorenyl, substituted phenyl, substituted naphthyl and substituted fluorenyl, wherein the substituents in the substituted phenyl, substituted naphthyl and substituted fluorenyl are respectively and independently selected from halogen atoms and C 1 -C 5 Alkyl, C 1 -C 5 At least one of an alkoxy group, a phenyl group, a phenoxy group, and an acyl group.
5. The method for preparing chiral quaternary carbon cyanide according to claim 1, wherein: the mol ratio of the aza-carbene catalyst to the alkali reagent to the conjugated olefine aldehyde compound A to the cyanogen compound B is (0.1-20): 1-100: (1-100); and/or the number of the groups of groups,
the temperature of the beta-asymmetric functionalization reaction is between-80 ℃ and 35 ℃ and the time is between 6 hours and 48 hours.
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