阅读说明：本技术 一种含开链手性季碳中心类化合物及其制备方法 (Compound containing open-chain chiral quaternary carbon center and preparation method thereof ) 是由 余达刚 陈小旺 李静 蓝宇 朱磊 贵永远 敬科 蒋元旭 伯知豫 于 2019-11-21 设计创作，主要内容包括：本发明公开了一种含开链手性季碳中心类化合物及其制备方法,本发明利用二氧化碳参与1,1-二取代1,3二烯的催化不对称官能化来实现开链手性季碳中心的高效高选择性构建。本发明方法原料易得、条件温和、得到的产物易于衍生转化。为手性药物创制提供可供选择的新途径,也为二氧化碳的高效利用提供新思路。(The invention discloses a compound containing an open-chain chiral quaternary carbon center and a preparation method thereof, and the compound is used for realizing the efficient and high-selectivity construction of the open-chain chiral quaternary carbon center by using carbon dioxide to participate in the catalytic asymmetric functionalization of 1, 1-disubstituted 1,3 diene. The method has the advantages of easily obtained raw materials, mild conditions and easily derived and converted obtained products. Provides an alternative new way for the creation of chiral drugs and also provides a new idea for the efficient utilization of carbon dioxide.)

1. A preparation method of compounds containing open-chain chiral quaternary carbon centers is characterized by comprising the following steps: 1, 1-disubstituted 1, 3-dienes compound and CO₂In the presence of a copper catalyst, a chiral ligand, a silaneIn the presence of (A) in a solvent to obtain the product; wherein the reaction temperature is 50-65 ℃ and the reaction time is 8-12 h.

2. The preparation method of the compound containing the open-chain chiral quaternary carbon center according to claim 1, which comprises the following steps: 1-aryl-1-alkyl substituted 1, 3-dienes or 1, 1-dialkyl substituted 1, 3-dienes with CO₂Reacting in a solvent in the presence of a copper catalyst, a chiral ligand and silane to obtain the product; the reaction formula is as follows:

wherein R is₁Is aryl, hydrogen, alkyl, halogen, methoxy, trifluoromethyl, trifluoromethoxy, methylmercapto, morpholine, ester group and derivatives thereof; r₂Is alkyl, benzocycloalkyl and derivatives thereof; r₃H and methyl; r₄Are heteroaryl, alkyl, alkenyl and derivatives thereof.

3. The preparation method of the compound containing the open-chain chiral quaternary carbon center according to claim 2, characterized in that: the alkyl is straight-chain alkyl, branched-chain alkyl, cycloalkyl or long-chain alkyl containing alkenyl with 1-41 carbon atoms; the aryl group is an aryl group having 6 to 20 carbon atoms; the heteroaryl group is a heteroaryl group having 6 to 20 carbon atoms; the alkenyl group is an alkenyl group having 6 to 41 carbon atoms.

4. The preparation method of the compound containing the open-chain chiral quaternary carbon center according to claim 1, characterized in that: the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the copper catalyst is 18-22:1, the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the ligand is 15-18:1, and the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the silane is 1: 6-9.

5. The method for preparing the compound containing the open-chain chiral quaternary carbon center according to claim 4, wherein: the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the copper catalyst is 20:1, the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the ligand is 16.6:1, and the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the silane is 1: 8.

6. The preparation method of the compound containing the open-chain chiral quaternary carbon center according to claim 1, characterized in that: the copper catalyst is copper acetate, cuprous mesitylene, cuprous thiophene-2-formate or copper tetraacetonitrile tetrafluoroborate.

7. The preparation method of the compound containing the open-chain chiral quaternary carbon center according to claim 1, characterized in that: the chiral ligand is (R) - (-) -5,5 '-bis [ di (3, 5-di-tert-butyl-4-methoxyphenyl) phosphorus ] -4,4' -di-1, 3-benzodioxane, (S) -binaphthyl (3, 5-xylyl) phosphine, (R) - (+) - (6,6 '-dimethoxybiphenyl-2, 2' -yl) bis (diphenylphosphine), Josiphos-SL-J007-1, (+) -1, 13-bis (diphenyl) phosphine (5aR,8aR,14aR) -5a,6,7,8,8a, 9-hexahydro-5H- [1] benzopyrano [3,2-D ] xanthene, (+) -1, 2-bis ((2S,5S) -2, 5-diphenylphosphine) ethane or (-) -1, 2-bis ((2R,5R) -2, 5-dimethylphosphite) benzene.

8. The preparation method of the compound containing the open-chain chiral quaternary carbon center according to claim 1, characterized in that: the silane is methyldimethoxysilane, methyldiethoxysilane, triethoxysilane, or polymethylpolysiloxane; the solvent is cyclohexane, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate or N, N-dimethylformamide.

9. The compound containing open-chain chiral quaternary carbon center prepared by the method of any one of claims 1-8, and has the structural general formula:

wherein R is₁Is aryl, hydrogen,Alkyl, halogen, methoxy, trifluoromethyl, trifluoromethoxy, methylmercapto, morpholine, ester group and derivatives thereof; r₂Is alkyl, benzocycloalkyl and derivatives thereof; r₃H and methyl; r₄Is heteroaryl, alkyl, alkenyl and derivatives thereof; the alkyl is straight-chain alkyl, branched-chain alkyl, cycloalkyl or long-chain alkyl containing alkenyl with 1-41 carbon atoms; the aryl group is an aryl group having 6 to 20 carbon atoms; the heteroaryl group is a heteroaryl group having 6 to 20 carbon atoms; the alkenyl group is an alkenyl group having 6 to 41 carbon atoms.

10. The use of the compound containing an open-chain chiral quaternary carbon center of claim 9 in the preparation of chiral drugs.

Technical Field

The invention belongs to the technical field of organic chemistry, and particularly relates to a compound containing an open-chain chiral quaternary carbon center and a preparation method thereof.

Background

The chiral quaternary carbon center widely exists in natural products and drug molecules, and has important influence on the physiological activity of the natural products and the metabolic stability of the drug molecules. Although numerous asymmetric catalytic processes have been established to date, the construction of multifunctional substituted chiral quaternary carbon centers by direct carbon-carbon bonding remains a hotspot and difficulty in the field of organic synthesis. The reason for this is that the sharp increase in steric hindrance when synthesizing quaternary carbon chiral centers makes the reaction necessary to overcome higher energy barriers. At the same time, the resulting four carbon atom-substituted carbon atom centers are highly sterically crowded, which makes the construction of quaternary carbon centers a kinetically and thermodynamically unfavorable process. On the other hand, for an open-chain chiral quaternary carbon center, four different carbon atom substituents have a higher degree of freedom in space, which makes the construction of an open-chain chiral quaternary carbon center more difficult. Furthermore, the methods of construction of chiral quaternary carbon centers that have been developed are mostly completely dependent on the use of fine chemicals. Therefore, there is a need to develop a highly atomic and highly economic synthetic method for chiral quaternary carbon centers using inexpensive and readily available non-processed industrial raw materials.

In recent years, 1, 3-dienes have received great attention from the academic and industrial circles of organic synthesis due to their readily available raw materials and reaction diversity. Recently, the construction of tertiary chiral centers by asymmetric functionalization of 1, 3-dienes has been extensively studied. However, the construction of open-chain chiral quaternary carbon centers is carried out by asymmetric functionalization of 1, 3-dienes, and only 1 case is successful in achieving the construction of open-chain chiral quaternary carbon centers by iridium-catalyzed asymmetric functionalization of 1, 3-dienes with highly reactive formaldehyde generated in situ. However, asymmetric functionalization of other inert carbon compounds with 1,3 dienes to build open-chain chiral quaternary carbon centers has not been developed.

Carbon dioxide is a common greenhouse gas, and is widely applied to synthesis of various chemicals with high added values as a carbon resource which is rich in reserves, cheap, easy to obtain, non-toxic and renewable. However, the efficient use of carbon dioxide, particularly in the synthesis of chiral molecules in which carbon dioxide is involved, remains a significant challenge due to its high stability. The asymmetric conversion of carbon dioxide, especially the catalytic asymmetric carbon-carbon bond formation of carbon dioxide, is a great difficulty in the chemical and chemical synthesis field.

Disclosure of Invention

The invention aims to: aiming at the defects in the prior art, provides a compound containing an open-chain chiral quaternary carbon center and a preparation method thereof.

The technical scheme adopted by the invention is as follows:

a preparation method of compounds containing open-chain chiral quaternary carbon centers comprises the following steps: 1, 1-disubstituted 1, 3-dienes compound and CO₂Reacting in a solvent in the presence of a copper catalyst, a chiral ligand and silane to obtain the product; wherein the reaction temperature is 50-65 ℃ and the reaction time is 8-12 h.

Further, the method specifically comprises the following steps: 1-aryl-1-alkyl substituted 1, 3-dienes or 1, 1-dialkyl substituted 1, 3-dienes with CO₂Reacting in a solvent in the presence of a copper catalyst, a chiral ligand and silane to obtain the product; the reaction formula is as follows:

wherein R is₁Is aryl, hydrogen, alkyl, halogen, methoxy, trifluoromethyl, trifluoromethoxy, methylmercapto, morpholine, ester group and derivatives thereof; r₂Is alkyl, benzocycloalkyl and derivatives thereof; r₃H and methyl; r₄Is heteroaryl, alkylAlkyl, alkenyl and derivatives thereof.

Further, the alkyl group is a straight-chain alkyl group, a branched-chain alkyl group, a cyclic alkyl group, a long-chain alkyl group containing an alkenyl group, having 1 to 41 carbon atoms; aryl is an aryl group having 6 to 20 carbon atoms; heteroaryl is heteroaryl having 6 to 20 carbon atoms; alkenyl is alkenyl having 6 to 41 carbon atoms. Preferably, the alkyl group is a straight-chain alkyl group, a branched-chain alkyl group, a cyclic alkyl group, a long-chain alkyl group containing an alkenyl group, having 1 to 15 carbon atoms; aryl is an aryl group having 6 to 15 carbon atoms; heteroaryl is heteroaryl having 6 to 15 carbon atoms; alkenyl is alkenyl having 6 to 15 carbon atoms.

Further, the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the copper catalyst is 18-22:1, and the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the ligand is 15-18:1, and the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the silane is 1: 6-9.

Further, the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the copper catalyst is 20:1, the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the ligand is 16.6:1, and the molar ratio of the 1, 1-disubstituted 1, 3-diene compound to the silane is 1: 8.

Further, the copper catalyst is copper acetate, cuprous mesitylene, cuprous thiophene-2-formate or copper tetraacetonitrile tetrafluoroborate; preferably copper acetate.

Further, the chiral ligand is (R) - (-) -5,5 '-bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphorus ] -4,4' -di-1, 3-benzodioxane, (S) -binaphthyl (3, 5-xylyl) phosphine, (R) - (+) - (6,6 '-dimethoxybiphenyl-2, 2' -yl) bis (diphenylphosphine), Josiphos-SL-J007-1, (+) -1, 13-bis (diphenyl) phosphine (5aR,8aR,14aR) -5a,6,7,8,8a, 9-hexahydro-5H- [1] benzopyrano [3,2-D ] xanthene, (+) -1, 2-bis ((2S,5S) -2, 5-diphenylphosphino) ethane or (-) -1, 2-bis ((2R,5R) -2, 5-dimethylphosphite) benzene; preferably, (+) -1, 2-bis ((2S,5S) -2, 5-diphenylphosphino) ethane.

Further, the silane is methyldimethoxysilane, methyldiethoxysilane, triethoxysilane, or polymethylpolysiloxane, preferably methyldimethoxysilane; the solvent is cyclohexane, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate or N, N-dimethylformamide, preferably cyclohexane.

The compound containing the open-chain chiral quaternary carbon center prepared by the method has the structural general formula:

wherein R is₁Is aryl, hydrogen, alkyl, halogen, methoxy, trifluoromethyl, trifluoromethoxy, methylmercapto, morpholine, ester group and derivatives thereof; r₂Is alkyl, benzocycloalkyl and derivatives thereof; r₃H and methyl; r₄Is heteroaryl, alkyl, alkenyl and derivatives thereof; the alkyl is straight-chain alkyl, branched-chain alkyl, cycloalkyl or long-chain alkyl containing alkenyl with 1-41 carbon atoms; aryl is an aryl group having 6 to 20 carbon atoms; heteroaryl is heteroaryl having 6 to 20 carbon atoms; alkenyl is alkenyl having 6 to 41 carbon atoms.

Further, the specific structural formula of the compound containing the open-chain chiral quaternary carbon center is as follows:

the compound containing the open-chain chiral quaternary carbon center is applied to the preparation of chiral drugs.

In the preparation of compoundsWhen the benzene ring in the substrate has a substituent, phenyl, alkyl, methoxy, trifluoromethyl, trifluoromethoxy, methylmercapto, morpholine, ester group and halogen substituted substrate with various electric substitutions of ortho, meta and para can obtain corresponding products with good yield and very high enantioselectivity. For naphthalene ring substituted 1, 3-diene compounds, both 1-position and 2-position can be reacted smoothlyThe method is carried out conveniently. When R is in the handle₂When the compound is replaced by a more hindered ethyl, n-butyl, isobutyl or a tetrahydronaphthalene, indane and other substrates with rigid frameworks, the compound also shows good reactivity. In addition, substrates for heteroaromatic rings: the ferrocene, piperonyl, thiophene, pyridine and indole can also obtain target products with better yield and excellent enantioselectivity. When 1,1, 4-trisubstituted intramolecular 1, 3-dienes are used as substrates, the corresponding products are also obtained in excellent yields and very high enantioselectivities.

Compound (I)

The preparation method of (3) is the same as the above preparation method. Except that the starting materials were changed from a 1 aryl-1-alkyl substituted 1,3 diene to a 1, 1-dialkyl substituted 1,3 diene.

In preparing the compound, when R is in the substrate₄When the substituent on the benzene ring is methoxy, trifluoromethyl or halogen, the homoallylic alcohol compound containing the open-chain chiral quaternary carbon center can be obtained with better to excellent yield, trans-selectivity and excellent enantioselectivity. When R is₄Substituents such as phenethyl, methylcyclohexane, linear hydroxyl, etc. which are more flexible, also react well. When R is₄In the case of heterocycles, such as piperonyl and indole, the products are also obtained with excellent chiral control. When R is₄In the case of bulky sterically hindered groups such as benzhydryl, adamantane, the corresponding products can also be obtained with extremely excellent yields, trans-selectivities and corresponding selectivities. In addition, when R is₄In the case of cyclohexene conjugated with 1,3 dienes, good results were also obtained. The reaction was shown to have excellent regioselectivity. A series of 1, 1-dialkyl substituted 1,3 dienes derived simply from natural open chain terpenoids (geraniol, nerol, farnesol, solanesol, etc.) also gave very good results.

The mechanism of the method of the invention is as follows:

the secondary allyl copper intermediate INT2 is obtained by carrying out high-enantioselective 1,2 addition on 1, 1-disubstituted 1,3 diene through a copper hydrogen substance INT 1. The allylic copper intermediate INT2 is then passed through a six-membered ring transition with carbon dioxide to afford the copper carboxylate intermediate INT 3. The silane is then transmetallized with the copper carboxylate intermediate INT3 to give the silicon carboxylate intermediate INT4 and the copper hydride species INT1 is regenerated to complete the first catalytic cycle.

Copper hydrogen substance INT1 is added to carboxylic silicon ester intermediate INT4 to obtain alkoxy copper intermediate INT5, then alkoxy copper intermediate INT5 is subjected to copper β -O elimination to obtain aldehyde intermediate INT7 and silicon oxygen copper intermediate INT6, then silicon oxygen copper intermediate INT6 is subjected to transmetallation with silane to obtain disiloxane, and the regenerated copper hydrogen substance completes a second catalytic cycle.

And adding the copper hydrogen substance INT1 and an aldehyde intermediate INT7 to obtain an alkoxy copper intermediate INT 8. Subsequent transmetalation of the alkoxy copper intermediate INT8 with silane affords the homoallylic silyl ether intermediate INT9 and regeneration of the copper hydride species completes the third catalytic cycle. Finally, desiliconizing intermediate INT9 with a solution of saturated ammonium fluoride in methanol yields a homoallyl alcohol product containing a chiral quaternary carbon center. The specific reaction process is as follows:

in summary, due to the adoption of the technical scheme, the invention has the beneficial effects that:

1. the invention realizes the high-efficiency construction of compounds containing open-chain chiral quaternary carbon centers under mild conditions;

2. the synthesis method of the invention utilizes inert carbon dioxide as a carbon-carbon synthon, and has certain academic value and economic environmental significance;

3. the invention has the advantages of high chemical, regional, cis-trans and enantioselectivity, wide substrate range, good functional group compatibility, easy amplification, later derivative transformation and the like for the synthesis of chiral quaternary carbon center compounds, and lays a solid foundation for the potential application of the chiral quaternary carbon center compounds in the fields of chiral drug creation and materials.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.