Chiral germanium-boron compound and synthesis method thereof

Abstract

The invention provides a chiral germanium-boron compound and a synthesis method thereof, the chiral germanium-boron compound has a structure # imgabs0 # as shown in a formula I or a formula II, the chiral germanium-boron compound provided by the invention completely breaks through a specific structure of a chiral site, can be formed on a common chemical group site, significantly expands the variety of amphiphilic reagents, and has a good application prospect. The chiral germanium-boron compound prepared by the method can be widely applied to the field of synthesis of chiral compounds and has an important application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of organometallic reagents, and particularly relates to a chiral germanium-boron compound and a synthesis method thereof. Background Art

[0002] Chiral bis-nucleophiles are new reaction modules in the field of cross-coupling, providing new ideas for the modular synthesis and rapid diversification of enantiomerically enriched functional molecules.

[0003] In 2007, the Morken research group first developed chiral bis-boron reagents, which have been very popular in the fields of medicinal chemistry and materials chemistry due to their air humidity stability, low toxicity, and appropriate reactivity. However, the chemoselectivity of such reagents in cross-coupling reactions depends on reaction site regulation or protecting group strategies. (See: Morken et al. Development, Mechanism, and Scope of the Palladium-Catalyzed Enantioselective Allene Diboration. J. Am. Chem. Soc. 2007, 129, 8766 - 8773)

[0004]

[0005] Chiral hetero-bis-nucleophiles can regulate chemoselectivity and even further achieve reaction orthogonality by taking advantage of the differences in the reaction properties of different metal reagents.

[0006] In 2021, the Morken research group reported chiral zinc-boron reagents. These bis-nucleophiles exhibited excellent stereospecific reactivity and functional group compatibility. However, the reactive zinc reagents made it impossible to expose these reagents to air for separation and storage, and it was also difficult to further achieve Zn / B orthogonal cross-coupling reactions. (See: Morken et al. Enantiomerically Enriched α-Borylzinc Reagents by Nickel-Catalyzed Carbozincation of Vinylboronic Esters. J. Am. Chem. Soc. 2021, 143, 14189 - 14195)

[0007]

[0008] In 2023, the Biscoe research group reported chiral tin-boron reagents, demonstrating Sn / B orthogonal stereospecific cross-coupling. However, the chiral tin-boron reagents that can be prepared currently are limited to special benzyl molecular structures, and the potential toxicity of organotin reagents limits their application scenarios. (See: Biscoe et al. A general approach to stereospecific Pd-catalyzed cross-coupling reactions of benzylic stereocenters. Chem. Sci., 2023, 14, 14124 - 14130)

[0009]

[0010] In 2024, the Bin Xiao research group reported chiral germanium-boron dinucleophiles and studied germanium-boron orthogonal stereospecific cross-coupling. Such reagents have sufficient stability for conventional separation operations such as extraction and silica gel column chromatography. However, currently, the chiral germanium-boron reagents that can be achieved are limited to benzylic and cyclic sites. (See: Bin Xiao et al. Orthogonal sp3-Ge / B Bimetallic Modules: Enantioselective Construction and Enantiospecific Cross-Coupling. Angew. Chem. Int. Ed. 2024, e202317284)

[0011]

[0012] The development of such compounds is restricted by the sites of the reagents constructed, and the orthogonal stereospecific cross-coupling of non-activated chiral hetero-dinucleophiles has thus not been further explored. Summary of the Invention

[0013] The purpose of the present invention is to further enrich the types of germanium-boron compounds, broaden the application scope of germanium-boron compounds, and improve the applicability of germanium-boron compounds in the synthesis of chiral compounds.

[0014] To achieve the above objectives, in one aspect, the present invention provides a chiral germanium-boron compound, which is a compound having the structure shown in Formula I or Formula II as follows:

[0015]

[0016] Wherein, R1 is selected from one of H, alkyl, alkoxy-substituted alkyl, silyl, and aryl; R2 is aralkyl.

[0017] In a preferred embodiment, the alkyl group includes C1-C4 alkyl; the alkoxy-substituted alkyl is M-CH2-, where M is C m H 2m+1 O n , where m is an integer from 1 to 6, and n is 1 or 2; the silyl group is N-CH2-, where N is C x H 2x+3 Si, where x is an integer from 3 to 5; the aryl group includes phenyl and benzyl.

[0018] In a preferred embodiment, the R2 is an aralkyl group having 7 to 10 carbon atoms; preferably, the R2 is benzyl or phenylpropyl.

[0019] In a preferred embodiment, the R1 is selected from the group consisting of H, methyl, n-butyl, phenyl, benzyl,

[0020] and one of them.

[0021] In a preferred embodiment, the chiral germanium boron compound of the structures shown in Formula I and Formula II is in the S configuration, R configuration or racemic configuration.

[0022] On the other hand, the present invention also provides a method for synthesizing the above chiral germanium boron compound, comprising the following steps:

[0023] (1) Under an inert atmosphere, 1-aza-5-germa-5-bromobicyclo[3.3.3]undecane or triarylalkylgermanium bromide is added to a reactor, and a solvent, and the reaction is heated to 40-80 °C and reacted for 6-18 hours to obtain compounds of the structures shown in the following Formulas III and IV;

[0024]

[0025] Among them, when the reactant is 1-aza-5-germa-5-bromobicyclo[3.3.3]undecane, R1 is selected from the group consisting of H, methyl, n-butyl, phenyl, benzyl, and one of them, to obtain a compound of the structure shown in Formula III. When the reactant is triarylalkylgermanium bromide, R1 is H and R2 is benzyl or phenylpropyl.

[0026] (2) Under an inert atmosphere, a Cu(I) catalyst, a phosphine ligand and pinacol borane are added to a reactor, and then an organic solvent is added to dissolve the above reactants and reacted at room temperature for a certain time. Then, an alkali metal alkoxide is added and a certain amount of organic solvent is supplemented, and the reaction is continued for a certain time. Then, the compound of the structure shown in Formula III or IV obtained in step (1) is added, and after reacting for a certain time, a compound of the structure shown in Formula I or Formula II is obtained.

[0027] Among them, when the reactant added is the compound with the structure shown in Formula III, the compound with the structure shown in Formula I is obtained; when the reactant added is the compound with the structure shown in Formula IV, the compound with the structure shown in Formula II is obtained.

[0028] In a preferred embodiment, the phosphine ligand has the structure shown below:

[0029] Among them, the Ar is selected from one of them. By selecting phosphine ligands with different configurations, the configuration of the chiral carbon atoms of the finally prepared germanium boron compound can be controlled.

[0030] In a preferred embodiment, the Cu(I) catalyst in step (2) is selected from one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, and copper thiophene-2-carboxylate. Those skilled in the art know that on this basis, other common monovalent copper salts can also be used as the catalyst in the synthesis method of the germanium boron compound involved in the present invention.

[0031] In a preferred embodiment, the alkali metal alkoxide is selected from one of potassium methoxide, sodium methoxide, lithium methoxide, potassium isopropoxide, sodium isopropoxide, lithium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, and lithium tert-butoxide.

[0032] In a preferred embodiment, the solvent is selected from one of n-hexane, diethyl ether, toluene, tetrahydrofuran, and methyl tert-butyl ether.

[0033] The beneficial technical effect of the present invention is that, compared with the reported germanium boron compounds that can only form chiral sites at the benzyl position and cyclic sites, the chiral germanium boron compounds provided by the present invention completely break through the specific structure of chiral sites. Specifically, they can be formed at common sites such as common alkyl groups and aralkyl groups, expanding the chiral sites, and thus greatly expanding the types of bis-nucleophiles. The chiral germanium boron compounds provided by the present invention can be separated by common separation operations such as extraction and column chromatography, are stable under air and humidity conditions, and both germanium and boron sites can undergo stereospecific cross-coupling reactions with aryl halides. Therefore, they can be widely used in the field of chiral compound synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figures 1 to 3 They are respectively the hydrogen, carbon, and boron nuclear magnetic resonance spectra of the target product prepared in Example 1.

[0035] Figures 4 to 6 They are respectively the hydrogen, carbon, and boron nuclear magnetic resonance spectra of the target product prepared in Example 7.

[0036] Figures 7 to 9 They are respectively the hydrogen, carbon, and boron nuclear magnetic resonance spectra of the target product prepared in Application Example 1.

[0037] Figures 10 to 11 1H and 13C NMR spectra of the target product prepared in Application Example 2, respectively. Detailed implementation manners

[0038] To further understand the present invention, the non-activated chiral germanium boron compounds, synthesis methods and applications provided by the present invention will be described below in conjunction with embodiments. The protection scope of the present invention is not limited by the following embodiments.

[0039] Example 1

[0040] Preparation of compound {(S)-5-(4-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane}, and its structural formula is The specific preparation process includes the following steps:

[0041] 1) Preparation of (3-bromobut-3-en-1-yl)benzene: 30 mL (1 M) of a tetrahydrofuran solution of benzylmagnesium chloride (purchased from Anhui Zesheng Technology Co., Ltd.) was added to a tetrahydrofuran solution (6 mL) of 2,3-dibromopropene (20 mmol) (purchased from Anhui Zesheng Technology Co., Ltd.) and copper(I) chloride (2 mmol) (purchased from Anhui Zesheng Technology Co., Ltd.). The mixture was stirred at room temperature for 5 hours. After the reaction was completed, deionized water was added to quench the reaction, and the mixture was extracted with diethyl ether and ammonium chloride solution. The organic phase was retained, dried, evaporated to dryness, and purified by silica gel column chromatography (R f = 0.8) to obtain the liquid product (3-bromobut-3-en-1-yl)benzene with a yield of 52%.

[0042] 2) Preparation of 5-(4-phenylbut-1-en-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane: 15 mmol of (3-bromobut-3-en-1-yl)benzene, 20 mmol of magnesium powder, and 10 mmol of 5-bromo-1-aza-5-germabicyclo[3.3.3]undecane were stirred in 20 mL of tetrahydrofuran and reacted at 60 °C for 12 hours. After the reaction was completed, the mixture was extracted with petroleum ether and water. The organic phase was retained, dried, and evaporated to dryness to obtain the liquid product with a yield of 92%.

[0043] 3) Preparation of S-5-(4-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germanebicyclo[3.3.3]undecane: 1 mmol of cuprous thiophene-2-carboxylate (purchased from Beijing Bailingwei Technology Co., Ltd.) and 1.5 mmol of (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]-3,3'-bis(1,2-methylenedioxybenzene) (purchased from Beijing Bailingwei Technology Co., Ltd.) were weighed into a Schlenk bottle, argon was replaced on the vacuum line three times, and under an inert atmosphere, a mixture of 1% argon and 2% argon was added. 15mmol of pinacol borane (purchased from Beijing Bailingwei Technology Co., Ltd.) and 25mL of methyl tert-butyl ether (purchased from Anhui Zesheng Technology Co., Ltd.) were added. After the addition was completed, the stopcock was screwed on and allowed to react at room temperature for 5 minutes. Then, 2mmol of tert-butyl lithium alcohol (purchased from Adamas) and 25mL of methyl tert-butyl ether (purchased from Anhui Zesheng Technology Co., Ltd.) were added under an inert atmosphere. After 15 minutes of reaction at room temperature, 10mmol of 5-(4-phenylbut-1-ene-2-yl)-1-aza-5-germanium bicyclo[3.3.3]undecane was added. After the addition was completed, the stopcock was screwed on and allowed to react at room temperature for 24 hours. After the reaction was completed, it was extracted with ethyl acetate and water, the organic phase was retained, dried, spin-dried, and passed through a silica gel column (R f =0.5) to separate the product S-5-(4-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germanebicyclo[3.3.3]undecane in a yield of 80%. Figures 1 to 3 They are respectively the hydrogen, carbon and boron nuclear magnetic resonance spectra of S-5-(4-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germanebicyclo[3.3.3]undecane prepared according to Example 1 of the present invention. It can be seen from the above nuclear magnetic resonance spectra that the target compound can be successfully prepared by the above method.

[0044] Example 2

[0045] The specific steps are as in Example 1, except that anhydrous tetrahydrofuran is used instead of methyl tert-butyl ether in step 3, and the yield of the final target product is 45%.

[0046] Example 3

[0047] The specific steps are as in Example 1, except that anhydrous ether is used instead of methyl tert-butyl ether in step 3, and the yield of the final target product is 70%.

[0048] Example 4

[0049] For the specific steps, refer to Example 1. The difference is that potassium tert-butoxide is used instead of lithium tert-butoxide in Step 3, and the yield of the final target product is 60%.

[0050] Example 5

[0051] For the specific steps, refer to Example 1. The difference is that lithium methoxide is used instead of lithium tert-butoxide in Step 3, and the yield of the final target product is 12%.

[0052] Example 6

[0053] For the specific steps, refer to Example 1. The difference is that the dosage of (R)-(-)-4,4'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bis(1,2-methylenedioxyphenyl) in Step 3 is changed to 1 mmol, and the yield of the final target product is 58%.

[0054] Example 7

[0055] For the specific steps, refer to Example 1. The difference is that Step 1 is omitted, and 2-bromopropene is used instead of (3-bromobut-3-en-1-yl)benzene in Step 2. The final product obtained is (S)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane. The structure is shown in The yield is 84%. Figures 4 to 6 They are the hydrogen, carbon, and boron nuclear magnetic resonance spectra of S-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane prepared according to Example 7 of the present invention, respectively.

[0056] Example 8

[0057] For the specific steps, refer to Example 1. The difference is that Step 1 is omitted, and 2-bromobutene is used instead of (3-bromobut-3-en-1-yl)benzene in Step 2. The final product obtained is (S)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane. The specific chemical formula structure is The yield is 57%.

[0058] Example 9

[0059] For the specific steps, refer to Example 1. The difference is that phenylmagnesium chloride is used instead of benzylmagnesium chloride in Step 1, and the finally obtained product is (S)-5-(1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane, and the specific chemical formula structure is The yield is 47%.

[0060] Example 10

[0061] For the specific steps, refer to Example 1. The difference is that n-butylmagnesium chloride is used instead of benzylmagnesium chloride in Step 1, and the finally obtained product is (S)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)heptan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane, and the specific chemical formula structure is The yield is 66%.

[0062] Example 11

[0063] For the specific steps, refer to Example 1. The difference is that (3-methoxypropyl)magnesium chloride is used instead of benzylmagnesium chloride in Step 1, and the finally obtained product is (S)-5-(6-methoxy-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane, and the specific chemical formula structure is The yield is 61%.

[0064] Example 12

[0065] For the specific steps, refer to Example 1. The difference is that (2-(trimethylsilyl)ethyl)magnesium chloride is used instead of benzylmagnesium chloride in Step 1, and the finally obtained product is (S)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trimethylsilyl)butan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane, and the specific chemical formula structure is The yield is 54%

[0066] Example 13

[0067] For the specific steps, refer to Example 1. The difference is that (2-(1,3-dioxan-2-yl)ethyl)magnesium chloride is used instead of benzylmagnesium chloride in Step 1, and the finally obtained product is (S)-5-(5-(1,3-dioxan-2-yl)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane, and the specific chemical formula structure is The yield is 49%.

[0068] Example 14

[0069] For the specific steps, refer to Example 1. The difference is that Step 1 is omitted, 2-bromopropene is used to replace (3-bromobut-3-en-1-yl)benzene in Step 2, and tris(3-phenylpropyl)bromogermane is used to replace 5-bromo-1-aza-5-germabicyclo[3.3.3]undecane in Step 2. The finally obtained product is (S)-tris(3-phenylpropyl)(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)germane, and the specific chemical formula structure is The yield is 50%.

[0070] Example 15

[0071] For the specific steps, refer to Example 1. The difference is that Step 1 is omitted, 2-bromopropene is used to replace (3-bromobut-3-en-1-yl)benzene in Step 2, and tribenzylbromogermane is used to replace 5-bromo-1-aza-5-germabicyclo[3.3.3]undecane in Step 2. The finally obtained product is (S)-tribenzyl(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)germane, and the specific chemical formula structure is The yield is 84%.

[0072] Application Example 1

[0073] An application example of the germanium site in the compound {(S)-5-(4-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane} prepared in Example 1 acting as a nucleophile to carry out a coupling reaction with an aryl compound while the boron site is retained. The chemical structural formula of the target compound finally obtained in this application example is The specific preparation process includes the following steps:

[0074] 1) Preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propionate: 30 mmol of (tert-butoxycarbonyl)tyrosine methyl ester (purchased from Anhui Zesheng Technology Co., Ltd.), 60 mmol of trifluoromethanesulfonic anhydride (purchased from Anhui Zesheng Technology Co., Ltd.), and 60 mmol of pyridine (purchased from Anhui Zesheng Technology Co., Ltd.) are mixed in 60 mL of dichloromethane and stirred at zero degree for 2 hours. After the reaction is completed, it is extracted with ethyl acetate and water, the organic phase is retained, dried, concentrated by rotary evaporation, and separated by silica gel column chromatography with n-hexane / ethyl acetate 10:1 (R f = 0.4) to obtain the product, and the yield is 42%.

[0075] 2) Weigh 1 mmol of S-5-(4-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane, 1.3 mmol of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propionate, 0.03 mmol of tris(dibenzylideneacetone)dipalladium(0) (purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.), 0.12 mmol of bis(3,5-bis(trifluoromethyl)phenyl)(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-YL)phosphine (Shanghai Tengzhun Biotechnology Co., Ltd.), 2 mmol of potassium fluoride (purchased from Adamas), and 2 mmol of copper(I) chloride (purchased from Anhui Zesheng Technology Co., Ltd.) into a Schlenk flask. Flush and replace with argon three times on the vacuum line. Under an inert atmosphere, add 6 mL of acetonitrile to it. After the addition, screw on the stopper and place it in an oil bath at 120 °C for reaction for 20 hours. After the reaction, extract with ethyl acetate and water, retain the organic phase, dry, evaporate to dryness, and separate by silica gel column chromatography with n-hexane / ethyl acetate 8:1 to obtain the product with a yield as high as 72%. Figures 7 to 9 1H, 13C, and 11B NMR spectra of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)phenyl)propionate prepared according to this application example, respectively. Through the above spectra, it can be confirmed that the target product was successfully prepared, indicating that the germanium-boron compound prepared in the present invention can well maintain the chiral site to participate in the reaction. The specific reaction equation is shown as follows.

[0076]

[0077] Application Example 2

[0078] An application example of the coupling reaction of the compound {(R)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane} as a nucleophile with aryl halides. The chemical structural formula of the target compound finally obtained in this application example is This compound is a key intermediate for the synthesis of physiologically active molecules (TAAR1 agonists) (see: Guido Galley et al. Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists. ACS Medicinal Chemistry Letters 2016 7(2), 192-197). The specific preparation process of the target compound includes the following steps:

[0079] 1) Preparation of 5-(but-1-en-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane: 15 mmol of 2-bromobut-1-ene (purchased from Anhui Zesheng Technology Co., Ltd.), 20 mmol of magnesium powder (Sinopharm), and 10 mmol of 5-bromo-1-aza-5-germabicyclo[3.3.3]undecane were stirred in 20 mL of tetrahydrofuran and reacted at 60 °C for 12 hours. After the reaction, it was extracted with petroleum ether and water, the organic phase was retained, dried, and concentrated to dryness to obtain a liquid product with a yield of 95%.

[0080] 2) Preparation of (R)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germanebicyclo[3.3.3]undecane: 1 mmol of cuprous thiophene-2-carboxylate (Beijing Bailingwei Technology Co., Ltd.) and 1.5 mmol of (S)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]-3,3'-bis(1,2-methylenedioxybenzene) (Beijing Bailingwei Technology Co., Ltd.) were weighed into a Schlenk bottle, and argon was replaced on the vacuum line three times. 15 mmol of pinacol borane (Beijing Bailingwei Technology Co., Ltd.) and 25 mL of methyl tert-butyl ether (purchased from Anhui Zesheng Technology Co., Ltd.) were added thereto. After the addition was completed, the stopcock was screwed on and the reaction was allowed to proceed at room temperature for 5 minutes. Then, 2 mmol of tert-butyl lithium alcohol (Adamas) and 25 mL of methyl tert-butyl ether (purchased from Anhui Zesheng Technology Co., Ltd.) were added under an inert atmosphere. After the reaction was carried out at room temperature for 15 minutes, 5-(but-1-en-2-yl)-1-aza-5-germanebicyclo[3.3.3]undecane was added. After the addition was completed, the stopcock was screwed on and the reaction was allowed to proceed at room temperature for 24 hours. After the reaction, the mixture was extracted with ethyl acetate and water, the organic phase was retained, dried, and spin-dried. The product (R)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germanebicyclo[3.3.3]undecane was separated with a ratio of 50:1 of n-hexane / ethyl acetate to obtain the product (R)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germanebicyclo[3.3.3]undecane. The yield was 47%. The specific chemical structure is

[0081] 3) Weigh 1 mmol of (R)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane, 1.3 mmol of bromobenzene (purchased from Anhui Zesheng Technology Co., Ltd.), 0.03 mmol of tris(dibenzylideneacetone)dipalladium(0) (Shanghai Bide Pharmaceutical Technology Co., Ltd.), 0.12 mmol of bis(3,5-bis(trifluoromethyl)phenyl)(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-YL)phosphine (purchased from Shanghai Tengzhun Biotechnology Co., Ltd.), 2 mmol of potassium fluoride (Adamas), and 2 mmol of copper(I) chloride (purchased from Anhui Zesheng Technology Co., Ltd.) into a Schlenk flask. Flush and replace with argon three times on the vacuum line. Under an inert atmosphere, add 6 mL of acetonitrile to it. After the addition, screw on the stopper and place it in an oil bath at 120 °C for reaction for 20 hours. After the reaction, evaporate the solvent. Then add 10 mmol of sodium hydroxide (purchased from Anhui Zesheng Technology Co., Ltd.), 10 mL of tetrahydrofuran, 6 mL of distilled water, and 6 mL of 6% hydrogen peroxide solution, and react at room temperature for 2 hours. After the reaction, extract with ethyl acetate and water, retain the organic phase, dry, evaporate, and pass through a silica gel column with n-hexane / ethyl acetate at a ratio of 5:1 (Rf = 0.6) to obtain the product with a yield of 52%. Figures 10 to 11 They are the hydrogen and carbon nuclear magnetic resonance spectra of (R)-2-phenylbutan-1-ol prepared according to this application example. Through the above spectra, it can be confirmed that the target product has been successfully prepared, indicating that the germanium-boron compound prepared by the present invention can well maintain the chiral site to participate in the reaction. The specific reaction equation is shown as follows.

[0082]

[0083] Application Example 3

[0084] An application example of using the boron site in the compound {(S)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-1-aza-5-germabicyclo[3.3.3]undecane} in Example 7 as a nucleophile to carry out a coupling reaction with an aryl halide compound and retaining the germanium site in the germanium-boron compound. The chemical structural formula of the target compound finally obtained in this application example is

[0085] i) Preparation of 1-bromo-3-(1-phenylvinyl)benzene: Under an argon atmosphere, 22 mmol of triphenylmethylphosphine bromide (purchased from Anhui Zesheng Technology Co., Ltd.) was dissolved in 80 mL of anhydrous tetrahydrofuran in a Schlenk bottle, the Schlenk bottle was cooled to -78 degrees, and then 20 mmol of n-butyl lithium in hexane solution (2.4 M) (purchased from Anhui Zesheng Technology Co., Ltd.) was slowly added dropwise, and the reaction was carried out at room temperature for 30 minutes, and then 10 mmol of 3-bromobenzophenone (purchased from Anhui Zesheng Technology Co., Ltd.) was dissolved in 10 mL of anhydrous tetrahydrofuran at -78 degrees and added. Then, the reaction was allowed to react overnight at room temperature, the reaction was quenched with saturated ammonium chloride, the reaction solution was extracted with hexane, the organic phase was dried with anhydrous sodium carbonate, the organic phase solvent was removed, and petroleum ether was used as a developing solvent (R f =0.8) was subjected to column chromatography to obtain 1-bromo-3-(1-phenylvinyl)benzene in a yield of 62%.

[0086] ii) 0.1 mmol of palladium acetate (purchased from Anhui Zesheng Technology Co., Ltd.), 0.1 mmol of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (Shanghai Bide Pharmaceutical Technology Co., Ltd.), and 5 mmol of sodium hydroxide (purchased from Anhui Zesheng Technology Co., Ltd.) were weighed into a Schlenk bottle, and argon gas was replaced three times on the vacuum line. Under an inert atmosphere, 3.4 mL of toluene was added thereto. After the addition was completed, the stopcock was screwed on and the reaction was carried out at room temperature for 30 minutes. Subsequently, 1-bromo-3-(1-phenylvinyl)benzene 1.5 mmol, S-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-1-aza-5-germanebicyclo[3.3.3]undecane 1 mmol, 3.4 mL of toluene and 1.7 mL of distilled water were added under an argon atmosphere. After the addition was completed, the stopcock was screwed on and the reaction was carried out in an oil bath at 100 degrees for 26 hours. After the reaction is completed, the mixture is extracted with ethyl acetate and water, the organic phase is retained, dried, and spin-dried, and the product is separated by passing through a silica gel column (Rf=0.9) with n-hexane, with a yield of up to 98%. The specific reaction equation is shown below.

[0087]

[0088] Through the specific application of the above Examples 1-3, it can be found that, on the one hand, the germanium site of the germanium boron compound prepared by the present invention has a good chiral retention ability, and the boron site can also decide whether to participate in the nucleophilic reaction according to actual needs. Therefore, the germanium boron compound designed by the present invention has very good application flexibility, which greatly improves the application scenarios of such compounds.

[0089] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A chiral germanium boron compound, characterized in that, A compound having the structure shown in Formula I or Formula II as follows: wherein, R1 is selected from one of H, alkyl, alkoxy-substituted alkyl, silyl, and aryl; R2 is aralkyl.

2. The chiral germanium boron compound according to claim 1, characterized in that: the alkyl includes C1-C4 alkyl; The alkoxy-substituted alkyl is M-CH2-, where M is C m H 2m+1 O n , where m is an integer from 1 to 6, and n is 1 or 2; The silyl group is N-CH2-, where N is C x H 2x+3 Si, where x is an integer from 3 to 5; the aryl includes phenyl and benzyl.

3. The chiral germanium boron compound according to claim 1, wherein R2 is aralkyl with 7-10 carbon atoms; preferably, R2 is benzyl or phenylpropyl.

4. The chiral germanium boron compound according to claim 1, wherein The R1 is selected from one of H, methyl, n-butyl, phenyl, benzyl, and the like.

5. The chiral germanium boron compound according to any one of claims 1-4, characterized in that, The chiral germanium boron compound shown in Formula I and Formula II is in S configuration, R configuration or racemic configuration.

6. A method for synthesizing a chiral germanium boron compound as described in any one of claims 1-5, characterized in that, Comprising the following steps: (1) Under an inert atmosphere, 1-aza-5-germa-5-bromobicyclo[3.3.3]undecane or triarylgermyl bromide and a solvent are added to a reactor, and the reaction is heated to 40-80 °C and then reacted for 6-18 hours to obtain compounds having the structures shown in the following formulas III and IV; and a solvent, heat the reaction to 40 - 80 °C and react for 6 - 18 hours to obtain compounds with the structures shown in the following formulas III and IV; Among them, when the reactant is 1-aza-5-germa-5-bromobicyclo[3.3.3]undecane, R1 is selected from one of H, methyl, n-butyl, phenyl, benzyl, to obtain the compound with the structure shown in Formula III. When the reactant is triarylalkylgermyl bromide, R1 is H and R2 is benzyl or phenylpropyl; (2) Under an inert atmosphere, add a Cu(I) catalyst, a phosphine ligand and pinacol borane into a reactor, then add an organic solvent to dissolve the above reactants and react at room temperature for a certain time, then add an alkali metal alkoxide and supplement a certain amount of organic solvent and continue to react for a certain time, and then add the compound shown in Formula III or Formula IV obtained in step (1), and after reacting for a certain time, a compound shown in Formula I or Formula II is obtained; wherein, when the added reactant is the compound shown in Formula III, the compound shown in Formula I is obtained, and when the added reactant is the compound shown in Formula IV, the compound shown in Formula II is obtained.

7. The method for synthesizing the chiral germanium boron compound according to claim 6, wherein The phosphine ligand has the structure shown as follows: and / or wherein, the Ar is selected from one of them.

8. The method for synthesizing the chiral germanium boron compound according to claim 6, wherein, The Cu(I) catalyst in step (2) is selected from one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, and copper thiophene-2-carboxylate.

9. The synthesis method of the chiral germanium boron compound according to claim 6, wherein, The alkali metal alkoxide is selected from one of potassium methoxide, sodium methoxide, lithium methoxide, potassium isopropoxide, sodium isopropoxide, lithium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, and lithium tert-butoxide.

10. The synthesis method of the chiral germanium boron compound according to claim 6, characterized in that, The solvent is selected from one of n-hexane, ether, toluene, tetrahydrofuran, and methyl tert-butyl ether.

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