Method for synthesizing heterocyclic skeleton containing chiral tertiary alcohol through asymmetric reaction

Abstract

The invention relates to the technical field of asymmetric organic synthesis, in particular to a method for synthesizing a heterocyclic skeleton containing chiral tertiary alcohol through asymmetric reaction, which comprises the following steps: acquiring structural information of a substrate to be reacted and combination information of a nickel catalyst and a chiral ligand; optimizing an electronic environment of a key reaction site in the substrate to be reacted according to the combination information of the nickel catalyst and the chiral ligand, and obtaining optimized reaction activity information; controlling the selectivity of the asymmetric cyclization reaction according to the reaction activity information so as to construct a chiral tertiary alcohol heterocyclic ring containing tetra-substituted olefin; the chiral tertiary alcohol heterocyclic structure containing the tetra-substituted olefin is efficiently and highly selectively constructed, and the chiral tertiary alcohol heterocyclic structure has important application value in drug synthesis and related fields.

Description

Technical Field

[0001] This invention relates to the field of asymmetric organic synthesis technology, specifically to an asymmetric reaction synthesis method containing a chiral tertiary alcohol heterocyclic skeleton. Background Technology

[0002] Heterocyclic skeletons containing chiral tertiary alcohols are important structural units in many organic compounds and are widely found in natural products and chiral drug derivatives. For example, (+)-Varitriol, a compound isolated from marine strains, exhibits significant cytotoxicity against various cancer cell lines; Jaspine B, extracted from sponges, has a strong inhibitory effect on melanoma cells; and (+)-Burseran, a lignan isolated from plants of the genus *Ceratophyllum*, possesses antitumor activity. Furthermore, L-proline, as a natural cyclic chiral amino acid, and its derivatives are widely used as chiral ligands in asymmetric synthesis, while Hygrine is a drug molecule with sedative effects. These compounds and their analogues generally exhibit broad biological activities and play an important role in drug development. Therefore, developing an efficient and universal synthetic method to construct heterocyclic skeletons containing chiral tertiary alcohols has significant scientific and practical value.

[0003] However, existing synthetic methods still face numerous challenges in constructing chiral tertiary alcohol heterocycles containing tetrasubstituted alkenes. Traditional methods typically rely on multi-step reactions or the use of expensive and complex catalysts, resulting in low synthetic efficiency, high cost, and difficulty in achieving highly selective construction of target molecules. Furthermore, existing technologies also have limitations in substrate applicability, failing to meet the demands of diverse synthesis. These issues restrict the further application of related compounds in drug development and materials science.

[0004] To address the aforementioned problems, this invention proposes a nickel-catalyzed asymmetric cyclization reaction strategy, which utilizes an inexpensive and readily available nickel catalyst with a chiral monophosphine ligand (such as... S The synergistic effect of β-BI-DIME enables the efficient and highly selective construction of chiral tertiary alcohol heterocycles containing tetrasubstituted alkenes. This method not only exhibits excellent stereoselectivity and substrate universality but also significantly simplifies synthetic steps and reduces production costs, providing strong technical support for the development of novel drug molecules and functional materials. Summary of the Invention

[0005] The purpose of this invention is to provide an asymmetric reaction method for synthesizing chiral tertiary alcohol heterocyclic skeletons, achieving efficient and highly selective construction of chiral tertiary alcohol heterocyclic structures containing tetrasubstituted alkenes, which has important application value in drug synthesis and related fields.

[0006] The objective of this invention can be achieved through the following technical solutions: An asymmetric reaction synthesis method for a chiral tertiary alcohol heterocyclic skeleton includes the following steps: Obtain structural information of the reaction substrate and information on the combination of nickel catalyst and chiral ligand; Based on the combination information of the nickel catalyst and the chiral ligand, the electronic environment of the key reaction sites in the substrate to be reacted is optimized, and the optimized reaction activity information is obtained. Based on the reactivity information, the selectivity of the asymmetric cyclization reaction is controlled to construct a chiral tertiary alcohol heterocycle containing a tetrasubstituted olefin.

[0007] As a further technical solution of the present invention: the substrate to be reacted is an organic molecule containing double or triple bonds, with the general structural formula R1-CO-(CH2). n -XC≡C-R2, where X is an element such as O, N, or C; and R1 and R2 are alkyl, aryl, or functional substituents.

[0008] As a further technical solution of the present invention: the nickel catalyst is a Ni(0) complex selected from Ni(cod)2.

[0009] As a further technical solution of the present invention: the chiral ligand is ( S )-BIDIME.

[0010] As a further technical solution of the present invention: optimizing the electronic environment of key reaction sites in the substrate to be reacted includes calculating the interaction energy between the nickel catalyst and the substrate through density functional theory, with the formula E(total)=E(substrate)+E(catalyst)+E(interaction).

[0011] As a further technical solution of the present invention: the acquisition of the reaction activity information includes a small-scale reaction test in a mixed solvent of dioxane and tert-butanol, with reaction conditions of 0.1 mmol substrate, 7.5 mol% nickel catalyst and 7.5 mol% chiral ligand, reaction temperature of 80 °C and reaction time of 12 hours.

[0012] As a further technical solution of the present invention, controlling the selectivity of the asymmetric cyclization reaction includes adjusting the reaction solvent, temperature, time parameters, and adding alkali and boric acid reagents as additives.

[0013] As a further technical solution of the present invention: the reaction solvent is a mixed solvent selected from dioxane plus tert-butanol, and the base is selected from LiO. t Bu; the boric acid reagent used is PhB(OH)2.

[0014] As a further technical solution of the present invention, it also includes a reaction vessel, a temperature control system, a stirring device, and an anhydrous and oxygen-free Schlenk reaction system; the reaction vessel is made of high-temperature and high-pressure resistant glass material and has a specially designed stirring paddle inside; the temperature control system consists of a heating jacket and a temperature sensor; the anhydrous and oxygen-free system is achieved by evacuating the Schlenk reaction system and then introducing inert gas.

[0015] As a further technical solution of the present invention: the inert gas is selected from nitrogen or argon, and the temperature range of the temperature control system is room temperature to 150°C.

[0016] The beneficial effects of this invention are: This invention relates to the field of organic synthesis technology, and particularly to a method and apparatus for constructing chiral tertiary alcohol heterocycles containing tetrasubstituted olefins via a nickel-catalyzed asymmetric cyclization reaction. By obtaining the structural information of the substrate and the combination information of the nickel catalyst and chiral ligands, the electronic environment of key reaction sites in the substrate is optimized based on the combination information, and the optimized reactivity information is obtained. Based on the reactivity information, the selectivity of the asymmetric cyclization reaction is controlled, thereby efficiently constructing chiral tertiary alcohol heterocycles containing tetrasubstituted olefins. The technical solution of this invention optimizes the electronic environment of key reaction sites in the substrate by using the combination information of the nickel catalyst and chiral ligands, making the electron distribution of the reaction sites more compatible with the catalyst's action mode, thus significantly improving the regioselectivity and stereoselectivity of the reaction. The technical solution of this invention precisely controls the selectivity of the asymmetric cyclization reaction by obtaining the reactivity information, thereby achieving efficient and highly selective construction of chiral tertiary alcohol heterocycle structures containing tetrasubstituted olefins, which has important application value in drug synthesis and related fields. Attached Figure Description

[0017] The invention will now be further described with reference to the accompanying drawings.

[0018] Figure 1 This is the synthetic route for N-heterocyclic substrates of the present invention; Figure 2 This is the synthetic route for O-heterocyclic substrates of the present invention; Figure 3 This is a reaction equation diagram of the present invention; Figure 4 It is the standard product 2a of the present invention. 1 H NMR spectrum; Figure 5 It is the standard product 2a of the present invention. 13 C NMR spectrum; Figure 6 This is the enantioselectivity chromatogram of the standard product 2a of the present invention determined by HPLC; Figure 7 This is a single-crystal structure diagram of the standard product 2a of the present invention; Figure 8 It is the standard product 2s of this invention. 1 H NMR spectrum; Figure 9 It is the standard product 2s of this invention. 13 C NMR spectrum; Figure 10 This is the enantioselectivity chromatogram of the standard product 2s of the present invention determined by HPLC. Figure 11 This is the reaction diagram of the present invention. Detailed Implementation

[0019] To enable those skilled in the art to better understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0020] N -For heterocyclic substrate synthesis routes, please refer to [link / reference]. Figure 1 and Figure 11 As shown: 4-Methylbenzenesulfonamide (S1) (21.8 g, 127 mmol, 1.0 equivalent), triethylamine (20 ml, 140 mmol, 1.1 equivalent), and 4-dimethylaminopyridine (1.57 g, 12.7 mmol, 0.1 equivalent) were dissolved in 150 mL of dichloromethane solution and stirred. Then, 250 mL of di-tert-butyl dicarbonate in dichloromethane was slowly added dropwise to the reaction system over 25 minutes and stirred for 2 hours. The reaction was quenched with 250 mL of 1M HCl, extracted with EtOAc, washed with saturated NaCl solution, dehydrated with anhydrous MgSO4, filtered, and the solvent was removed by vacuum distillation. The residue was obtained by (…). n Recrystallization of 3Hexane / CH2Cl yields S2, a white solid (30.0 g, 87%). S3: S2 (35.4 g, 130.6 mmol, 1.0 equivalent) and K2CO3 (27 g, 195.8 mmol, 1.5 equivalent) were dissolved in 100 mL of DMF and stirred at room temperature for 4 h. Then, propargyl bromide (11.3 mL, 143.7 mmol, 1.1 equivalent) was added to the above solution and stirred at room temperature for 10 h. The mixture was quenched with H2O, extracted with EtOAc, washed with saturated NaCl solution, dehydrated with anhydrous MgSO4, filtered, and the solvent was removed by vacuum distillation. The residue was then passed through (…).n Recrystallization of -Hexane / CH2Cl yielded S3 as a white solid (23.2 g, 85%). S4: Dissolve S3 (6.3 g, 30 mmol, 1.0 equivalent), 2-bromophenyl ethyl ketone (6.2 g, 31.5 mmol, 1.05 equivalent), and Bu4NI (1.108 g, 3 mmol, 0.1 equivalent) in 60 mL of DMF. And at 0 o Under C conditions, K2CO3 (6.2 g, 45 mmol, 1.5 equivalents) was added and stirred for 1 h. The mixture was quenched with H2O, extracted with EtOAc, washed with saturated NaCl solution, and then subjected to anhydrous Mg2+. S O4 removes water, filtration, vacuum distillation removes solvent, and the residue is passed through ( n Recrystallization of -Hexane / CH2Cl yields S4, a white solid (8.55 g, 87%). 1a: 1a was synthesized via a Sonogashira coupling reaction. S4 (1.64 g, 5 mmol), PdCl2(PPh3)2 (175 mg, 0.25 mmol, 5 mol%), and CuI (48 mg, 0.25 mmol, 5 mol%) were added to 10 mL of dioxane. Then, triethylamine (20 mL) and iodobenzene (824 μl, 7.5 mmol) were added. After 6 hours, the reaction mixture was cooled to room temperature, quenched with 1 M HCl, extracted with EtOAc, washed with saturated NaCl solution, dehydrated with anhydrous MgSO4, filtered, and the solvent was removed by vacuum distillation. The residue was subjected to column chromatography (90:10). n -Hexane:EtOAc) was purified to give 1a as a white powder (1.93 g, 96%).

[0021] O -For heterocyclic substrate synthesis routes, please refer to [link / reference]. Figure 2 As shown: S6: An n-Hexane solution of nBuLi (84.0 mL, 10 mmol, 1.05 equiv, 2.5 M) was slowly added dropwise to a solution of phenylacetylene (22.0 mL, 200 mmol, 1.0 equiv) in 150 mL of THF over -78°C for 1 hour. The reaction mixture was brought to 0°C, and oligooxyformaldehyde (7.87 g, 240 mmol, 1.20 equiv) was added. The reaction was then carried out at room temperature for 1 h, followed by stirring at 50°C for 3 h. After cooling to room temperature, the mixture was quenched with saturated NH4Cl solution (500 mL), extracted with EtOAc, washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered, and distilled under reduced pressure. The crude product was purified by column chromatography (eluent: PE / EA 20 / 1) to give compound S6 as a pale yellow oil (S6, 20.6 g, 78% yield).

[0022] S7: Under nitrogen atmosphere, S6 (12.5 g, 94.6 mmol, 1.05 equivalence) was added dropwise to a 0 °C NaH (4.32 g, 108.2 mmol, 1.20 equivalence, 60%) THF (150 mL) solution. The reaction mixture was heated to room temperature and stirred for 1 h until no gas was produced. Then, ethyl 2-bromoacetate (10.0 mL, 90.2 mmol, 1.00 equivalence) was added. After stirring for 3 hours, the mixture was quenched with saturated NH4Cl solution, extracted with EtOAc, washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered, and distilled under reduced pressure. The crude product was purified by column chromatography (eluent: PE / EA15 / 1) to give compound S7 as a pale yellow oil (4-S2, 14.7 g, 75%).

[0023] S8: Under nitrogen atmosphere, S8 (8.7 g, 40.0 mmol, 1.00 equivalent) and N,O 6.5 g of dimethyl hydroxylamine hydrochloride (60.0 mmol, 1.50 equivalents) was added to a 150 mL solution of THF and added dropwise over 30 minutes at -20 °C. i PrMgCl (90.0 mL, 180 mmol, 3.00 equivalents, 2.0 M) solution. The reaction system was stirred at -20 °C for 30 min, then quenched with saturated NH4Cl solution, extracted with EtOAc, washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered, and distilled under reduced pressure. The crude product was purified by column chromatography (elution: PE / EA5 / 1 to 3 / 1) to give 4-S3 as a white solid (S8, 6.16 g, 66% yield).

[0024] 1s: Under nitrogen atmosphere, PhMgBr (3.2 mL, 3.21 mmol, 1.5 equivalence, 1.0 M) was added to a 10 mL solution of S8 (500 mg, 2.14 mmol, 1.00 equivalence) THF at 0 °C. After stirring at 0 °C for 1 hour, the reaction was quenched with 2 M HCl, extracted with EtOAc, washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered, and distilled under reduced pressure. The crude product was purified by column chromatography (20:1, PE:EtOA) to give compound 1s as a white solid (498 mg, 93% yield).

[0025] The reaction equation of this invention is as follows: Figure 3 As shown: In a glove box, Ni(cod)₂ (4.2 mg, 0.015 mmol, 7.5 mol%), ( S )-BI-DIME (5.4 mg, 0.015 mmol, 7.5 mol%) and dioxane / tBuOH 5:1 (1.2 mL) were added to a 5 mL glass vial containing a magnetic stir bar and stirred until completely dissolved. Then PhB(OH)₂ (48.8 mg, 0.40 mmol, 2.00 equiv) and LiOMe (18.9 mg, 0.50 mmol, 2.50 equiv) were added, followed by substrate 1 (0.2 mmol, 1.00 equiv). The reaction mixture turned reddish-brown and was reacted at 65 °C for 12 h. After the reaction was completed, the mixture was quenched with saturated NaHCO₃ solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product. This crude product was then purified by column chromatography to obtain chiral compound 2. For standard product characterization, please refer to [link / reference]. Figure 4-10 As shown: The 2a chiral compound was a white solid, yield: 96%, enantiomeric ratio: 99:1er. [α] D 25 =+15.9 (c=1.0, CH2Cl2); the enantiomeric ratio was determined by HPLC (e.g., Figure 6 Chiral column: AD-H, 5℃, flow rate: 1 mL / min, mobile phase: hexanes / isopropanol: 60 / 40, 254 nm, 5.28 min ( S ), 12.75min R ).

[0026] See NMR data Figure 4-5 : 1HNMR (500MHz, CDCl3) δ7.68 (d, J=8.2Hz, 2H), 7.36 (t, J=8.1Hz, 4H), 7.29 (d, J=4.6Hz, 1H), 7.24–7.19 (m, 2H), 7.19–7.10 (m, 5H), 7.05–6.93 (m, 3H), 6.84 (d, J=7.1Hz, 2H), 4.15 (dd, J=43.5, 14.8Hz, 2H), 3.46 (dd, J=81.2, 9.8Hz, 2H), 2.68 (s, 1H), 2.49 (s, 3H). 13 CNMR (126MHz, CDCl3) δ 144.1, 143.9, 141.6, 140.1, 140.0, 1389.0, 132.1, 129.9, 129.0, 128.8, 128.3, 128.0, 127.9, 127.7, 127.3, 127.2, 125.3, 80.8, 64.6, 53.3, 21.7. HRMS (ESI) calculation: [M+Na, C 30 H 27 [NNaO3S] + :504.1603; Actual measurement: 504.1601. Crystallization with n-heptane / CH2Cl2 (4:1) yielded crystals suitable for X-ray crystallography (e.g. Figure 7 It reveals the absolute configuration of chiral products.

[0027] 2s white solid, yield: 87%, enantiomeric ratio: 91:9 er. [α] D 25 = +12.6 (c = 1.0, CH2Cl2); Enantiomeric ratio was determined by HPLC (e.g., Figure 10 Chiral column: AD-H, 25 oC, flow rate: 1 mL / min, mobile phase: hexanes / isopropanol: 70 / 30, 254 nm, 4.59 min ( S ), 5.20min ( R ). See NMR data Figure 8-9 : 1H NMR (500 MHz, CDCl3) δ 7.24 (s, 2H), 7.18-7.12( m,5H), 7.10 – 6.99 (m, 5H), 6.87 (d, J = 7.5 Hz, 2H), 4.82 (s, 2H), 4.10 (d, J= 9.4 Hz, 1H), 3.91 (d, J = 9.4 Hz, 1H), 2.58 (s, 1H), 2.36 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 144.0, 143.7, 139.3, 138.7, 137.4, 137.2, 129.1, 129.1, 128.0, 127.7, 126.9, 126.6, 125.2, 84.0, 81.7, 73.3, 21.2. HRMS (ESI) calculation: [M+Na, C 24 H 22 NaO2] + : 365.1512; Actual measurement: 365.1520. This invention relates to a method and apparatus for constructing chiral tertiary alcohol heterocycles containing tetrasubstituted olefins via a nickel-catalyzed asymmetric cyclization reaction. The core of this method lies in optimizing the combination of the nickel catalyst and chiral ligands, as well as the electronic environment of key reaction sites in the substrate, to achieve efficient and highly selective synthesis of the target product. The specific embodiments of this invention are described in detail below, with reference to the accompanying drawings (in cases where no drawings are provided).

[0028] Firstly, in the technical solution of this invention, obtaining the structural information of the substrate to be reacted is the crucial first step. The substrate is typically an organic molecule containing a triple bond, and these molecules need to possess potential cyclization reaction active sites. For example, ketone compounds with terminal double bonds can be selected as substrates, and their general structural formula can be represented as R1-CO-(CH2). n -XC≡C-R2, where X is an element such as O, N, or C, and R1 and R2 are alkyl, aryl, or functional substituents. The substrate was chosen to ensure efficient electron rearrangement and cyclization reactions in the nickel-catalyzed system. During the experiments, the substrate structure was characterized using nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) to confirm its purity and chemical structure met expectations.

[0029] Next, the electronic environment of key reaction sites in the substrate is optimized based on the combination information of the nickel catalyst and chiral ligand. The choice of nickel catalyst is crucial because it determines the regioselectivity and stereoselectivity of the reaction. In this invention, Ni(0) complexes, such as Ni(cod)2, are recommended as catalyst precursors, as these precursors exhibit good solubility and stability. Meanwhile, the choice of chiral ligand is equally important. The preferred chiral ligand in this invention is (…). S )-BIDIME, this ligand possesses a well-defined chiral center and strong coordination ability, enabling effective modulation of the electronic environment and spatial configuration of nickel catalysts. For example, when using ( S When )-BIDIME is used as a chiral ligand, the complex formed by it with Ni(cod)2 can significantly enhance the electrophilicity of the double-bonded carbon atoms in the substrate, thereby promoting the occurrence of cyclization reactions.

[0030] After optimizing the electronic environment of the reaction site, further information on the optimized reaction activity is needed. This process can be completed through a combination of theoretical calculations and experimental verification. The theoretical calculation uses density functional theory (DFT) to simulate the interaction between the nickel catalyst and the substrate, with the following formula: E(total) = E(substrate) + E(catalyst) + E(interaction), where E(substrate) represents the energy of the substrate, E(catalyst) represents the energy of the catalyst, and E(interaction) represents the interaction energy between the two. By calculating the E(interaction) values ​​for different combinations of nickel catalysts and chiral ligands, the optimal catalyst system is screened. The experimental verification involves testing the reaction rate and product selectivity under different conditions using small-scale reactions. For example, under standard conditions, 0.1 mmol of substrate, 7.5 mol% Ni(cod)₂, and 7.5 mol% ( S )-BIDIME was dissolved in a mixed solvent of dioxane and tert-butanol, and a base and phenylboronic acid reagent were added. The reaction temperature was controlled at 80°C and stirred for 12 hours. The reaction progress was then monitored by thin-layer chromatography (TLC). If the yield of the target product reached more than 90%, the catalyst system was considered to have good reactivity.

[0031] Based on the above reactivity information, precisely controlling the selectivity of the asymmetric cyclization reaction is a key step in achieving efficient synthesis of the target product. Specifically, by adjusting parameters such as the reaction solvent, temperature, and time, and by introducing appropriate additives, the regioselectivity and stereoselectivity of the reaction can be further improved. For example, when a mixture of dioxane and tert-butanol is used as the solvent, its ability to stabilize the transition intermediate helps improve the regioselectivity of the reaction. While the reaction rate increases significantly when the reaction temperature is increased from room temperature to 80°C, excessively high temperatures may lead to an increase in side reactions; therefore, a balance between reaction efficiency and selectivity needs to be considered. Furthermore, adding an appropriate amount of base, such as LiO2, can also contribute to the regioselectivity. t Bu can further activate the carbonyl functional group in the substrate, thereby accelerating the cyclization reaction.

[0032] In practice, the technical solution of this invention is applicable to various scenarios, and is particularly valuable in the field of drug synthesis. For example, this method can efficiently construct chiral tertiary alcohol heterocyclic structures containing tetrasubstituted alkenes, which are widely found in natural products and drug molecules. Taking the anticancer drug paclitaxel as an example, its core structure contains multiple chiral centers and complex ring systems. Traditional synthetic methods often require multiple steps and have low yields. However, using the nickel-catalyzed asymmetric cyclization reaction provided by this invention, the key chiral tertiary alcohol heterocyclic fragment can be directly constructed in a one-step reaction, greatly simplifying the synthetic route and improving overall efficiency. In specific implementation, a suitable substrate molecule is first designed and synthesized, then the reaction is carried out according to the aforementioned optimized conditions, and finally the target product is obtained by column chromatography separation and purification.

[0033] It is worth noting that the technical solution of this invention is not limited to a single type of substrate or reaction condition, but has broad applicability and flexibility. For example, for substrate molecules containing different substituents, different reaction requirements can be met by adjusting the ratio of nickel catalyst to chiral ligand or changing the specific type of ligand. Furthermore, this invention also provides a device specifically designed for this reaction. Although specific drawings are not included in the accompanying description, the design concept of this device aims to improve the safety and controllability of the reaction. The device mainly includes a reaction vessel, a temperature control system, a stirring device, and a gas introduction pipeline. The reaction vessel is made of high-temperature and high-pressure resistant glass and has a specially designed stirring paddle inside for uniformly mixing the reaction liquid. The temperature control system consists of a heating jacket and a temperature sensor, which can monitor and adjust the reaction temperature in real time. The gas introduction pipeline is used to introduce an inert gas, such as nitrogen or argon, into the reaction system to prevent oxygen in the air from interfering with the reaction process.

[0034] In summary, this invention successfully achieved the efficient construction of chiral tertiary alcohol heterocycles containing tetrasubstituted olefins through the synergistic effect of nickel catalysts and chiral ligands. In the specific implementation process, through precise control of substrate structure, catalyst system, and reaction conditions, not only were the regioselectivity and stereoselectivity of the reaction significantly improved, but important technical support was also provided for drug synthesis and related fields. Furthermore, the device design provided by this invention ensures the safety and controllability of the reaction, demonstrating promising application prospects and technical advantages.

[0035] The foregoing has provided a detailed description of one embodiment of the present invention, but this description is merely a preferred embodiment and should not be construed as limiting the scope of the invention. All equivalent variations and modifications made within the scope of the claims of this invention should still fall within the patent coverage of this invention.

Claims

1. An asymmetric reaction synthesis method for a chiral tertiary alcohol heterocyclic skeleton, characterized in that, Includes the following steps: Obtain structural information of the reaction substrate and information on the combination of nickel catalyst and chiral ligand; Based on the combination information of the nickel catalyst and the chiral ligand, the electronic environment of the key reaction sites in the substrate to be reacted is optimized, and the optimized reaction activity information is obtained. Based on the reactivity information, the selectivity of the asymmetric cyclization reaction is controlled to construct a chiral tertiary alcohol heterocycle containing a tetrasubstituted olefin.

2. The method for asymmetric reaction synthesis of a chiral tertiary alcohol heterocyclic skeleton according to claim 1, characterized in that, The substrate to be reacted is an organic molecule containing a triple bond, with the general structural formula R1-CO-(CH2). n -XC≡C-R2, where X is an element related to O, N, or C; and R1 and R2 are alkyl, aryl, or functional substituents.

3. The method for asymmetric reaction synthesis of a chiral tertiary alcohol heterocyclic skeleton according to claim 1, characterized in that, The nickel catalyst is a Ni(0) complex, selected from Ni(cod)2.

4. The method for asymmetric reaction synthesis of a chiral tertiary alcohol heterocyclic skeleton according to claim 1, characterized in that, The chiral ligand is ( S )-BIDIME.

5. The asymmetric reaction synthesis method for a chiral tertiary alcohol heterocyclic skeleton according to claim 1, characterized in that, Optimizing the electronic environment of key reaction sites in the substrate to be reacted includes calculating the interaction energy between the nickel catalyst and the substrate using density functional theory, with the formula E(total) = E(substrate) + E(catalyst) + E(interaction).

6. The method for asymmetric reaction synthesis of a chiral tertiary alcohol heterocyclic skeleton according to claim 1, characterized in that, The reactivity information was obtained by conducting a small-scale reaction test in toluene solvent under the following conditions: 0.1 mmol substrate, 7.5 mol% nickel catalyst and 7.5 mol% chiral ligand, reaction temperature of 80 °C and reaction time of 12 hours.

7. The method for asymmetric reaction synthesis of a chiral tertiary alcohol heterocyclic skeleton according to claim 1, characterized in that, Controlling the selectivity of the asymmetric cyclization reaction includes adjusting the reaction solvent, temperature, time parameters, and adding base and boric acid reagents as additives.

8. The method for asymmetric reaction synthesis of a chiral tertiary alcohol heterocyclic skeleton according to claim 7, characterized in that, The reaction solvent is a mixed solvent selected from dioxane plus tert-butanol, and the base is selected from LiO. t Bu; the boric acid reagent used is PhB(OH)2.

9. The asymmetric reaction synthesis method for a chiral tertiary alcohol heterocyclic skeleton according to claim 7, characterized in that, It also includes a reaction vessel, a temperature control system, a stirring device, and an anhydrous and oxygen-free Schlenk reaction system; the reaction vessel is made of high-temperature and high-pressure resistant glass material and has a specially designed stirring paddle inside; the temperature control system consists of a heating jacket and a temperature sensor; the anhydrous and oxygen-free system is achieved by evacuating the Schlenk reaction system and then introducing inert gas.

10. The method for asymmetric reaction synthesis of a chiral tertiary alcohol heterocyclic skeleton according to claim 9, characterized in that, The inert gas is selected from nitrogen or argon, and the temperature range of the temperature control system is from room temperature to 150°C.

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