Method for asymmetrically synthesizing pyrrolizidine alkaloid

Abstract

The invention discloses a method for asymmetrically synthesizing pyrrolizidine alkaloid, and belongs to the field of organic synthesis. According to the method, phenyl (pyrrolidine-1-yl) ketone and an alkenyl boron reagent are taken as initial raw materials, under the catalytic action of a nickel catalyst and a chiral ligand, a nitrogen alpha-alkylation reaction of the phenyl (pyrrolidine-1-yl) ketone is firstly carried out, boric acid ester in a product is oxidized into alcohol, then benzyl is adopted for protecting the alcohol generated in situ, and the phenyl (pyrrolidine-1-yl) ketone is obtained. And then sequentially carrying out a benzoylation reaction, a bromination reaction, an intramolecular cyclization reaction and a debenzylation reaction, so as to obtain the pyrrolizidine alkaloid. Compared with the previous synthesis method, the method disclosed by the invention has the advantages of commercially available raw materials, simple and efficient steps, easiness in further derivatization, simplicity in operation and suitability for synthesis of a large amount of pyrrolizidine alkaloid.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for asymmetric synthesis of pyrrolizidine alkaloids by using a nickel-catalyzed hydrogen atom transfer strategy and phenyl (pyrrolidin-1-yl) ketone and an alkenyl boron reagent as raw materials. Background Art

[0002] As common structural components of natural products, pyrrolizidine alkaloids have extensive biological and pharmacological activities and application values. They have attracted the attention and favor of synthetic chemists due to their strong activity and low abundance. However, in the existing technology, there are many shortcomings in the synthesis methods of pyrrolizidine alkaloids such as (–)-1-hydroxypyrrolizidine, (–)-perhydro-8-indolizinol, (–)-trachelanthamidine and (–)-tashiromine, such as difficulty in obtaining raw materials, cumbersome synthesis steps, low efficiency, and difficulty in derivatization. A new and efficient synthesis method is urgently needed to overcome these defects. Summary of the invention

[0003] The object of the present invention is to overcome the above-mentioned defects and provide a method for asymmetric synthesis of pyrrolizidine alkaloids.

[0004] The purpose of the present invention is achieved through the following technical solutions:

[0005] A method for asymmetric synthesis of pyrrolizidine alkaloids, using phenyl (pyrrolidin-1-yl) ketone and an alkenyl boron reagent as starting materials, firstly undergoing nitrogen α-alkylation reaction of phenyl (pyrrolidin-1-yl) ketone under the catalytic action of a nickel catalyst and a chiral ligand, then oxidizing the boric acid ester in the product to an alcohol, then protecting the in-situ generated alcohol with a benzyl group, and then sequentially performing debenzoylation, bromination, intramolecular cyclization and debenzylation reactions to obtain pyrrolizidine alkaloids. The pyrrolizidine alkaloids include (–)-1-hydroxypyrrolizidine, (–)-perhydro-8-indolizinol, (–)-trachelanthamidine, and (–)-tashiromine.

[0006] Furthermore, the method for asymmetric synthesis of pyrrolizidine alkaloids comprises the following steps:

[0007] (1) Phenyl(pyrrolidin-1-yl)methanone, alkenyl borate ester 2 or alkenyl borate ester 6, a nickel catalyst, a chiral ligand, polymethylhydrogensiloxane, di-tert-butyl peroxide, and cesium carbonate react in a solvent to obtain compound 3 or compound 7.

[0008] Among them, alkenyl borate ester 2 is (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane, with the structural formula The structural formula of compound 3 is The alkenyl borate ester 6 is (E)-2-(4-((4-methoxybenzyl)oxy)but-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, with the structural formula The structural formula of compound 7 is

[0009] (2) A: Compound 3 or Compound 7 and sodium borate are reacted in a solvent to obtain a secondary alcohol of Compound 3 or Compound 7.

[0010] Or B: Compound 3 or compound 7, iodomethane and n-butyl lithium are first reacted in a solvent to carry out reaction 1, and then sodium hydroxide and hydrogen peroxide are added to carry out reaction 2 to obtain the primary alcohol of compound 3 or compound 7.

[0011] (3) A: The primary alcohol of compound 3 or the secondary alcohol of compound 3, sodium hydride and benzyl bromide react in a solvent to obtain compound 4 or compound 10. The structural formula of compound 4 is The structural formula of compound 10 is

[0012]

[0013] Or B: The primary alcohol of compound 7 or the secondary alcohol of compound 7, sodium hydride, benzyl bromide, and tetrabutylammonium iodide react in a solvent to obtain compound 8 or compound 12. The structural formula of compound 8 is The structural formula of compound 12 is

[0014] (4) A: Compound 4 or Compound 10, Cp 2 ZrHCl is reacted in solvent one to obtain an intermediate product; the intermediate product and tetrabutylammonium fluoride are reacted in solvent two to obtain compound 5 or compound 11. The structural formula of compound 5 is The structural formula of compound 11 is

[0015] or B: Compound 8 or Compound 12, Cp 2 ZrHCl is reacted in solvent one to obtain intermediate products; the intermediate products, anisole, and trifluoroacetic acid are reacted in solvent two to obtain compound 9 or compound 13. The structural formula of compound 9 is The structural formula of compound 13 is

[0016] (5) Compound 5 or Compound 9 or Compound 11 or Compound 13, carbon tetrabromide, triphenylphosphine, and triethylamine are reacted in solvent one to obtain an intermediate product; the intermediate product, palladium hydroxide, and hydrochloric acid are reacted in solvent two under a hydrogen atmosphere to obtain a pyrrolizidine alkaloid (–)-1-hydroxypyrrolizidine or (–)-perhydro-8-indolizinol or (–)-trachelanthamidine or (–)-Tashiromine.

[0017] In step (1), the nickel catalyst preferably includes one or more of nickel chloride, nickel bromide, nickel chloride glycol dimethyl ether, nickel bromide glycol dimethyl ether, cyclooctadiene nickel, nickel acetylacetonate, nickel perchlorate, nickel iodide, and nickel acetate tetrahydrate, and is more preferably nickel bromide glycol dimethyl ether.

[0018] In step (1), the chiral ligand preferably includes one or more of the chiral ligands shown in the following structures, and more preferably is the chiral ligand L, namely (4S,4'S)-4,4'-diphenyl-4,4',5,5'-tetrahydro-2,2'-dioxazole.

[0019]

[0020] In step (1), the solvent includes but is not limited to a mixed solvent composed of one or more of ethyl acetate, trifluorotoluene, acetone, etc., and is more preferably ethyl acetate.

[0021] In step (1), the amount of each material is preferably: 1 equivalent of alkenyl boron reagent, 5 equivalents of phenyl (pyrrolidin-1-yl) ketone, 0.015-0.02 equivalents of nickel catalyst, 0.02 equivalents of chiral ligand, 3-10 equivalents of di-tert-butyl peroxide, 3-10 equivalents of polymethylhydrogensiloxane, and 1 equivalent of cesium carbonate.

[0022] In step (1), the reaction conditions are preferably stirring at 0-25° C. for 120-144 hours.

[0023] Step (1) further comprises the operation of separating and purifying the reaction solution. The separation and purification operation preferably comprises diluting the reaction solution with an organic solvent, filtering, evaporating the organic phase, column chromatography, etc. The organic solvent preferably comprises ethyl acetate, dichloromethane, methanol, triethylamine, etc.

[0024] Preferably, step (1) is: under an inert atmosphere, a nickel catalyst and a chiral ligand are added to water ethyl acetate, stirred and mixed, and phenyl (pyrrolidin-1-yl) ketone, alkenyl borate 2 or alkenyl borate 6, polymethylhydrogensiloxane, di-tert-butyl peroxide, and cesium carbonate are added; the reaction mixture is stirred and reacted at 15-35° C. under sealed conditions; after the reaction is completed, the reaction solution is diluted with ethyl acetate and filtered through diatomaceous earth, the organic phase is evaporated under reduced pressure, and purified by silica gel column chromatography to obtain compound 3 or compound 7.

[0025] In step (2)A, the solvent is preferably a mixture of tetrahydrofuran / water, and the volume ratio of the two is preferably 1:1.

[0026] In step (2) A, the amount of each material used is preferably: 1 equivalent of compound 3 or compound 7, 2.5 equivalents of sodium borate.

[0027] In step (2) A, the reaction conditions are preferably stirring at 15-35° C. for 4-8 hours.

[0028] Step (2) A also includes separation and purification of the reaction solution. The separation and purification preferably includes diluting the reaction solution with a mixture of water and an organic solvent, separating the organic phase, drying, concentrating, column chromatography, etc. The organic solvent preferably includes ethyl acetate, petroleum ether, dichloromethane, triethylamine, methanol, etc.

[0029] Preferably, step (2) A is: compound 3 or compound 7 and sodium borate tetrahydrate are added to a tetrahydrofuran / water solution, the reaction is stirred at 15-35° C., the mixture is diluted with water and ethyl acetate (1:1, v / v), the organic layer is separated, the organic phase is dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain a secondary alcohol of compound 3 or compound 7.

[0030] In step (2)B, the organic solvent is preferably tetrahydrofuran.

[0031] In step (2) B, the preferred usage ratio of the materials is: 1 equivalent of compound 3 or compound 7, 2 equivalents of monochloroiodomethane, and 2 equivalents of n-butyllithium.

[0032] In step (2) B, the conditions of reaction 1 are preferably stirring at 15-35° C. for 12-16 hours; the conditions of reaction 2 are preferably stirring at 0-4° C. for 1-3 hours.

[0033] Step (2) B also includes separation and purification of the reaction solution. The separation and purification preferably includes dilution with a mixture of water and an organic solvent, separation of the organic phase, drying, concentration, column chromatography, etc. The organic solvent preferably includes ethyl acetate, dichloromethane, n-hexane, methanol, triethylamine, etc.

[0034] Preferably, step (2) B is: under an inert gas atmosphere, compound 3 or compound 7 and iodomethane are added to tetrahydrofuran, then n-butyl lithium is added at -78°C and stirred to mix, and then the temperature is raised to 15-35°C for reaction. After the reaction is completed, sodium hydroxide solution and hydrogen peroxide solution are added to the reaction system at 0-4°C, and the reaction is stirred at 0-4°C. After the reaction is completed, the reaction solution is diluted with water and ethyl acetate (1:1, v / v), the organic layer is separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain the secondary alcohol of compound 3 or compound 7.

[0035] In step (3)A, the solvent is preferably tetrahydrofuran.

[0036] In step (3)A, the preferred usage ratio of the materials is: 1 equivalent of the secondary alcohol or primary alcohol of compound 3, 1.5 equivalents of sodium hydride, and 1.5 equivalents of benzyl bromide.

[0037] In step (3) A, the reaction conditions are preferably stirring at 15-35° C. for 15-25 hours.

[0038] Step (3) A also includes separation and purification of the reaction solution. The separation and purification preferably includes extraction with an organic solvent, drying of the organic phase, filtration, concentration, column chromatography, etc. The organic solvent preferably includes ethyl acetate, dichloromethane, petroleum ether, methanol, triethylamine, etc.

[0039] Preferably, step (3) A comprises: adding the primary alcohol of compound 3 or the secondary alcohol of compound 3, sodium hydride and benzyl bromide to tetrahydrofuran at 0-4°C, heating to 15-35°C and stirring for reaction, and quenching the reaction with water; extracting the reaction solution with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate in vacuo to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain compound 4 or compound 10.

[0040] In step (3)B, the organic solvent is preferably DMF.

[0041] In step (3) B, the amount of each material used is preferably: 1 equivalent of the primary alcohol or secondary alcohol of compound 7, 1.5-2.0 equivalents of sodium hydride, 5 equivalents of benzyl bromide, and 1 equivalent of tetrabutylammonium iodide.

[0042] In step (3) B, the reaction conditions are preferably stirring at 15-35° C. for 12-16 hours.

[0043] Step (3) B also includes the operation of separating and purifying the reaction solution. The separation and purification operation preferably includes diluting the reaction solution with water, extracting with an organic solvent, separating the organic phase, drying, filtering, concentrating, column chromatography, etc. The organic solvent preferably includes ethyl acetate, dichloromethane, petroleum ether, methanol, triethylamine, etc.

[0044] Preferably, step (3) B is: adding the primary alcohol of compound 7 or the secondary alcohol of compound 7 to DMF at 0-4°C, heating to 15-35°C and stirring to mix, adding benzyl bromide and tetrabutylammonium iodide, stirring and reacting at 15-35°C, quenching the reaction with aqueous sodium bicarbonate solution, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate and filtering, and concentrating the filtrate in vacuo to obtain a crude product, which is purified by silica gel column chromatography to obtain compound 8 or compound 12.

[0045] In step (4)A, the solvent 1 and the solvent 2 are preferably tetrahydrofuran.

[0046] In step (4) A, the amount of each material is preferably: 1 equivalent of compound 4 or compound 10, Cp 2 ZrHCl 2 equivalents, tetrabutylammonium fluoride 1.2-1.5 equivalents.

[0047] In step (4) A, the conditions for reaction 1 are preferably stirring at 15-35° C. for 1-3 hours, and the conditions for reaction 2 are preferably stirring at 15-35° C. for 20-40 minutes.

[0048] In step (4) A, after the reaction 1 is completed, a separation operation is further included, and the separation operation preferably includes adding an alkaline solution to the reaction solution, extracting with an organic solvent, evaporating the organic phase, etc. After the reaction 2 is completed, a separation and purification operation is also included, and the separation and purification operation preferably includes diluting the reaction solution with an organic solvent, washing with water, drying the organic phase, filtering, concentrating, column chromatography, etc. The organic solvent preferably includes ethyl acetate, dichloromethane, petroleum ether, methanol and triethylamine, etc.

[0049] Preferably, step (4) A is: Compound 4 or Compound 10 is added to tetrahydrofuran, and Cp is added under an inert gas atmosphere at 0-4°C. 2 ZrHCl, stirred at 15-35°C for reaction, then added with NaOH solution for neutralization, the obtained mixture was extracted with ethyl acetate, and the organic phase was evaporated under reduced pressure to obtain the intermediate product. The intermediate product and tetrabutylammonium fluoride were added to tetrahydrofuran, stirred at 15-35°C for reaction, quenched with water, diluted with ethyl acetate, washed with water, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 5 or compound 11.

[0050] In step (4) B, the first solvent is preferably tetrahydrofuran, and the second solvent is preferably dichloromethane.

[0051] In step (4) B, the amount of each material is preferably: 1 equivalent of compound 8 or compound 12, Cp 2 ZrHCl 2 equivalents, anisole 10 equivalents; trifluoroacetic acid concentration is preferably 0.15-0.2 mol / L.

[0052] In step (4) B, the conditions of reaction 1 are preferably stirring at 15-35° C. for 1-3 hours, and the conditions of reaction 2 are preferably stirring at 15-35° C. for 1-3 hours.

[0053] In step (4) B, after the reaction 1 is completed, a separation operation is further included, and the separation operation preferably includes adding an alkaline solution to the reaction solution, extracting with an organic solvent, evaporating the organic phase, etc. After the reaction 2 is completed, a separation and purification operation is also included, and the separation and purification operation preferably includes concentrating the reaction solution, dissolving with an organic solvent, adding a saturated sodium carbonate solution to shake and separate the organic phase, drying, column chromatography, etc. The organic solvent is preferably chloroform.

[0054] Preferably, step (4) B is: Compound 8 or Compound 12 is added to tetrahydrofuran, and Cp is added under an inert gas atmosphere at 0-4°C. 2 ZrHCl, stirred at 15-35°C for reaction, then added with NaOH solution for neutralization, the obtained mixture was extracted with ethyl acetate, and the organic phase was evaporated under reduced pressure to obtain the intermediate product. The intermediate product, anisole, and trifluoroacetic acid were added to dichloromethane, stirred at 15-35°C for reaction, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in chloroform, after sufficient shaking, the organic phase was separated, dried, filtered, and then evaporated under vacuum, and then purified by silica gel column chromatography to obtain compound 9 or compound 13.

[0055] In step (5), the first solvent is preferably dichloromethane, and the second solvent is preferably methanol.

[0056] In step (5), the dosage of each material is preferably: compound 5 or compound 9 or compound 11 or compound 131 equivalents, carbon tetrabromide 2.0-2.5 equivalents, triphenylphosphine 2.0-2.5 equivalents, triethylamine 0.04 equivalents, palladium hydroxide 0.1-0.2 equivalents; the hydrochloric acid concentration is preferably 1.5-2.5 mol / L.

[0057] In step (5), the conditions of reaction one are preferably standing at 4-10°C for 1-4 days, and the conditions of reaction two are preferably stirring at 15-35°C for 1-4 days.

[0058] In step (5), after the reaction 1 is completed, the operation of separation and purification is also included, and the separation and purification operation preferably includes adding water to the reaction solution to quench the reaction, extracting with an organic solvent, drying the organic phase, filtering, concentrating, column chromatography, etc., and the organic solvent preferably includes dichloromethane, ethyl acetate, methanol, triethylamine, etc. After the reaction 2 is completed, the operation of separation and purification is also included, and the separation and purification operation preferably includes filtering, adding potassium carbonate to the filtrate and stirring, re-filtering, concentrating, column chromatography, etc.

[0059] Preferably, step (5) is: Compound 5 or Compound 9 or Compound 11 or Compound 13 is added to dichloromethane, carbon tetrabromide and triphenylphosphine are added at 0-4°C and stirred and mixed, triethylamine is added, and then stirred and mixed at 0-4°C, and allowed to stand for 1-4 days for reaction, water is added to quench the reaction, and the mixture is extracted with dichloromethane. After the organic phase is dried, it is purified by silica gel column chromatography to obtain an intermediate product. The intermediate product, palladium hydroxide, and hydrochloric acid are added to methanol, stirred and reacted at 15-35°C in a hydrogen atmosphere for 1-4 days, the reaction solution is filtered through diatomaceous earth, potassium carbonate is added to the filtrate and stirred for 1-2 hours, the organic phase is filtered, and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a pyrrolizidine alkaloid (-)-1-hydroxypyrrolizidine or (-)-perhydro-8-indolizinol or (-)-trachelanthamidine or (-)-Tashiromine.

[0060] The method is applied in the synthesis of pyrrolizidine alkaloids.

[0061] The present invention has the following advantages and beneficial effects over the prior art: the method for synthesizing pyrrolizidine alkaloids used in the present invention has significant advantages. First, the raw materials used are all commercially available, which greatly reduces the difficulty and cost of obtaining raw materials; second, the synthesis steps are simple and efficient, and compared with the traditional method, the synthesis route is significantly shortened and the production efficiency is improved; third, the method is easy to further carry out derivatization operations, which can meet the diverse synthesis needs; finally, the whole operation process is simple and easy, and is suitable for large-scale industrial production of the above-mentioned specific pyrrolizidine alkaloids, especially the synthesis of (–)-1-hydroxypyrrolizidine, (–)-perhydro-8-indolizinol, (–)-trachelanthamidine and (–)-tashiromine, which has broad application prospects and market value. DETAILED DESCRIPTION

[0062] The technical solution of the present invention will be described in detail below in conjunction with specific embodiments to further illustrate the technical features and advantages of the present invention, but the protection scope of the present invention is not limited to the following embodiments.

[0063] Example 1: Synthesis of (–)-1-hydroxypyrrolizidine

[0064]

[0065] Under inert atmosphere, add NiBr to a 10 mL reaction tube. 2 ·dme (6.1 mg, 0.02 mmol), ligand (4S, 4'S)-4,4'-diphenyl-4,4',5,5'-tetrahydro-2,2'-dioxazole L (5.8 mg, 0.02 mmol) and anhydrous ethyl acetate (concentration of 0.05 M). The reaction mixture was stirred in an argon-filled glove box at room temperature for 1 hour. Subsequently, phenyl (pyrrolidin-1-yl) ketone 1 (87.6 mg, 0.5 mmol), alkenyl borate ester 2 (29.8 mg, 0.1 mmol), polymethylhydrogensiloxane PMHS (40 μL, 0.5 mmol), di-tert-butyl peroxide DTBP (54 μL, 0.3 mmol) and anhydrous cesium carbonate (32.6 mg, 0.1 mmol) were added. The reaction tube was sealed and taken out of the glove box. The reaction mixture was stirred at 20°C for 144 hours. The resulting mixture was diluted with ethyl acetate and filtered through diatomaceous earth, and the diatomaceous earth filter cake was further washed with ethyl acetate. The combined organic phase was evaporated under reduced pressure and purified by silica gel column chromatography, eluted and purified with petroleum ether / ethyl acetate (20:1-10:1) to obtain a colorless oily compound 3 (24.6 mg, 52% yield, 94% ee, 87 / 13 d.r.).

[0066] The data characterization of compound 3 is as follows:

[0067] 1 H NMR (600 MHz, CDCl 3)(90:10mixture of rotamers)δ7.56–7.49(m,2.00H),7.40–7.35(m,3.00H),4.32(q,J=7.8Hz,0.90H),4.02(s,0.10H),3.94(s,0.10H),3.79–3.72(m,1.00H),3.68–3.63(m,0.90H),3.58–3.55(m,0.10H),3.52–3.47(m,0.90H),3.45–3.43(m,0.10H),3.40–3.36(m,0.90H),2.15–2.09(m,1.00H),1.90–1.86(m,1.00H),1.85–1.80(m,1.00H),1.79–1.71(m,2.00H),1.68–1.62(m,2.00H),1.26(s,10.80H),1.20(s,1.20H),0.90(s,8.10H),0.83(s,0.90H),0.06(s,5.40H),-0.05(s,0.60H).

[0068] 13 C NMR(151MHz,CDCl 3 )δ169.7,137.6,129.7,128.0,127.5,82.8,63.3,59.1,50.9,31.2,30.3,26.1,25.7,25.1,25.0,18.4,-5.2.

[0069] HRMS:(ESI)calcd for C 26 H 45 BNO 4 Si + [M+H] + 474,3205;found 474.3199.

[0070] At room temperature, sodium borate tetrahydrate (38.4 mg, 0.25 mmol) was added to a solution of compound 3 (47.3 mg, 0.1 mmol, 1.0 equiv.) obtained above in tetrahydrofuran / water (1:1, 2.0 mL). The reaction was stirred at room temperature for 6 hours and then diluted with water (5 mL) and ethyl acetate (5 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 2:1) gave a colorless oily secondary alcohol. Sodium hydride (4.8 mg, 0.12 mmol, 60% in oil) and benzyl bromide (14.4 μL, 0.12 mmol) were added to a solution of the secondary alcohol (29.0 mg, 0.080 mmol) obtained in the above step in tetrahydrofuran (0.6 mL) at 0°C. The reaction was also warmed to room temperature and stirred at this temperature for 20 hours. The reaction was then quenched with water (2 mL). The mixture was extracted with ethyl acetate (3×2 mL), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1-10:1) to obtain yellow oily compound 4 (29.9 mg, 66% yield).

[0071] The data characterization of compound 4 is as follows:

[0072] 1 H NMR (600 MHz, CDCl 3 )(90:10mixture of rotamers)δ7.46–7.39(m,2.75H),7.38–7.32(m,6.00H),7.31–7.27(m,1.25H),4.68–4.61(m,1.80H),4.47–4.43(m,0.20H) ,4.42–4.37(m,0.90H),4.33–4.29(m,0.90H),4.01–3.98(m,0.10H),3.94–3.90(m,0.10H),3.76–3.69(m,1.80H),3.63–3.56 (m,0.20H),3.49–3.43(m,1.80H),3.39–3.31(m,0.20H),2.22–2.15(m,1.00H),2.01–1.90(m,2.00H),1.81–1.73(m,2.00H), 1.68–1.62(m,1.00H),0.90(s,8.10H),0.83(s,0.90H),0.06(s,2.70H),0.05(s,2.70H),-0.05(s,0.30H),-0.07(s,0.30H).

[0073] 13 C NMR (151 MHz, CDCl 3 )δ169.8,139.1,137.2,130.0,128.4,128.2,127.5,127.4,127.3,75.4,73.8,61.5,60.1,51.4,36.1,26.0,25.6,24.3,18.3,-5.27,-5.33.

[0074] HRMS:(ESI)calcd for C 27 H 40 NO 3 Si + [M+H] + 454.2772; found 454.2769.

[0075] Compound 4 (45.4 mg, 0.1 mmol, 1.0 equiv.) and ultra-dry tetrahydrofuran (1.0 mL) were added to a 10 mL reaction bottle equipped with a dry stirring magnet. Cp 2 ZrHCl (51.6 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then 10% NaOH solution (2 mL) was added. The resulting mixture was extracted with ethyl acetate (3×5 mL), and the combined organic phases were evaporated under reduced pressure to give a yellow oily crude product, which was used in the next step without further purification. TBAF (120 μL, 0.12 mmol, 1M in THF) was added to the above crude product with tetrahydrofuran (0.2 mL) as solvent. The reactants were stirred at room temperature for 30 minutes, then quenched with water (1 mL) and diluted with ethyl acetate (3 mL). The mixture was washed with water (2×2 mL), and the extracted organic phases were combined, dried over anhydrous sodium sulfate, and filtered. Concentrated in vacuo and purified by column chromatography (DCM / MeOH / Et 3 The reaction mixture was stirred for 2 h at 4 °C for 1 h (N=20 / 1 / 0.01-10 / 1 / 0.01) to give a yellow oil 5 (15.7 mg, 67% yield).

[0076] The data characterization of compound 5 is as follows:

[0077] 1 H NMR (600 MHz, CDCl 3)δ7.36–7.31(m,4H),7.30–7.27(m,1H),4.63(d,J=11.5Hz,1H),4.47(d,J=11.5Hz,1H),4.26(s,2H),3.83–3.77(m,1H),3.66–3. 60(m,2H),3.47–3.41(m,1H),3.01(t,J=7.0Hz,2H),2.00–1.91(m,3H),1.87–1.82(m,1H),1.81–1.75(m,1H),1.74–1.67(m,1H).

[0078] 13 C NMR (151 MHz, CDCl 3 )δ138.2,128.5,127.82,127.80,79.4,71.3,61.4,58.3,45.6,33.8,27.7,24.8.

[0079] HRMS:(ESI)calcd for C 14 H 22 NO 2 + [M+H] + 236.1645; found 236.1630.

[0080] Compound 5 (23.5 mg, 0.1 mmol, 1.0 equiv.) and ultra-dry dichloromethane (3.4 mL) were added to a 10 mL reaction bottle equipped with a dry stirring magnet. Carbon tetrabromide (82.9 mg, 0.24 mmol) and triphenylphosphine (63.0 mg, 0.24 mmol) were added at 0°C. The reaction solution was stirred at 0°C for 20 minutes, and then triethylamine (575 μL) was added. The reaction solution was stirred at 0°C for another hour and then allowed to stand at 4°C for 2 days. Post-treatment process: The reaction was quenched with water (5 mL) and extracted with dichloromethane (3×5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude yellow oil, which was used in the next step without further purification. To a solution of the above crude product (12.2 mg, 0.056 mmol) in methanol (1.0 mL) was added palladium hydroxide (16.5 mg, 0.011 mmol, 10% in Pd(OH) 2 / C) and 3 drops of hydrochloric acid (2M). The reaction mixture was stirred under a hydrogen atmosphere (10 atm) and room temperature for 2 days. After the reaction was completed, it was filtered through celite. Potassium carbonate (77.2 mg, 0.68 mmol, 10 equiv.) was added to the filtrate and stirred vigorously for 1 hour. After the mixture was filtered, the filtrate was concentrated in vacuo to obtain a crude product, which was then purified by silica gel column chromatography (dichloromethane / methanol / triethylamine = 2:1:1 to 1:1:1) to obtain a colorless oil (-)-1-hydroxypyrrolizidine (6.5 mg, 52% yield).

[0081] The data characterization of the compound (-)-1-hydroxypyrrolizidine is as follows:

[0082] 1 H NMR (400 MHz, CDCl 3 )δ5.80(s,1H),3.91–3.80(m,1H),3.24–3.16(m,1H),3.14–3.05(m,1H),2.97–2.85 (m,1H),2.54–2.37(m,2H),1.96–1.86(m,2H),1.73–1.57(m,3H),1.41–1.29(m,1H).

[0083] 13 C NMR (101 MHz, CDCl 3 )δ76.9,72.5,55.3,52.6,33.9,30.4,25.6.

[0084] Example 2: Synthesis of (–)-perhydro-8-indolizinol

[0085]

[0086] Under inert atmosphere, add NiBr to a 10 mL reaction tube. 2·dme (6.1 mg, 0.02 mmol), ligand (4S,4'S)-4,4'-diphenyl-4,4',5,5'-tetrahydro-2,2'-dioxazole L (5.8 mg, 0.02 mmol) and anhydrous ethyl acetate (concentration of 0.05 M). The reaction mixture was stirred in an argon-filled glove box at room temperature for 1 hour. Subsequently, phenyl (pyrrolidin-1-yl) ketone 1 (87.6 mg, 0.5 mmol), alkenyl borate ester 6 (31.8 mg, 0.1 mmol), polymethylhydrosiloxane PMHS (40 μL, 0.5 mmol), di-tert-butyl peroxide DTBP (54 μL, 0.3 mmol) and anhydrous cesium carbonate (32.6 mg, 0.1 mmol) were added. The reaction tube was sealed and taken out of the glove box. The reaction mixture was stirred at 20°C for 144 hours. The resulting mixture was diluted with ethyl acetate and filtered through diatomaceous earth, and the diatomaceous earth filter cake was further washed with ethyl acetate. The combined organic phase was evaporated under reduced pressure and purified by silica gel column chromatography, eluted and purified with petroleum ether / ethyl acetate (10:1-5:1) to obtain colorless oily compound 7 (29.6 mg, 60% yield, 93% ee, 93 / 7 d.r.).

[0087] The data characterization of compound 7 is as follows:

[0088] 1 H NMR (600 MHz, CDCl 3 )(80:20mixture of rotamers)δ7.58–7.50(m,1.80H),7.42–7.34(m,3.20H),7.29–7.25(m,2.00H),6.89–6.83(m,2.00H),4.43(s,1.60H), 4.40(s,0.20H),4.35(q,J=6.6Hz,0.80H),4.32(s,0.20H),4.07–3.98(m,0.20H),3.98–3.91(m,0.20H),3.80(s,3.00H ),3.54–3.43(m,2.80H),3.41–3.36(m,1.00H),2.16–2.06(m,1.00H),1.99–1.91(m,1.00H),1.84–1.77(m,2.00H),1.7 5–1.69(m,2.00H),1.67–1.63(m,1.00H),1.61–1.55(m,1.00H),1.48–1.40(m,1.00H),1.26(s,9.60H),1.21(s,2.40H).

[0089] 13C NMR (151 MHz, CDCl 3 )δ169.8,159.0,137.7,130.9,129.8,129.3,128.0,127.6,113.7,82.8,72.4,70.4,58.9,55.3,50.7,30.0,29.3,25.3,25.1,25.0,24.7.

[0090] HRMS:(ESI)calcd for C 29 H 41 BNO 5 + [M+H] + 494,3072; found 494.3080.

[0091] Sodium borate tetrahydrate (38.4 mg, 0.25 mmol) was added to a solution of compound 7 (49.3 mg, 0.1 mmol, 1.0 equiv.) in tetrahydrofuran / water (1:1, 2.0 mL) at room temperature. The reaction was stirred at room temperature for 6 hours and then diluted with water (5 mL) and ethyl acetate (5 mL). The organic layer was separated, the aqueous phase was extracted with ethyl acetate (3×5 mL), the combined organic phases were dried over anhydrous sodium sulfate, and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 2:1) to obtain a colorless oily secondary alcohol. Sodium hydride (5.1 mg, 0.13 mmol, 60% in oil) was added to a solution of the secondary alcohol (32.6 mg, 0.085 mmol) obtained in the above step in DMF (0.3 mL) at 0°C. The suspension was warmed to room temperature and stirred for 1 hour, then benzyl bromide (50 μL, 0.43 mmol, 5.0 equiv.) and tetrabutylammonium iodide (31.4 mg, 0.085 mmol, 1.0 equiv.) were added. The reaction mixture was stirred at room temperature for 16 hours, then quenched with saturated aqueous sodium bicarbonate solution (1 mL) and diluted with water (2 mL). The reaction solution was extracted with ethyl acetate (2 mL), washed with water (2×2 mL), and the organic phases after extraction were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain a yellow oily compound 8 (36.2 mg, 77% yield).

[0092] The data characterization of compound 8 is as follows:

[0093] 1 H NMR (600 MHz, CDCl 3)(80:20mixture of rotamers) δ7.51–7.44(m,2.00H),7.42–7.37(m,3.00H),7.36–7.33(m,4.00H),7.31–7.26(m,3.00H),6.88–6.82(m,2. 00H),4.78–4.72(m,0.40H),4.64(s,1.60H),4.43(s,1.60H),4.37(s,0.40H),4.35–4.32(m,0.80H),4.30–4.27(m,1.00 H),4.16–4.12(m,0.20H),3.80(s,2.40H),3.79(s,0.60H),3.50–3.45(m,3.60H),3.43–3.39(m,0.40H),2.23–2.15(m,1 .00H),1.99–1.91(m,2.00H),1.85–1.80(m,1.00H),1.73–1.69(m,1.00H),1.68–1.62(m,2.00H),1.60–1.56(m,1.00H).

[0094] 13 C NMR (151 MHz, CDCl 3 )δ169.9,159.1,139.2,137.1,130.7,130.1,129.3,128.4,128.2,127.52,127.4 9,127.4,113.8,78.2,73.8,72.5,70.0,61.3,55.3,51.3,29.4,26.4,25.7,24.1.

[0095] HRMS:(ESI)calcd for C 30 H 36 NO 4 + [M+H] + 474.2639; found 474.2628.

[0096] In a 10 mL reaction bottle equipped with a dry stirring magnet, compound 8 (47.4 mg, 0.1 mmol, 1.0 equiv.) obtained in the above step and ultra-dry tetrahydrofuran (1.0 mL) were added. Under argon protection, Cp 2ZrHCl (51.6 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then 10% sodium hydroxide solution (2 mL) was added. The resulting reaction solution was extracted with ethyl acetate (3×5 mL), and the organic phases were combined and evaporated under reduced pressure to obtain a yellow oil, which was used for the next step without further purification. Anisole (112 μL, 1.0 mmol, 10 equiv.) and trifluoroacetic acid (0.6 mL) were added to a solution of the yellow oil in dichloromethane (0.7 mL). The reaction mixture was stirred at room temperature for 2 hours. It was then concentrated under reduced pressure. The crude product was dissolved in chloroform (5 mL) and then poured into a saturated sodium carbonate solution (4 mL). After sufficient shaking, the organic phase was separated and the aqueous phase was extracted with chloroform / methanol = 5:1 (2×5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography (dichloromethane / methanol / triethylamine=20:1:0.01 to 10:1:0.01) to obtain compound 9 (14.9 mg, 60% yield) as a yellow oil.

[0097] The data characterization of compound 9 is as follows:

[0098] 1 H NMR (600 MHz, CDCl 3 )δ7.45–7.30(m,4H),7.30–7.27(m,1H),4.63(d,J=11.3Hz,1H),4.53(d,J=11.3Hz,1H),3.73–3.66(m,2H),3.65–3.61(m,1H),3. 42(q,J=7.3Hz,1H),3.10–3.03(m,2H),2.77(s,2H),2.03–1.99(m,1H),1.91–1.86(m,1H),1.84–1.79(m,2H),1.77–1.63(m,4H).

[0099] 13 C NMR (151 MHz, CDCl 3 )δ138.2,128.5,127.8,127.8,79.4,71.9,62.2,61.3,45.9,28.1,27.9,27.3,24.9.

[0100] HRMS:(ESI)calcd for C 15 H 24 NO 2 + [M+H] + 250.1802; found 250.1800.

[0101] Compound 9 (24.9 mg, 0.1 mmol, 1.0 equiv.) obtained in the above step and ultra-dry dichloromethane (3.4 mL) were added to a 10 mL reaction bottle equipped with a dry stirring magnet. Carbon tetrabromide (82.9 mg, 0.24 mmol, 2.4 equiv.) and triphenylphosphine (63.0 mg, 0.24 mmol, 2.4 equiv.) were added at 0°C. After the reaction was stirred for 20 minutes, triethylamine (575 μL) was added. The reaction solution was stirred at 0°C for 1 hour and then placed at 4°C for 1 day. The post-treatment of the reaction was as follows: the reaction solution was quenched with water (5 mL) and extracted with dichloromethane (3×5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1 to 10:1) to obtain a yellow oil. To a solution of the above yellow oil (15.7 mg, 0.068 mmol, 1.0 equiv.) in methanol (1.2 mL) was added palladium hydroxide (20 mg, 0.014 mmol, 0.2 equiv., 10% in Pd(OH) 2 / C), 3 drops of hydrochloric acid (2M). The mixture was stirred in a hydrogen atmosphere (10atm.) at room temperature for 2 days. The reaction solution was filtered through diatomaceous earth. Potassium carbonate (93.8mg, 0.68mmol) was added to the filtrate and stirred vigorously for 1 hour. After filtering the organic phase, it was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol / triethylamine = 20:1:0.01~10:1:0.01) to obtain a colorless oil (-)-perhydro-8-indolizinol (8.9mg, 63% yield).

[0102] The data characterization of the compound (-)-perhydro-8-indolizinol is as follows:

[0103] 1 H NMR (400 MHz, C 6 D 6 )δ3.46–3.35(m,1H),2.99–2.90(m,1H),2.85–2.73(m,2H),2.12–2.01(m,1H) ,2.01–1.87(m,2H),1.78–1.58(m,5H),1.52–1.42(m,2H),1.25–1.12(m,1H).

[0104] 13 C NMR (101 MHz, C 6 D 6)δ73.0,70.8,54.5,52.1,34.6,28.9,24.8,21.2.

[0105] Example 3: Synthesis of (–)-trachelanthamidine

[0106]

[0107] Under argon atmosphere, iodomethane (14.6 μL, 0.2 mmol, 2.0 equiv.) was added to a solution of compound 3 (47.3 mg, 0.1 mmol, 1.0 equiv.) in ultra-dry tetrahydrofuran (1.0 mL) at room temperature. Then, n-butyl lithium (2.4 M, 83.3 μL, 0.2 mmol, 2.0 equiv.) was slowly added at -78 °C. Stirring was continued at this temperature for 30 minutes, and then the temperature was raised to room temperature and left overnight. Sodium hydroxide solution (1.0 mL, 2.0 M) and hydrogen peroxide (0.5 mL, 30% w / v) were added to the reaction system at 0 °C. The resulting reaction solution was stirred at 0 °C for 2 hours, and then diluted with water (5 mL) and ethyl acetate (5 mL). The aqueous phase was extracted with ethyl acetate (3×5 mL), and the organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product, which was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10: 1 to 2: 1) to give a primary alcohol as a colorless oil. Sodium hydride (4.0 mg, 0.10 mmol, 1.5 equiv., 60% in oil) and benzyl bromide (12 μL, 0.10 mmol, 1.5 equiv.) were added to a solution of the primary alcohol (24.5 mg, 0.065 mmol, 1.0 equiv.) in tetrahydrofuran (0.5 mL) at 0°C. The suspension was warmed to room temperature and stirred for 20 hours, and then the reaction was quenched with water (2 mL). It was then extracted with ethyl acetate (3×2 mL), and the organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1 to 10: 1) to give compound 10 ((27.6 mg, 59% yield)) as a yellow oil.

[0108] The data characterization of compound 10 is as follows:

[0109] 1 H NMR (600 MHz, CDCl 3)(90:10mixture of rotamers)δ7.39–7.36(m,3.00H),7.35–7.28(m,7.00H),4.53(d,J=11.9Hz,0.90H),4.45(d,J=11.8Hz,0.90H),4.43–4.39(m,0.90H),4.37(s,0.20H),4.15(s,0.10H),3.97–3.83(m,0.20H),3.79–3.72(m,1.80H),3.58–3.54(m,1.80H),3.48–3.41(m,0.20H),3.38–3.34(m,0.90H),3.31–3.28(m,0.90H),3.24–3.11(m,0.20H),2.63–2.55(m,1.00H),2.02–1.98(m,2.00H),1.81–1.78(m,1.00H),1.76–1.70(m,1.00H),1.68–1.59(m,2.00H),0.90(s,8.10H),0.83(s,0.90H),0.08–0.05(m,5.40H),-0.05(s,0.60H).

[0110] 13 C NMR(151MHz,CDCl 3 )δ170.1,138.5,137.4,129.9,128.3,128.1,127.9,127.5,127.5,73.3,70.6,62.0,59.5,51.2,36.7,32.6,26.9,26.0,25.3,18.4,-5.20,-5.24.

[0111] HRMS:(ESI)calcd for C 28 H 42 NO 3 Si + [M+H] + 468.2928;found 468.2916.

[0112] Compound 10 (46.8 mg, 0.1 mmol, 1.0 equiv.) and ultra-dry tetrahydrofuran (1.0 mL) were added to a 10 mL reaction bottle equipped with a dry stirring magnet. Under an argon atmosphere, zirconocene chloride (51.6 mg, 0.2 mmol, 2.0 equiv.) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. A 10% sodium hydroxide solution (2 mL) was added and extracted with ethyl acetate (3×5 mL). The organic phases after extraction were combined and then concentrated under reduced pressure to obtain a yellow oil, which was used in the next step without further purification. Tetrabutylammonium fluoride solution (120 μL, 0.12 mmol, 1.2 equiv., 1M in THF) was added to a solution of the yellow oil in tetrahydrofuran (0.2 mL). The reaction was stirred at room temperature for 30 minutes, then quenched with water (1 mL) and diluted with ethyl acetate (3 mL). The reaction solution was then washed with water (2×2 mL), and the organic phases after extraction were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol / triethylamine=20:1:0.01-10:1:0.01) to obtain a yellow oil 11 (16.7 mg, 67% yield).

[0113] The data characterization of compound 11 is as follows:

[0114] 1 H NMR (600 MHz, CDCl 3 )δ7.37–7.33(m,2H),7.32–7.27(m,3H),5.53(s,2H),4.47(s,2H),3.79–3.73(m,1H),3.59–3.55(m,1H),3.54–3.45(m,3H),3.19–3.14(m, 1H),3.12–3.06(m,1H),2.27–2.21(m,1H),2.04–1.97(m,2H),1.92–1 .87(m,1H),1.81–1.75(m,1H),1.73–1.68(m,1H),1.65–1.59(m,1H).

[0115] 13 C NMR (151 MHz, CDCl 3 )δ137.6,128.5,128.0,127.8,73.5,71.4,61.2,59.6,44.2,39.1,32.7,28.2,24.4.

[0116] HRMS:(ESI)calcd for C 15 H24 NO 2 + [M+H] + 250.1802; found 250.1800.

[0117] Compound 11 (24.9 mg, 0.1 mmol, 1.0 equiv.) and dichloromethane (3.4 mL) were added to a 10 mL reaction bottle equipped with a dry stirring magnet. Carbon tetrabromide (82.9 mg, 0.24 mmol, 2.4 equiv.) and triphenylphosphine (63.0 mg, 0.24 mmol, 2.4 equiv.) were added at 0°C, and the reaction solution was stirred for 20 minutes. Triethylamine (575 μL) was then added, and the mixture was stirred at 0°C for 1 hour, and then placed at 4°C for 2 days. After the reaction was completed, it was quenched with water (5 mL) and extracted with dichloromethane (3×5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol / triethylamine = 20:1:0.01 to 10:1:0.01) to obtain a yellow oil. To a solution of the yellow oil obtained in the above step (13.4 mg, 0.058 mmol, 1.0 equiv.) in methanol (1.0 mL) was added palladium hydroxide (16.5 mg, 0.011 mmol, 10% in Pd(OH) 2 / C), 3 drops of hydrochloric acid (2M). The reaction was stirred at room temperature for 2 days under a hydrogen atmosphere (10 atm.). The reaction solution was then filtered through celite. Potassium carbonate (77.2 mg, 0.68 mmol, 10 equiv.) was added to the filtrate and stirred vigorously for 1 hour. The organic phase was filtered and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol / triethylamine = 2:1:1 to 1:1:1) to obtain a colorless oil (-)-trachelanthamidine (7.5 mg, 54% yield).

[0118] The data characterization of the compound (-)-trachelanthamidine is as follows:

[0119] 1 H NMR (400 MHz, CDCl 3)δ3.65–3.54(m,2H),3.37–3.24(m,1H),3.21–3.16(m,1H),3.13–3.07(m,1H),2.98–2.88(m,1H),2.70–2. 43(m,2H),2.03–1.88(m,3H),1.88–1.78(m,1H),1.78–1.68(m,1H),1.67–1.57(m,1H),1.56–1.46(m,1H).

[0120] 13 C NMR (101 MHz, CDCl 3 )δ67.6,65.2,54.7,54.4,48.3,31.9,30.0,25.6.

[0121] Example 4: Synthesis of (–)-Tashiromine

[0122]

[0123] Under argon atmosphere, iodomethane (14.6 μL, 0.2 mmol, 2.0 equiv.) was added to a solution of compound 7 (49.3 mg, 0.1 mmol, 1.0 equiv.) in ultra-dry tetrahydrofuran (1.0 mL) at room temperature. Then, n-butyl lithium (83.3 μL, 0.2 mmol, 2.0 equiv., 2.4 M) was slowly added at -78 °C. The reaction solution was stirred at this temperature for 30 minutes, then warmed to room temperature and left overnight. Sodium hydroxide solution (1.0 mL, 2.0 M) and hydrogen peroxide (0.5 mL, 30% w / v) were added at 0 °C. The reaction mixture was stirred at this temperature for 2 hours, then diluted with water (5 mL) and ethyl acetate (5 mL). The aqueous phase was extracted with ethyl acetate (3×5 mL), and the organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-2:1) to obtain a primary alcohol as a colorless oil. The colorless oily primary alcohol (24.6 mg, 0.062 mmol, 1.0 equiv.) obtained in the above step was dissolved in DMF (0.2 mL) at 0°C, and then sodium hydride (3.7 mg, 0.093 mmol, 1.5 equiv., 60% in oil) was added to the reaction system. The suspension was warmed to room temperature and stirred for 1 hour, and then benzyl bromide (36 μL, 0.31 mmol, 5.0 equiv.) and tetrabutylammonium iodide (22.9 mg, 0.062 mmol, 1.0 equiv.) were added. The reaction solution was stirred at room temperature for 16 hours, and then quenched with saturated sodium bicarbonate aqueous solution (1 mL) and water (2 mL). Then, the mixture was extracted with ethyl acetate (2 mL), washed with water (2×2 mL), and the organic phases were combined after extraction, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10:1-5:1) to obtain yellow oily compound 12 (25.8 mg, 53% yield).

[0124] The data characterization of compound 12 is as follows:

[0125] 1 H NMR (600 MHz, CDCl 3)(90:10mixture of rotamers)δ7.41–7.26(m,11.20H),7.25–7.19(m,0.80H),6.88–6.84(m,2.00H),4.63–4.54(m,0.20H),4.52(d,J=11.9Hz,0.90H),4.49–4.42(m,2.90H),4.42–4.39(m,0.90H),4.32–4.31(m,0.10H),4.10(s,0.10H),3.80(s,2.70H),3.79(s,0.30H),3.57–3.48(m,3.60H),3.46–3.42(m,0.40H),3.38–3.33(m,0.90H),3.31–3.26(m,0.90H),3.15(s,0.10H),2.65–2.61(m,0.10H),2.60–2.49(m,0.90H),2.02–1.95(m,2.00H),1.82–1.72(m,3.00H),1.65–1.55(m,2.00H),1.50–1.43(m,1.00H).

[0126] 13 C NMR(151MHz,CDCl 3 )δ170.0,159.1,138.5,137.4,130.8,129.9,129.3,128.4,128.1,127.9,127.54,127.51,113.8,73.3,72.5,70.3,70.3,59.4,55.3,51.2,38.8,27.7,26.5,25.8,25.4.

[0127] HRMS:(ESI)calcd for C 31 H 38 NO 4 + [M+H] + 488.2795;found 488.2792.

[0128] Compound 12 (48.7 mg, 0.1 mmol, 1.0 equiv.) and ultra-dry tetrahydrofuran (1.0 mL) were added to a 10 mL reaction vial equipped with a dry stirring magnet. Zirconocene chloride (51.6 mg, 0.2 mmol, 2.0 equiv.) was added at 0°C under an argon atmosphere. The reaction was stirred at room temperature for 2 hours. 10% sodium hydroxide solution (2 mL) was added and extracted with ethyl acetate (3×5 mL). The organic phases were combined and concentrated under reduced pressure to give a yellow oil, which was used in the next step without further purification. Anisole (112 μL, 1.0 mmol, 10 equiv.) and trifluoroacetic acid (0.6 mL) were added to a solution of the yellow oil obtained in the above step in dichloromethane (0.7 mL). The reaction was stirred at room temperature for 2 hours. The volatiles were then removed in vacuo at about 30°C. The crude product was dissolved in chloroform (5 mL) and then poured into saturated sodium carbonate solution (4 mL). After sufficient shaking, the organic phase was separated and the aqueous phase was extracted with chloroform / methanol = 5:1 (2×5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography (dichloromethane / methanol / triethylamine = 20:1:0.01 to 10:1:0.01) to obtain yellow oily compound 13 (13.4 mg, 51% yield).

[0129] The data characterization of compound 13 is as follows:

[0130] 1 H NMR (600 MHz, CDCl 3 )δ7.36–7.32(m,2H),7.31–7.27(m,3H),4.73(s,2H),4.46(s,2H),3.65–3.58(m,2H),3.50–3.46(m,1H),3.46–3.41(m,1H),3.29 –3.25(m,1H),3.11–3.05(m,2H),1.98–1.95(m,1H),1.92–1.85(m,2H),1.84–1.78(m,1H),1.70–1.62(m,2H),1.59–1.48(m,3H).

[0131] 13 C NMR (151 MHz, CDCl 3 )δ138.1,128.4,127.8,127.7,73.3,70.2,61.8,61.5,45.0,41.1,29.2,29.2,25.4,24.8.

[0132] HRMS:(ESI)calcd for C 16 H26 NO 2 + [M+H] + 264.1958; found 264.1954.

[0133] Compound 13 (26.3 mg, 0.1 mmol, 1.0 equiv.) and dichloromethane (3.4 mL) were added to a 10 mL reaction bottle equipped with a dry stirring magnet. Carbon tetrabromide (82.9 mg, 0.24 mmol, 2.4 equiv.) and triphenylphosphine (63.0 mg, 0.24 mmol, 2.4 equiv.) were added at 0°C, and the reaction solution was stirred for 20 minutes. Triethylamine (575 μL) was then added, and the mixture was stirred at 0°C for 1 hour, and then allowed to stand at 4°C for 2 days. After the reaction was completed, it was quenched with water (5 mL) and extracted with dichloromethane (3×5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1 to 10:1) to obtain a yellow oil. To a solution of the yellow oil obtained in the above step (13.2 mg, 0.054 mmol, 1.0 equiv.) in methanol (0.9 mL) was added palladium hydroxide (14 mg, 0.010 mmol, 0.2 equiv., 10% in Pd(OH) 2 / C), 3 drops of hydrochloric acid (2M). The reaction was stirred at room temperature for 2 days under a hydrogen atmosphere (10 atm.). The reaction solution was then filtered through celite. Potassium carbonate (74.5 mg, 0.54 mmol, 10 equiv.) was added to the filtrate and stirred vigorously for 1 hour. The organic phase was filtered and then concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (dichloromethane / methanol / triethylamine = 20:1:0.01 to 10:1:0.01) gave a colorless oil (-)-Tashiromine (11.8 mg, 48% yield).

[0134] The data characterization of compound (-)-Tashiromine is as follows:

[0135] 1 H NMR (400 MHz, CDCl 3 )δ3.61–3.57(m,1H),3.46–3.38(m,1H),3.08–2.99(m,2H),2.74(s,1H),2.08–1.99 (m,1H),1.92–1.84(m,2H),1.79–1.53(m,6H),1.50–1.40(m,2H),1.06–0.95(m,1H).

[0136] 13C NMR (101 MHz, CDCl 3 )δ66.4,65.3,54.0,52.6,44.4,28.9,27.5,25.0,20.6.

[0137] The above four examples have fully demonstrated the feasibility and effectiveness of the asymmetric synthesis method proposed in the present invention, and that the target pyrrolizidine alkaloid product with high optical purity can be stably prepared.

[0138] The technical solution disclosed in the present invention is not limited to the specific contents described in the above embodiments. Without departing from the spirit and scope of the present invention, those skilled in the art can make appropriate adjustments and improvements to the reaction conditions, raw material dosage, reaction equipment, etc. according to actual needs. These improvements and changes should all be covered within the scope of protection of the present invention.

Claims

1. A method for asymmetric synthesis of pyrrolizidine alkaloids, characterized in that: The method uses phenyl (pyrrolidin-1-yl) ketone and an alkenyl boron reagent as starting materials, and under the catalytic action of a nickel catalyst and a chiral ligand, firstly undergoes a nitrogen α-alkylation reaction of the phenyl (pyrrolidin-1-yl) ketone, then oxidizes the boric acid ester in the product to an alcohol, and then uses a benzyl group to protect the in-situ generated alcohol, and then sequentially performs debenzoylation, bromination, intramolecular cyclization and debenzylation reactions to obtain a pyrrolizidine alkaloid.

2. The method for asymmetric synthesis of pyrrolizidine alkaloids according to claim 1, characterized in that: The pyrrolizidine alkaloids include (–)-1-hydroxypyrrolizidine, (–)-perhydro-8-indolizinol, (–)-trachelanthamidine, and (–)-tashiromine.

3. The method for asymmetric synthesis of pyrrolizidine alkaloids according to claim 1, characterized in that: The following steps are involved: (1) Phenyl(pyrrolidin-1-yl)methanone, alkenyl borate 2 or alkenyl borate 6, a nickel catalyst, a chiral ligand, polymethylhydrogensiloxane, di-tert-butyl peroxide, and cesium carbonate react in a solvent to obtain compound 3 or compound 7; The structural formula of alkenyl borate ester 2 is The structural formula of compound 3 is The structural formula of alkenyl borate ester 6 is The structural formula of compound 7 is (2) A: Compound 3 or Compound 7 and sodium borate react in a solvent to obtain a secondary alcohol of Compound 3 or Compound 7; Or B: Compound 3 or Compound 7, iodomethane and n-butyl lithium are first subjected to reaction 1 in a solvent, and then sodium hydroxide and hydrogen peroxide are added to carry out reaction 2 to obtain the primary alcohol of Compound 3 or Compound 7; (3) A: The primary alcohol or secondary alcohol of compound 3, sodium hydride and benzyl bromide are reacted in a solvent to obtain compound 4 or compound 10; The structural formula of compound 4 is The structural formula of compound 10 is or B: reacting the primary alcohol or secondary alcohol of compound 7, sodium hydride, benzyl bromide and tetrabutylammonium iodide in a solvent to obtain compound 8 or compound 12; The structural formula of compound 8 is The structural formula of compound 12 is (4) A: Compound 4 or Compound 10 and Cp2ZrHCl react in a solvent to obtain an intermediate product; The intermediate product and tetrabutylammonium fluoride are reacted in solvent 2 to obtain compound 5 or compound 11; The structural formula of compound 5 is The structural formula of compound 11 is or B: Compound 8 or compound 12 and Cp2ZrHCl are reacted in solvent one to obtain an intermediate product; The intermediate product, anisole and trifluoroacetic acid are reacted in solvent 2 to obtain compound 9 or compound 13; The structural formula of compound 9 is The structural formula of compound 13 is (5) Compound 5 or Compound 9 or Compound 11 or Compound 13, carbon tetrabromide, triphenylphosphine, and triethylamine are reacted in solvent one to obtain an intermediate product; the intermediate product, palladium hydroxide, and hydrochloric acid are reacted in solvent two under a hydrogen atmosphere to obtain a pyrrolizidine alkaloid (–)-1-hydroxypyrrolizidine or (–)-perhydro-8-indolizinol or (–)-trachelanthamidine or (–)-Tashiromine.

4. The method for asymmetric synthesis of pyrrolizidine alkaloids according to claim 3, characterized in that: In step (1), the nickel catalyst comprises one or more of nickel chloride, nickel bromide, nickel chloride dimethyl ether, nickel bromide dimethyl ether, cyclooctadiene nickel, nickel acetylacetonate, nickel perchlorate, nickel iodide, and nickel acetate tetrahydrate; The chiral ligand includes one or more of the chiral ligands shown in the following structures:

5. The method for asymmetric synthesis of pyrrolizidine alkaloids according to claim 3, characterized in that: In step (1), the amount of each material is as follows: 1 equivalent of alkenyl boron reagent, 5 equivalents of phenyl (pyrrolidin-1-yl) ketone, 0.015-0.02 equivalents of nickel catalyst, 0.02 equivalents of chiral ligand, 3-10 equivalents of di-tert-butyl peroxide, 3-10 equivalents of polymethylhydrogensiloxane, and 1 equivalent of cesium carbonate.

6. The method for asymmetric synthesis of pyrrolizidine alkaloids according to claim 3, characterized in that: In step (2) A, the amount of each material is as follows: 1 equivalent of compound 3 or compound 7, 2.5 equivalents of sodium borate; In step (2) B, the amount of each material used is as follows: 1 equivalent of compound 3 or compound 7, 2 equivalents of monochloroiodomethane, and 2 equivalents of n-butyllithium.

7. The method for asymmetric synthesis of pyrrolizidine alkaloids according to claim 3, characterized in that: In step (3) A, the amount of each material used is: 1 equivalent of the secondary alcohol or primary alcohol of compound 3, 1.5 equivalents of sodium hydride, and 1.5 equivalents of benzyl bromide; In step (3) B, the amount of each material used is as follows: 1 equivalent of the primary alcohol or secondary alcohol of compound 7, 1.5-2.0 equivalents of sodium hydride, 5 equivalents of benzyl bromide, and 1 equivalent of tetrabutylammonium iodide.

8. The method for asymmetric synthesis of pyrrolizidine alkaloids according to claim 3, characterized in that: In step (4) A, the amount of each material is as follows: 1 equivalent of compound 4 or compound 10, 2 equivalents of Cp2ZrHCl, and 1.2-1.5 equivalents of tetrabutylammonium fluoride; In step (4) B, the amount of each material used is: 1 equivalent of compound 8 or compound 12, 2 equivalents of Cp2ZrHCl, and 10 equivalents of anisole.

9. The method for asymmetric synthesis of pyrrolizidine alkaloids according to claim 3, characterized in that: In step (5), the amounts of the materials are as follows: 1 equivalent of compound 5 or compound 9 or compound 11 or compound 13, 2.0-2.5 equivalents of carbon tetrabromide, 2.0-2.5 equivalents of triphenylphosphine, 0.04 equivalents of triethylamine, and 0.1-0.2 equivalents of palladium hydroxide.

10. Use of the method according to any one of claims 1 to 9 in the synthesis of pyrrolizidine alkaloids.

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