Method for synthesizing amatoxin intermediate through Rh / Cu concerted catalysis

Abstract

The invention discloses a method for synthesizing an amatoxin intermediate through Rh / Cu concerted catalysis, and belongs to the technical field of allylic alkylation reaction, an Rh / Cu concerted catalysis system is used for carrying out chiral selectivity and stereoselectivity allylic alkylation reaction on p-diphenyl imine glycine tert-butyl ester and racemic carboxylic acid allyl ester, and the amatoxin intermediate is synthesized. The rhodium catalyst controls the configuration of electrophilic carbon atoms in allyl ester, the copper catalyst controls the configuration of nucleophilic carbon atoms in unstable enol salt, and finally the amatoxin intermediate is obtained. According to the method for synthesizing the amatoxin intermediate through Rh / Cu concerted catalysis, an Rh / Cu concerted catalysis system can achieve ortho-position three-level three-dimensional center construction, multiple aryl and aliphatic substituted branched chain allyl products are obtained through the Rh / Cu concerted catalysis system, the yield is good or higher, cis-trans isomerization selectivity is high, and the method is suitable for industrial production. The enantiomeric selectivity is good to excellent.

Description

Technical Field

[0001] The present invention relates to the technical field of allyl alkylation reactions, and in particular to a method for synthesizing an amanita toxin intermediate using Rh / Cu synergistic catalysis. Background Art

[0002] In recent years, bimetallic synergistic catalysis has attracted extensive attention due to its advantages in reaction activity and selectivity regulation, and has been successfully applied to stereodivergent synthesis: He's team reported that Rh / Cu-catalyzed allylic substitution reactions achieved stereodivergent synthesis of fluorine-containing chiral centers and adjacent chiral centers; Wei, Wang, and others developed a Cu / Ir synergistic catalytic system to synthesize non-protein-derived α-amino acids containing ortho-quaternary / tertiary stereocenters; Zhang's team used an Ir(I) / Cu(II) dual catalyst system to achieve asymmetric allylic alkylation of diphenyliminoglycine ester to construct two ortho-chiral centers.

[0003] Compared to single-catalyst systems, bimetallic synergistic catalysis can more precisely control the stereoselectivity of the reaction through the synergistic effect of two metals, providing new ideas for the synthesis of complex chiral compounds. However, although there has been progress in rhodium-catalyzed asymmetric allylic alkylation reactions, their application is limited to the construction of a single chiral center, and research on the simultaneous construction of two ortho-chiral centers using rhodium catalysts has not been reported. The asymmetric synthesis of compounds containing two ortho-chiral centers remains a difficult problem in synthetic chemistry, and the development of efficient and highly selective catalytic systems is urgently needed. Summary of the Invention

[0004] The present invention aims to provide a method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis. The Rh / Cu synergistic catalytic system can realize the construction of a tertiary stereocenter at the ortho position. A variety of aromatic and aliphatic substituted branched allylic products are obtained through the Rh / Cu synergistic catalytic system with good to high yields, high cis-trans isomerization selectivity, and good to excellent enantiomeric selectivity.

[0005] To achieve the above object, the present invention provides a method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis, comprising the following steps: S1, preparation of Rh / Cu synergistic catalytic system; S2, adding the substrate, diphenylimino glycine tert-butyl ester, K3PO4 and THF into the Rh / Cu catalytic synergistic system to carry out asymmetric allylic alkylation reaction to obtain the precursor; S3, mixing the precursor with potassium antimonate dihydrate, AD-mix-β, and N-methylmorpholine-N-oxide, and adding the mixed solution to obtain a mixture, followed by post-treatment to obtain a dihydroxy compound; S4, placing the dihydroxy compound, acetyl chloride, and pyridine in a dichloromethane solution for reaction, neutralizing with aqueous ammonia, purifying after neutralization, and post-treating the purified product to obtain a residue; S5, dissolving the residue in dioxane and adding Na2CO3 and Fmoc-OSu, stirring and reacting, and post-treating the residue to obtain an intermediate product; S6. Dissolve the intermediate product obtained in step 5 in trifluoroacetic acid, stir, remove the solvent under reduced pressure, and purify by column chromatography to obtain an amatoxin intermediate.

[0006] Preferably, the specific operation of S1 is: S11. Preparation of a copper complex: In a nitrogen-filled glove box, add Cu(CH3CN)4PF6 and a chiral ligand into a flask, add ultra-dry THF, and stir to obtain a copper complex; S12, preparing a rhodium complex: adding [Rh(cod)Cl]2 and a chiral ligand to another flask, adding ultra-dry THF, and stirring to obtain a rhodium complex; S13. Prepare Rh / Cu synergistic catalytic system: transfer the copper complex solution into the rhodium complex flask via a syringe, and stir and mix to obtain the Rh / Cu synergistic catalytic system.

[0007] Preferably, in S11, the molar ratio of Cu(CH3CN)4PF6 to the chiral ligand is 1:1, the amount of ultra-dry THF is 0.5-1 mL, and the stirring time is 10-30 min; In S12, the molar ratio of [Rh(cod)Cl]2 to the chiral ligand is 1:1, the amount of ultra-dry THF used is 0.5-1 mL, and the stirring time is 5-10 min; In S11, S12 and S13, stirring is performed at 0-25°C.

[0008] Preferably, in S11 and S12, the chiral ligand includes one of (R)-L1, (S,Rp)-L2, (R,Sp)-L2, (R,Sp)-L3, (R)-L4, (S,S)-L5, (S,S)-L6, (R,R)-L7, (4S,5S)-L8, (4S,2R)-L9, and (2R,5R)-L10, and the same chiral ligand is selected in S11 and S12.

[0009] Preferably, in S2, the substrate comprises one of allyl chloride and its derivatives and allyl acetate and its derivatives, wherein allyl chloride and its derivatives include 、 、 、 、 、 、 、 、 、 、 、 ; Allyl acetate and its derivatives include 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0010] Preferably, in S2, the molar ratio of the substrate and diphenylimino glycine tert-butyl ester is (1-2): 1, the molar ratio of diphenylimino glycine tert-butyl ester to K3PO4 is 1: (1-2), and the amount of THF is 5-15 mL. After the asymmetric allylic alkylation reaction is completed, the product is washed with saturated NH4Cl solution, dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to obtain a crude product, and the crude product is eluted by silica gel column chromatography with petroleum ether-petroleum ether / ethyl acetate to finally obtain the precursor, wherein the volume ratio of petroleum ether-petroleum ether / ethyl acetate is 99: 1.

[0011] Preferably, in S3, the molar amount of the precursor is 1-3 mmol, the amount of potassium antimonate dihydrate is 4-5 mg, the amount of AD-mix-β is 9-10 mg, the amount of the mixed solution is 1-5 mL, the mixed solution is mixed with ether and water, the volume ratio of ether to water is (2-1): 1, the mixture is first diluted with 5-15 mL of ethyl acetate, and then 1-2 mL of saturated sodium sulfite solution is added and stirred, and after stirring, 5 mL of dichloromethane is used for extraction, and the extraction is performed three times. The organic phases obtained by the extraction are combined and dried with 1-2 mL of anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain a dihydroxy compound, and the eluent for silica gel column chromatography is n-hexane: ethyl acetate = (50-60): (40-50).

[0012] Preferably, in S4, the molar ratio of the dihydroxy compound, acetyl chloride and pyridine is 1:3:3, acetyl chloride is added in batches at 0°C, and after the addition, the mixture is heated and stirred. After the reaction is completed, an ammonia solution is added to quench, and the organic layer is separated with dichloromethane. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed to obtain a crude product. The crude product is dissolved in 1-3 mL of tetrahydrofuran, 1-3 mL of 1N hydrochloric acid is added and stirred at room temperature, and then solid calcium carbonate is added for neutralization. After neutralization, 5 mL of ethyl acetate is used to extract three times, and the extracts are combined.

[0013] Preferably, in S5, the combined extracts are dried over anhydrous sodium sulfate, and after drying, concentrated under reduced pressure to obtain a residue, which is dissolved in 3-5 mL of dioxane, and 2-4 mmol of Na2CO3 and 1-2 mmol of Fmoc-OSu are added, stirred for 1-3 h, and the solvent is removed. The residue after the solvent is removed is dissolved in 5-15 mL of ethyl acetate, washed with 0.1-0.2 M KHSO4 and brine, and then concentrated. The concentrated product is eluted by flash chromatography with (8-12):1 PE / EA to obtain an intermediate product.

[0014] Preferably, in S6, the stirring time is 1-2 h, and the eluent for column chromatography is: CH2Cl2 / MeOH=(95-98):(2-5).

[0015] The rhodium catalyst coordinates with the double bond of vinyl acetate or vinyl chloride to form η2π-vinyl rhodium complex II. This then undergoes an oxidative addition reaction, during which the leaving group leaves, to form η3π-vinyl rhodium complex III. Simultaneously, the aldehyde amine ester coordinates with copper complex IV and is then deprotonated with a base to yield a chiral carbon-based nucleophile V. V further undergoes nucleophilic addition with η3π-vinyl rhodium complex III to generate the chiral target compound, while simultaneously regenerating active rhodium complex I and copper complex IV. The copper complex IV and rhodium complex I synergistically control the stereoselectivity of the nucleophilic attack during the C-C bond formation step.

[0016] Therefore, the present invention adopts the above-mentioned Rh / Cu synergistic catalytic method for synthesizing amatoxin intermediates, and uses the Rh / Cu synergistic catalytic system for the chirally selective and stereoselective propylene alkylation reaction of tert-butyl p-diphenyliminoglycine with racemic carboxylic acid allyl ester. The rhodium catalyst controls the configuration of the electrophilic carbon atom in the allyl ester, while the copper catalyst controls the configuration of the nucleophilic carbon atom in the unstable enolate. The Rh / Cu synergistic catalytic system can realize the construction of the ortho-tertiary stereocenter. A variety of aromatic and aliphatic substituted branched allyl products are obtained through the Rh / Cu synergistic catalytic system with good to high yields, high cis-trans isomer selectivity, and good to excellent enantiomeric selectivity.

[0017] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is a process flow chart of Example 1 of a method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to the present invention; Figure 2 This is the hydrogen spectrum of compound 3a in Example 1 of the method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis of the present invention; Figure 3 This is the carbon spectrum of compound 3a in Example 1 of the method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to the present invention; Figure 4 This is a method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to the present invention. Example 1: Hydrogen spectrum of tert-butyl (2S,3S,4R)-2-((diphenylmethyl)amino)-4,5-dihydroxy-3-methylpentanoate; Figure 5 This is a method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to the present invention. Example 1: Carbon spectrum of tert-butyl (2S,3S,4R)-2-((diphenylmethyl)amino)-4,5-dihydroxy-3-methylpentanoate; Figure 6 This is a method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to the present invention. Example 1: Hydrogen spectrum of tert-butyl (2S,3S,4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpent-4-enoate; Figure 7 This is a method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to the present invention. Example 1: Carbon spectrum of tert-butyl (2S,3S,4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpent-4-enoate; Figure 8 This is a method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to the present invention. Example 1: Hydrogen spectrum of ((2S,3S,4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4,5-diacetoxy-3-methylpentanoic acid; Figure 9 This is a method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to the present invention. Example 1: Carbon spectrum of ((2S,3S,4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4,5-diacetoxy-3-methylpentanoic acid; Figure 10 This is the hydrogen spectrum of compound 3b of Example 3 of the method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis of the present invention; Figure 11 This is the carbon spectrum of compound 3b of Example 3 of the method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis of the present invention; Figure 12 This is the hydrogen spectrum of compound 3c of Example 4 of the method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis of the present invention; Figure 13 This is the carbon spectrum of compound 3c of Example 4 of the method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis of the present invention; Figure 14 This is the hydrogen spectrum of compound 3d in Example 5 of the method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis of the present invention; Figure 15 This is the carbon spectrum of compound 3d in Example 5 of the method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis of the present invention; Figure 16 This is the hydrogen spectrum of compound 3e in Example 6 of the method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis of the present invention; Figure 17 This is the carbon spectrum of compound 3e in Example 6 of the method for synthesizing an amatoxin intermediate in a Rh / Cu synergistic catalytic method of the present invention. DETAILED DESCRIPTION

[0019] The technical solution of the present invention is further described below with reference to the accompanying drawings and embodiments.

[0020] Unless otherwise defined, technical or scientific terms used in the present invention shall have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.

[0021] All reactions and manipulations involving organometallic compounds or moisture-sensitive compounds were performed under a dry nitrogen atmosphere. Glassware was oven-dried for 2 hours before use. All reagents were purchased from commercial suppliers without further purification. The anhydrous solvents, toluene, THF, and 1,4-dioxane, were redistilled from sodium and benzophenone. Anhydrous DMF, CH3CN, tBuOH, and DCE were purchased from Inochem and used as received. 1 H. 13 C and 19 F NMR spectra were measured at 500 MHz using CDCl3 solvent.

[0022] Multiplicity is indicated using the following abbreviations: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, and m = multit. Purification was performed by flash column chromatography using 200-300 mesh silica gel. For high-resolution mass spectrometry, electrospray ionization (ESI) mass spectra were recorded on a Thermo Scientific Q Exactive HF Orbitrap-FTMS.

[0023] In the present invention, unless otherwise specified, other test materials and instruments and equipment are conventional test materials in this field and can be purchased through commercial channels.

[0024] Example 1 like Figure 1 As shown, the present invention provides a method for synthesizing an amatoxin intermediate by Rh / Cu synergistic catalysis, comprising the following steps: S1. Preparation of Rh / Cu synergistic catalytic system. The specific operation of S1 is as follows: S11. Preparation of copper complex: In a nitrogen-filled glove box, 0.16 mmol of Cu(CH3CN)4PF6 and 0.16 mmol of chiral ligand (R,Sp)-L2 were added to a flask, and 0.5 mL of ultra-dry THF was added, and the mixture was stirred at 0°C for 15 min to obtain a copper complex; S12, preparing a rhodium complex: adding 0.16 mmol [Rh(cod)Cl]2 and 0.16 mmol chiral ligand (R,Sp)-L2 to another flask, adding 0.5 mL ultra-dry THF, and stirring at room temperature for 15 min to obtain a rhodium complex; S13. Prepare Rh / Cu synergistic catalytic system: transfer the copper complex solution into the rhodium complex flask via a syringe, and stir and mix at 0° C. to obtain the Rh / Cu synergistic catalytic system.

[0025] S2. 6mmol (E)-1-chlorobut-2-ene, 4mmol diphenyliminoglycine tert-butyl ester, 6mmol K3PO4 and 10mL THF were added to the Rh / Cu catalytic synergistic system and stirred at 0°C for 24h for asymmetric allylic alkylation reaction. After the asymmetric allylic alkylation reaction, the product was washed with saturated NH4Cl solution, dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to obtain a crude product. The crude product was eluted with petroleum ether-petroleum ether / ethyl acetate (99:1) on a silica gel column to finally obtain compound 3a: tert-butyl (2S,3R)-2-((diphenylmethyl)amino)-3-methylpent-4-enoate. Compound 3a is a colorless oil with a precursor yield of 70%, an enantiomeric excess (ee) of 99%, and a diastereoisomer ratio (dr) of 10:1. The hydrogen spectrum and carbon spectrum of compound 3a are shown as follows: Figure 2 、Figure 3 As shown, the data are: ¹H NMR (600 MHz, CDCl3) δ 7.68–7.65 (m, 2H), 7.44–7.41 (m, 3H), 7.38 (ddd, J = 6.5, 3.8, 1.2 Hz, 1H), 7.32 (dd, J = 10.3, 4.6 Hz, 2H), 7.16–7.13 (m, 2H), 5.69 (ddd, J =17.6, 10.3, 7.6 Hz, 1H), 5.06–5.02 (m, 1H), 4.97–4.94 (m, 1H), 3.86–3.80 (m, 1H), 2.95–2.88 (m, 1H), 1.44 (s, 9H), 1.10 (d, J = 6.8 Hz, 3H).

[0026] 13 C NMR (151 MHz, CDCl3) δ 170.7, 170.3, 140.9, 139.9, 136.9, 130.3, 128.9, 128.6, 128.5, 128.1, 128.1, 114.8, 81.1, 70.8, 41.8, 28.2, 15.9.

[0027] High-resolution mass spectrometry (ESI + ) The calculated value is C 23 H 28 NO2 (M+H) + : 350.2115; measured value: 350.2121.

[0028] S3, 2 mmol of compound 3a was mixed with 0.05 equivalent of potassium antimonate dihydrate, 2 mol% AD-mix-β, 6 mmol The mixture was mixed with N-methylmorpholine-N-oxide, and 3 mL of a mixed solution of ether and water in a volume ratio of 2:1 was added to obtain a mixture. The mixture was first diluted with 10 mL of ethyl acetate, and then 1 mL of a saturated sodium sulfite solution was added and stirred. After vigorous stirring for 20 minutes, the mixture was extracted with 5 mL of dichloromethane three times. The organic phases obtained by the extractions were combined and dried over anhydrous sodium sulfate. The crude product was then evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=60:40) to obtain a white solid product, tert-butyl (2S,3S,4R)-2-((diphenylmethyl)amino)-4,5-dihydroxy-3-methylvalerate. The yield of tert-butyl (2S,3S,4R)-2-((diphenylmethyl)amino)-4,5-dihydroxy-3-methylvalerate was 83%, and the diastereoisomer ratio (dr) was 4:1.

[0029] The hydrogen and carbon spectra of tert-butyl (2S,3S,4R)-2-((diphenylmethyl)amino)-4,5-dihydroxy-3-methylpentanoate are as follows: Figure 4 and Figure 5 As shown, the data are: 1 H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 1.9 Hz, 3H), 7.40 (t, J = 7.1 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.16 (d, J = 3.1 Hz, 2H), 4.16 (d, J= 3.2 Hz, 1H), 3.79 (dd, J = 8.0, 3.8 Hz, 1H), 3.77 – 3.69 (m, 1H), 3.54 (dd,J = 11.2, 5.2 Hz, 1H), 2.20–2.12 (m, 1H), 1.43 (d, J = 6.4 Hz, 9H), 1.05 (d, J = 7.0 Hz, 3H).

[0030] 13 C NMR (151 MHz, CDCl3) δ 170.7, 170.3, 139.0, 135.9, 130.9, 129.0, 128.9, 128.7, 128.3, 127.7, 81.6, 74.5, 69.2, 65.0, 39.9, 28.2, 13.9.

[0031] High-resolution mass spectrometry (ESI + ) The calculated value is C 23 H 30 NO4 (M+H) + : 384.2169; measured value: 384.2178. [α] 25 D = +10.7 (c 1.0, CH3CN).

[0032] S4, 1 mmol of tert-butyl (2S, 3S, 4R)-2-((diphenylmethyl)amino)-4, 5- dihydroxy-3-methylpentanoate, 3 mmol of acetyl chloride, 3 mmol of pyridine were placed in 5 mL of dichloromethane solution, acetyl chloride was added in batches at 0°C, after addition, the mixture was heated and stirred, after the reaction was completed, the ammonia solution was quenched, and extracted with 5 mL of dichloromethane three times, the organic layer was separated, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed to obtain a crude product, the crude product was dissolved in 2 mL of tetrahydrofuran, 2 mL of 1N hydrochloric acid was added at room temperature, stirred for 2 h, then solid calcium carbonate was added for neutralization, and after neutralization, 5 mL of ethyl acetate was extracted three times, and the extract was combined.

[0033] S5, the extract was dried by Na2SO4, and then concentrated under reduced pressure, the residue was dissolved in 4 mL of dioxane, 3 mmol of Na2CO3 and 1.2 mmol of Fmoc-OSu were added and stirred for 2 h, the solvent was removed, the residue after reaction was dissolved in 10 mL of ethyl acetate, washed with 0.1M KHSO4 and brine, after washing, concentrated and eluted with 10:1 PE / EA by flash chromatography to obtain the intermediate tert-butyl (2S, 3S, 4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpent-4-enoate, the yield of tert-butyl (2S, 3S, 4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpent-4-enoate was 72%.

[0034] The hydrogen spectrum and carbon spectrum of tert-butyl (2S, 3S, 4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpent-4-enoate are shown in Figure 6 and Figure 7 The data are as follows: ¹H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 7.5 Hz, 2H), 7.61 (dd, J = 11.6, 7.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 5.24 (d, J = 9.9 Hz, 1H), 4.84 (d, J = 9.2 Hz, 1H), 4.65 (dd, J = 9.8, 2.2 Hz, 1H), 4.48 (d, J = 11.4 Hz, 1H), 4.35 (dt, J = 17.9, 10.5 Hz, 2H), 4.22 (t, J = 7.1 Hz, 1H), 4.09 (dd, J = 12.4, 4.5 Hz, 1H), 2.54–2.45 (m, 1H), 2.11 (s, 3H), 2.08 (s, 3H), 1.50 (s, 9H), 0.91 (d, J =7.1 Hz, 3H).

[0035] 13 C NMR (151 MHz, CDCl3) δ 170.9, 170.8, 170.5, 156.4, 144.1, 143.9, 141.4, 141.4, 127.8, 127.8, 127.2, 125.4, 125.2, 120.1, 120.0, 82.7, 71.9, 67.4, 63.4,54.8, 47.3, 36.2, 28.2, 21.2, 20.9, 11.1.

[0036] HRMS (ESI + ) The calculated value is C 29 H 35 NNaO8 + (M+Na) + : 548.2255; measured value: 548.2262. [α] 25 D = +0.7 (c 1.0, CH3CN).

[0037] S6. The intermediate product obtained in step 5 was dissolved in trifluoroacetic acid and stirred. The solvent was removed under reduced pressure, and the product was purified by column chromatography to obtain a white solid amatoxin intermediate ((2S,3S,4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4,5-diacetoxy-3-methylpentanoic acid. The yield of ((2S,3S,4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4,5-diacetoxy-3-methylpentanoic acid was 90%.

[0038] The hydrogen and carbon spectra of ((2S,3S,4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4,5-diacetoxy-3-methylpentanoic acid are as follows: Figure 8 and Figure 9 As shown, the data are: 1 H NMR (600 MHz, DMSO) δ 13.05 (s, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.74 (dd, J = 18.8, 7.2 Hz, 2H), 7.65 (d, J = 9.4 Hz, 1H), 7.41 (t, J = 7.0 Hz, 2H), 7.33 (d, J =4.6 Hz, 2H), 4.77 (d, J = 7.5 Hz, 1H), 4.48 – 4.44 (m, 1H), 4.38 (d, J = 11.9Hz, 1H), 4.28–4.24 (m, 1H), 4.22–4.15 (m, 2H), 4.05 (dd, J = 12.1, 4.3 Hz, 1H), 3.43 (s, 1H), 2.00 (s, 3H), 1.96 (s, 3H), 0.93 (d, J = 6.6 Hz, 3H).

[0039] 13 C NMR (151 MHz, DMSO) δ 173.1, 170.2, 169.7, 156.6, 144.1, 143.7, 140.7, 140.7, 127.7, 127.6, 127.2, 127.1, 125.6, 125.3, 120.1, 120.1, 71.5, 66.0, 62.8,54.1, 46.7, 39.5, 34.9, 20.7, 20.6, 10.9.

[0040] HRMS(ESI + ) calculated value is C 25 H 27 NNaO8 + (M+Na) + : 492.1629; Measured value: 492.1635. [α] 25 D =+4.3 (c 1.0, CH3CN).

[0041] Example 2 The only difference between Example 2 and Example 1 is that (S, Rp)-L2 is used to prepare the copper complex and the rhodium complex in Example 2, and the other conditions are the same.

[0042] Example 3 The only difference between Example 3 and Example 1 is that the substrate used in Example 3 is The remaining conditions were the same. The product obtained was compound 3b: tert-butyl (2S,3R)-2-((diphenylmethyl)amino)-5-methyl-3-vinylhexanoate, with a yield of 71%, a diastereoisomer ratio (dr) of 20:1, and an enantiomeric excess (ee) of 99%.

[0043] The hydrogen and carbon spectra of tert-butyl (2S,3R)-2-((diphenylmethyl)amino)-5-methyl-3-vinylhexanoate are as follows: Figure 10 、 Figure 11 As shown, the data are: HPLC [DAICEL CHIRALPAK OD-H, hexane / isopropanol = 96 / 4, 254 nm, 0.5 mL / min; t R1 =21.551min (minor peak), t R2 =24.383min (minor peak), t R3 =27.863min (minor peak), t R4 =33.248min (main peak)].

[0044] 1 H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 5.3 Hz, 3H), 7.39 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.16–7.12 (m, 2H), 5.52 (dt, J = 17.4, 9.7 Hz, 1H), 5.09 – 4.99 (m, 2H), 3.86 (d, J = 6.1 Hz, 1H), 2.89 – 2.79 (m, 1H), 1.56 (tdd, J = 9.8, 6.8, 3.4 Hz, 1H), 1.50–1.39 (m, 10H), 1.29–1.21 (m, 1H), 0.88 (dd, J =9.8, 6.7 Hz, 6H).

[0045] 13 C NMR (151 MHz, CDCl3) δ 170.6, 170.4, 139.9, 139.7, 136.9, 130.3, 129.0, 128.5, 128.4, 128.1, 116.4, 80.9, 70.8, 46.1, 39.6, 28.2, 25.4, 24.2, 21.4.

[0046] HRMS (ESI + ) calculated value is C 26 H 34 NO2(M+H) + : 392.2584; Measured value: 392.2591. [α] 25 D = -21.5 (c 1.5, CH2Cl2).

[0047] Example 4 The only difference between Example 4 and Example 1 is that the substrate used in Example 4 is The remaining conditions were the same. The product obtained was compound 3c: tert-butyl (2S,3R)-2-((diphenylmethyl)amino)-3-(phenoxymethyl)pent-4-enoate, with a yield of 75%, a diastereoisomer ratio (dr) greater than 20:1, and an enantiomeric excess (ee) of 98%.

[0048] The hydrogen and carbon spectra of tert-butyl (2S,3R)-2-((diphenylmethyl)amino)-3-(phenoxymethyl)pent-4-enoate are as follows: Figure 12 、 Figure 13 As shown, the data are: 1 H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 7.5 Hz, 2H), 7.43–7.37 (m, 4H), 7.31 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.8 Hz, 2H), 7.09 (d, J = 6.8 Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 6.85 (d, J = 8.2 Hz, 2H), 5.88–5.80 (m, 1H), 5.21 (d, J = 17.3 Hz, 1H), 5.13 (d, J = 10.4 Hz, 1H), 4.20–4.12 (m, 3H), 3.31 (t, J = 12.2 Hz, 1H), 1.43 (s, 9H).

[0049] 13 C NMR (151 MHz, CDCl3) δ 171.3, 170.3, 159.1, 139.6, 136.5, 136.4, 130.5, 129.5, 129.0, 128.7, 128.39, 128.1, 120.7, 117.9, 114.8, 81.4, 67.9, 67.4, 47.3,28.2. HRMS (ESI + ) The calculated value is C29 H 32 NO3 + (M+H) + : 442.2377; measured value: 442.2382, [α] 25 D =-0.5(c 0.2, CH2Cl2).

[0050] Example 5 The only difference between Example 5 and Example 1 is that the substrate used in Example 5 is , all other conditions were the same, and the product obtained was compound 3d: tert-butyl (2S,3R)-2-((diphenylmethyl)amino)-3-phenylpent-4-enoate, with a yield of 94%, a diastereoisomer ratio (dr) greater than 20:1, and an enantiomeric excess (ee) of 94% ee.

[0051] The hydrogen and carbon spectra of tert-butyl (2S,3R)-2-((diphenylmethyl)amino)-3-phenylpent-4-enoate are as follows: Figure 14 、 Figure 15 As shown, the data are: HPLC [DAICEL CHIRALPAK IC, hexane / isopropanol = 98 / 2, 254 nm, 0.75 mL / min; t R1 =6.560min (minor), t R2 =7.957 min (main)].

[0052] ¹H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 7.5 Hz, 2H), 7.41 – 7.29 (m,6H), 7.21 (d, J = 7.4 Hz, 2H), 7.12–7.17 (m, 3H), 6.84 (d, J = 5.9 Hz, 2H), 6.30 (dt, J = 17.9, 9.1 Hz, 1H), 5.17 (d, J = 12.7 Hz, 2H), 4.23 (d, J = 6.1 Hz, 1H), 4.09 (t, J = 7.2Hz, 1H), 1.30 (s, 9H).

[0053] 13C NMR (126 MHz, CDCl3) δ 170.8, 170.0, 141.4, 139.8, 137.9, 136.7, 130.3, 129.0, 128.8, 128.5, 128.3, 128.3, 128.1, 127.9, 126.6, 117.2, 81.1, 71.1, 53.8, 28.0.

[0054] HRMS (Q-TOF Premier) calculated values ​​were C 28 H 30 NO2 (M+H) + : 412.2271; measured value: 412.2272, [α] 25 D =-12.6 (c 1.0, CH2Cl2).

[0055] Example 6 The only difference between Example 6 and Example 1 is that the substrate used in Example 6 is The other conditions were the same, and the product obtained was compound 3e: tert-butyl (2S,3R)-3-(3-bromophenyl)-2-((diphenylmethyl)amino)pent-4-enoate, with a yield of 82%, a diastereoisomer ratio (dr) of 19:1, and an enantiomeric excess (ee) of 96%ee.

[0056] The hydrogen and carbon spectra of tert-butyl (2S,3R)-3-(3-bromophenyl)-2-((diphenylmethyl)amino)pent-4-enoate are as follows: Figure 16 、 Figure 17 As shown, the data are: HPLC [DAICEL CHIRALPAK IC, hexane / isopropanol = 98 / 2, 254 nm, 0.75 mL / min; t R1 =6.250min (minor), t R2 =7.762min(main)].

[0057] 1 H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 7.2 Hz, 2H), 7.44–7.36 (m, 4H), 7.36–7.24 (m, 4H), 7.10 (d, J = 3.5 Hz, 2H), 6.86 (d, J = 5.1 Hz, 2H), 6.35–6.24 (m, 1H), 5.21 (t, J = 13.7 Hz, 2H), 4.21 (d, J = 5.7 Hz, 1H), 4.10–4.02 (m, 1H), 1.35 (s, 9H).

[0058] 13 C NMR (126 MHz, CDCl3) δ 171.2, 169.7, 143.9, 139.6, 137.1, 136.5,131.9, 130.4, 129.8, 129.6, 129.0, 128.6, 128.4, 128.1, 127.8, 127.3, 122.3,117.9, 81.4, 70.7, 53.3, 28.0. HRMS (ESI + ) The calculated value is C 28 H 29 BrNO2 (M+H) + : 490.1376; measured value: 490.1385. [α] 25 D =-36.4 (c 0.5, CH2Cl2).

[0059] Examples 3-6 all demonstrate that the precursor in S2 can be successfully prepared, laying a solid raw material foundation for subsequent operations.

[0060] Comparing Examples 1 and 2, the results are shown in Table 1. As can be seen from Table 1, the use of chiral ligands of different configurations ((S,Rp)-L2 and (R,Sp)-L2) results in significant changes in the enantiomeric excess (ee%) of the product. Specifically, when (R,Sp)-L2 is used, the ee reaches 99%, while when (S,Rp)-L2 is used, the ee is -99%. This indicates that the configuration of the ligand plays a decisive role in the enantioselectivity of the reaction.

[0061] Table 1 Effects of different ligands on the products of Example 1-2 ;

[0062] Therefore, the present invention adopts the above-mentioned Rh / Cu synergistic catalytic method for synthesizing amatoxin intermediates. The Rh / Cu synergistic catalytic system can realize the construction of a tertiary stereocenter at the ortho position. A variety of aromatic and aliphatic substituted branched allylic products are obtained through the Rh / Cu synergistic catalytic system with good to high yields, high cis-trans isomerization selectivity, and good to excellent enantiomeric selectivity.

[0063] It should be pointed out finally that the above examples are only used to illustrate the technical solutions of the present application but not to limit it, and although the present application has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solutions of the present application can still be modified or replaced equivalently, and these modifications or equivalent replacements should not make the modified technical solutions deviate from the spirit and scope of the technical solutions of the present application.

Claims

1. A method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis, characterized in that: The following steps are involved: S1, preparation of Rh / Cu synergistic catalytic system; S2, adding the substrate, diphenylimino glycine tert-butyl ester, K3PO4 and THF into the Rh / Cu catalytic synergistic system to carry out asymmetric allylic alkylation reaction to obtain the precursor; S3, mixing the precursor with potassium antimonate dihydrate, AD-mix-β, and N-methylmorpholine-N-oxide, and adding the mixed solution to obtain a mixture, followed by post-treatment to obtain a dihydroxy compound; S4, placing the dihydroxy compound, acetyl chloride, and pyridine in a dichloromethane solution for reaction, neutralizing with aqueous ammonia, purifying after neutralization, and post-treating the purified product to obtain a residue; S5, dissolving the residue in dioxane and adding Na2CO3 and Fmoc-OSu, stirring and reacting, and post-treating the residue to obtain an intermediate product; S6. Dissolve the intermediate product obtained in step 5 in trifluoroacetic acid, stir, remove the solvent under reduced pressure, and purify by column chromatography to obtain an amatoxin intermediate.

2. The method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to claim 1, characterized in that: The specific operations of S1 are: S11. Preparation of a copper complex: In a nitrogen-filled glove box, add Cu(CH3CN)4PF6 and a chiral ligand into a flask, add ultra-dry THF, and stir to obtain a copper complex; S12, preparing a rhodium complex: adding [Rh(cod)Cl]2 and a chiral ligand to another flask, adding ultra-dry THF, and stirring to obtain a rhodium complex; S13. Prepare Rh / Cu synergistic catalytic system: transfer the copper complex solution into the rhodium complex flask via a syringe, and stir and mix to obtain the Rh / Cu synergistic catalytic system.

3. The method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to claim 1, characterized in that: In S11, the molar ratio of Cu(CH3CN)4PF6 to chiral ligand is 1:1, the amount of ultra-dry THF used is 0.5-1 mL, and the stirring time is 10-30 min; In S12, the molar ratio of [Rh(cod)Cl]2 to the chiral ligand is 1:1, the amount of ultra-dry THF used is 0.5-1 mL, and the stirring time is 5-10 min; In S11, S12 and S13, stirring is performed at 0-25°C.

4. The method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to claim 2, characterized in that: In S11 and S12, the chiral ligand includes one of (R)-L1, (S,Rp)-L2, (R,Sp)-L2, (R,Sp)-L3, (R)-L4, (S,S)-L5, (S,S)-L6, (R,R)-L7, (4S,5S)-L8, (4S,2R)-L9, and (2R,5R)-L10, and the same chiral ligand is selected in S11 and S12.

5. The method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to claim 1, characterized in that: In S2, the substrate includes one of allyl chloride and its derivatives and allyl acetate and its derivatives, wherein allyl chloride and its derivatives include 、 、 、 、 、 、 、 、 、 、 、 ; Allyl acetate and its derivatives include 、 、 、 、 、 、 、 、 、 、 、 、 、 .

6. The method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to claim 1, characterized in that: In S2, the molar ratio of the substrate and diphenyliminoglycine tert-butyl ester is (1-2):1, the molar ratio of diphenyliminoglycine tert-butyl ester and K3PO4 is 1:(1-2), and the amount of THF used is 5-15 mL.

7. The method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to claim 1, characterized in that: In S3, the molar amount of the precursor is 1-3 mmol, the amount of potassium antimonate dihydrate is 4-5 mg, the amount of AD-mix-β is 9-10 mg, the amount of the mixed solution is 1-5 mL, and the mixed solution is prepared by mixing diethyl ether and water, and the volume ratio of diethyl ether to water is (2-1):

1.

8. The method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to claim 1, characterized in that: In S4, the molar ratio of the dihydroxy compound, acetyl chloride and pyridine is 1:3:3, and acetyl chloride is added in batches at 0°C.

9. The method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to claim 1, characterized in that: In S5, the residue was dissolved in 3-5 mL of dioxane, 2-4 mmol of Na2CO3 and 1-2 mmol of Fmoc-OSu were added, and the mixture was stirred for 1-3 h, and the solvent was removed.

10. The method for synthesizing an amatoxin intermediate using Rh / Cu synergistic catalysis according to claim 1, characterized in that: In S6, the stirring time is 1-2 h, and the eluent for column chromatography is: CH2Cl2 / MeOH=(95-98):(2-5).

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