CN118047738A - Asymmetric synthesis method of (1R, 2S, 3R) -1- ((R) -ethylene oxide-2-yl) -4-pentene-1, 3-diol - Google Patents
Asymmetric synthesis method of (1R, 2S, 3R) -1- ((R) -ethylene oxide-2-yl) -4-pentene-1, 3-diol Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000011914 asymmetric synthesis Methods 0.000 title claims abstract description 14
- 239000005977 Ethylene Substances 0.000 title claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- -1 1, 6-heptadiene-3, 5-diol compound Chemical class 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 13
- 230000003197 catalytic effect Effects 0.000 claims abstract description 12
- 150000002978 peroxides Chemical group 0.000 claims abstract description 11
- 239000007800 oxidant agent Substances 0.000 claims abstract description 6
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 230000003647 oxidation Effects 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000005882 aldol condensation reaction Methods 0.000 claims description 6
- 238000005915 ammonolysis reaction Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 5
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- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
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- 150000001875 compounds Chemical class 0.000 abstract description 32
- 239000004593 Epoxy Substances 0.000 abstract description 6
- PEPISENPCDEXJK-UHFFFAOYSA-N hepta-1,6-diene-3,5-diol Chemical class C=CC(O)CC(O)C=C PEPISENPCDEXJK-UHFFFAOYSA-N 0.000 abstract description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
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- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 description 3
- XNAVFKFQASKYMW-UHFFFAOYSA-N C(O)[ClH]CO Chemical compound C(O)[ClH]CO XNAVFKFQASKYMW-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
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- LXBIFEVIBLOUGU-DPYQTVNSSA-N migalastat Chemical compound OC[C@H]1NC[C@H](O)[C@@H](O)[C@H]1O LXBIFEVIBLOUGU-DPYQTVNSSA-N 0.000 description 2
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
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- FAVAVMFXAKZTMV-UHFFFAOYSA-N dibutylboranyl trifluoromethanesulfonate Chemical compound CCCCB(CCCC)OS(=O)(=O)C(F)(F)F FAVAVMFXAKZTMV-UHFFFAOYSA-N 0.000 description 1
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an asymmetric synthesis method of (1R, 2S, 3R) -1- ((R) -ethylene oxide-2-yl) -4-pentene-1, 3-diol, wherein the epoxy compound is prepared by taking a No. four substituted 1, 6-heptadiene-3, 5-diol compound as a raw material and carrying out catalytic oxidation reaction in an organic solvent at the temperature of 10-25 ℃; the mol ratio of the catalytic oxidation raw material to the catalyst to the oxidant is 1:0.01-0.06:1.0-2.0; the catalyst is one or two of Berkessel-Katsuki, nitro-Salallen-Ti, and the oxidant is peroxide. In the invention, symmetrical 1, 6-heptadiene-3, 5-diol compounds are used as raw materials, one of double bonds is selectively oxidized, and an epoxy compound is constructed, so that the dissymmetry of the meso compound is realized.
Description
Technical Field
The invention relates to a synthetic method of an organic compound, in particular to an asymmetric synthetic method of (1R, 2S, 3R) -1- ((R) -ethylene oxide-2-yl) -4-pentene-1, 3-diol.
Background
Polyhydroxy compounds containing continuous chiral centers are widely found in natural products, bioactive molecules and drugs, such as the drug miogastat (Galafold, migalastat) for the treatment of fabry disease with genetic disease, D-glycerol-D-mannose-heptose with antibacterial activity, and polyhydroxy perhydroazepines or heptaiminocyclils with glycosidase and glycosyltransferase inhibition. The synthesis research of the compound containing the continuous chiral center has important significance.
The epoxy compound is much more active than general ethers due to ring tension, can undergo ring-opening reaction with various reagents, and is a very general synthetic intermediate. The epoxy compound containing continuous chiral center is used as substrate, and can be used for rapidly synthesizing drugs with antiviral, bacterial and enzyme inhibitors, such as five-membered nucleoside, hexose, piperidine and cyclohexylimine, etc. under proper conditions. Thus, the preparation of epoxy compounds having a continuous chiral center is the basis for the synthesis of polyhydroxy compounds containing a continuous chiral center.
In 1980, karl Barry Sharpless et al reported for the first time that asymmetric epoxidation (SHARPLESS EPOXIDATION), titanium tetraisopropoxide and diethyl tartrate were used in concert as catalysts, tert-butyl hydroperoxide as the oxidant, and primary and secondary allyl alcohols as the substrate, was used to effect the asymmetric epoxidation (J.am.chem.Soc.1980, 102, 5974-5976.). This reaction is often used in the kinetic resolution of racemic alcohols.
In 2005 Katsuki et al synthesized a dimer-Ti-trans-DACH SALALEN catalyst, using hydrogen peroxide as the oxidant, to catalyze the asymmetric epoxidation of non-conjugated terminal olefins, with high yields and good enantioselectivity for various types of substrates (angel. Chem. Int. Ed.2005,44,4935.).
In 2013, berkessel et al optimized and designed a novel Salalen catalyst with high yields and excellent enantioselectivities in the asymmetric epoxidation of non-conjugated terminal olefins (CHEMCATCHEM, 2016,8,3706-3709.).
In 2023, the Berkessel group reported a more recently developed NO 2 -Salalen catalyst that further improved the activity and stereoregulating ability of the epoxidation catalyst. In the asymmetric epoxidation of non-conjugated terminal olefins, the epoxidation products are obtained in low catalyst amounts, high yields and excellent enantioselectivity (angelw.chem.int.ed., 2023,62, e 202306854.).
Disclosure of Invention
The invention aims to: the invention aims to provide a synthetic method of asymmetric (1R, 2S, 3R) -1- ((R) -oxirane-2-yl) -4-pentene-1, 3-diol with single double bond selectively oxidized.
According to the technical scheme, the asymmetric synthesis method of (1R, 2S, 3R) -1- ((R) -ethylene oxide-2-yl) -4-pentene-1, 3-diol is prepared by carrying out catalytic oxidation reaction in an organic solvent by taking a quaternary substituted 1, 6-heptadiene-3, 5-diol compound as a raw material and peroxide as an oxidant at room temperature, wherein the catalyst of the catalytic oxidation reaction is one or two of Berkessel-Katsuki, nitro-Salallen-Ti, and the molar ratio of the raw material to the catalyst to the peroxide is 1:0.01-0.06:1.0-2.0.
In the invention, symmetrical 1, 6-heptadiene-3, 5-diol compounds are used as raw materials, one of double bonds is selectively oxidized, an epoxy compound is constructed, and the dissymmetry of a meso compound is realized.
Preferably, the same amount of promoter as the catalyst is also added in the catalytic oxidation reaction, and the promoter is one or a combination of more of n-butyl ammonium bisulfate, benzoic acid and 2, 6-di-tert-butyl pyridine. The reaction can be smoothly performed without adding a cocatalyst, and the expected product can be obtained, and after adding the cocatalyst, the yield of the desymmetrized oxirane compound can be improved.
Preferably, the structural general formula of the substituent at the fourth position of the raw material is as follows: n=0 to 3, r= Me, ph, OBn, o-F-Ph or p-Me-Ph.
Preferably, the Berkessel-Katsuki, nitro-Salalen-Ti catalyst has the structure:
preferably, the step of synthesizing the Nitro-Salallen-Ti catalyst is:
(1) Under the protection of inert gas, adding Ti (OiPr) 4, chloroform solvent and Nitro-salalen ligand in proportion, stirring at room temperature for not less than 30 minutes, wherein the adding proportion of Ti (OiPr) 4 and Nitro-salalen ligand is 1:1, and the adding proportion of solvent is 1mmol:20mL;
(2) Adding water into the product obtained in the step (1) in proportion, and continuously stirring for not less than 30 minutes, wherein the water adding proportion is 1 mmol/40 drops;
(3) Filtering out redundant water in the product obtained in the step (2) by using anhydrous sodium sulfate, continuously adding 10 mu L of hydrogen peroxide with the mass fraction of 50+/-5%, and stirring for not less than 3 hours;
(4) Removing the solvent obtained in the step (3) to obtain the Nitro-Salalen-Ti catalyst.
Preferably, the step of synthesizing the Berkessel-Katsuki catalyst is.
(1) Under the protection of inert gas, adding Ti (OiPr) 4, chloroform solvent and salalen ligand in proportion, stirring at room temperature for at least 30 minutes, wherein the adding proportion of Ti (OiPr) 4 and salalen ligand is 1:1, and the adding proportion of solvent is 1mmol:20mL;
(2) Adding water into the product obtained in the step (1) in proportion, and continuously stirring for not less than 30 minutes, wherein the water adding proportion is 1 mmol/40 drops;
(3) Filtering off excessive water in the product obtained in the step (2), and removing the solvent to obtain Berkessel-Katsuki catalyst.
Preferably, the molar ratio of the raw materials to the catalyst to the peroxide is 1:0.015-0.025:1.2-1.5, and the peroxide is 30-60% hydrogen peroxide aqueous solution by mass fraction. More preferably, the peroxide is a 40-55% aqueous hydrogen peroxide solution by mass.
Preferably, the organic solvent is one or more of dichloromethane, 1, 2-dichloroethane and chloroform.
Preferably, the catalytic oxidation reaction duration is not less than 45 hours.
Preferably, the starting material is prepared from acrolein and methyl hydrogen substituted ethyl acetate by successive aldol condensation, hydroxyl protection, ammonolysis, grignard alkenylation, deprotection and reduction reactions.
Preferably, the catalytic oxidation reaction temperature is 10 to 30 ℃.
More preferably, the aldol condensation reaction equation and steps are:
(1) Ethyl acetate with methyl hydrogen replaced is added into the reaction system, Molecular sieve, dichloromethane, cooling to not higher than-78 ℃;
(2) Dripping n-BuBOTf according to a molar ratio of 1:1.3 by using ethyl acetate with methyl hydrogen replaced, wherein the dripping time is not less than 30min, the DIEA is added according to a molar ratio of 1:1.6, the dripping time is not less than 30min, and the reaction is not less than 3.5 hours after the dripping is completed;
(3) According to ethyl acetate with methyl hydrogen replaced, dropwise adding acrolein according to a molar ratio of 1:5, wherein the dropwise adding time is not less than 30min, the reaction time is not less than 2 hours,
(4) Heating the product obtained in the step (3) to not higher than 0 ℃ and reacting for not less than 8 hours to obtain an aldol condensation product, namely racemized (2R, 3S) -3-hydroxy-4-ethyl pentenoate.
More preferably, the hydroxyl protection reaction equation and steps are:
(1) Adding an aldol condensation product, 2, 6-lutidine and methylene dichloride into a reaction system, dissolving, and cooling to not higher than-78 ℃, wherein the molar ratio of the aldol condensation product to the 2, 6-lutidine is 1:1.5;
(2) Adding TBSOTf dropwise according to a molar ratio of 1:1.2 for at least 30min, recovering the temperature to room temperature after the dripping is completed, and reacting for at least 2 hours; to obtain the hydroxyl protection product, namely racemized (2R, 3S) -3- ((tert-butyl dimethyl silyl) oxy) -4-ethyl pentenoate.
More preferably, the ammonolysis equation and the steps are:
(1) Under the ice water bath condition, adding a hydroxyl protection product, tetrahydrofuran and dimethylol hydrochloride into a reaction system, wherein the molar ratio of the hydroxyl protection product to the dimethylol hydrochloride is 1:1.5;
(2) Adding isopropyl magnesium chloride solution dropwise according to a molar ratio of 1:3 for at least 30min, recovering the temperature to room temperature after the dripping is completed, and reacting for at least 2 hours; to obtain ammonolysis product, racemization (2R, 3S) -3- ((tert-butyl dimethyl silyl) oxy) -N-methoxy-N-methyl-4-pentenamide.
The Grignard alkenyl reaction equation and the steps are as follows:
(1) Under the ice water bath condition, ammonolysis product, tetrahydrofuran and dissolution are added into the reaction system
(2) According to ammonolysis products, dropwise adding vinyl magnesium bromide solution according to a molar ratio of 1:3 for at least 30min, recovering the temperature to room temperature after the dropwise adding is finished, and reacting for at least 2 hours; to obtain alkenyl product, racemized (4S, 5R) -5- ((tert-butyl dimethyl silyl) oxy) -1, 6-heptadien-3-ketone.
More preferably, the hydroxyl deprotection reaction equation and steps are:
Adding an alkenyl product, tetrahydrofuran and hydrogen fluoride triethylamine into the reaction system, and stirring and reacting for 12 hours at 40 ℃; wherein the molar ratio of the alkenylation product to the triethylamine hydrogen fluoride is 1:5, and the hydroxy deprotection product, racemized (4R, 5S) -5-hydroxy-1, 6-heptadien-3-ketone is obtained.
More preferably, the reduction reaction equation and the step are respectively:
(1) Adding a hydroxy deprotection product, tetrahydrofuran, dissolving and cooling to not higher than-78 ℃;
(2) And (3) dropwise adding DIBAL-H solution according to a molar ratio of 1:2.7 for at least 60min, and reacting for at least 5H after the dropwise adding to obtain a reduction product, wherein meso (3R, 4R, 5S) -1, 6-heptadiene-3, 5-diol is obtained.
(1R, 2S, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol compound synthesized according to the previous procedure may be used to synthesize the polyol.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: 1. the selective oxidation of the meso compound is realized, and symmetrical meso raw materials are used for single-side selective oxidation to obtain a desymmetrical product; 2. the functional group derivatization is good, the hydroxyl and the epoxy group can be further converted into five-membered nucleoside and six-carbon carbohydrate compounds, and the five-membered nucleoside and six-carbon carbohydrate compounds can be used for constructing molecules with special three-dimensional structures; 3. the catalytic effect is good, and a small amount of catalyst can catalyze the product to obtain a target product; 4. the method can be carried out at room temperature in an open system, and is simple to operate.
Drawings
FIG. 1 is a chiral ELSD alignment chart of the product (1R, 2S, 3R) -2-methyl-1- ((R) -oxiran-2-yl) pent-4-ene-1, 3-diol in an example of the invention.
FIG. 2 is a chiral HPLC comparison of the product (1R, 2S, 3R) -1- ((R) -oxiran-2-yl) -2-phenyl-4-pentene-1, 3-diol in the examples of this invention.
FIG. 3 is a chiral HPLC comparison of the product (1S, 2S, 3R) -2- (benzyloxy) -1- ((R) -oxiran-2-yl) pent-4-ene-1, 3-diol in the examples of this invention.
FIG. 4 is a chiral HPLC comparison of the product (1R, 2S, 3R) -1- ((R) -oxiran-2-yl) -2-phenethyl-4-pentene-1, 3-diol in examples of this invention.
FIG. 5 is a chiral HPLC comparison of the product (1R, 2S, 3R) -2- (4- (benzyloxy) butyl) -1- ((R) -oxiran-2-yl) pent-4-ene-1, 3-diol in the examples of this invention.
FIG. 6 is a chiral HPLC comparison of the product (1R, 2S, 3R) -2- (2-fluorophenyl) -1- ((R) -oxiran-2-yl) pent-4-en-1, 3-diol in an example of the present invention.
FIG. 7 is a chiral HPLC comparison of the product (1R, 2S, 3R) -1- ((R) -oxiran-2-yl) -2- (p-tolyl) pent-4-en-1, 3-diol in the examples of this invention.
FIG. 8 is a general diagram of the synthetic route of the target product of the present invention.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings. Without additional description, the actual use of the following examples is commercially available in analytical purity and is used without purification.
Example 1 Synthesis of raw material meso (3R, 4R, 5S) -1, 6-heptadiene-3, 5-diol Compound and screening of reaction conditions
1.1 Raw material synthesis. The intermediate compound 1 is synthesized, and the reaction equation is as follows:
General procedure A. Substituted ethyl acetate (1.0 equiv,19.6 mmol) was weighed and activated Molecular sieves 1g was added to a reaction flask of methylene chloride (35 mL) and then placed at-78deg.C, n-BuBOTf (Dibutylboryl trifluoromethanesulfonate, CAS 60669-69-4,1.3equiv,25.5 mmol) was slowly added dropwise in this order, for 30min, DIEA (Diisopropylethylamine 1.6.6 equiv,31.3 mmol) for 30min, stirred for 3.5h, and finally freshly distilled acrolein (5.0 equiv,98 mmol) was added dropwise for 30min, stirred at this temperature for 2h, and then stirred overnight while transferring to an ice bath. After the reaction is completed, water and MeOH are sequentially added to H 2O2 (1:1) for quenching reaction, and the mixture is separated and purified by column chromatography (25% PE/EtOAc) to obtain light yellow or colorless oily (+ -) -1, racemic (2R, 3S) -3-hydroxy-4-ethyl pentenoate compounds with the yield of 65-95%.
Intermediate 2 was synthesized according to the following equation:
General procedure B, weighing compound (+ -) -1 (1.0 equiv) and 2, 6-lutidine (1.5 equiv) to dissolve in dichloromethane, moving the reaction flask to-78 ℃, slowly dropping TBSOTf (tert-Butyldimethylsilyl triflate, CAS 69739-34-0.2 equiv) for 30min, restoring room temperature to react for 2h, after TLC monitoring reaction completion, concentrating the reaction solution under reduced pressure, separating and purifying (10% PE/EtOAc) by column chromatography to obtain compound (+ -) -2, racemic (2R, 3S) -3- ((tert-butyldimethylsilyl) oxy) -4-pentenoic acid ethyl ester compound with yield of 90-98%.
Intermediate 3 was synthesized according to the following equation:
General procedure C A100 ml round bottom flask was taken, compound (+ -) -2 (1.0 equiv) was dissolved in tetrahydrofuran, dimethylhydroxylamine hydrochloride (1.5 equiv) was added, then placed in an ice-water bath, slowly and dropwise add isopropylmagnesium chloride (2.0 mol/L IN DIETHYL ETHER,3.0 equiv) for 30min, and after reaction was completed at room temperature was restored to 2h, column chromatography was performed to isolate and purify (18% PE/EtOAc) the complete reaction, obtaining compound (+ -) -3, racemic (2R, 3S) -3- ((tert-butyldimethylsilyl) oxy) -N-methoxy-N-methyl-4-pentenamide compound in 80-92% yield.
Intermediate compound 4 was synthesized according to the following equation:
General procedure D, compound (±) -3 (1.0 equiv) was dissolved in tetrahydrofuran in a 100ml round bottom flask, then placed in an ice-water bath, vinylmagnesium bromide (1.0 mol/L in THF,3.0 equiv) was slowly added dropwise for 30min, the reaction was resumed at room temperature for 2h, and after completion of the reaction by TLC monitoring, column chromatography was performed to separate and purify (8% pe/EtOAc) to give compound (±) -4, racemic (4R, 5S) -5- ((tert-butyldimethylsilyl) oxy) -1, 6-heptadien-3-one in 40-68% yield.
Intermediate compound 5 was synthesized according to the following equation:
General procedure E, taking 50ml of a centrifugal tube of poly tetrafluorobromoethylene, dissolving a compound (+/-) -4 (1.0 equiv) in tetrahydrofuran, adding hydrogen fluoride triethylamine (5.0 equiv), stirring at 40 ℃ for reaction for 12 hours, quenching NaHCO 3 after the reaction is monitored completely by TLC, extracting EtOAc, drying anhydrous Na 2SO4, concentrating under reduced pressure to obtain the compound (+/-) -5, and directly adding the racemic (4R, 5S) -5-hydroxy-1, 6-heptadien-3-one compound without other post-treatment.
The intermediate compound 6 is synthesized, and the reaction equation is as follows:
General procedure F) Compound (. + -.) -5 (1.0 equiv,10 mmol) was dissolved in 167mL tetrahydrofuran, the reaction flask was moved to-78deg.C, DIBAL-H (1.0 mol/L in Hexane,2.7equiv,27 mmol) was slowly added dropwise and reacted at this temperature with stirring for 5H, after completion of the reaction by TLC monitoring, 1M HCl solution was quenched, etOAc was extracted 5 times, dried over anhydrous Na 2SO4, and column chromatography was performed to isolate and purify (40% PE/EtOAc) to give Compound (. + -.) -6, meso (3R, 4R, 5S) -1, 6-heptadiene-3, 5-diol compound in 50-69%.
1.2 Reaction condition screening. Control experiments were performed using 4-phenyl-substituted 1, 6-heptadiene-3, 5-diol 6b as a template material, and the optimal reaction conditions were selected, and the selection procedure is shown in Table 1.
Example 2 substrate adaptation range determination.
From the results of table 1, substituent adaptation range determination of target compound 7 was performed under optimal reaction conditions. The synthesis reaction equation and the operation steps of the target compound 7 are as follows:
The general procedure G is to take a dried 10mL Shi Laike tube, add compound (+ -) -6 (1.0 equiv,0.1 mmol) and Nitro-Salalen titanium catalyst (2.5mol％,0.0025mmol)、(n-Bu)4NHSO4(2.5mol％,0.0025mmol)、50％H2O2(1.5equiv,0.15mmol) into dichloromethane (0.5 mL) respectively, react for 48h at room temperature, and obtain (1R, 2S, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol compound 7 after the reaction is monitored by TLC and is separated and purified by column chromatography, wherein the substrate adaptation range is see characterization data, the yield is 70-72%, and dr=3.6:1.
TABLE 1 template reaction condition screening
[A] 82% ee; [b] the yield was isolated; [c] dr=3.6:1; [d] dr=2.6:1; [e] dr=2.4:1; [f] dr=2.2:1; [g] dr=6:1.
By using a Nitro-Salalen titanium catalyst and 50% H 2O2 catalyst system, under the condition of room temperature, high-enantioselectivity (76-99% ee) of (1R, 2S, 3R) -1- ((R) -ethylene oxide-2-yl) -4-pentene-1, 3-diol compounds are efficiently synthesized, and the obtained product contains chiral hydroxyl groups and alkylene oxide groups and can be continuously derivatized to generate more small organic molecule intermediates. The types and proportions of the eluent used for separation and characterization data of the compounds 6 to 7 are shown in the following data.
1H NMR and 13C NMR
6a rac-(3R*,4r,5S*)-4-Methylhepta-1,6-diene-3,5-diol.Colorless oil,64％yield,Rf＝0.20(40％EtOAc/PE).1H NMR(400MHz,CDCl3)δ5.83(ddd,J＝17.2,10.6,5.2Hz,2H),5.23(dt,J＝17.3,1.6Hz,2H),5.11(dt,J＝10.6,1.6Hz,2H),4.40(ddt,J＝4.5,3.0,1.6Hz,2H),3.29(s,2H),1.65(qt,J＝7.1,2.8Hz,1H),0.85(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ139.47,114.69,76.46,42.20,5.41.
6b rac-(3R*,4r,5S*)-4-phenylhepta-1,6-diene-3,5-diol.Colorless oil,54％yield,Rf＝0.20(40％EtOAc/PE).HMRS(ESI)m/z calculated for C13H16O2Na([M+Na]+):227.1043,Found:227.1043.1H NMR(400MHz,CDCl3)δ7.39–7.26(m,5H),5.77(ddd,J＝17.0,10.4,6.6Hz,2H),5.24(dt,J＝17.2,1.4Hz,2H),5.12(dt,J＝10.4,1.3Hz,2H),4.67–4.60(m,2H),2.72(t,J＝5.3Hz,1H),2.05(s,2H).13C NMR(101MHz,CDCl3)δ139.16,139.14,136.31,130.44,128.26,127.24,116.33,74.53,74.49,57.14,57.12.IR(thin film)1450,1437,1419,1407,1392,1380,1333,1273,1088,1049 cm-1.
6c rac-(3R*,4r,5S*)-4-(benzyloxy)hepta-1,6-diene-3,5-diol.Colorless oil,69％yield,Rf＝0.20(40％EtOAc/PE).HMRS(ESI)m/z calculated for C14H18O3Na([M+Na]+):257.1148,Found:257.1148.1H NMR(400MHz,CDCl3)δ7.33(p,J＝4.5Hz,5H),5.94(ddd,J＝17.4,10.5,5.8Hz,2H),5.39(dt,J＝17.2,1.6Hz,2H),5.24(dt,J＝10.5,1.5Hz,2H),4.68(s,2H),4.29(d,J＝5.2Hz,2H),3.36(t,J＝4.5Hz,1H),2.64(d,J＝5.6Hz,2H).13C NMR(101MHz,CDCl3)δ137.80,137.63,128.55,128.13,128.12,116.75,84.37,75.41,72.72.IR(thin film)3688,2972,2900,1454,1405,1249,1066,1050,925,879,739,699 cm-1.
6d rac-(3R*,4r,5S*)-4-phenethylhepta-1,6-diene-3,5-diol.Colorless oil,51％yield,Rf＝0.20(40％EtOAc/PE).HMRS(ESI)m/z calculated for C15H20O2Na([M+Na]+):255.1356,Found:255.1356.1H NMR(400MHz,CDCl3)δ7.31–7.23(m,2H),7.20–7.08(m,3H),5.91(ddd,J＝17.2,10.6,5.1Hz,2H),5.30(dt,J＝17.2,1.7Hz,2H),5.18(dt,J＝10.5,1.6Hz,2H),4.49(ddd,J＝5.0,3.0,1.6Hz,2H),3.01(d,J＝8.7Hz,2H),2.69–2.59(m,2H),1.79–1.71(m,2H),1.68(tt,J＝5.5,2.8Hz,1H).13C NMR(101MHz,CDCl3)δ142.41,139.60,128.44,128.25,125.75,114.74,75.96,47.02,35.73,24.29.IR(thin film)1496,1453,1142,1032,995,922,750,699 cm-1.
6e rac-(3R*,4r,5S*)-4-(4-(benzyloxy)butyl)hepta-1,6-diene-3,5-diol.Colorless oil,51％yield,Rf＝0.20(40％EtOAc/PE).HMRS(ESI)m/z calculated forC18H26O3Na([M+Na]+):313.1774,Found:313.1774.1H NMR(400MHz,CDCl3)δ7.37–7.26(m,5H),5.93(ddd,J＝17.3,10.6,5.2Hz,2H),5.28(dt,J＝17.2,1.6Hz,2H),5.15(dt,J＝10.6,1.6Hz,2H),4.55–4.37(m,2H),3.44(t,J＝6.6Hz,2H),2.60(s,2H),1.59(dt,J＝13.4,5.0Hz,3H),1.47–1.33(m,4H).13C NMR(101MHz,CDCl3)δ139.67,138.57,128.33,127.63,127.49,114.68,75.83,72.86,70.19,48.04,29.98,26.25,22.29.IR(thin film)2949,2834,1452,1032,640 cm-1.
6f rac-(3R*,4r,5S*)-4-(2-fluorophenyl)hepta-1,6-diene-3,5-diol.Colorless oil,45％yield,Rf＝0.20(40％EtOAc/PE);HMRS(ESI)m/z calculated for C13H15O2FNa([M+Na]+):245.0948,Found:245.0948.1H NMR(400MHz,CDCl3)δ7.66(td,J＝7.5,1.8Hz,1H),7.22(tdd,J＝7.4,5.3,1.9Hz,1H),7.11(td,J＝7.6,1.3Hz,1H),7.02(ddd,J＝9.7,8.1,1.3Hz,1H),5.78(ddd,J＝16.9,10.4,6.1Hz,2H),5.21(dt,J＝17.1,1.4Hz,2H),5.09(dt,J＝10.5,1.4Hz,2H),4.69(t,J＝5.5Hz,2H),3.28(t,J＝4.9Hz,1H),2.44(s,2H).13C NMR(101MHz,CDCl3)δ162.80,160.37,138.74,131.16,131.13,128.47,128.38,123.77,123.74,123.68,123.54,116.15,115.19,114.95,74.60,47.07.IR(thin film)2796,1604,1490,1454,1229,1176,1098,1017,927,758cm-1.
6g rac-(3R*,4r,5S*)-4-(p-tolyl)hepta-1,6-diene-3,5-diol.Colorless oil,41％yield,Rf＝0.20(40％EtOAc/PE);HMRS(ESI)m/z calculated for C14H18O2Na([M+Na]+):241.1199,Found:241.1199.1H NMR(400MHz,CDCl3)δ7.34–7.17(m,2H),7.14(d,J＝7.6Hz,2H),5.77(ddd,J＝17.1,10.4,6.6Hz,2H),5.25(dt,J＝17.2,1.4Hz,2H),5.14–4.99(m,2H),4.62(t,J＝6.1Hz,2H),2.70(t,J＝5.4Hz,1H),2.33(s,3H),1.93(d,J＝3.2Hz,2H).13C NMR(101MHz,CDCl3)δ139.22,136.87,132.95,130.24,129.10,116.33,74.43,56.77,21.08.IR(thin film)2972,1615,1372,1053,1032,1016 cm-1.
7a(1R,2S,3R)-2-methyl-1-((R)-oxiran-2-yl)pent-4-ene-1,3-diol.Yellow oil,72％yield,dr＝2.4:1,Rf＝0.20(50％EtOAc/PE).76％ee,HPLC analysis:IA(n-hexane/2-propanol＝88/12,1.0mL/min,ELSD),t(major)8.94min,t(minor)2.82min;HRMS(ESI)m/z calculated for C8H14O3Na([M+Na]+):181.0835,Found:181.0835;1H NMR(400MHz,CDCl3)δ5.75(ddd,J＝17.0,10.4,7.5Hz,1H),5.31–5.12(m,2H),4.54(td,J＝7.4,1.2Hz,1H),3.83–3.62(m,4H),2.25(td,J＝7.2,6.0Hz,1H),0.94(d,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ135.57,117.45,84.61,82.02,78.17,62.68,44.99,12.68,1.01.IR(thinfilm)2948,2834,1660,1453,1370,114,1032,1020,691 cm-1.
7b(1R,2S,3R)-1-((R)-oxiran-2-yl)-2-phenylpent-4-ene-1,3-diol.Colorless oil,78％yield,dr＝3.6:1,Rf＝0.20(50％EtOAc/PE).82％ee,HPLC analysis:IM-3(n-hexane/2-propanol＝83/17,1.0mL/min,210nm),t(major)7.56min,t(minor)12.25min;HRMS(ESI)m/z calculated for C13H16O3Na([M+Na]+):243.0992,Found:243.0992;1H NMR(400MHz,CDCl3)δ7.36–7.29(m,2H),7.26–7.17(m,3H),5.43(ddd,J＝17.2,10.4,6.9Hz,1H),5.16(dt,J＝17.1,1.6Hz,1H),4.99(dt,J＝10.5,1.4Hz,1H),4.78(td,J＝7.7,7.1,1.4Hz,1H),4.51(t,J＝7.1Hz,1H),4.04–3.81(m,3H),3.51(t,J＝7.7Hz,1H),2.11(s,1H),2.00(s,1H).13C NMR(101MHz,CDCl3)δ135.79,128.89,128.47,126.99,117.34,83.96,82.20,62.38,57.36.IR(thin film)2948,28354,1660,1453,1370,1114,1032,1020,691 cm-1.
7c(1S,2S,3R)-2-(benzyloxy)-1-((R)-oxiran-2-yl)pent-4-ene-1,3-diol.Colorless oil,80％yield,dr＝5.7:1,Rf＝0.20(50％EtOAc/PE).99％ee,HPLC analysis:IM-3(n-hexane/2-propanol＝88/12,1.0mL/min,209nm),t(major)10.87min,t(minor)15.90min;HRMS(ESI)m/z calculated for C14H18O4Na([M+Na]+):273.1097,Found:273.1097;1H NMR(400MHz,CDCl3)δ7.39–7.26(m,5H),6.04(ddd,J＝17.5,10.4,7.5Hz,2H),5.40(ddd,J＝17.3,1.7,1.0Hz,1H),5.31(ddd,J＝10.4,1.7,0.9Hz,1H),4.64–4.54(m,2H),4.51(dd,J＝7.3,4.6Hz,1H),4.30(dd,J＝4.1,2.5Hz,1H),3.87(td,J＝5.0,4.4,3.2Hz,2H),3.82(dd,J＝11.7,3.4Hz,1H),3.78–3.68(m,1H),2.23(s,1H),2.01(s,1H).13C NMR(101MHz,CDCl3)δ137.49,133.38,128.47,127.90,127.64,119.08,86.14,84.94,81.89,76.44,72.01,62.72.IR(thin film)2949,2843,1365,1142,1054,1032,1017 cm-1.
7d(1R,2S,3R)-1-((R)-oxiran-2-yl)-2-phenethylpent-4-ene-1,3-diol.Colorless oil,68％yield,dr＝2.6:1,Rf＝0.20(50％EtOAc/PE).HPLC analysis:IM-3(n-hexane/2-propanol＝88/12,1.0mL/min,209nm),t(major)10.27min,t(minor)16.20min;HRMS(ESI)m/z calculated for C15H20O3Na([M+Na]+):271.1305,Found:271.1305;1H NMR(400MHz,CDCl3)δ7.31–7.23(m,2H),7.22–7.12(m,3H),5.79(ddd,J＝17.1,10.3,8.0Hz,1H),5.29(dt,J＝17.1,1.3Hz,1H),5.22(dt,J＝10.3,1.2Hz,1H),4.59(t,J＝7.9Hz,1H),3.94(t,J＝7.0Hz,1H),3.86–3.78(m,1H),3.72(dd,J＝9.1,4.6Hz,2H),2.66(t,J＝8.0Hz,2H),2.23(p,J＝7.6Hz,1H),1.82–1.61(m,2H).13C NMR(101MHz,CDCl3)δ141.83,135.46,128.44,128.33,125.97,118.04,84.06,81.73,76.25,62.40,49.55,33.76,29.81.IR(thin film)2949,2834,1652,1453,1371,1114,1032,1018,657 cm-1.
7e(1R,2S,3R)-2-(4-(benzyloxy)butyl)-1-((R)-oxiran-2-yl)pent-4-ene-1,3-diol.Colorless oil,44％yield,dr＝2.0:1,Rf＝0.20(50％EtOAc/PE).86％ee,HPLC analysis:IA(n-hexane/2-propanol＝91/9,1.0mL/min,210nm),t(major)18.31min,t(minor)29.95min;HRMS(ESI)m/z calculated for C18H26O3Na([M+Na]+):329.1723,Found:329.1723;1H NMR(400MHz,CDCl3)δ7.40–7.26(m,5H),5.75(ddd,J＝17.0,10.3,7.8Hz,1H),5.24(dt,J＝17.1,1.3Hz,1H),5.17(dt,J＝9.6,1.0Hz,1H),4.55(t,J＝7.8Hz,1H),4.49(d,J＝3.3Hz,2H),3.86(t,J＝6.8Hz,1H),3.83–3.75(m,1H),3.70(dq,J＝7.6,4.1Hz,2H),3.46(t,J＝6.3Hz,2H),2.36(s,1H),2.16(p,J＝6.9Hz,2H),1.76(s,1H),1.61(p,J＝6.7,6.3Hz,2H),1.50–1.33(m,4H).13C NMR(101MHz,CDCl3)δ138.41,135.55,128.36,127.67,127.57,117.67,84.14,81.80,76.34,72.90,70.10,62.55,50.18,29.70,27.58,24.24.IR(thin film)2831,1770,1616,1365,1268,1148,1057,1033,859,775 cm-1.
7f(1R,2S,3R)-2-(2-fluorophenyl)-1-((R)-oxiran-2-yl)pent-4-ene-1,3-diol.Colorless oil,76％yield,dr＝2.5:1,Rf＝0.20(50％EtOAc/PE).91％ee,HPLC analysis:IM-3(n-hexane/2-propanol＝91/9,1.0mL/min,209nm),t(major)11.76min,t(minor)17.83min;HRMS(ESI)m/z calculated for C13H15FO3Na([M+Na]+):261.0897,Found:261.0897;1H NMR(400MHz,CDCl3)δ7.35–7.18(m,2H),7.11(t,J＝7.5Hz,1H),7.06–6.96(m,1H),5.41(ddd,J＝17.3,10.3,7.3Hz,1H),5.16(d,J＝17.0Hz,1H),4.96(dd,J＝10.3,1.5Hz,1H),4.88(t,J＝7.9Hz,1H),4.60(t,J＝7.5Hz,1H),4.01–3.77(m,3H),2.09(s,1H),1.97(s,1H).13C NMR(101MHz,CDCl3)δ135.41,128.92,128.88,128.63,128.55,124.12,124.09,117.70,115.45,115.22,83.59,81.20,81.19,74.57,62.13,49.90.IR(thin film)2965,2924,1748,1603,1492,1371,1261,1032,799,755 cm-1.
7g(1R,2S,3R)-1-((R)-oxiran-2-yl)-2-(p-tolyl)pent-4-ene-1,3-diol.Colorless oil,78％yield,dr＝2.8:1,Rf＝0.20(50％EtOAc/PE).88％ee,HPLC analysis:IM-3(n-hexane/2-propanol＝90/10,1.0mL/min,206nm),t(major)14.08min,t(minor)25.95min;HRMS(ESI)m/z calculated for C14H18O3Na([M+Na]+):257.1148,Found:257.1147;1H NMR(400MHz,CDCl3)δ7.09(q,J＝8.1Hz,4H),5.45(ddd,J＝17.2,10.4,6.9Hz,1H),5.15(dt,J＝17.1,1.5Hz,1H),5.00(dt,J＝10.4,1.4Hz,1H),4.79–4.67(m,1H),4.46(t,J＝7.1Hz,1H),4.01–3.77(m,3H),3.47(t,J＝7.8Hz,1H),2.13(s,1H),2.02(s,1H).13C NMR(101MHz,CDCl3)δ136.61,135.94,134.51,129.18,128.77,117.26,83.87,82.18,62.40,56.92,21.04.IR(thin film)2968,1748,1367,1261,1032,951,801 cm-1./>
Claims (10)
1. An asymmetric synthesis method of (1R, 2S, 3R) -1- ((R) -ethylene oxide-2-yl) -4-pentene-1, 3-diol is characterized in that a four-position substituted 1, 6-heptadiene-3, 5-diol compound is used as a raw material, peroxide is used as an oxidant, catalytic oxidation reaction is carried out in an organic solvent at room temperature, the catalyst of the catalytic oxidation reaction is one or two combinations of Berkessel-Katsuki, nitro-Salalen-Ti, and the molar ratio of the raw material, the catalyst and peroxide is 1:0.01-0.06:1.0-2.0.
2. The asymmetric synthesis process of (1R, 2s, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol of claim 1, wherein the catalytic oxidation is further added with the same amount of co-catalyst as the catalyst, and the co-catalyst is one or a combination of more of n-butyl ammonium bisulfate, benzoic acid, 2, 6-di-t-butyl pyridine.
3. The asymmetric synthesis method of (1R, 2s, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol according to claim 1, wherein the raw material substituent at position four has a general structural formula: n=0, 1,2,3, r= Me, ph, OBn, o-F-Ph or p-Me-Ph.
4. The asymmetric synthesis method of (1R, 2s, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol according to claim 1, wherein the Berkessel-Katsuki, nitro-Salalen-Ti catalyst has the structure:
5. The asymmetric synthesis method of (1R, 2s, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol according to claim 1, wherein the molar ratio of the raw material, the catalyst and the peroxide is 1:0.015 to 0.025:1.2 to 1.5, and the peroxide is an aqueous hydrogen peroxide solution with a mass fraction of 30 to 60%.
6. The asymmetric synthesis method of (1R, 2s, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol according to claim 5, wherein the peroxide is an aqueous hydrogen peroxide solution with a mass fraction of 40 to 55%.
7. A process for the asymmetric synthesis of (1R, 2s, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol according to claim 1, wherein the organic solvent is one or a combination of more of dichloromethane, 1, 2-dichloroethane, chloroform.
8. A process for the asymmetric synthesis of (1R, 2s, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol according to claim 1, wherein the catalytic oxidation reaction is of a duration of not less than 45 hours.
9. A process for the asymmetric synthesis of (1R, 2s, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol according to claim 1, characterized in that the starting material is prepared from acrolein and methyl hydrogen substituted ethyl acetate, which are sequentially subjected to aldol condensation, hydroxyl protection, ammonolysis, grignard alkenylation, deprotection and reduction reactions.
10. The asymmetric synthesis method of (1R, 2s, 3R) -1- ((R) -oxiran-2-yl) -4-pentene-1, 3-diol according to claim 1, wherein the room temperature is 10 to 30 ℃.
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