CN110724152B - Method for synthesizing chiral fused polycyclic tropanes by dearomatization cycloaddition - Google Patents
Method for synthesizing chiral fused polycyclic tropanes by dearomatization cycloaddition Download PDFInfo
- Publication number
- CN110724152B CN110724152B CN201911257338.4A CN201911257338A CN110724152B CN 110724152 B CN110724152 B CN 110724152B CN 201911257338 A CN201911257338 A CN 201911257338A CN 110724152 B CN110724152 B CN 110724152B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- reaction
- tropane
- chiral
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for synthesizing chiral condensed polycyclic tropane by dearomatization cycloaddition, belonging to the technical field of organic synthesis. The chiral condensed polycyclic tropane compound 3 is obtained by taking cyclic imine ylide 1 and nitrobenzofuran 2 as raw materials and performing asymmetric 1, 3-dipolar [3+2] cycloaddition reaction under the catalysis of copper salt and axial chiral diphosphine. The method has the advantages of high diastereoselectivity and high enantioselectivity, and the product simultaneously has four continuous chiral centers, so that a simple and convenient synthetic approach is provided for chiral condensed polycyclic tropane.
Description
Technical Field
The invention particularly relates to a method for synthesizing chiral condensed polycyclic tropane through dearomatization cycloaddition, belonging to the technical field of asymmetric synthesis in organic chemistry.
Background
Polycyclic structures with tropanes as basic skeletons are widely present in natural products and drug molecules with important physiological functions. The compounds play a key role in the clinical treatment of immune, neurological and mental diseases and the like.
At present, chiral tropane compounds are synthesized by taking chiral reagents as raw materials, the structures are simpler, and the literature reports of synthesizing the fused ring polycyclic tropane compounds with complex structures by a catalytic asymmetric method are less. The prior published reports only include Waldmann and the like which respectively synthesize indolo-tropane compounds by using cycloaddition reaction of cycloimine ylide and nitrostyrene [3+2], Dunwei and the like which respectively synthesize indolo-tropane compounds by using [3+3] cycloaddition of 2-alkenyl indole and cycloimine ylide; and bin, etc. the benzo tropane compounds are synthesized by utilizing dearomatization reaction of isoquinoline.
In view of the dearomatization cycloaddition reaction of benzofuran compounds, the research on constructing a novel chiral thickening polycyclic tropane compound is still insufficient, so that the research on the field is still needed, and a simple and effective synthesis method is developed.
Disclosure of Invention
In order to solve the technical problems, the invention firstly provides a chiral condensed polycyclic tropane compound with a novel structure, which has the following structure:
wherein R is1Selected from halogen, alkyl or alkoxy; r2And R3Are all selected from alkyl; r4Selected from halogen, nitro, alkyl or alkoxy.
Nitro-substituted benzofuran 2 and cyclic imine ylide 1 are adopted as raw materials, and in the presence of copper salt, organic phosphine ligand and alkali, chiral condensed polycyclic tropane compounds 3 are obtained through asymmetric 1, 3-dipolar cycloaddition dearomatization reaction. The method provides a mild, simple and efficient way for synthesizing chiral condensed polycyclic tropane compounds.
A process for the synthesis of chiral fused polycyclic tropanes by dearomatization cycloaddition comprising the following operations: nitro-substituted benzofuran 2 and cyclic imine ylide 1 are used as raw materials and react in the presence of copper salt, organic phosphine ligand and alkali to obtain chiral condensed polycyclic tropane 3; the reaction equation is as follows:
wherein R is1Selected from halogen, C1-C4 alkyl or C1-C4 alkoxy; r2And R3Are all selected from C1-C7 alkyl; r4Selected from halogen, nitro, C1-C4 alkyl or C1-C4 alkoxy.
Preferably, in the above technical solution, R1Selected from 5-Me, 5-OCH3、5-Br、4-OCH36-Cl, etc.; r2Selected from Me, Et, Bn, etc.; r3Selected from Et, n-type, etc.; r4Selected from 5-Me, 5-OCH3、5-F、5-Cl、5-Br、5-NO2、6-Me、6-OCH3、6-Br、7-OCH37-Br, etc.
Further, in the above technical scheme, the organophosphine ligand is selected from L1-L9, and has the following structure:
among the above-mentioned L1-L9 phosphorus catalysts, the preferred catalysts are L6-L9.
Further, in the above technical solution, the copper salt is selected from Cu (OAc)2、Cu(OTf)2、Cu(MeCN)4ClO4、Cu(MeCN)4PF6And the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, triethylamine and the like.
Further, in the technical scheme, the molar ratio of the nitro-substituted benzofuran compound 2, the cyclic imine ylide 1, the copper salt, the organic phosphine ligand and the alkali is 1:2-2.2:0.005-0.05:0.005-0.05: 0.05-0.15.
Further, in the above technical scheme, the reaction is carried out in an organic solvent, and the organic solvent is selected from one or more of methyl tert-butyl ether, chloroform, dichloromethane, dichloroethane, acetonitrile, diethyl ether or toluene. The preferred solvent is methyl tert-butyl ether.
Further, in the above technical scheme, the reaction temperature is selected from 25 ℃ to-40 ℃. The preferred temperature is 0 ℃.
Further, in the above technical scheme, the reaction is carried out under the protection of inert gas, and the inert gas is preferably nitrogen.
Further, the obtained chiral condensed polycyclic tropane compounds 3 can be derived to obtain different types of derived products, the nitro group is removed to generate a denitrified product 4, the nitro group is reduced to generate a product 5 reduced to amino, and the ester group is reduced to obtain a product 6 reduced to hydroxyl.
Further, tributyltin hydride and AIBN were used for the conversion of product 4, and zinc dust and concentrated hydrochloric acid were used for the conversion of product 5. The conversion of product 6 was performed with lithium aluminum hydride.
Further, in the above technical scheme, the compound 4 generated by denitrating with tributyltin hydride and AIBN is selected from 80 ℃, and the compound 5 generated by nitro reduction is selected from 0 ℃. The ester group reduction to produce compound 6 is selected from-78 ℃.
The invention has the beneficial effects that:
the invention takes nitro-substituted benzofuran 2 and cyclic imine ylide 1 as raw materials, chiral condensed polycyclic tropane compounds 3 can be obtained in one step after asymmetric dearomatization [3+2] cycloaddition reaction, and simultaneously have 4 continuous chiral centers, the structure is novel, and no published data report is found.
The reaction raw materials are easy to obtain, the diastereoselectivity and enantioselectivity of the product are high, the dr value of the product can be up to more than 20:1, and the reaction yield and enantioselectivity can be up to 91% and 98% ee respectively. The product is derived after denitrating, nitryl reducing and ester group reducing to obtain polycyclic tropane 4-6 of different types.
Drawings
FIG. 1 is a single-crystal X-ray diffraction pattern of compound 3ak in example 11.
Detailed Description
Example 1
Taking the example of 3aa generated by 2-nitrobenzofuran 2a and cyclic imine ylide 1a, the reaction conditions are optimized, and the reaction equation is as follows:
aunless otherwise stated, the steps of the reaction are as follows: 1a (0.22mmol),2a (0.1mmol), metallic copper (5 mol%), ligand (5 mol%), base (10 mol%), 1.0mL of solvent in N2The reaction is carried out for 10 hours at 0 ℃ under protection.bThe separation yield is as follows,cthe dr value was determined by nuclear magnetic testing of the crude product.dAs determined by chiral HPLC analysis.e1a (0.44mmol),2a (0.2mmol), metallic copper (1 mol%), ligand (1 mol%), base (10 mol%), 2.0mL of solvent.
In the course of screening of the reaction conditions, the effect of the catalyst on the reaction was first examined (entries 1-9). Meanwhile, the influence of different solvents, reaction temperature (-40 ℃ to +25 ℃, influence of enantioselectivity and yield not more than 2%), raw material equivalent ratio, catalyst amount (0.01-0.05 equivalent, enantioselectivity is basically unchanged, yield is 85-87%) and different bases (such as potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and the like, influence of enantioselectivity and yield not more than 2%) on the reaction are considered, and finally L9 is determined to be the optimal catalyst, MTBE is the optimal reaction solvent, and 0 ℃ is the optimal reaction temperature.
Examination of reaction conditions (taking entry 17 as an example): to a 10mL Schlenk tube were added 2-nitrobenzofuran 2a (32.6mg, 0.2mmol), ligand L9(1.9mg,0.002mmol), Cu (OAc)2(0.36mg,0.002mmol) and K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1a (106.8mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/5 vol.) to give 70.5mg of the product 3aa as an orange solid in 87% yield, dr values 14/1, 97% ee. [ alpha ]]D 28＝57.00(c＝0.80,CH2Cl2).m.p.:115-116℃.HPLC CHIRALCEL ID,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,temperature＝25℃,λ＝256nm,retention time:8.123min(major),9.938min(minor).TLC:Rf＝0.24(petroleum ether:ethyl acetate＝4:1).1H NMR(400MHz,CDCl3)7.93(s,1H),7.33–7.29(m,1H),7.27–7.23(m,1H),7.10–7.05(m,2H),6.92(d,J＝7.2Hz,1H),6.89–6.85(m,2H),6.40–6.36(m,1H),6.85(s,1H),4.03(s,3H),3.77(s,1H),3.12(d,J＝15.6Hz,1H),2.94(d,J＝15.6Hz,1H),1.72(s,3H).13C NMR(150MHz,CDCl3)173.2,159.7,136.2,132.7,129.7,129.0,126.0,124.4,123.5,122.6,122.5,119.9,118.3,111.1,109.8,107.5,69.9,67.8,62.8,53.4,28.4,15.6.HRMS:exactmass calcd for C22H20N3O5(M+H)+requires m/z 406.1397,found m/z406.1388.
Example 2
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2a (32.6mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1b (112.7mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/4 vol.) to give 70.2mg of the product 3ba as an orange solid in 85% yield, dr values 16/1, 95% ee. [ alpha ]]D 28＝-8.33(c＝0.72,CH2Cl2).m.p.:83-84℃.HPLCCHIRALCEL ID,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,temperature＝25℃,λ＝256nm,retention time:7.963min(major),12.017min(minor).TLC:Rf＝0.23(petroleum ether:ethyl acetate＝4:1).1H NMR(400MHz,CDCl3)7.84(s,1H),7.34–7.29(m,1H),7.13(d,J＝8.4Hz,1H),6.93–6.85(m,3H),6.84(s,1H),6.43–6.37(m,1H),4.85(s,1H),4.03(s,3H),3.74(s,1H),3.08(d,J＝15.6Hz,1H),2.91(d,J＝15.6Hz,1H),2.29(s,3H),1.70(s,3H).13C NMR(150MHz,CDCl3)173.3,159.8,134.6,132.7,129.7,129.0,129.0,126.3,124.4,124.2,123.5,122.5,118.1,110.7,109.8,107.0,69.9,67.7,62.8,53.4,28.4,21.5,15.7.HRMS:exact mass calcd for C23H22N3O5(M+H)+requires m/z420.1554,found m/z 420.1563.
Example 3
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2a (32.6mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1c (119.7mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/4 vol.) to give 77.4mg of the product 3ca as an orange solid in 89% yield, dr 17/1, 96% ee. [ alpha ]]D 28＝-25.45(c＝0.88,CH2Cl2).m.p.:94-96℃.HPLCCHIRALCEL ID,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,temperature＝25℃,λ＝256nm,retention time:8.765min(major),13.665min(minor).TLC:Rf＝0.23(petroleum ether:ethyl acetate＝4:1).1H NMR(400MHz,CDCl3)7.89(s,1H),7.31(d,J＝6.8Hz,1H),7.12(d,J＝8.8Hz,1H),6.93–6.84(m,2H),6.72(dd,J＝8.8,2.4Hz,1H),6.49(d,J＝2.4Hz,1H),6.40–6.35(m,1H),4.84(s,1H),4.03(s,3H),3.78(br s,1H),3.71(s,3H),3.09(d,J＝15.6Hz,1H),2.91(d,J＝15.6Hz,1H),1.69(s,3H).13C NMR(150MHz,CDCl3)173.2,159.7,154.1,133.4,131.4,129.8,129.0,126.5,124.4,123.5,122.5,112.5,111.8,109.8,107.3,100.4,69.9,67.8,62.8,55.8,53.4,28.4,15.6.HRMS:exact masscalcd for C23H22N3O6(M+H)+requires m/z 436.1503,found m/z 436.1509.
Example 4
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2a (32.6mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1d (140.8mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/4 vol.) to give 81.2mg of the product 3da as an orange solid in 84% yield, dr values 17/1, 98% ee. [ alpha ]]D 28＝-43.67(c＝0.60,CH2Cl2).m.p.:103-105℃.HPLCCHIRALCEL ID,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,temperature＝25℃,λ＝254nm,retention time:6.293min(major),7.543min(minor).TLC:Rf＝0.29(petroleum ether:ethyl acetate＝4:1).1H NMR(400MHz,CDCl3)8.03(s,1H),7.30(d,J＝6.4Hz,1H),7.19(s,1H),7.17–7.10(m,2H),6.96–6.87(m,2H),6.42–6.34(m,1H),4.84(s,1H),4.03(s,3H),3.80(s,1H),3.06(d,J＝16.0Hz,1H),2.91(d,J＝16.0Hz,1H),1.71(s,3H).13C NMR(150MHz,CDCl3)173.0,159.6,134.8,134.1,129.9,128.9,127.7,125.5,124.4,123.3,122.7,121.0,113.1,112.6,109.8,107.2,69.80,67.80,62.9,53.5,28.2,15.5.HRMS:exact mass calcd for C22H18BrN3NaO5(M+Na)+requires m/z 506.0322,foundm/z506.0318.
Example 5
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2a (32.6mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1e (119.7mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/4 vol.) to give 79.2mg of 3ea as an orange solid in 91% yield, dr 17/1, 96% ee. [ alpha ]]D 28＝42.86(c＝0.84,CH2Cl2).m.p.:89-91℃.HPLCCHIRALCEL IA,n-hexane/2-propanol＝80/20,flow rate＝0.6mL/min,temperature＝25℃,λ＝250nm,retention time:15.745min(minor),18.868min(major).TLC:Rf＝0.24(petroleum ether:ethyl acetate＝4:1).1H NMR(400MHz,CDCl3)7.90(s,1H),7.34(d,J＝6.8Hz,1H),6.95(t,J＝8.0Hz,1H),6.92–6.86(m,2H),6.84(d,J＝8.4Hz,1H),6.44–6.38(m,1H),6.28(d,J＝7.6Hz,1H),4.84(s,1H),4.02(s,3H),3.75–3.63(m,4H),3.26(d,J＝16.4Hz,1H),3.17(d,J＝16.4Hz,1H),1.68(s,3H).13C NMR(150MHz,CDCl3)173,4,159.7,154.5,137.6,130.9,129.6,129.0,124.6,123.7,123.3,122.4,116.6,109.7,107.5,104.4,100.2,70.0,67.6,62.5,55.4,53.3,30.2,15.7.HRMS:exact mass calcd forC23H22N3O6(M+H)+requires m/z 436.1503,found m/z 436.1505.
Example 6
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2a (32.6mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1f (121.5mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/6 vol.) to give 71.1mg of 3fa as an orange solid in 81% yield, dr value 15/1, 92% ee. [ alpha ]]D 28＝43.08(c＝1.04,CH2Cl2).m.p.:91-93℃.HPLCCHIRALCEL OD-H,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,temperature＝25℃,λ＝256nm,retention time:7.593min(major),11.335min(minor).TLC:Rf＝0.22(petroleum ether:ethyl acetate＝6:1).1H NMR(400MHz,CDCl3)8.00(s,1H),7.31–7.28(m,1H),7.25–7.23(m,1H),6.96(d,J＝8.4Hz,1H),6.93–6.85(m,3H),6.41–6.37(m,1H),4.83(s,1H),4.03(s,3H),3.84(br s,1H),3.08(d,J＝15.6Hz,1H),2.91(d,J＝15.6Hz,1H),1.71(s,3H).13C NMR(150MHz,CDCl3)173.0,159.6,136.5,133.4,129.8,128.9,128.4,124.6,124.4,123.4,122.6,120.8,119.2,111.1,109.9,107.7,69.9,67.9,62.8,53.5,28.2,15.5.HRMS:exact mass calcd for C22H18ClN3NaO5(M+Na)+requires m/z462.0827,found m/z 462.0829.
Example 7
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2a (32.6mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Iminoylide 1g (112.7mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution via syringe at 0 deg.CStirred for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/4 vol.) to give 72.9mg of the product 3ga as a pale yellow solid in 87% yield, dr values 14/1, 98% ee. [ alpha ]]D 28＝13.2(c＝1.00,CH2Cl2).m.p.:89-91℃.HPLC CHIRALCELID,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,temperature＝25℃,λ＝250nm,retention time:7.065min(major),8.370min(minor).TLC:Rf＝0.25(petroleumether:ethyl acetate＝4:1).1H NMR(600MHz,CDCl3)8.05(s,1H),7.32–7.29(m,1H),7.23(d,J＝8.4Hz,1H),7.09–7.05(m,2H),6.92–6.89(m,1H),6.88–6.85(m,2H),6.37–6.33(m,1H),4.84(s,1H),4.53–4.45(m,2H),3.82(br s,1H),3.12(d,J＝15.6Hz,1H),2.95(d,J＝15.6Hz,1H),1.71(s,3H),1.49(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)172.7,159.7,136.2,132.7,129.6,129.1,126.0,124.3,123.6,122.5,122.5,119.8,118.3,111.1,109.8,107.6,69.9,67.9,62.9,62.4,28.3,15.6,14.4.HRMS:exact mass calcd forC23H22N3O5(M+H)+requires m/z 420.1554,found m/z 420.1556.
Example 8
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2a (32.6mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1j (131.2mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/5 vol.) to give 71.0mg of 3ja as a pale yellow solid in 77% yield, dr value 11/1, 90% ee.[ɑ]D 28＝14.12(c＝0.78,CH2Cl2).m.p.:96-97℃.HPLCCHIRALCEL IA,n-hexane/2-propanol＝90/10,flow rate＝0.6mL/min,temperature＝25℃,λ＝254nm,retention time:10.170min(minor),40.132min(major).TLC:Rf＝0.21(petroleum ether:ethyl acetate＝5:1).1H NMR(400MHz,CDCl3))7.97(s,1H),7.31–7.27(m,1H),7.24(d,J＝8.0Hz,1H),7.11–7.01(m,2H),6.89(t,J＝7.6Hz,1H),6.86–6.76(m,2H),6.37–6.21(m,1H),4.83(s,1H),4.03(s,3H),3.61(s,1H),3.13(d,J＝15.6Hz,1H),2.93(d,J＝15.6Hz,1H),2.28–2.14(m,1H),1.68–1.56(m,3H),1.38–1.25(m,4H),0.87(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)173.3,159.6,136.4,131.4,129.5,129.3,126.0,124.2,123.6,122.6,122.4,119.7,118.2,111.0,109.5,109.1,71.9,69.8,62.4,53.4,32.4,29.6,28.3,25.3,22.6,14.1.HRMS:exact mass calcd for C26H28N3O5(M+H)+requires m/z 462.2023,found m/z 462.2021.
Example 9
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2b (35.4mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1a (106.8mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/5 vol.) to give 69.6mg of the product 3ab as an orange solid in 83% yield, dr values 14/1, 94% ee. [ alpha ]]D 28＝65.56(c＝0.90,CH2Cl2).m.p.:113-115℃.HPLCCHIRALCEL ID,n-hexane/2-propanol＝80/20,flow rate＝0.6mL/min,temperature＝25℃,λ＝250nm,retention time:13.765min(major),20.677min(minor).TLC:Rf＝0.28(petroleum ether:ethyl acetate＝4:1).1H NMR(400MHz,CDCl3)7.94(s,1H),7.28–7.21(m,1H),7.12–7.06(m,3H),6.93(t,J＝7.2Hz,1H),6.67(d,J＝9.2Hz,1H),6.26(d,J＝8.4Hz,1H),4.82(s,1H),4.03(s,3H),3.75(s,1H),3.11(d,J＝15.6Hz,1H),2.95(d,J＝16.0Hz,1H),2.21(s,3H),1.71(s,3H).13C NMR(150MHz,CDCl3)173.3,157.9,136.2,132.8,132.0,130.2,129.2,126.1,124.7,123.3,122.6,119.8,118.4,111.1,109.4,107.5,69.8,67.7,62.9,53.4,28.3,20.9,15.7.HRMS:exact mass calcd for C23H21N3NaO5(M+Na)+requires m/z442.1373,found m/z 442.1370.
Example 10
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2d (36.2mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1a (106.8mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and, after completion of the reaction, the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/4 vol.) to give 73.6mg of the product 3ad as an orange solid in 87% yield, dr 14/1, 92% ee. [ alpha ]]D 28＝22.50(c＝1.30,CH2Cl2).m.p.:95-97℃.HPLCCHIRALCEL ID,n-hexane/2-propanol＝80/20,flow rate＝0.8mL/min,temperature＝25℃,λ＝250nm,retention time:9.445min(major),12.578min(minor).TLC:Rf＝0.25(petroleum ether:ethyl acetate＝4:1).1H NMR(400MHz,CDCl3)7.95(s,1H),7.28–7.24(m,1H),7.10(t,J＝8.0Hz,2H),7.03(dd,J＝7.6,2.4Hz,1H),6.95(t,J＝7.2Hz,1H),6.58(td,J＝8.8,2.8Hz,1H),6.31(dd,J＝8.8,4.0Hz,1H),4.83(s,1H),4.03(s,3H),3.73(s,1H),3.14(d,J＝15.6Hz,1H),2.95(d,J＝15.6Hz,1H),1.71(s,3H).13C NMR(150MHz,CDCl3)173.0,160.2,136.2,132.5,129.2,125.9,125.8,125.3,123.0,122.8,122.7,120.2,118.4,113.5,111.2,107.4,69.7,67.7,62.2,53.5,28.4,15.7.HRMS:exact mass calcdfor C22H18FN3NaO5(M+Na)+requires m/z 446.1123,found m/z 446.1127.
Example 11
To a 10mL Schlenk tube was added 2-nitrobenzofuran 2k (38.6mg, 0.2mmol), ligand L9(1.9mg,0.002mmol) metal Cu (OAc)2(0.36mg,0.002mmol) and a base K2CO3(2.8mg,0.02mmol,10 mol%). The tube was sealed with a threaded rubber stopper, replaced 3 times with nitrogen, then MTBE (1.0mL) was added via syringe and the mixture was stirred at 25 ℃ for 40 minutes. Imine ylide 1a (106.8mg,0.44mmol) was dissolved in MTBE (1.0mL), and the mixture was added to the reaction solution by syringe and stirred at 0 ℃ for 10 hours. The reaction was followed by TLC and after completion of the reaction mixture was purified by preparative thin layer chromatography using ethyl acetate/petroleum ether (1/4 vol.) to give 72.2mg of 3ak as a grey solid in 83% yield, dr values 17/1, 92% ee. [ alpha ]]D 28＝-70.00(c＝0.60,CH2Cl2).m.p.:130-132℃.HPLC CHIRALCELID,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,temperature＝25℃,λ＝256nm,retention time:9.568min(major),13.188min(minor).TLC:Rf＝0.23(petroleumether/ethyl acetate＝4:1).1H NMR(400MHz,CDCl3)8.07(s,1H),7.17(d,J＝8.0Hz,1H),7.10–7.02(m,2H),6.96–6.88(m,2H),6.80(t,J＝7.6Hz,1H),6.47(d,J＝8.4Hz,1H),4.85(s,1H),4.02(s,3H),3.83(s,1H),3.45(s,3H),3.12(d,J＝15.6Hz,1H),2.98(d,J＝15.6Hz,1H),1.74(s,3H).13C NMR(100MHz,CDCl3)173.2,148.5,143.9,136.3,132.6,129.1,126.1,124.9,123.1,122.5,119.8,118.3,116.5,113.2,111.3,107.7,70.0,68.0,63.4,56.2,53.4,28.4,15.6.HRMS:exact mass calcd for C23H22N3O6(M+H)+requires m/z436.1503,found m/z 436.1507.
Example 12
To a 10mL Schlenk tube were added 3aa (40.5mg,0.1mmol), ethanol (1.5mL) and concentrated hydrochloric acid (0.08mL) in that order, and zinc powder (0.26g,4mmol) was added slowly at zero degrees. The mixture was stirred at 0 ℃ for 30 min. After completion of the reaction, the mixture was filtered through celite and saturated NaHCO3The solution was quenched, extracted with dichloromethane and water, the organic phase was dried over anhydrous sodium sulfate and the reaction mixture was purified by preparative thin layer chromatography on methanol/dichloromethane (vol. 1/20) to give 28.9mg of product 6 as a white solid in 77% yield in 97% ee. [ alpha ]]D 28＝-53.24(c＝1.00,CH2Cl2).m.p.:106-108℃.HPLCCHIRALCEL IE,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,temperature＝25℃,λ＝256nm,retention time:9.575min(minor),17.278min(major).TLC:Rf＝0.29(dichloromethane:methanol＝20:1).1H NMR(400MHz,DMSO-d6)10.99(s,1H),10.04(s,1H),9.35(s,1H),7.33(d,J＝8.0Hz,1H),7.07(d,J＝7.6Hz,1H),7.02(t,J＝8.0Hz,1H),6.87(t,J＝7.2Hz,1H),6.83–6.76(m,1H),6.66(d,J＝7.6Hz,1H),5.98(t,J＝7.2Hz,1H),5.46(d,J＝6.8Hz,1H),4.70(s,1H),3.73(s,3H),3.45(s,1H),2.87(d,J＝15.6Hz,1H),2.10(d,J＝15.6Hz,1H),1.74(s,3H).13C NMR(150MHz,DMSO-d6)174.4,162.4,154.6,137.2,136.0,128.3,127.0,126.7,123.2,120.7,118.6,117.5,113.9,111.3,105.9,66.6,61.0,52.1,49.3,48.6,26.6,17.4.HRMS:exact mass calcd for C22H22N3O3(M+H)+requires m/z 376.1656,found m/z 376.1654.
Example 13
To a 10mL Schlenk tube was added 3aa (40.5mg,0.1mmol), the tube was sealed with a threaded rubber stopper and replaced with nitrogen 3 times. Adding dry THF (1.0mL) solution with a needle, cooling the reaction solution to-78 deg.C, and slowly adding LiAlH4(0.2 ml). The mixture was stirred at-78 ℃ for 30 min. After completion of the reaction, it was quenched with 15% sodium hydroxide solution (0.15ml), extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate, and the reaction mixture was purified by preparative thin layer chromatography using methanol/dichloromethane (vol. 1/20) to give 24.9mg of product 6 as a gray solid in 66% yield and 94% ee. [ alpha ]]D 26＝-40.00(c＝0.90,CH2Cl2).m.p.:111-113℃ HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flowrate＝0.8mL/min,temperature＝25℃,λ＝256nm,retention time:6.442min(minor),15.342min(major).TLC:Rf＝0.26(dichloromethane:methanol＝20:1).1H NMR(400MHz,DMSO-d6)11.11(s,1H),7.34–7.31(m,1H),7.29(d,J＝8.0Hz,1H),7.03(d,J＝8.0Hz,1H),6.99(t,J＝7.6Hz,1H),6.93–6.86(m,2H),6.81(t,J＝7.2Hz,1H),6.45–6.41(m,1H),5.51(t,J＝5.6Hz,1H),4.83(s,1H),3.92(dd,J＝10.8,5.6Hz,1H),3.86(dd,J＝11.2,5.6Hz,1H),3.66(s,1H),2.62(d,J＝15.6Hz,1H),2.49(d,J＝15.2Hz,1H),1.59(s,3H).13C NMR(150MHz,DMSO-d6)159.0,135.9,134.9,130.0,128.4,125.6,125.5,124.4,121.7,120.9,118.3,117.6,111.1,108.8,106.3,68.0,67.1,66.9,60.1,27.3,15.9.HRMS:exact masscalcd for C21H19N3NaO4(M+Na)+requires m/z 400.1268,found m/z 400.1265.
Example 14
To a 10mL Schlenk tube were added 3aa (40.5mg,0.1mmol), tributyltin hydride (135. mu.L, 0.5mmol) and AIBN (24.6mg,0.15mmol), in that order, toluene (1mL), and the mixture was stirred at 80 ℃ for 1 h. Follow the reaction by TLC, after completion of the reaction, cool the mixture to room temperature, quench with saturated KF solution, ethyl acetate and waterExtraction and drying of the organic phase over anhydrous sodium sulphate and purification of the reaction mixture by preparative thin layer chromatography in methanol/dichloromethane (vol. 1/15) gave 25.6mg of beige solid product 6 in 71% yield in 97% ee. [ alpha ]]D 26＝-68.47(c＝0.80,CH2Cl2).m.p.:191-192℃.HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,temperature＝25℃,λ＝256nm,retention time:7.182min(minor),17.387min(major).TLC:Rf＝0.28(dichloromethane:methanol＝15:1).1H NMR(400MHz,CDCl3)7.93(s,1H),7.30(d,J＝7.2Hz,1H),7.21(d,J＝7.6Hz,1H),7.10–7.00(m,2H),6.90(t,J＝7.2Hz,1H),6.75(t,J＝7.2Hz,1H),6.68(t,J＝7.2Hz,1H),6.19(d,J＝8.0Hz,1H),5.09(d,J＝10.4Hz,1H),4.41(d,J＝10.4Hz,1H),3.95(s,3H),3.04(d,J＝15.6Hz,1H),2.94(d,J＝15.6Hz,1H),2.34(br s,1H),1.81(s,3H).13C NMR(150MHz,CDCl3)175.1,161.1,137.1,135.9,128.9,126.4,125.4,124.9,121.7,120.2,119.4,118.0,110.8,108.7,106.3,94.7,69.0,62.4,53.7,52.9,29.5,20.0.HRMS:exact mass calcd for C22H21N2O3(M+H)+requires m/z361.1547,found m/z 361.1544.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (7)
1. A method of synthesizing a chiral fused polycyclic tropane 3 by dearomatization cycloaddition, comprising the steps of: taking a nitro-substituted benzofuran compound 2 and cyclic imine 1 as raw materials, and reacting in the presence of copper salt, an axial chiral diphosphine ligand and alkali to obtain chiral condensed polycyclic tropane 3; the reaction equation is as follows:
wherein R is1Selected from halogen, alkyl or alkoxy; r2And R3Are all selected from alkyl; r4Selected from halogen, nitro, alkyl or alkoxy; ar in the axial chiral diphosphine ligand is selected from 3,5-Me2C6H3、3,5-(t-Bu)2C6H3、4-MeO-3,5-(t-Bu)2C6H2Or 3,4,5- (MeO)3C6H2(ii) a Said copper salt is selected from Cu (MeCN)4ClO4、Cu(OAc)2、Cu(OTf)2Or Cu (MeCN)4PF6(ii) a The base is selected from potassium carbonate.
2. A process for the synthesis of a fused polycyclic tropane by dearomatization cycloaddition according to claim 1, wherein: the molar ratio of the nitro-substituted benzofuran compound 2 to the cyclic imine 1 to the copper salt to the diphosphine ligand to the alkali is 1:2-2.2:0.005-0.05:0.005-0.05: 0.05-0.15.
3. A process for the synthesis of a fused polycyclic tropane by dearomatization cycloaddition according to claim 1, wherein: the reaction is carried out in an organic solvent selected from one or more of methyl tert-butyl ether, chloroform, dichloromethane, dichloroethane, acetonitrile, diethyl ether or toluene.
4. A process for the synthesis of a fused polycyclic tropane by dearomatization cycloaddition according to claim 1, wherein: the reaction temperature is selected from 25 ℃ to-40 ℃, and the reaction is carried out under the protection of inert gas.
5. A method of synthesizing compound 4, comprising: a chiral condensed polycyclic tropane compound 3 is obtained by adopting the method of any one of claims 1 to 4, and then the compound 3 is subjected to a heating reaction in the presence of tributyltin hydride and AIBN to obtain a denitrification base product 4, wherein the specific structure is as follows:
wherein R is1Selected from halogen, alkyl or alkoxy; r2And R3Are all selected from alkyl; r4Selected from halogen, nitro, alkyl or alkoxy.
6. A method of synthesizing compound 5, comprising: obtaining chiral condensed polycyclic tropane compounds 3 by adopting the method of any one of claims 1 to 4, and then reacting the compounds 3 in the presence of zinc powder and concentrated hydrochloric acid to obtain nitro which is reduced into amino products 5; the concrete structure is as follows:
wherein R is1Selected from halogen, alkyl or alkoxy; r2And R3Are all selected from alkyl; r4Selected from halogen, nitro, alkyl or alkoxy.
7. A method of synthesizing compound 6, comprising: obtaining a chiral fused polycyclic tropane compound 3 by the method of any one of claims 1 to 4, and then reacting the compound 3 in the presence of lithium aluminum hydride to obtain a product 6 with reduced ester group to hydroxyl; the concrete structure is as follows:
wherein R is1Selected from halogen, alkyl or alkoxy; r2And R3Are all selected from alkyl; r4Selected from halogen, nitro, alkyl or alkoxy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911257338.4A CN110724152B (en) | 2019-12-10 | 2019-12-10 | Method for synthesizing chiral fused polycyclic tropanes by dearomatization cycloaddition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911257338.4A CN110724152B (en) | 2019-12-10 | 2019-12-10 | Method for synthesizing chiral fused polycyclic tropanes by dearomatization cycloaddition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110724152A CN110724152A (en) | 2020-01-24 |
| CN110724152B true CN110724152B (en) | 2020-09-01 |
Family
ID=69225960
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911257338.4A Active CN110724152B (en) | 2019-12-10 | 2019-12-10 | Method for synthesizing chiral fused polycyclic tropanes by dearomatization cycloaddition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110724152B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592236A (en) * | 2014-10-14 | 2015-05-06 | 河南师范大学 | Method for synthesis of chiral heterocyclic nucleoside analogue by asymmetric [3+2] cycloaddition |
| CN109369661A (en) * | 2018-12-05 | 2019-02-22 | 河南师范大学 | The method of [3+2] cycloaddition dearomatization synthesis of chiral hydrogenation benzofuran compounds |
| CN110156730A (en) * | 2019-07-05 | 2019-08-23 | 河南师范大学 | A kind of synthetic method of chiral tricyclic benzofuran compounds |
-
2019
- 2019-12-10 CN CN201911257338.4A patent/CN110724152B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592236A (en) * | 2014-10-14 | 2015-05-06 | 河南师范大学 | Method for synthesis of chiral heterocyclic nucleoside analogue by asymmetric [3+2] cycloaddition |
| CN109369661A (en) * | 2018-12-05 | 2019-02-22 | 河南师范大学 | The method of [3+2] cycloaddition dearomatization synthesis of chiral hydrogenation benzofuran compounds |
| CN110156730A (en) * | 2019-07-05 | 2019-08-23 | 河南师范大学 | A kind of synthetic method of chiral tricyclic benzofuran compounds |
Non-Patent Citations (2)
| Title |
|---|
| Catalytic Enantioselective Synthesis of Functionalized Tropanes Reveals Novel Inhibitors of Hedgehog Signaling;Rishikesh Narayan，等;《Angew. Chem. Int. Ed.》;20131021;第52卷(第49期);第12892-12896页 * |
| Rishikesh Narayan，等.Catalytic Enantioselective Synthesis of Functionalized Tropanes Reveals Novel Inhibitors of Hedgehog Signaling.《Angew. Chem. Int. Ed.》.2013,第52卷(第49期),第12892-12896页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110724152A (en) | 2020-01-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hu et al. | Phosphine-catalyzed Rauhut-Currier domino reaction: a facile strategy for the construction of carbocyclic spirooxindoles skeletons. | |
| CN113248508A (en) | N-protected heterocycles, method for the production thereof and method for the production of C-nucleoside derivatives | |
| Tamura et al. | Design and synthesis of chiral 1, 10-phenanthroline ligand, and application in palladium catalyzed asymmetric 1, 4-addition reactions | |
| Malik et al. | Ruthenium-catalyzed one-pot ring-closing metathesis/syn-dihydroxylation in the synthesis of bicyclic iminosugars | |
| Li et al. | Phosphine-containing Lewis base catalyzed cyclization of benzofuranone type electron-deficient alkenes with allenoates: a facile synthesis of spirocyclic benzofuranones | |
| Gupta et al. | Rapid and selective synthesis of spiropyrazolines and pyrazolylphthalides employing Seyferth–Gilbert reagent | |
| Liu et al. | DABCO-catalyzed unusual [4+ 2] cycloaddition reaction: non-substituted allenoate acts as a four-carbon synthon and facile synthesis of spirooxindoles | |
| Kaur et al. | Cinchonidine thiourea catalyzed asymmetric addition of phenols to oxindole derivatives | |
| Beemelmanns et al. | Highly diastereoselective samarium diiodide induced ketyl cyclisations of indole and pyrrole derivatives–scope and limitations | |
| CN110724152B (en) | Method for synthesizing chiral fused polycyclic tropanes by dearomatization cycloaddition | |
| Yu et al. | Multicatalytic tandem reaction of N′-(2-alkynylbenzylidene) hydrazide with indole | |
| Carlsen et al. | Studies toward the AB ring system of the tetrapetalone natural products | |
| CN104710417B (en) | Azaindole derivatives and synthesis method thereof | |
| CN115197153B (en) | Preparation method of 1, 4-diazacycloalkane compound | |
| Tsai et al. | Rhodium‐Catalyzed Domino Hydroformylation/Double‐Cyclization Reaction of Arylacetylenecarboxamides: Diastereoselectivity Studies and Application in the Synthesis of 1‐Azabicyclo [xy 0] alkanes | |
| CN109651385A (en) | A kind of preparation method of pyrans [3,2-a] carbazole compound | |
| CN110156730B (en) | Synthesis method of chiral tricyclic benzofuran compound | |
| CN113045530B (en) | Method for preparing naphthopyran compounds by ruthenium catalysis | |
| Li et al. | Synthesis of 1, 1-disubstituted-2, 6-diarylcyclohexane-4-ones catalyzed by KF/basic Al2O3 under ultrasound | |
| Valencia et al. | Synthesis and characterization of symmetrical and unsymmetrical low-valent rhenium-oxo dimers, Re2O2 (RC. ident. CR) 4 | |
| JPWO2005085204A1 (en) | Method for producing nitrogen-containing 5-membered ring compound | |
| CN108976198B (en) | Synthetic method of 3- (4-pyridine) indole compound | |
| CN108440549B (en) | Synthesis method of spiro indole compound | |
| Li et al. | Enantioselective Si− H Insertion of Arylvinyldiazoesters Promoted by Rhodium (I)/Diene Complexes | |
| Łysek et al. | Transformation of the 7-isopropylidene group in 5-dethia-5-oxacephams |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |