CN113583015A - Method for synthesizing chiral oxygen-containing eight-membered ring compound through palladium-catalyzed asymmetric allylic cycloaddition reaction - Google Patents
Method for synthesizing chiral oxygen-containing eight-membered ring compound through palladium-catalyzed asymmetric allylic cycloaddition reaction Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
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Abstract
The invention provides a method for synthesizing a chiral oxygen-containing eight-membered ring compound by palladium-catalyzed asymmetric allylic cycloaddition reaction, which comprises the following steps: in a solvent, under the catalysis of a palladium catalysis system, the gamma-methylene-delta-valerolactone compound I and the o-quinone methide II generate [4+4]]Performing cycloaddition reaction to obtain a chiral oxygen-containing eight-membered ring compound III; the palladium catalytic system consists of a palladium catalyst and a chiral ligand, wherein the chiral ligand has a structure shown in a formula IV. The invention constructs the oxygen-containing eight-membered ring compound by the palladium-catalyzed asymmetric allylic cycloaddition reaction, and has the advantages of convenient operation, simplicity, high yield, cheap and easily-obtained reaction raw materials, low catalyst cost, wide substrate application range, good diastereoselectivity, high enantioselectivity and the like.
Description
Technical Field
The invention relates to a method for synthesizing a chiral oxygen-containing eight-membered ring compound by palladium-catalyzed asymmetric allylic cycloaddition reaction, belonging to the technical field of organic synthesis.
Background
Chiral oxygen-containing eight-membered ring structures are widely present in active natural products and drug molecules, such as indole alkaloid Decursine having antimalarial activity, dibenzocyclooctadiene type lignan (Isoschizandrin) exhibiting good antiulcer activity, and antibiotic drug Retaparin approved by FDA for marketing, etc. However, the acquisition of chiral oxygen-containing eight-membered ring compounds through natural product separation or biosynthesis is time-consuming, labor-consuming, and expensive, and has low yield and great limitations. In the traditional synthetic method, due to unfavorable enthalpy effect and entropy effect and trans-ring interaction in the synthetic process, the efficient construction of the chiral macrocyclic compound has certain difficulty (De, N.; Yoo, E.J. ACS Catal.2018,8, 48-58.). Therefore, the novel, simple and efficient asymmetric cycloaddition reaction is developed for synthesizing the macrocyclic compound, so that the defects of the existing chiral macrocyclic compound synthesis method can be effectively overcome, the theoretical basis and the methodological basis can be provided for the total synthesis of related natural products, and a new way is provided for the synthesis of related drug intermediates and other functional molecules.
Since the first discovery by the Huisgen project group in 1963, the construction of various chiral cyclic compounds by dipolar ion-mediated cycloaddition has become a very efficient and extensive synthetic strategy (Qian, D.Y.; Zhang, J.L.Acc.chem.Res.2020,53, 2358-2371). The most classical 1, 4-dipolar cycloaddition process follows the wood Ward-Hoffman rule, and the catalytic process can easily adjust regio-and stereoselectivity (Wei, L.; Chang, X.; Wang, C.J.Acc.chem.Res.2020,53, 1084-. In 2012, Hayashi group reported that gamma-methylene-delta-valerolactone was used as a 1,4 synthon to perform asymmetry with isocyanate [4+2 ] catalyzed by both zero-valent palladium and chiral phosphoramidite ligands]A series of chiral valerolactams were synthesized by cycloaddition (Shintani, R.; Ito, T.; Nagamoto, M.; Otomoa, H.; Hayashi, T.Chem. Commun.2012,48, 9936-9938.). In 2021, our topic groups reported in Et3In the presence of B, using Pd2(dba)3·CHCl3Under the catalysis of the phosphoramidite ligand,the asymmetry [4+4] under palladium catalysis is realized by using gamma-methylene-delta-valerolactone and anthracene compound]Cycloaddition reactions (Gao, C.; Wang, X.; Liu, J.; Li, X. ACS Cat. 2021,11, 2684-.
At present, no report is made on the asymmetric [4+4] cycloaddition reaction for constructing oxygen-containing eight-membered ring compounds. Therefore, it is of great significance to develop a synthetic method for preparing oxygen-containing eight-membered ring compounds based on asymmetric [4+4] cycloaddition reactions.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for synthesizing a chiral oxygen-containing eight-membered ring compound by palladium-catalyzed asymmetric allylic cycloaddition reaction. The invention takes the palladium catalyst with simple structure and low price and the chiral ligand which is simple and easy to synthesize as a catalytic system to realize the high-efficiency asymmetric synthesis of the chiral oxygen-containing eight-membered ring compound.
Description of terms:
room temperature: having a meaning well known in the art, meaning 25. + -. 5 ℃.
The technical scheme adopted by the invention is as follows:
a method for synthesizing chiral oxygen-containing eight-membered ring compounds by palladium-catalyzed asymmetric allylic cycloaddition reaction comprises the following steps:
in a solvent, under the catalysis of a palladium catalysis system, carrying out [4+4] cycloaddition reaction on a gamma-methylene-delta-valerolactone compound I and an o-quinone methide II to obtain a chiral oxygen-containing eight-membered ring compound III; the palladium catalytic system consists of a palladium catalyst and a chiral ligand, and the chiral ligand has a structure shown in a formula IV;
wherein, in the structural formula of the compound of formula I, Ar1Is substituted phenyl or substituted hexabasic aromatic heterocycle, and the heteroatom of the hexabasic aromatic heterocycle is O, N or S; the substituent groups of the substituted phenyl and the substituted hexabasic aromatic heterocycle are respectively and independently one or two of trifluoromethyl, halogen, cyano and nitro; r is AOr ethyl;
in the structural formula of the compound of formula II, Ar2Is phenyl, substituted phenyl, 1-naphthyl or a five-membered aromatic heterocycle, wherein the heteroatom of the five-membered aromatic heterocycle is O, N or S; the substituent of the substituted phenyl is methoxy, halogen or C1-C4 alkyl;
in the formula III of the compound, the substituent Ar1R is the same as in the compound of formula I, and substituent Ar2The same as in the compound of formula II.
Preferred according to the invention are compounds of the formula I in which Ar is Ar1Is 4-trifluoromethylphenyl, 4-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 4-cyanophenyl, 3-nitrophenyl, 3, 5-dichlorophenyl, 3, 5-dibromophenyl, 3, 5-difluorophenyl, 3, 4-difluorophenyl, 3-chloro-5-fluorophenyl or 6-chloro-3-pyridyl;
in the structural formula of the compound of formula II, Ar2Is phenyl, 4-methoxyphenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl or 2-thienyl.
According to the invention, the solvent is preferably ethylbenzene, toluene, tetrahydrofuran, 1, 4-dioxane, chlorobenzene or p-xylene; the ratio of the volume of the solvent to the mole number of the gamma-methylene-delta-valerolactone compound I is 5-20 mL:1 mmol; the solvent is subjected to anhydrous and anaerobic treatment.
According to the invention, the palladium catalyst is preferably Pd2(dba)3·CHCl3、PdCp(η3-C3H5) Or Pd (PPh)3)4(ii) a The molar ratio of palladium in the palladium catalyst to the gamma-methylene-delta-valerolactone compound I is 0.01-0.1: 1; the molar ratio of palladium to the chiral ligand in the palladium catalyst is 1: 2-2.2.
According to the present invention, the preparation method of the chiral ligand is a prior art, and can be prepared by referring to patent document CN 112940002A.
According to the invention, the molar ratio of the gamma-methylene-delta-valerolactone compound I to the o-quinone methide II is preferably 1: 1.
Preferred according to the invention are gamma-methylene-delta-pentanesLactone compound I and o-quinone methide II are subjected to [4+4]]The reaction system of the cycloaddition reaction is also added
A molecular sieve; the above-mentioned
The ratio of the mass of the molecular sieve to the mole number of the gamma-methylene-delta-valerolactone compound I is 1-2 g:1 mmol;
the addition of the molecular sieve can improve the reaction rate and the reaction yield, and can further remove trace water in the reaction system.
Preferably, according to the present invention, the cycloaddition reaction is performed under an inert gas atmosphere, and the inert gas is nitrogen or argon.
According to the present invention, the temperature of the cycloaddition reaction is preferably-20 ℃ to room temperature, and more preferably-20 ℃.
According to the invention, the cycloaddition reaction time is preferably 2-40 h, and more preferably 10-24 h.
According to the invention, after the [4+4] cycloaddition reaction of the gamma-methylene-delta-valerolactone compound I and the o-quinone methide II, the product can be separated and characterized by a conventional separation and purification method. Preferably, the post-treatment steps of the reaction liquid obtained after the [4+4] cycloaddition reaction of the gamma-methylene-delta-valerolactone compound I and the o-quinone methide II are as follows: and (3) separating the reaction liquid by silica gel column chromatography to obtain a chiral oxygen-containing eight-membered ring compound III, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent is 0.03-0.1: 1.
According to a preferred embodiment of the present invention, the method comprises the following steps:
under the protection of inert gas, mixing a palladium catalyst, a chiral ligand and a solvent, stirring for 15min at room temperature, transferring the obtained mixture into a flask filled with a gamma-methylene-delta-valerolactone compound I and an o-quinone methide II, and stirring for reaction under the protection of inert gas at-20-room temperature; and (3) separating the reaction liquid by silica gel column chromatography to obtain a chiral oxygen-containing eight-membered ring compound III, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent is 0.03-0.1: 1.
According to the invention, the gamma-methylene-delta-valerolactone compound I is synthesized by a known method from 2-methylene-1, 3-propanediol and corresponding aryl carboxylic ester (see a document: J.Am.chem.Soc.2007,129, 12356-12357), and the reaction route is shown as follows:
in the above formula, the substituent R, Ar1As described above.
According to the invention, the o-quinone methide II is synthesized by known methods from the corresponding aryl formaldehyde (see the literature: chem. Eur. J.2008,14,5405-5408), and the reaction route is shown as follows:
in the above formula, substituent Ar2As described above.
The invention has the following technical characteristics and beneficial effects:
the invention provides a novel method for constructing an eight-membered oxygen-containing heterocyclic compound by palladium-catalyzed asymmetric allylic cycloaddition reaction, which has the following advantages: (1) the palladium catalyst with simple structure and low price and the chiral ligand which is simple and easy to synthesize are used as a catalytic system, so that the catalyst has the advantages of low cost, high efficiency and small using amount of the catalyst; (2) good diastereoselectivity and high selectivity to the sex (ee > 90%); (3) the reaction raw materials are cheap and easy to obtain, the atom economy is good, and the substrate application range is wide; (4) mild reaction conditions, convenient and simple operation and high yield.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and starting materials, unless otherwise specified, are commercially available or may be prepared according to known methods.
The solvents used in the examples were treated in an anhydrous and oxygen-free manner, the treatment being known from the prior art.
The yields described in the examples are molar yields.
The chiral ligands used in the examples were prepared as follows:
slowly dropwise adding 5.8mL of triethylamine into 50mL of 0.2mol/L phosphorus trichloride dichloromethane solution at 0-5 ℃, wherein the dropwise adding time is 20min, heating to room temperature after the dropwise adding is finished, then adding 2.1g of a compound of a formula V, continuously stirring for 5h at room temperature, adding 3.2g of a compound of a formula VI, stirring for 12h at room temperature, and finishing the reaction; and (2) performing rotary evaporation on the obtained reaction liquid to remove the solvent, purifying by using a silica gel chromatographic column to obtain a chiral ligand IV with an ee value of 99%, wherein an eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent is 0.02: 1.
The reaction scheme is as follows:
example 1
Synthesis of methyl (9S,10S) -9- (3, 5-dichlorophenyl) -7-methylene-10- ((E) -styryl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxazole [4',5':4,5] benzo [1,2-b ] oxooctanoate-9-carboxylate (IIIaa)
The reaction route is as follows:
the operation steps are as follows:
under the protection of nitrogen, toPd was added to a dry 5mL reaction flask2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL of ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was transferred to a flask containing methyl 3- (3, 5-dichlorophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate Ia (63.0mg, 0.2mmol), (E) -6- ((E) -3-phenylalkenylene) -benzo [ d ] d][1,3]Dioxolan-5- (6H) -one IIa (50.4mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE ═ 0.03-0.1:1, v/v) to obtain the objective product (84mg, 0.16mmol) with a yield of 80%.
The characterization data of the product (IIIaa) obtained are as follows:
white solid, m.p. 102-; 84mg, 80% yield; dr>20:1,96％ee；
(0.1,CH2Cl2)；[Daicel
IC-U(0.3cm x 10cm),n-hexane/2-propanol＝99/1,v＝0.3mL·min-1,λ＝254nm,t(major)＝8.5min,t(minor)＝5.6min]；
1H NMR(400MHz,CDCl3)δ7.32(s,1H),7.29-7.19(m,5H),7.18-7.15(m,1H),6.97(s,2H),6.60(s,1H),6.39(br,1H),6.14(br,2H),5.93(s,1H),5.88(s,1H),5.16(s,1H),4.87(s,1H),4.71(br,1H),4.59(d,J＝12.0Hz,1H),4.35(d,J＝12.0Hz,1H),3.70(s,3H),2.92(d,J＝12.2Hz,1H),2.59(br,1H)；
13C NMR(100MHz,CDCl3)δ173.3,152.0,147.3,144.0,143.6,142.5,137.5,134.5,133.8,128.5,127.6,127.5,127.4,126.8,126.4,126.3,119.4,109.5,103.3,101.5,81.2,61.0,51.9,38.2,29.8；
HRMS(ESI)m/z calcd.for C29H24Cl2O5[M+H]+:523.1074,found:523.1075。
Example 2
Synthesis of methyl (9S,10S) -9- (3, 5-dibromophenyl) -7-methylene-10- ((E) -styryl) -7,8,9, 10-tetrahydro-6H- [1,3] bisoxazole [4',5':4,5] benzo [1,2-b ] oxooctanoate-9-carboxylate (IIIba)
The reaction route is as follows:
the operation steps are as follows:
pd was added to a dry 5mL reaction flask under nitrogen protection2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was then transferred to a flask containing methyl 3- (3, 5-dibromophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate Ib (80.8mg, 0.2mmol), (E) -6- ((E) -3-phenylalkenylene) -benzo [ d ] d][1,3]Dioxolan-5- (6H) -one IIa (50.4mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE ═ 0.03 to 0.1:1, v/v) to obtain the objective product (116mg, 0.19mmol) with a yield of 95%.
The characterization data of the product (IIIba) obtained are as follows:
white solid, m.p. ═ 150-; 116mg, 95% yield; dr>20:1,98％ee；
(0.1,CH2Cl2)；[Daicel
IC-U(0.3cm x 10cm),n-hexane/2-propanol＝98/2,v＝0.3mL·min-1,λ＝254nm,t(major)＝5.6min,t(minor)＝4.3min]；
1H NMR(400MHz,CDCl3)δ7.30(d,J＝8.6Hz,2H),7.22(m,4H),7.18-7.13(m,1H),6.97(d,J＝7.9Hz,2H),6.61(s,1H),6.45(br,1H),6.07(br,2H),5.91(s,1H),5.86(s,1H),5.18(s,1H),4.86(s,1H),4.78(br,1H),4.62(d,J＝12.4Hz,1H),4.30(d,J＝12.4Hz,1H),3.67(s,3H),2.88(d,J＝11.8Hz,1H),2.58(d,J＝11.8Hz,1H)；
13C NMR(100MHz,CDCl3)δ173.2,152.0,147.3,144.0,142.5,137.5,133.8,133.0,130.2,130.0,128.5,127.4,127.4,126.4,126.2,122.4,119.4,109.3,103.3,101.5,81.1,61.0,51.9,38.3,29.8；
HRMS(ESI)m/z calcd.for C29H24Br2O5[M+H]+:611.0063,found:611.0058。
Example 3
Synthesis of methyl (9S,10S) -9- (4-trifluoromethylphenyl) -7-methylene-10- ((E) -styryl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxazole [4',5':4,5] benzo [1,2-b ] oxooctanoate-9-carboxylate (IIIca)
The reaction route is as follows:
the operation steps are as follows:
pd was added to a dry 5mL reaction flask under nitrogen protection2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL of ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was then transferred to a flask containing methyl 3- (4-trifluoromethylphenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate ic acid (62.8mg, 0.2mmol), (E) -6- ((E) -3-phenylalkenylene) -benzo [ d ] d][1,3]Dioxolan-5- (6H) -one IIa (50.4mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; separating and purifying the reaction solution by silica gel column chromatography (eluent EA/PE is 0.03-0.1:1, v/v) to obtainThe desired product (99mg, 0.19mmol) was obtained in 95% yield.
The characterization data of the product obtained (IIIca) are as follows:
white solid, m.p. 209-; 99mg, 95% yield; dr ═ 7:1, 97% ee;
(0.1,CH2Cl2)；[Daicel
IC-U(0.3cm x 10cm),n-hexane/2-propanol＝97/3,v＝0.3mL·min-1,λ＝254nm,t(major)＝8.5min,t(minor)＝3.6min]；
1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.3Hz,2H),7.25–7.21(m,2H),7.19-7.14(m,5H),6.62(s,1H),6.41(br,1H),6.09(br,2H),5.93(s,1H),5.88(s,1H),5.19(s,1H),4.88(s,1H),4.79(br,1H),4.63(d,J＝12.4Hz,1H),4.35(d,J＝12.4Hz,1H),3.69(s,3H),2.93(d,J＝12.0Hz,1H),2.67(d,J＝12.0Hz,1H)；
13C NMR(100MHz,CDCl3)δ173.8,152.1,147.2,143.88,142.9,137.6,133.6,129.57(q,J＝32.7Hz),128.7,128.5,127.9,127.7,127.3,126.6,126.3,124.7(q,J＝3.5Hz),124.2(q,J＝280.0Hz),119.3,109.4,103.3,101.5,81.2,61.4,51.7,38.5,29.8；
HRMS(ESI)m/z calcd.for C30H25F3O5[M+H]+:523.1727,found:523.1729。
example 4
Synthesis of methyl (9S,10S) -9- (4-cyanophenyl) -7-methylene-10- ((E) -styryl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxa [4',5':4,5] benzo [1,2-b ] oxooctan-9-carboxylate (IIIda)
The reaction route is as follows:
the operation steps are as follows:
under the protection of nitrogen, to be dryPd is added into a 5mL reaction bottle2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL of ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was then transferred to a flask containing methyl 3- (4-cyanophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate Id (54.2mg, 0.2mmol), (E) -6- ((E) -3-phenylalkenylene) -benzo [ d ] ne][1,3]Dioxolan-5- (6H) -one IIa (50.4mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE 0.03-0.1:1, v/v) to obtain the objective product (86mg, 0.18mmol) with a yield of 90%.
The characterization data of the product (IIIda) obtained are as follows:
white solid, m.p. 102-; 86mg, 90% yield; dr ═ 5:1, 95% ee;
(0.1,CH2Cl2)；[Daicel
IC-U(0.3cm x 10cm),n-hexane/2-propanol＝93/7,v＝0.3mL·min-1,λ＝254nm,t(major)＝52.8min,t(minor)＝24.2min]；
1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.3Hz,2H),7.27-7.20(m,3H),7.19-7.15(m,4H),6.61(s,1H),6.41(br,1H),6.06(br,2H),5.92(s,1H),5.87(s,1H),5.19(s,1H),4.88(s,1H),4.77(br,1H),4.62(d,J＝11.8Hz,1H),4.35(d,J＝11.8Hz,1H),3.69(s,3H),2.92(d,J＝11.8Hz,1H),2.67(br,1H)；
13C NMR(100MHz,CDCl3)δ173.4,152.1,147.2,145.5,143.8,142.6,137.4,133.8,131.4,129.0,128.5,127.4,127.2,126.2,126.2,119.4,118.6,111.3,109.1,103.4,101.5,81.1,61.5,51.8,38.3,29.7；
HRMS(ESI)m/z calcd.for C30H25NO5[M+H]+:480.1805,found:480.1805。
example 5
Synthesis of methyl (9S,10S) -9- (3-nitrophenyl) -7-methylene-10- ((E) -styryl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxa [4',5':4,5] benzo [1,2-b ] oxooctyl-9-carboxylate (IIIea)
The reaction route is as follows:
the operation steps are as follows:
pd was added to a dry 5mL reaction flask under nitrogen protection2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL of ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was then transferred to a flask containing methyl 3- (3-nitrophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate ie (58.2mg, 0.2mmol), (E) -6- ((E) -3-phenylalkenylene) -benzo [ d ] ne][1,3]Dioxolan-5- (6H) -one IIa (50.4mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE 0.03-0.1:1, v/v) to obtain the objective product (91mg, 0.182mmol) with a yield of 91%.
The characterization data of the product (IIIea) obtained are as follows:
white solid, m.p. 219-; 91mg, 91% yield; dr 10:1, 96% ee;
(0.1,CH2Cl2)；[Daicel
IC-U(0.3cm x 10cm),n-hexane/2-propanol＝96/4,v＝0.3mL·min-1,λ＝254nm,t(major)＝13.8min,t(minor)＝6.8min]；
1H NMR(400MHz,CDCl3)δ8.18(d,J＝7.7Hz,1H),7.95(s,1H),7.51(t,J＝7.9Hz,1H),7.45-7.41(m,1H),7.21(m,5H),6.62(s,1H),6.41(br,1H),6.10(br,2H),5.90(s,1H),5.87(s,1H),5.20(s,1H),4.89(s,1H),4.80(s,1H),4.63(d,J＝11.8Hz,1H),4.40(br,1H),3.71(s,3H),2.98(d,J＝11.0Hz,1H),2.73(br,1H)；
13C NMR(100MHz,CDCl3)δ173.4,152.0,147.8,147.3,143.9,142.5,137.4,134.6,134.6,134.0,128.6,128.5,127.4,127.3,126.3,126.1,122.9,122.4,119.5,109.1,103.4,101.5,81.1,61.2,51.9,38.5,29.7；
HRMS(ESI)m/z calcd.for C29H25NO7[M+H]+:500.1704,found:500.1705。
example 6
Synthesis of methyl (9S,10S) -9- (6-chloropyridin-3-yl) -7-methylene-10- ((E)) -styryl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxa [4',5':4,5] benzo [1,2-b ] oxooctyl-9-carboxylate (IIIfa)
The reaction route is as follows:
the operation steps are as follows:
pd was added to a dry 5mL reaction flask under nitrogen protection2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was then transferred to a flask containing methyl 3- (6-chloropyridin-3-yl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate if (56.3mg, 0.2mmol), (E) -6- ((E) -3-phenylalkenylene) -benzo [ d ] c][1,3]Dioxolan-5- (6H) -one IIa (50.4mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE 0.03-0.1:1, v/v) to obtain the objective product (72mg, 0.146mmol), yield 73%。
The characterization data of the product (IIIfa) obtained are as follows:
white solid, m.p. ═ 110-; 72mg, 73% yield; dr 4:1, 93% ee; [ alpha ] to]D20.0＝+129.6(0.1,CH2Cl2)；[Daicel
IA-3(0.46cm x 25cm),n-hexane/2-propanol＝90/10,v＝1mL·min-1,λ＝254nm,t(major)＝18.6min,t(minor)＝15.7min]；
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.30(s,2H),7.28-7.21(m,4H),7.20-7.15(m,1H),6.63(s,1H),6.47(br,1H),6.04(br,2H),5.91(s,1H),5.88(s,1H),5.21(s,1H),4.85(s,2H),4.66-4.59(m,1H),4.31(d,J＝12.0Hz,1H),3.70(s,3H),2.86(d,1H),2.60(br,1H)；
13C NMR(100MHz,CDCl3)δ173.1,152.1,150.3,149.4,147.2,143.9,142.3,138.7,137.2,136.3,134.3,128.5,127.5,126.9,126.3,125.9,123.1,119.6,108.7,103.4,101.5,81.0,59.5,51.8,38.7,29.6；
HRMS(ESI)m/z calcd.for C28H24ClNO5[M+H]+:490.1416,found:490.1416。
Example 7
Synthesis of methyl (9S,10S) -9- (3, 5-dichlorophenyl) -7-methylene-10- ((E) -2- (naphthalen-1-yl) vinyl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxido [4',5':4,5] benzo [1,2-b ] oxooctan-9-carboxylate (IIIab)
The reaction route is as follows:
the operation steps are as follows:
pd was added to a dry 5mL reaction flask under nitrogen protection2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL of ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was transferred to a flask containing 3- (3, 5-dichlorophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-Carboxylic acid methyl ester Ia (63.0mg, 0.2mmol), (E) -6- ((E) -3- (naphthalen-1-yl) propylidene) benzo [ d][1,3]Dioxo-5- (6H) -one IIb (60.4mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE 0.03-0.1:1, v/v) to obtain the objective product (62mg, 0.11mmol) with a yield of 55%.
The characterization data of the product (IIIab) obtained are as follows:
white solid, m.p. ═ 88-90 ℃; 62mg, yield 55%; dr 16:1, 91% ee;
(0.1,CH2Cl2)；[Daicel Chiralpak IA-3(0.46cm x 25cm),n-hexane/2-propanol＝97/3,v＝1.0mL·min-1,λ＝254nm,t(major)＝15.8min,t(minor)＝11.0min]；
1H NMR(400MHz,CDCl3)δ7.78(dd,J＝6.3,3.3Hz,2H),7.71(dd,J＝6.4,3.0Hz,1H),7.43(dd,J＝6.3,3.3Hz,3H),7.35(d,J＝14.9Hz,2H),7.07(s,3H),6.62(s,1H),6.23(s,2H),5.94(d,J＝1.4Hz,1H),5.90(d,J＝1.4Hz,1H),5.15(s,1H),4.92(s,1H),4.70(br,1H),4.56(d,J＝11.6Hz,1H),4.42(d,J＝11.6Hz,1H),3.72(s,3H),3.01(d,J＝12.6Hz,1H),2.69(d,J＝12.6Hz,1H)；
13C NMR(100MHz,CDCl3)173.3,151.8,147.4,144.0,142.5,135.4,134.7,133.5,131.4,131.2,130.6,128.4,127.7,127.6,126.7,126.6,126.3,125.9,125.7,125.6,124.1,123.9,119.4,109.9,103.4,101.6,81.2,61.0,52.0,37.7,30.0；
HRMS(ESI)m/z calcd.for C33H27Cl2O5[M+H]+:573.1230,found:573.1232。
example 8
Synthesis of methyl (9S,10S) -10- ((E) -4-bromobutyryl) -9- (3, 5-dichlorophenyl) -7-methylene-7, 8,9, 10-tetrahydro-6H- [1,3] dioxa [4',5':4,5] benzo [1,2-b ] oxooctyl-9-carboxylate (IIIac)
The reaction route is as follows:
the operation steps are as follows:
pd was added to a dry 5mL reaction flask under nitrogen protection2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL of ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was transferred to a flask containing methyl 3- (3, 5-dichlorophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate Ia (63.0mg, 0.2mmol), (E) -6- ((E) -3- (4-bromophenyl) propylene) benzo [ d ] d][1,3]Dioxo-5 (6H) -one IIc (66.2mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE ═ 0.03-0.1:1, v/v) to obtain the objective product (99mg, 0.165mmol) with a yield of 82%.
The characterization data of the product (IIIac) obtained are as follows:
white solid, m.p. ═ 110-; 99mg, 82% yield; dr>20:1,95％ee；
(0.1,CH2Cl2)；[Daicel Chiralpak IB-3(0.46cm x 25cm),n-hexane/2-propanol＝95/5,v＝1.0mL·min-1,λ＝254nm,t(major)＝17.0min,t(minor)＝10.7min]；
1H NMR(400MHz,CDCl3)δ7.40-7.31(m,3H),7.07(d,J＝8.2Hz,2H),6.95(s,2H),6.60(s,1H),6.31(br,1H),6.14(br,2H),5.93(s,1H),5.89(s,1H),5.16(s,1H),4.88(s,1H),4.68(br,1H),4.58(d,J＝12.9Hz,1H),4.36(d,J＝12.9Hz,1H),3.70(s,3H),2.93(d,J＝12.9Hz,1H),2.58(d,J＝12.9Hz,1H)；
13C NMR(100MHz,CDCl3)δ173.2,151.9,147.4,144.0,142.4,136.4,134.5,132.6,131.6,128.3,127.9,127.8,127.6,126.7,126.0,121.1,119.5,109.2,103.4,101.6,81.2,61.0,52.0,38.0,29.8；
HRMS(ESI)m/z calcd.for C29H24BrCl2O5[M+H]+:601.0179,found:601.0184。
Example 9
Synthesis of methyl (9S,10S) -9- (3, 5-dichlorophenyl) -7-methylene-10- ((E) -2- (thiophen-2-yl) vinyl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxa [4',5':4,5] benzo [1,2-b ] oxooctan-9-carboxylate (IIIad)
The reaction route is as follows:
the operation steps are as follows:
pd was added to a dry 5mL reaction flask under nitrogen protection2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL of ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was transferred to a column containing methyl 3- (3, 5-dichlorophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate Ia (63.0mg, 0.2mmol), (E) -6- ((E) -3- (thien-2-yl) propylene) benzo [ d][1,3]Dioxo-5 (6H) -one IId (51.6mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE 0.03-0.1:1, v/v) to obtain the objective product (75mg, 0.142mmol) with a yield of 71%.
The characterization data of the product (IIIad) obtained are as follows:
white solid, m.p. ═ 100-; 75mg, 71% yield; dr>20:1,93％ee；
(0.1,CH2Cl2)；[Daicel Chiralpak IA-3(0.46cm x 25cm),n-hexane/2-propanol＝95/5,v＝1.0mL·min-1,λ＝254nm,t(major)＝16.7min,t(minor)＝8.7min]；
1H NMR(400MHz,CDCl3)δ7.33(s,1H),7.07(d,J＝4.9Hz,1H),7.02-6.86(m,3H),6.81(s,1H),6.60(s,1H),6.55(br,1H),6.06(br,1H),5.96-5.84(m,3H),5.17(s,1H),4.85(s,1H),4.70(br,1H),4.60(d,J＝12.9Hz,1H),4.31(d,J＝10.5Hz,1H),3.70(s,3H),2.88(d,J＝12.9Hz,1H),2.52(d,J＝12.9Hz,1H)；
13C NMR(100MHz,CDCl3)δ173.2,152.0,147.2,143.9,143.1,142.5,142.5,134.4,127.6,127.3,127.0,126.9,126.8,125.9,125.4,124.0,119.5,109.1,103.3,101.5,81.1,61.0,51.9,38.4,29.7；
HRMS(ESI)m/z calcd.forC27H23Cl2O5S[M+H]+:529.0638,found:529.0634。
Example 10
Synthesis of methyl (9S,10S) -9- (3, 5-dichlorophenyl) -10- ((E) -4-methoxystyryl) -7-methylene-7, 8,9, 10-tetrahydro-6H- [1,3] dioxa [4',5':4,5] benzo [1,2-b ] oxooctyl-9-carboxylate (IIIae)
The reaction route is as follows:
the operation steps are as follows:
pd was added to a dry 5mL reaction flask under nitrogen protection2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL of ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was transferred to a flask containing methyl 3- (3, 5-dichlorophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate Ia (63.0mg, 0.2mmol), (E) -6- ((E) -3- (4-methoxyphenyl) propylene) benzo [ d ] c [ d][1,3]Dioxo-5 (6H) -one IIe (56.4mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE 0.03-0.1:1, v/v) to obtain the objective product (64mg, 0.112mmol) with a yield of 56%.
The characterization data of the product obtained (IIIae) are as follows:
white solid, m.p. ═ 86-88 ℃; 64mg, 56% yield; dr 19:1, 93% ee;
(0.1,CH2Cl2)；[Daicel Chiralpak IA-U(0.3cm x 10cm),n-hexane/2-propanol＝90/10,v＝0.3mL·min-1,λ＝254nm,t(major)＝6.7min,t(minor)＝7.8min]；
1H NMR(400MHz,CDCl3)δ7.32(s,1H),7.15(d,J＝8.7Hz,2H),6.96(s,2H),6.78(d,J＝8.7Hz,2H),6.60(s,1H),6.35(br,1H),6.15(br,2H),5.92(d,J＝1.4Hz,1H),5.88(d,J＝1.5Hz,1H),5.16(s,1H),4.87(s,1H),4.67(br,1H),4.59(d,J＝12.1Hz,1H),4.34(d,J＝13.1Hz,1H),3.77(s,3H),3.70(s,3H),2.91(d,J＝12.9Hz,1H),2.57(d,J＝12.9Hz,1H)；
13C NMR(100MHz,CDCl3)δ173.3,159.1,151.9,147.2,143.9,142.5,134.3,133.1,130.3,127.6,127.5,127.1,126.9,126.5,125.2,119.4,113.9,109.3,103.3,101.5,81.1,61.1,55.3,51.9,38.1,27.0；
HRMS(ESI)m/z calcd.for C30H27Cl2O6[M+H]+:553.1179,found:553.1180。
example 11
Synthesis of methyl (9S,10S) -9- (3, 5-dichlorophenyl) -7-methylene-10- ((E) -4-methylstyryl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxa [4',5':4,5] benzo [1,2-b ] oxooctyl-9-carboxylate (IIIaf)
The reaction route is as follows:
the operation steps are as follows:
pd was added to a dry 5mL reaction flask under nitrogen protection2(dba)3·CHCl3(0.005mmol, 5.2mg), chiral ligand (0.022mmol,12.7mg) and 2mL of ethylbenzene were stirred at room temperature for 15 minutes, and the resulting mixture was transferred to a flask containing methyl 3- (3, 5-dichlorophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylate Ia (63.0mg, 0.2mmol), (E) -6- ((E) -3- (4-methylphenyl) propylene) benzo [ d ] d][1,3]Dioxo-5 (6H) -one IIf (53.2mg,0.2mmol) and
in a flask with molecular sieve (300mg), the reaction mixture was stirred under nitrogen for 16h at-20 ℃; the reaction mixture was separated and purified by silica gel column chromatography (eluent EA/PE 0.03-0.1:1, v/v) to obtain the objective product (78mg, 0.146mmol) with a yield of 73%.
The characterization data of the product (IIIaf) obtained are as follows:
white solid, m.p. ═ 108-; 78mg, 73% yield; dr>20:1,95％ee；
(0.1,CH2Cl2)；[Daicel Chiralpak IA-3(0.46cm x 25cm),n-hexane/2-propanol＝97/3,v＝1.0mL·min-1,λ＝254nm,t(major)＝20.8min,t(minor)＝12.9min]；
1H NMR(400MHz,CDCl3)δ7.31(s,1H),7.11(d,J＝7.9Hz,2H),7.04(d,J＝7.9Hz,2H),6.97(s,2H),6.59(s,2H),6.41-6.31(m,2H),6.06(br,1H),5.90(s,1H),5.86(s,1H),5.15(s,1H),4.86(s,1H),4.69(br,1H),4.57(d,J＝12.7Hz,1H),4.33(d,J＝12.9Hz,1H),3.69(s,3H),2.91(d,J＝12.9Hz,1H),2.57(d,J＝13.0Hz,1H),2.28(s,3H)；
13C NMR(100MHz,CDCl3)δ13C NMR(101MHz,CDCl3)δ173.2,151.9,147.1,143.9,142.5,137.1,134.7,134.3,133.6,129.1,127.4,127.1,126.8,126.3,126.3,126.2,119.3,109.3,103.2,101.4,81.0,61.0,51.8,38.2,26.9,21.2；
HRMS(ESI)m/z calcd.for C30H27O7Cl2[M+H]+:537.1230,found:537.1235。
Example 12
Synthesis of (9S,10S) -9- (3, 5-dichlorophenyl) -7-methylene-10- ((E) -styryl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxazole [4',5',4,5] benzo [1,2-b ] oxooctanoic acid-9-carboxylic acid (IIIaa) As described in example 1, except that: the reaction temperature was room temperature, the yield of the obtained product was 70%, and the ee value of the product was 87%.
Comparative example 1
Synthesis of (9S,10S) -9- (3, 5-dichlorophenyl) -7-methylene-10- ((E) -styryl) -7,8,9, 10-tetrahydro-6H- [1,3] dioxazole [4',5',4,5] benzo [1,2-b ] oxooctanoic acid-9-carboxylic acid (IIIaa) As described in example 1, except that: the reaction can not be carried out without adding chiral ligand, and the product can not be obtained.
Comparative example 2
(9S,10S) -9- (3, 5-dichlorophenyl) -7-methylene-10- ((E) -styryl) -7,8,9, 10-tetrahydro-6H- [1,3]Dioxazoles [4',5',4,5]]Benzo [1,2-b ]]Synthesis of oxooctanoic acid-9-carboxylic acid (IIIaa) As described in example 1, except that: without addition of
The molecular sieve has the reaction time of 40 hours, the yield of the obtained product is 35 percent, and the reaction yield and the reaction rate are lower than those of the product in the example 1 of the invention.
The above embodiments are only some examples of the present invention, and the present invention is not limited thereto in any way, and any simple modification, equivalent change and modification to the above embodiments according to the technical spirit of the present invention are within the technical scope of the present invention.
Claims (10)
1. A method for synthesizing chiral oxygen-containing eight-membered ring compounds by palladium-catalyzed asymmetric allylic cycloaddition reaction comprises the following steps:
in a solvent, under the catalysis of a palladium catalysis system, carrying out [4+4] cycloaddition reaction on a gamma-methylene-delta-valerolactone compound I and an o-quinone methide II to obtain a chiral oxygen-containing eight-membered ring compound III; the palladium catalytic system consists of a palladium catalyst and a chiral ligand, and the chiral ligand has a structure shown in a formula IV;
wherein, in the structural formula of the compound of formula I, Ar1Is substituted phenyl or substituted hexabasic aromatic heterocycle, and the heteroatom of the hexabasic aromatic heterocycle is O, N or S; the substituent groups of the substituted phenyl and the substituted hexabasic aromatic heterocycle are respectively and independently one or two of trifluoromethyl, halogen, cyano and nitro; r is methyl or ethyl;
in the structural formula of the compound of formula II, Ar2Is phenyl, substituted phenyl, 1-naphthyl or a five-membered aromatic heterocycle, wherein the heteroatom of the five-membered aromatic heterocycle is O, N or S; the substituent of the substituted phenyl is methoxy, halogen or C1-C4 alkyl;
in the formula III of the compound, the substituent Ar1R is the same as in the compound of formula I, and substituent Ar2The same as in the compound of formula II.
2. The method of claim 1, wherein Ar in the formula of the compound of formula I is Ar1Is 4-trifluoromethylphenyl, 4-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 4-cyanophenyl, 3-nitrophenyl, 3, 5-dichlorophenyl, 3, 5-dibromophenyl, 3, 5-difluorophenyl, 3, 4-difluorophenyl, 3-chloro-5-fluorophenyl or 6-chloro-3-pyridyl;
in the structural formula of the compound of formula II, Ar2Is phenyl, 4-methoxyphenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl or 2-thienyl.
3. The method for synthesizing chiral oxygen-containing eight-membered ring compound according to claim 1, wherein the solvent is ethylbenzene, toluene, tetrahydrofuran, 1, 4-dioxane, chlorobenzene or p-xylene; the ratio of the volume of the solvent to the mole number of the gamma-methylene-delta-valerolactone compound I is 5-20 mL:1 mmol.
4. The method of claim 1, wherein the palladium catalyst is Pd2(dba)3·CHCl3、PdCp(η3-C3H5) Or Pd (PPh)3)4(ii) a The molar ratio of palladium in the palladium catalyst to the gamma-methylene-delta-valerolactone compound I is 0.01-0.1: 1; the molar ratio of palladium to the chiral ligand in the palladium catalyst is 1: 2-2.2.
5. The method for synthesizing chiral oxygen-containing eight-membered ring compound according to claim 1, wherein the molar ratio of γ -methylene- δ -valerolactone compound i to o-quinone methide ii is 1: 1.
6. The method for synthesizing chiral oxygen-containing eight-membered ring compound according to claim 1, wherein γ -methylene- δ -valerolactone compound i and o-quinone methide ii are subjected to [4+4]]The reaction system of the cycloaddition reaction is also added
A molecular sieve; the above-mentioned
The ratio of the mass of the molecular sieve to the number of moles of the gamma-methylene-delta-valerolactone compound I is 1-2 g:1 mmol.
7. The method for synthesizing a chiral oxygen-containing eight-membered ring compound according to claim 1, wherein the cycloaddition reaction is carried out under an inert gas atmosphere, and the inert gas is nitrogen or argon.
8. The process for the synthesis of chiral oxygen-containing eight-membered ring compound according to claim 1, wherein the temperature of the cycloaddition reaction is-20 ℃ to room temperature, preferably-20 ℃.
9. The method for synthesizing chiral oxygen-containing eight-membered ring compound according to claim 1, wherein the cycloaddition reaction time is 2-40 h, preferably 10-24 h.
10. The method for synthesizing a chiral oxygen-containing eight-membered ring compound according to claim 1, wherein the post-treatment step of the reaction solution obtained after the [4+4] cycloaddition reaction of the γ -methylene- δ -valerolactone compound i and the o-quinone methide ii is as follows: and (3) separating the reaction liquid by silica gel column chromatography to obtain a chiral oxygen-containing eight-membered ring compound III, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent is 0.03-0.1: 1.
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| CN115043850A (en) * | 2021-08-18 | 2022-09-13 | 山东大学 | Method for synthesizing chiral oxygen-containing eight-membered ring compound through palladium-catalyzed asymmetric allylic cycloaddition reaction |
| CN116082350A (en) * | 2023-01-13 | 2023-05-09 | 天津大学 | Chiral aza-octamembered ring compound and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115043850A (en) * | 2021-08-18 | 2022-09-13 | 山东大学 | Method for synthesizing chiral oxygen-containing eight-membered ring compound through palladium-catalyzed asymmetric allylic cycloaddition reaction |
| CN115043850B (en) * | 2021-08-18 | 2024-02-02 | 山东大学 | Method for synthesizing chiral oxygen-containing octatomic ring compound through palladium-catalyzed asymmetric allyl cycloaddition reaction |
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| CN116082350A (en) * | 2023-01-13 | 2023-05-09 | 天津大学 | Chiral aza-octamembered ring compound and preparation method thereof |
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