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A kind of asymmetric synthesis method of pyrroline derivatives with spiro ring structure

A synthesis method and a spiro ring structure technology are applied in the field of asymmetric synthesis of pyrroline derivatives to achieve the effects of mild conditions, high product application value and wide application range

Inactive Publication Date: 2021-01-19
CHONGQING UNIV
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Problems solved by technology

Although there are a few reports on the reaction of aurone and methyleneamine ylides to construct spirocyclic pyrrolidine derivatives, there are no examples of the reaction of this type of compound with important physiological activities and isocyanoacetate compounds to construct spirocyclic pyrroline derivatives. see the report

Method used

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  • A kind of asymmetric synthesis method of pyrroline derivatives with spiro ring structure
  • A kind of asymmetric synthesis method of pyrroline derivatives with spiro ring structure
  • A kind of asymmetric synthesis method of pyrroline derivatives with spiro ring structure

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of compound 3a

[0031]

[0032] step:

[0033]

[0034] Accurately weigh Ligand 1 (6.1 mg, 0.01 mmol) and silver acetate (0.83 mg, 0.005 mmol) into a 10 mL reaction tube equipped with a stirrer, add 2 mL of dichloromethane and stir at 25°C for 5 minutes. Then isocyanoacetate 2a (22.68mg, 0.12mmol) and starting material 1a (22.2mg, 0.1mmol) were added and reacted at 25°C, monitored by TLC until the reaction of starting material 1a was complete. The reaction solution was directly concentrated, and separated and purified by column chromatography to obtain 34.9 mg of product 3a with a yield of 85%.

[0035] White solid, melting point 58-59℃, R f =0.2 (petroleum ether: ethyl acetate = 3:2). 1 H NMR (400MHz, Chloroform-d) δ7.68(s,1H),7.65–7.60(m,2H),7.38(dd,J=6.5,3.1Hz,2H),7.29–7.16(m,9H), 7.09(t, J=7.5Hz, 1H), 4.01(s, 1H), 3.62(s, 3H), 3.08(d, J=13.4Hz, 1H), 2.97(d, J=13.4Hz, 1H); 13 C NMR(101MHz,Chloroform-d)δ197.14,172.04,171.39,160.38,138.79,135.82...

Embodiment 2

[0038] Preparation of compound 3b

[0039]

[0040] step:

[0041]

[0042]Ligand 2 (12.3mg, 0.02mmol) and silver oxide (2.3mg, 0.01mmol) were accurately weighed and placed in a 10mL reaction test tube equipped with a stirring bar, 1mL of tetrahydrofuran was added and stirred at 0°C for 5 minutes. Then isocyanoacetate 2a (22.68mg, 0.12mmol) and starting material 1b (25.2mg, 0.1mmol) were added and reacted at 0°C, monitored by TLC until the reaction of starting material 1b was complete. The reaction solution was directly concentrated, and separated and purified by column chromatography to obtain 43.6 mg of product 3b with a yield of 99%.

[0043] White solid, melting point 81-82°C, R f =0.3 (petroleum ether:ethyl acetate=5:1). 1 H NMR (400MHz, Chloroform-d) δ7.68 (s, 1H), 7.49 (d, J = 8.6Hz, 1H), 7.39–7.37 (m, 2H), 7.23 (ddd, J = 20.8, 13.8, 6.4 Hz,8H),6.62(dt,J=7.3,3.6Hz,1H),6.58(d,J=1.5Hz,1H),4.00(s,1H),3.87(s,3H),3.61(s,3H ), 3.07(d, J=13.4Hz, 1H), 2.95(d, J=13.4H...

Embodiment 3

[0046] Preparation of compound 3c

[0047]

[0048] step:

[0049]

[0050] Accurately weigh ligand 3 (21.8 mg, 0.03 mmol) and silver carbonate (4.1 mg, 0.015 mmol) into a 10 mL reaction tube equipped with a stirrer, add 0.5 mL of chloroform and stir at -20°C for 5 minutes. Then isocyanoacetate 2a (22.68mg, 0.12mmol) and starting material 1c (30.1mg, 0.1mmol) were added and reacted at -20°C, monitored by TLC until the reaction of starting material 1c was complete. The reaction solution was directly concentrated, and separated and purified by column chromatography to obtain 44.1 mg of product 3c with a yield of 90%.

[0051] White solid, melting point M.P.73-75℃, R f =0.5 (petroleum ether:ethyl acetate=5:1). 1 H NMR (400MHz, Chloroform-d) δ7.67(s,1H),7.45(d,J=8.2Hz,1H),7.38(s,1H),7.34–7.33(m,2H),7.30–7.28( m,3H),7.24–7.21(m,4H),7.19–7.15(m,2H),3.99(s,1H),3.60(s,3H),3.06(d,J=13.4Hz,1H),2.93 (d,J=13.4Hz,1H); 13 C NMR(101MHz,Chloroform-d)δ195.87,171.94,171.34,159.83,13...

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Abstract

A pyrroline derivative with a spirane structure has significant physiological activity in fields such as antibiosis and antiviral actions. The invention relates to an asymmetric synthesis method for apyrroline derivative. According to the asymmetric synthesis method, an ethyl isocyanoacetate compound and an aurone derivative are adopted for a 1,3-dipolar-cycloaddition reaction. Through the reaction, a spirane pyrroline derivative with three continuous chiral centers can be rapidly and efficiently established, and very good atom economy can be achieved. The asymmetric synthesis method is easyin substrate preparation, low in price, in addition, mild in reaction condition and simple in operation, a target compound can be prepared with a high yield and high enantioselectivity without anhydrous anaerobic operation, and the substrate application range is wide.

Description

technical field [0001] The invention belongs to the field of organic synthesis methodology and relates to an asymmetric synthesis method of pyrroline derivatives with a spiro ring structure participated by isocyanides. Background technique [0002] Pyrroline and pyrrolidine skeletons with spiro ring structure are widely found in natural products and biologically active compounds. They have important physiological activities in the fields of antibacterial and antiviral, and are also important intermediates in organic synthesis. Because of their unique In recent years, more and more attention has been paid by synthetic chemists due to their structural characteristics and important biological activities. [0003] In 2012, Wang (Chem.Commun., 2012, 48, 5175-5177) et al. reported that 3-alkenyl-2-indolinone and α-phenyl-substituted isocyanide were catalyzed by cinchona base-derived thiourea. The asymmetric 1,3-dipolar cycloaddition reaction of diethyl acetate, by changing the pr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07B53/00C07D491/107C07F17/02
CPCC07B53/00C07B2200/07C07D491/107C07F17/02
Inventor 王志鹏向四川邵攀霖贺耘
Owner CHONGQING UNIV
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