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Preparation method and use of n-heterocyclic carbene catalyzed indole-containing skeleton chiral spiro compound

A technology for spiro compounds and indole, which is applied in the field of preparation and application of chiral spiro compounds containing indole skeleton catalyzed by nitrogen heterocyclic carbene, and achieves high enantioselectivity, excellent yield and good universality Effect

Active Publication Date: 2019-12-10
GUIZHOU UNIV
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Problems solved by technology

Transition metal and chiral phosphoric acid catalysis have made breakthroughs, but there is still little research in the field of azacyclic carbene catalysis. By using azacyclic carbene to activate the nitrogen atom of indole and active ketone for addition reaction, with excellent yield Synthesis of N,O-acetal indole skeleton chiral spiro compounds with high enantioselectivity has been a difficult problem

Method used

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  • Preparation method and use of n-heterocyclic carbene catalyzed indole-containing skeleton chiral spiro compound
  • Preparation method and use of n-heterocyclic carbene catalyzed indole-containing skeleton chiral spiro compound
  • Preparation method and use of n-heterocyclic carbene catalyzed indole-containing skeleton chiral spiro compound

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Experimental program
Comparison scheme
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preparation Embodiment 1

[0031] Substituent R 1 for H,R 2 for H, R 3 For Bn, preparation implementation method and condition are with total embodiment 1;

[0032] Weigh respectively 0.15mmol (23.73mg) of indole-2-carboxaldehyde 1, 0.1mmol (21.86mg) of indole-2,3-dione 2, 0.05mmol (2.1mg) of nitrogen heterocyclic carbene catalyst E and 0.17mmol Add (69.5mg) oxidant DQ into a 10mL Schlenk reaction tube equipped with a magnetic stir bar, add 1mL solvent tetrahydrofuran THF, then add 0.15mmol (25μL) base N,N-diisopropylethylamine DIEA, gently shake the reaction wall , to mix thoroughly. Cover the bottle and place it in a 10°C isopropanol water bath to fully stir the reaction for 24h. After the completion of the reaction monitored by TLC, 1 mL of 1N hydrochloric acid was added to the reaction tube, stirred at room temperature for 5 minutes, the organic layer was extracted with ethyl acetate, spin-dried, a small amount of dichloromethane was fully dissolved and loaded by wet method, separated by column ...

preparation Embodiment 2

[0039] Substituent R 1 4-Br,R 2 for H, R 3 For Bn, preparation implementation method and condition are with total embodiment 1;

[0040] (R)-1-Benzyl-8'-bromo-1'H-spiro[indoline-3,3'-oxazolo[3,4-α]indole]-1',2dione (I 2 )

[0041] 7.07–6.92(m, 2H), 6.44(d, J=8.4Hz, 1H), 5.11(d, J=15.4Hz, 1H), 4.83(d, J=15.4Hz, 1H);

[0042] 13 C NMR (101MHz, CDCl 3 )δ166.9, 157.7, 142.7, 133.3, 132.8, 132.6, 131.1, 128.0, 127.3, 126.6, 125.6, 125.1, 124.3, 124.0, 123.3, 119.1, 116.7, 109.7, 108.2, 102.4, 87.1;

[0043] HRMS (ESI,m / z)calcd.for C 24 h 15 N 2 o 3 Br H + :459.0338,found:459.0332;

[0044] Chiral analysis was performed by HPLC, the specific conditions were: 97:3er (U-IC column, 25°C, hexans / i PrOH=90 / 10, 0.3mL / min, λ=254nm), Rt(minor)=17.3min, Rt(major)=14.3min.

preparation Embodiment 3

[0046] Substituent R 1 4-OCH 3 , R 2 for H, R 3 For Bn, preparation implementation method and condition are with total embodiment 1;

[0047] (R)-1-Benzyl-8'-methoxy-1'H-spiro[indoline-3,3'-oxazolo[3,4-α]indole]-1',2 Diketone (I 3 )

[0048] 1H), 5.11(d, J=15.5Hz, 1H), 4.82(d, J=15.5Hz, 1H), 3.95(s, 3H);

[0049] 13 C NMR (101MHz, CDCl 3 )δ167.9, 158.9, 155.2, 143.4, 134.1, 133.0, 128.7, 127.9, 127.3, 126.9, 125.7, 124.3, 123.9, 122.9, 120.3, 110.3, 102.5, 101.0, 100.8, 87.6, 53.1;

[0050] HRMS (ESI,m / z)calcd.for C 25 h 18 N 2 o 4 h + :411.1339,found:411.1329;

[0051] Chiral analysis was performed by HPLC, the specific conditions were: 97:3er (U-IC column, 25°C, hexans / i PrOH=90 / 10, 0.3mL / min, λ=254nm), Rt(minor)=41.9min, Rt(major)=32.9min.

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Abstract

The invention relates to a preparation method for the synthesis of an indole-containing skeleton chiral spiro compound (R)-1-aryl-1'H-spiro[dihydroindole-3,3'-oxazolo[3,4-alpha] indole]-1',2 diketonederivative by n-heterocyclic carbene with extremely small molecule catalysis and high enantioselectivity and a good biological activity use. A general structure formula is shown as follows (please seespecification for the formula), wherein R1 is a substituent of indole-2-formaldehyde, R2 is a substituent of indole-2,3-diketone, and R3 is a different protecting group of the indole-2,3- diketone, methyl, benzyl, and triphenylmethyl. The indole skeleton chiral spiro compound (R)-1-aryl-1'H-spiro[dihydroindole-3,3'-oxazolo[3,4-alpha] indole]-1',2 diketone derivative prepared by an asymmetric cyclization reaction has good universality, excellent yield which reaches up to 98%, enantioselectivity which reaches up to 99 % and good biological activity.

Description

technical field [0001] The invention relates to a preparation method and application of a nitrogen-heterocyclic carbene organic small molecule catalyzed synthesis of a chiral spiro compound containing an indole skeleton Background technique [0002] Organic heterocyclic molecules widely exist in medicines, pesticides, ligands, natural products and other functional molecules. The nitrogen atoms of heterocyclic compound indole molecules can undergo addition reactions with active ketones to form N, O-acetal products, namely Indole-skeleton chiral spiro compounds pose great challenges to product conversion and enantioselective control. In a large number of organic synthesis examples (ACSCatal.2016,6,5747-5763) and drug tests (J.Am.Chem.Soc.,1995,117,552-553, J.Am.Chem.Soc.,1996,118, 2825-2842, Chem.Rev., 2016, 116, 287-322) It has been confirmed that N, O-acetal is a structural unit widely present in functional molecules (Angew.Chem.Int.Ed., 2013, 52, 3250- 3254, Org. Lett., 2...

Claims

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Application Information

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IPC IPC(8): C07D491/20A01N43/90A01P1/00
CPCC07D491/20A01N43/90C07B2200/07Y02P20/55
Inventor 池永贵刘雍贵蒋仕春金智超
Owner GUIZHOU UNIV
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