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Preparation method and application of indole skeleton-containing chiral spiro compound catalyzed by nitrogen heterocyclic carbene

A kind of technology of spiro compound and indole, which is applied in the field of preparation and application of chiral spiro compound containing indole skeleton catalyzed by nitrogen heterocyclic carbene

Active Publication Date: 2022-05-17
GUIZHOU UNIV
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  • Abstract
  • Description
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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 application of indole skeleton-containing chiral spiro compound catalyzed by nitrogen heterocyclic carbene
  • Preparation method and application of indole skeleton-containing chiral spiro compound catalyzed by nitrogen heterocyclic carbene
  • Preparation method and application of indole skeleton-containing chiral spiro compound catalyzed by nitrogen heterocyclic carbene

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Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

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

[0032] Weigh out 0.15mmol (23.73mg) indole-2-carbaldehyde 1, 0.1mmol (21.86mg) indole-2,3-dione 2, 0.05mmol (2.1mg) azacyclic carbene catalyst E and 0.17mmol respectively (69.5 mg) oxidant DQ was added to a 10 mL Schlenk reaction tube equipped with a magnetic stirrer bar, 1 mL solvent tetrahydrofuran THF was added, followed by 0.15 mmol (25 μL) base N,N-diisopropylethylamine DIEA, and the reaction wall was gently shaken to mix thoroughly. Cover the bottle and place it in an isopropanol water bath at 10°C to fully stir the reaction for 24h. After the reaction was 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 then loaded with wet method, separated by column chromat...

preparation Embodiment 2

[0039] Substituent R 1 as 4-Br,R 2 for H, R 3 Be Bn, preparation method and condition are with general 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 under the following conditions: 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 for 4-OCH 3 ,R 2 for H, R 3 Be Bn, preparation method and condition are with general 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 )δ167.9,158.9,155.2,143.4,134.1,133.0,128.7,127.9,127.3,126.9,125.7,124.3,123.9,122.9,120.3,110.3,102.5,101.0,100.8,87.6,55.1

[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 under the following conditions: 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 present invention relates to the high enantioselectivity synthesis of indole skeleton-containing spiro compound (R)-1-aryl-1'H-spiro[dihydroindole-3,3'-spiro[dihydroindole-3,3'- The invention discloses a preparation method of oxazolo[3,4-α]indole]-1',2 diketone derivative and its good biological activity application. The general structural formula is as follows: where R 1 is a substituent for indole‑2‑carbaldehyde, R 2 is a substituent of indole-2,3-dione, R 3 are different protecting groups for indole‑2,3‑dione, methyl, benzyl, triphenylmethyl. Indole skeleton chiral spiro compound (R)-1-aryl-1'H-spiro[ Indoline-3,3'-oxazolo[3,4-α]indole]-1',2 dione derivatives, the derivatives of which have good universality and excellent yield up to 98%, Enantioselectivity 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 catalyzing 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 atom of the heterocyclic compound indole molecule can undergo an addition reaction with active ketones to form N, O-acetal products, namely Indole skeleton chiral spiro compounds present great challenges for product transformation and enantioselectivity control. In numerous organic synthesis examples (ACS Catal. 2016, 6, 5747-5763) and drug trials (J. Am. Chem. Soc., 1995, 117, 552-553, J. Am. Chem. Soc., 1996, 118, 2825-2842, Chem.Rev., 2016, 116, 287-322) confirmed that N,O-acetal is a building block widely present in functional molecules (Angew.Chem.Int.Ed., 2013,52,3250- 3254, Org. Le...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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