Fluorine/fluoroalkyl 1,3-diketone compound and method for synthesizing polychiral compound with fluorine/alkylfluoroquaternary carbon center

A chiral compound, fluorinated quaternary technology, applied in the field of preparation of chiral spirocyclic indole compounds, can solve problems such as unreported solutions, achieve excellent yield and stereoselectivity, good antibacterial activity, improve physicochemical and pharmacological effect of nature

Active Publication Date: 2022-04-15
NANJING TECH UNIV
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  • Application Information

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Problems solved by technology

The most challenging of all chiral fluorinated molecular structures is the construction of fluorinated / fluorinated alkyl-containing quaternary carbon centers, in which the simultaneous construction of multiple chiral centers including fluorinated / fluoroalkylated quaternary carbon centers is complex Molecular structure is particularly important, but no effective solution has been reported so far. The development and synthesis of such compounds with complex stereostructures containing fluorine / fluoroalkyl quaternary carbon will provide new opportunities for the discovery and development of synthetic chemistry and fluorine-containing drugs. opportunity

Method used

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  • Fluorine/fluoroalkyl 1,3-diketone compound and method for synthesizing polychiral compound with fluorine/alkylfluoroquaternary carbon center
  • Fluorine/fluoroalkyl 1,3-diketone compound and method for synthesizing polychiral compound with fluorine/alkylfluoroquaternary carbon center
  • Fluorine/fluoroalkyl 1,3-diketone compound and method for synthesizing polychiral compound with fluorine/alkylfluoroquaternary carbon center

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Embodiment 1

[0048]

[0049] Adopt following preparation method to prepare 3a:

[0050] To a dry test tube was added prochiral 1,3-diketone 1 (0.1 mmol), 2-bromounsaturated aldehyde 2 (25.3 mg, 0.12 mmol), NHC (5.0 mg, 10 mol%), NaOAc (12.3 mg,0.15mmol), MS (100mg), then add 1mL mesitylene as solvent to the mixture, the reaction system was stirred at room temperature for 24 hours, after the TLC monitoring reaction was complete, the reaction mixture was separated and purified using a silica gel column, and the eluent was ethyl acetate / petroleum ether / dichloromethane=1:8:1, the product is a white solid.

[0051] (2aS, 3R, 4R, 5aR, 10bR)-1'-methyl-3-phenyl-5a-(trifluoromethyl)-2a,3,5,5a-tetrahydro-2H,6H-spiro[ Fluorene[4a,4-b]oxo-4,3'-indole]-2,2',6-trione, 93% yield, >99% ee, >20:1 dr.[α] D 23 (c 1.0, CHCl 3 )=+83.0.HPLC condition:Chiralpak IB(Hex / iPrOH=95 / 5,1.0mL / min,t R (major)=15.9min).

[0052] 1 H NMR (400MHz, CDCl 3 )δ7.96(d,J=8.0Hz,1H),7.84-7.89(m,2H),7.69-7.73(m,1H),7.3...

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Abstract

The invention relates to a method and application of using fluorine / fluoroalkylated 1,3-diketone as a prochiral substrate to synthesize a multichiral compound with a fluorinated / fluoroalkyl quaternary carbon center and its application, which belongs to chemical synthesis field. The present invention uses nitrogen-heterocyclic carbene organic small molecule catalysts to catalyze the organic cascade reaction of desymmetry between 2-bromo-unsaturated aldehydes and prochiral 1,3-diketone substrates under mild conditions, and can simultaneously Construction of spiro indole compounds with 5 consecutive chiral centers including trifluoromethyl quaternary carbon. The present invention has good substrate universality. The trifluoromethyl group is replaced by fluorine atom, difluoromethyl group and monofluoromethyl group, and the target product can be obtained with excellent yield and stereoselectivity. Preliminary tests show that the reported chiral spiro indole compounds containing fluorinated / fluoroalkylated quaternary carbon centers have good antibacterial activity and have the potential to be applied in industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing polychiral compounds with fluorine / fluoroalkyl quaternary carbon centers using fluorine / fluoroalkylation of 1,3-diketone as a prochiral substrate and its application to the preparation of chiral A method for spiro indole compounds. Background technique [0002] Introducing fluorine atoms into the drug structure is a common method for new drug design. About 20%-25% of drug molecular structures contain fluorine. Common fluorine-containing functional groups include fluorine atom F, trifluoromethyl CF 3 , Difluoromethyl CF 2 H, a fluoromethoxy CH 2 F and other structures. Generally speaking, the introduction of fluorine atoms will change the lipophilicity, hydrogen bonding, metabolic stability, bioavailability, etc. of the compound. Asymmetric catalysis is the most important method for the preparation of chiral fluorides, which has received extensive at...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/107C07D209/96C07D409/04C07D417/12C07J43/00C07D209/34
CPCC07D491/107C07D209/96C07D409/04C07D417/12C07J43/003C07D209/34C07B2200/07
Inventor 黄杰付振乾王冠杰
Owner NANJING TECH UNIV
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