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Method for catalyzing asymmetric synthesis of chiral beta-alkynyl-beta-aminoketone derivative

An asymmetric and aminoketone technology, which is applied in the field of catalytic asymmetric synthesis of chiral β-alkynyl-β-aminoketone derivatives, can solve the problem of narrow application range of substrates and nucleophiles, high requirements for substrate structure, Complicated actual operation and other problems, to achieve the effect of improving solubility and catalytic activity, good compatibility, and wide application range

Active Publication Date: 2020-05-19
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are still major challenges in the construction of chiral β-alkynyl-β-amino ketone structural fragments: 1) The structural requirements of the substrate are relatively high, which greatly limits their practicability; 2) The substrate and nucleophilic The scope of application of the reagent is narrow, and the reactivity is general; 3) The actual operation of the reaction is relatively complicated, the yield is not high, and there are huge challenges in industrialization

Method used

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  • Method for catalyzing asymmetric synthesis of chiral beta-alkynyl-beta-aminoketone derivative
  • Method for catalyzing asymmetric synthesis of chiral beta-alkynyl-beta-aminoketone derivative
  • Method for catalyzing asymmetric synthesis of chiral beta-alkynyl-beta-aminoketone derivative

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Experimental program
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Embodiment 1

[0030]

[0031] Experimental procedure: in N 2 Under protection, the reaction system was sealed and the temperature was adjusted to minus 25°C, and β-phthalimide acetone substrate (0.1mmol, 1.0equiv) and chiral binaphthol catalyst were sequentially added to a 25mL reaction flask (R)-L3 (0.02mmol, 0.2equiv), phenylethynyl trifluoroborate potassium salt (0.3mmol, 3.0equiv), additive (the additive is: Molecular sieves (125 mg) and boron trifluoride diethyl ether (1.0 equiv)) were reacted with anhydrous trifluorotoluene (2.0 mL) as the solvent. Monitor the reaction by TLC analysis until after the reaction is complete, the reaction system is filtered through celite and concentrated, and the concentrated crude product obtained is separated and purified by column chromatography (eluent: n-hexane / ethyl acetate=70 / 30 (v / v )) to obtain the target compound 4aa as a colorless oily liquid with a yield of 92% and an ee value of 86%. [α] D 20 =+23.2(c 1.0, CHCl 3 ). 1 H NMR (400MHz...

Embodiment 2

[0033] The solvent in Example 1 was replaced by trifluorotoluene with chlorobenzene of equal volume, and all the other operating steps were the same as in Example 1. The product 4aa was obtained as a colorless oil with a yield of 93% and an ee value of 68%.

Embodiment 3

[0035] The solvent in Example 1 was replaced by trifluorotoluene with dichloromethane of the same volume, and the rest of the operating steps were the same as in Example 1. The product 4aa was obtained as a colorless oil with a yield of 91% and an ee value of 65%.

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Abstract

The invention discloses a method for catalyzing asymmetric synthesis of a chiral beta-alkynyl-beta-aminoketone derivative. A chiral binaphthol derivative shown in a formula (3) is used as a catalyst;in the presence of an organic solvent, a catalyst and an additive, alkynyl potassium fluoroborate represented by the formula (2) performs asymmetric 1, 4-addition reaction for an aza-ketene compound represented by the formula (1), and a beta-alkynyl-beta-aminoketone derivative shown as a formula (4) and containing a chiral center is generated, and the reaction formula is as follows as is shown inthe specification. A novel catalyst with a polyfluorobinaphthol skeleton is utilized, alkynyl potassium fluoborate with good functional group compatibility and stable properties is used as a nucleophilic reagent, and various chiral beta-alkynyl-beta-aminoketone derivatives are efficiently prepared under the action of various additives. The substrate is wide in application range, the reaction conditions are simple and mild, the obtained product with high optical activity can be further converted into multiple non-natural chiral beta-amino acid derivatives, and high scientific research and practical application value is achieved.

Description

technical field [0001] The invention relates to a method for catalytic asymmetric synthesis of chiral β-alkynyl-β-aminoketone derivatives. Background technique [0002] Chiral β-aminoketone derivatives are the core units of many proteins, polypeptides, ribosomes, natural products and drug molecules, and have important uses in the field of biomedicine. In the clinical application of polypeptide drugs, the introduction of chiral β-aminoketone derivatives can significantly improve the stability of polypeptide drugs, improve the ability of polypeptide drugs to pass through the blood-brain barrier and reduce the toxicity of drugs [LIU, W.X.; WANG, R. Med Res Rev, 2012, 32, 536-580]. In 1991, the Noyori group was the first to use Ru(O 2 CCH 3 ) 2 and (R)-BINAP achieved asymmetric hydrogenation of N-acyl-β-(amino)acrylates to synthesize chiral β-aminoketone derivatives and provided >99% ee values ​​[Lubell, W.D.; Kitamura , M.; Noyori, R. Tetrahedron Asymmetry, 1991, 2, 543...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48C07D405/06C07D403/06C07C303/36C07C311/17
CPCC07D209/48C07D405/06C07D403/06C07C303/36C07B2200/07C07C311/17
Inventor 毛斌孟鑫王建飞柏详陈志卫俞传明
Owner ZHEJIANG UNIV OF TECH
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