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Synthesis method of chiral benzocyclic beta-ketoester compounds

A synthesis method and compound technology are applied in the synthesis field of chiral benzocyclic β-ketoester compounds, can solve rare problems and the like, and achieve the effects of simple synthesis, mild reaction conditions, and cheap and easy-to-obtain catalysts

Inactive Publication Date: 2019-06-07
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although a variety of chiral quaternary carbon centers have been reported, there are few reports on the direct construction of cyclic quaternary carbon chiral centers by asymmetric propargyl substitution.

Method used

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  • Synthesis method of chiral benzocyclic beta-ketoester compounds
  • Synthesis method of chiral benzocyclic beta-ketoester compounds
  • Synthesis method of chiral benzocyclic beta-ketoester compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Cu(CH 3 EN) 4 BF 4 Complexation with L-2-1 is used as a catalyst to catalyze the reaction to generate 1-indanone-2-carboxylic acid methyl ester substituted product 2-propargyl-1-indanone-2-carboxylic acid methyl ester Ⅰ-1.

[0062] Add the metal precursor Cu(CH 3 EN) 4 BF 4(0.01 mmol, 5 mol %) and chiral ligand L-2-1 (0.012 mmol, 6 mol %), add 1.0 mL of anhydrous methanol under nitrogen protection, and stir at room temperature for 1 hour. Then the reaction tube was moved to a constant temperature reaction refrigerator at -20 °C, and propargyl alcohol ester IV-1 (0.2 mmol, 1.0 equiv), 1-indanone-2-carboxylic acid methyl ester III-1 (0.4 mmol, 2.0 equiv) equiv) and i Pr 2 NEt (0.4 mmol, 2.0 equiv) was dissolved in 2.0 mL of anhydrous methanol, then the solution was added to the above stirred catalyst solution under nitrogen protection, and the reaction was stirred at -20 °C for 12 h. After the reaction was completed, it was concentrated under reduced pressure unti...

Embodiment 2

[0066] L-1-1 reacts as a ligand to generate product I-1

[0067] The ligand L-2-1 in Example 1 was replaced with the ligand L-1-1, the temperature was room temperature, and the rest were the same as those in Example 1. The reaction gave compound I-1 in 39% yield, 7% ee.

[0068] The structural formula of L-1-1 is as follows:

[0069]

Embodiment 3

[0071] L-2-2 reacts as a ligand to generate product Ⅰ-1

[0072] The ligand L-2-1 in Example 1 was replaced by the ligand L-2-2, and the temperature was room temperature, and the rest were the same as those in Example 1. The reaction gave compound I-1 in 70% yield, 66% ee.

[0073] The structural formula of L-2-2 is as follows:

[0074]

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Abstract

The invention provides a synthesis method of chiral benzocyclic beta-ketoester compounds, and the compounds are benzocyclic beta-ketoester compounds containing the chiral quaternary carbon center at 2-position. The synthesis method is as follows: in the presence of an alkali additive, a chiral copper catalyst catalyzes an asymmetric propynyl substitution reaction of benzocyclic beta-ketoester compounds and acetylene propyl compounds in a reaction medium to synthesize the benzocyclic beta-ketoester compounds containing the chiral quaternary carbon center at 2-position. The chiral copper catalyst is prepared in situ from copper salts and chiral P, N, N-tridentate ligands in various polar and nonpolar solvents. The method can conveniently synthesize various functionalized benzocyclic beta-ketoester compounds containing the chiral quaternary carbon center at 2-position, and the enantiomer excess percentage is up to 95%. The method has the characteristics of simple operation, easy availability of raw materials, wide application range of substrates, high enantioselectivity and the like.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a method for synthesizing a chiral benzocyclic beta-ketoester compound. Background technique [0002] Quaternary chiral centers are widely found in important chemical preparations such as natural products, drug molecules and pesticides [(a) Newman, D.J., Cragg, G.M.J.Nat.Prod.2016,79,629-661.]. The quaternary carbon chiral centers of many compounds are often derived from chiral sources. [(a) Ding, H.X., Leverett, C.A., Kyne, R.E., Liu, K.K.-C., Fink, S.J., Flick, A.C., O'Donnell, C.J.Bioorg.Med.Chem.2015,23,1895-1922. (b) Stockdale, T.P., Williams, C.M. Chem. Soc. Rev. 2015, 44, 7737-7763.]. Therefore, the use of de novo synthesis, that is, the synthesis of quaternary carbon chiral centers from simple molecules, has become a very challenging problem in the field of organic synthesis. [(a) Ling, T., Rivas, F. Tetrahedron 2016, 72, 6729-6777. (b) Quasdorf, K.W., Overman, L.E. Na...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/757C07C67/343C07D307/85
Inventor 胡向平李坤刘振婷
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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