Method for asymmetrically opening ring of 3-substituted oxetane and application

An oxetane, asymmetric technology, applied in the field of asymmetric catalytic synthesis, can solve the problems of catalyst deactivation, weak ring-opening reaction activity, and high difficulty in selecting nucleophiles

Active Publication Date: 2017-09-08
HKUST SHENZHEN RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Second, the ring-opening reaction activity of 3-substituted oxetanes is relatively weak, and the selection of nucleophiles is difficult. The nucleophilic ability should not only meet the ring-opening reaction, but also not be too strong to cause catalyst deactivation;
[0007] Third, the reaction product itself is an alcohol, and its alcoholic hydroxyl group is also a competitive nucleophile, which may compete with the substrate nucleophile and interfere with the reaction

Method used

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  • Method for asymmetrically opening ring of 3-substituted oxetane and application
  • Method for asymmetrically opening ring of 3-substituted oxetane and application
  • Method for asymmetrically opening ring of 3-substituted oxetane and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Step Step 1, preparing the precursor compound S3 of the chiral phosphoric acid catalyst CAT:

[0033] (1) Prepare Grignard reagent S2. Under nitrogen protection, magnesium powder (1.44 g, 60.0 mmol) and anhydrous tetrahydrofuran (15 mL) were placed in a 250 mL round bottom flask, and a small amount of iodine and 1,2-dibromoethane were added as activators. Stir for 20 minutes, then slowly add a solution of 1-bromo-2,4,6-tricyclohexylbenzene (12.10g, 30.0mmol) in tetrahydrofuran (85mL) dropwise to the reaction flask, and the reaction solution is heated to reflux for 12 hours, then cooled Bring to room temperature for later use.

[0034] (2) Precursor compound S3 of chiral phosphoric acid catalyst CAT was prepared by compound S1 and Grignard reagent S2. Under nitrogen protection, compound S1 (2.37 g, 4.0 mmol) and bis(triphenylphosphine)nickel chloride (523 mg, 0.8 mmol) were placed in a 100 mL dry round bottom flask, and anhydrous tetrahydrofuran (20 mL) was added. Und...

Embodiment 2

[0070] In this embodiment, 3-(4-methylphenyl)oxetane is used as the substrate, and the above-mentioned steps are the same as in Example 1, and the catalyst dosage is 2mol%, and the reaction is carried out for 18 hours to obtain the corresponding The reaction product of Example 2, 50.2 mg of colorless oily substance, calculated yield 91%.

[0071] Similarly, after the preparation of this step is completed, the obtained oily product is analyzed by means of measuring specific rotation, high performance liquid chromatography to measure ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrometry. Among them, the analysis of the test is as follows:

[0072] 1. Specific rotation [α] measured by D line at 25°C D 25 :-24.1 (c=1.0, CHCl 3 );

[0073]2. HPLC analysis and determination of ee value: chiral column Daicel Chiralcel OD-H column; 5% i-PrOH in hexanes; 1.0mL / min; retention time: 10.9min (major), 11.8min (minor). Calculation The result was 94% ee. ...

Embodiment 3

[0082] In this Example 3, 3-(2-methoxyphenyl)oxetane was used as the substrate, followed the same procedure as above, with a catalyst dosage of 5 mol%, and reacted for 24 hours to obtain the corresponding reaction product, colorless 51.2mg of oil, yield 85%.

[0083] Similarly, after the preparation of this step is completed, the obtained oily product is analyzed by means of measuring specific rotation, high performance liquid chromatography to measure ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrometry. Among them, the analysis of the test is as follows:

[0084] 1. Specific rotation measured by D line at 25°C [α] D 25 : -11.4 (c=1.0, CHCl 3 ).

[0085] 2. HPLC analysis and determination of ee value: Chiral column Daicel Chiralcel OD-H column; 5% i-PrOH in hexanes; 1.0mL / min; retention time: 17.4min (major), 13.7min (minor), calculated The result is 90% ee.

[0086] 3. Proton spectrum and carbon spectrum of nuclear magnetic resonance ana...

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Abstract

The invention discloses a method for catalytically asymmetrically opening a ring of 3-substituted oxetane by using halogen. The method comprises the following steps: with 3-substituted oxetane and a halogen nucleophile as reaction substrates, under the action of a chiral acid catalyst, performing an asymmetric ring opening reaction to highly selectively synthesize chiral 2-substituted-3-halogenated propanol. The invention further provides preparation of a variety of chiral 2-substituted-3-Nu-propanol products through a reaction performed on the chiral 2-substituted-3-halogenated propanol product obtained in the asymmetric ring opening reaction and a variety of nucleophiles Nu. After adoption of the chiral ring opening method, the reaction for catalytically asymmetrically opening the ring of 3-substituted oxetane with the halogen nucleophile is achieved for the first time; through functional group transformation of halogenated groups in the products, the asymmetric ring opening reaction performed on the variety of nucleophiles and 3-substituted oxetane can be directly achieved; and a high-efficiency synthesis method is provided for preparing chiral 2-substituted-3-Nu-propanol compounds.

Description

technical field [0001] The invention belongs to the technical field of asymmetric catalytic synthesis, and in particular relates to an asymmetric ring-opening method of 3-substituted oxetane, and further applies the method to the preparation of chiral 2-substituted-3-Nu-propanol . Background technique [0002] 3-substituted oxetane is a derivative of oxetane with a substituent on the oxygen para-position carbon atom. The four-membered heterocyclic ring in its structure is a slightly twisted square structure with a strong ring Tension can cause a ring-opening reaction with a nucleophile, and the process of the ring-opening reaction is as follows: [0003] [0004] The reaction finally generates the product 2-take-3-Nu-propanol; where Nu represents a nucleophile, which is a molecule or anion with an unshared electron pair, as a donor for an electron pair; X is a substitution on the oxygen heterocycle The group is generally an aryl group, an alkyl group, a heterocycle, a h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B53/00C07C29/64C07C33/46C07C33/48C07C41/26C07C43/178C07C43/23C07C253/30C07C255/53C07C253/14C07C255/36C07C247/10C07C327/28C07C319/14C07C323/20C07D307/80C07D209/86C07D249/18C07D249/08C07F7/18
CPCC07B53/00C07B2200/07C07C29/64C07C41/26C07C247/10C07C253/14C07C253/30C07C319/14C07C327/28C07D209/86C07D249/08C07D249/18C07D307/80C07F7/1804C07F7/1892C07C33/46C07C43/23C07C255/53C07C33/483C07C43/1786C07C255/36C07C323/20
Inventor 孙建伟杨文
Owner HKUST SHENZHEN RES INST
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