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Method for desymmetrization of 3-substituted cyclobutanone, cyclobutene compound and use thereof

A cyclobutanone and desymmetry technology, applied in the field of chemical synthesis, can solve the problems of little research, difficult direct conversion of 3-substituted cyclobutanone, poor stability, etc., and achieves simple operation, wide substrate universality, High stability effect

Active Publication Date: 2022-07-29
FUDAN UNIV +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The enantioselective desymmetrization of cyclobutanone compounds is an effective way to endow them with molecular diversity, but so far, there are still few studies on such reactions for four-membered ring skeletons
In the literature, chiral lithium amides are used to enantioselectively deprotonate cyclobutanone compounds to construct corresponding cyclobutenol silyl ethers, but such compounds are poorly stable under acidic conditions and are difficult to obtain directly through coupling reactions. alkenyl derivatives
[0004] Therefore, it is necessary to solve the technical problem that the desymmetry of 3-substituted cyclobutanones is difficult to convert directly, and then achieve high enantioselectivity to construct cyclobutene phosphate compounds

Method used

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  • Method for desymmetrization of 3-substituted cyclobutanone, cyclobutene compound and use thereof
  • Method for desymmetrization of 3-substituted cyclobutanone, cyclobutene compound and use thereof
  • Method for desymmetrization of 3-substituted cyclobutanone, cyclobutene compound and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]

[0037] To a dry Schlenk reaction tube was added the chiral amine hydrochloride CA-4c·HCl (0.127 g, 0.440 mmol), THF (1.2 mL) sequentially. After cooling to -78 °C, n-butyllithium (2.28 M, 0.39 mL, 0.880 mmol) was added dropwise. After stirring for five minutes, the cooling bath was removed, and after returning to room temperature, stirring was continued for 15 minutes until the reaction system became clear. The reaction tube was then placed in a -90°C cold bath, and a solution of 3-substituted cyclobutanone 1a (58.5 mg, 0.400 mmol) in tetrahydrofuran (0.5 mL, 0.3 mL wash, 0.2 mL) was added dropwise over a period of 30 minutes washing). After the addition was completed, the reaction was held for 30 minutes, and the electrophile ClP(O)(OPh) was added dropwise over a period of 10 minutes. 2 (0.42 mL, 0.540 g, 2.00 mmol), after holding the reaction for 30 minutes, the temperature of the cooling bath was increased to -78°C. After continuing the reaction for about 3.5...

Embodiment 2

[0039]

[0040] The operation is the same as in Example 1. The raw materials and dosage are as follows: 3-substituted cyclobutanone 1b (64.0 mg, 0.400 mmol), chiral amine hydrochloride CA-4c HCl (0.127 g, 0.440 mmol), n-butyllithium (2.25 M, 0.39 mL) , 0.880mmol) and the electrophile ClP(O)(OPh) 2 (0.42 mL, 0.540 g, 2.00 mmol). Flash column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain chiral cyclobutene phosphate 2b (0.155 g, 85%): colorless oil; 93% ee (HPLC condition: OD -H column, cyclohexane / i-PrOH=95 / 5, 1.0mL / min, λ=210nm, t R (main)=10.5min,t R (minor) = 11.8min); (c 0.50, CHCl 3 ). 1 H NMR (400MHz, CDCl 3 )δ(ppm): 7.41-7.32(m, 4H), 7.30-7.19(m, 7H), 7.15-7.02(m, 3H), 5.40(s, 1H), 3.64(d, J=3.4Hz, 1H ), 3.27(ddd, J=13.2, 4.5, 1.5Hz, 1H), 2.57(d, J=13.2Hz, 1H), 2.32(s, 3H); 13 C NMR (101MHz, CDCl 3 )δ(ppm): 150.29(d, J=7.3Hz), 141.98(d, J=9.9Hz), 139.04, 136.19, 129.89, 129.06, 126.46, 125.68, 120.05(d, J=4.9Hz), 120.04( d, J=5.0H...

Embodiment 3

[0042]

[0043] The operation is the same as in Example 1. The raw materials and dosage are as follows: 3-substituted cyclobutanone 1c (47.4 mg, 0.272 mmol), chiral amine hydrochloride CA-4c HCl (96.0 g, 0.330 mmol), n-butyllithium (2.25 M, 0.29 mL) , 0.660 mmol) and the electrophile ClP(O)(OPh) 2 (0.31 mL, 0.400 g, 1.50 mmol). Flash column chromatography (eluent: petroleum ether / ethyl acetate = 95 / 5) to obtain chiral cyclobutene phosphate 2c (97.4 mg, 88%): colorless oil; 93% ee (HPLC condition: OJ -H column, cyclohexane / i-PrOH=9 / 1, 1.0mL / min, λ=210nm, t R (main)=7.0min,t R (minor) = 8.2min); (c 1.0, CHCl 3 ). 1 H NMR (400MHz, CDCl 3 )δ(ppm): 7.45-7.30(m, 4H), 7.30-7.17(m, 6H), 6.85(s, 3H), 5.41(s, 1H), 3.63-3.59(m, 1H), 3.26(ddd , J=13.2, 4.5, 1.5Hz, 1H), 2.59 (d, J=13.2Hz, 1H), 2.28 (s, 6H); 13 C NMR (101MHz, CDCl 3 )δ(ppm): 150.27(d, J=7.3Hz), 142.00, 141.87(d, J=9.9Hz), 137.91, 129.87, 128.27, 125.67, 124.34, 120.02(d, J=4.9Hz), 120.01( d, J=4.9Hz), 113.89 ...

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Abstract

The invention discloses a method for desymmetry of 3-substituted cyclobutanone, cyclobutene compounds and uses thereof. The method uses 3-substituted cyclobutanone as a starting material, and under the action of chiral lithium amide, Enantioselective deprotonation to obtain the corresponding lithium enolate intermediate; then using chlorophosphate as an electrophile to capture the lithium enolate intermediate to obtain cyclobutene compound (I), the reaction process is as follows : The method of the invention is simple to operate; the raw materials and reagents are simple and easy to obtain, and the preparation is convenient; the substrate is widely applicable; the functional group compatibility is good; the reaction has high enantioselectivity (up to 93% ee); Wait.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for desymmetrization of 3-substituted cyclobutanone, a cyclobutene compound and use thereof. Background technique [0002] Chiral lithium amides (CLAs) are widely used in asymmetric chemistry as chiral bases, chiral nucleophiles, and chiral ligands. The enantioselective deprotonation of cyclic ketones by chiral lithium amide to obtain the corresponding chiral enol silyl ethers has been extensively studied. Among them, the quenching and trapping mode of active species, the addition of metal salts and the co-solvent effect are considered to be crucial for the construction of high enantioselectivity of the product. [0003] Cyclobutane skeleton compounds have high ring tension and unique conformation, show unique chemical reactivity, and are important synthetic building blocks in organic chemistry and medicinal chemistry. The enantioselective desymm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/12C07F9/572C07D209/70C07D487/04
CPCC07F9/12C07F9/5728C07D209/70C07D487/04C07B2200/07
Inventor 陆平钟昶煦
Owner FUDAN UNIV
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