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Polysubstituted beta-hydroxy acid derivative with ortho-chiral center and ortho-chiral center and stereodiversity preparation method of polysubstituted beta-hydroxy acid derivative

A multi-substitution, hydroxy acid technology, applied in the field of methodological research and application, can solve problems such as single diastereomers

Pending Publication Date: 2022-07-08
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The above-mentioned method for preparing chiral β-hydroxy acid derivatives has obvious disadvantages: only a single diastereomer can be obtained for β-hydroxy acid derivatives with an adjacent two-handed chiral center

Method used

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  • Polysubstituted beta-hydroxy acid derivative with ortho-chiral center and ortho-chiral center and stereodiversity preparation method of polysubstituted beta-hydroxy acid derivative
  • Polysubstituted beta-hydroxy acid derivative with ortho-chiral center and ortho-chiral center and stereodiversity preparation method of polysubstituted beta-hydroxy acid derivative
  • Polysubstituted beta-hydroxy acid derivative with ortho-chiral center and ortho-chiral center and stereodiversity preparation method of polysubstituted beta-hydroxy acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Synthesis of (2R,3R)-N-benzyl-3-(benzyloxy)-2-(p-tolyl)pent-4-enamide

[0027]

[0028] First, add raw materials 2a (0.1mmol), 1,4-dioxane (0.5mL) and (S)- i Pr-BTM (0.005 mmol), then raw materials 1a (0.2 mmol) and (S)-L1-Pd (0.002 mmol) were added successively, and the reaction was carried out at room temperature for 12 hours under argon. Benzylamine (0.2 mmol) and diisopropylethylamine (0.2 mmol) were then added and the reaction continued for 12 hours. After the reaction was completed, the solvent was evaporated to dryness and subjected to silica gel column chromatography with the eluent (ethyl acetate / petroleum ether=1 / 5) to obtain 36 mg of a white solid with a yield of 93%. The melting point is 106-108°C, the diastereoselectivity ratio of the product is 13:1, and the enantioselectivity excess of the product is 98%. [α] 25 D =47.5(c 0.5, CHCl 3 ).

[0029] 1 H NMR (400MHz, CDCl 3 )δ7.32-7.16 (m, 12H), 7.10 (d, J=7.9Hz, 2H), 6.14 (t, J=5.8 Hz, 1...

Embodiment 2

[0032] Example 2: Synthesis of (2R, 3R)-N-benzyl-3-((4-methoxybenzyl)oxy)-2-(p-tolyl)pent-4enamide

[0033]

[0034] First, add raw materials 2a (0.1mmol), 1,4-dioxane (0.5mL) and (S)- i Pr-BTM (0.005 mmol), then raw materials 1b (0.2 mmol) and (S)-L1-Pd (0.002 mmol) were added in sequence, and the reaction was carried out at room temperature for 12 hours under argon. Then benzylamine (0.2 mmol) and diisopropylethylamine (0.2 mmol) were added, and the reaction was continued for 12 hours. After the reaction was completed, the solvent was evaporated to dryness and subjected to silica gel column chromatography. The eluent was (ethyl acetate / petroleum ether= 1 / 5) to obtain 29 mg of white solid with a yield of 71%. The melting point is 133-135°C, the diastereoselectivity ratio of the product is 13:1, and the enantioselectivity excess of the product is 97%. [α] 25 D =45.0(c 0.7, CHCl 3 ).

[0035] 1 H NMR (400MHz, CDCl 3 )δ7.25-7.18(m, 9H), 7.09(d, J=7.6Hz, 2H), 6.83(d, J...

Embodiment 3

[0038] Example 3: Synthesis of (2R,3R)-N-benzyl-2-(p-tolyl)-3-((4-(trifluoromethyl)benzyl)oxy)pent-4-enamide

[0039]

[0040] First, add raw materials 2a (0.1mmol), 1,4-dioxane (0.5mL) and (S)- i Pr-BTM (0.005 mmol), then the raw materials 1c (0.2 mmol) and (S)-L1-Pd (0.002 mmol) were added successively, and the reaction was carried out at room temperature for 12 hours under argon. Then benzylamine (0.2 mmol) and diisopropylethylamine (0.2 mmol) were added, and the reaction was continued for 12 hours. After the reaction was completed, the solvent was evaporated to dryness and subjected to silica gel column chromatography. The eluent was (ethyl acetate / petroleum ether= 1 / 5) to obtain 33 mg of white solid, yield 72%. The melting point is 151-153°C, the diastereoselectivity ratio of the product is 14:1, and the enantioselective excess of the product is >99%. [α] 25 D =51.8(c 0.8, CHCl 3 ).

[0041] 1 H NMR (400MHz, CDCl 3 )δ7.54(d, J=8.1Hz, 2H), 7.37(d, J=8.0Hz, 2H), ...

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Abstract

The invention relates to a polysubstituted beta-hydroxy acid derivative with ortho-chiral center and ortho-chiral center and a stereodiversity preparation method thereof. Starting from simple alkoxy allene and pentafluorophenyl ester, a class of polysubstituted beta-hydroxy acid derivatives with ortho-chiral centers and ortho-chiral centers are efficiently synthesized by utilizing a strategy of concerted catalysis of a palladium catalyst and a Lewis base catalyst. All stereoisomers of the multi-substituted beta-hydroxy acid derivative with ortho-chiral center and ortho-chiral center can be obtained by reasonably matching the configurations of the two chiral catalysts.

Description

technical field [0001] The present invention relates to a kind of multi-substituted β-hydroxy acid derivatives with ortho-secondary centers, which are efficiently prepared from simple alkoxy allenes and pentafluorophenyl esters through a strategy of synergistic catalysis by using palladium catalysts and Lewis base catalysts. It belongs to the field of methodological research and application technology. Background technique [0002] Chiral β-hydroxy acid derivatives are key intermediates in the synthesis of many natural products and biologically active substances, which can be widely used in various fields such as chemistry, agriculture, and pharmacy. For example, chiral β-hydroxybutyrate is often used to synthesize various biopheromones, such as the precursor of streptomycin griseogreen, (S)-citronellol and carbapenems. (Tetrahedron: Asymmetry, 2004, 15, 3397; Journal of Molecular Catalysis A: Chemical, 2007, 269, 97.) Meanwhile, mycolic acids containing this backbone are t...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C235/34C07D307/80C07D209/18
CPCC07C231/02C07D307/80C07D209/18C07C235/34Y02P20/584
Inventor 资伟伟朱明辉
Owner NANKAI UNIV
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