Novel asymmetric catalytic nucleophilic fluorine heterocyclization reaction system and application thereof in chiral non-natural amino acid module synthesis

An unnatural amino acid, asymmetric technology, applied in the field of new asymmetric catalyzed nucleophilic fluorine heterocyclization reaction system, to achieve the effect of environmental friendliness, mild reaction conditions and good stability

Active Publication Date: 2021-07-13
SHENZHEN TURIER BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To date, the synthesis of optically active unnatural amino acids in different configurations remains a challenging task

Method used

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  • Novel asymmetric catalytic nucleophilic fluorine heterocyclization reaction system and application thereof in chiral non-natural amino acid module synthesis
  • Novel asymmetric catalytic nucleophilic fluorine heterocyclization reaction system and application thereof in chiral non-natural amino acid module synthesis
  • Novel asymmetric catalytic nucleophilic fluorine heterocyclization reaction system and application thereof in chiral non-natural amino acid module synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1 Establishment of a novel asymmetric catalytic nucleophilic fluorine heterocyclization reaction system

[0094] The novel asymmetric catalytic nucleophilic fluorine heterocyclization reaction system includes chiral iodine catalyst CIC1 and boron trifluoride diethyl ether (BF 3 ·Et 2 O).

[0095] Wherein, the preparation method of the centrosymmetric chiral iodine catalyst CIC1 is as follows:

[0096] Synthesized according to the method in the reference (Banik, S.M.; Medley, J.W.; Jacobsen, E.N. Catalytic, Asymmetric Difluorination of Alkenes to Generate Difluoromethylated Stereocenters. Science 2016, 353, 51-54).

[0097] NMR characterization: 1 H NMR (500MHz, CDCl 3 )δNMR (500MHz, CDCl, J.W.; Jacobsen, E.N.Catalytic, Asymmetric Difluorination of Alkenes to Generate Difluoromethylated Stereocenters. Science 2016, 353, 51-54 Fluorine reagent, cheap and easy to get, good stability, low toxicity, is currently the cheapest fluorine in the market Reagent; mild ...

Embodiment 2

[0098] Example 2 Catalytic asymmetric nucleophilic fluoroheterocyclization of N-cinnamylbenzamide (1a) to generate chiral fluorooxazine derivatives

[0099] The catalytic asymmetric nucleophilic fluorine heterocyclization reaction in this embodiment is carried out according to the following reaction formula:

[0100]

[0101] The specific operation method is:

[0102] (1) In a 15mL reaction tube, add 1a (47.4mg, 0.2mmol, 1.0equiv.), catalyst CIC1 (20mol%) and 8mL DCE, cool down to -25°C and keep it at this temperature for 10 minutes, then add m-CPBA (0.24mmol, 1.2equiv.) and slowly drop into BF 3 ·Et 2 O (2 mmol, 10.0 equiv.). After the dropwise addition, the stopper of the reaction tube was tightened, and the stirring was continued at -25°C for 48 hours. After the reaction was completed, the reaction liquid was poured into 10 mL of saturated sodium bicarbonate solution, shaken in a separatory funnel and left to stand for layering, and the organic phase was continued to...

Embodiment 3

[0110] Example 3 Catalytic asymmetric nucleophilic fluoroheterocyclic reaction of N-cinnamyl-4-methoxybenzamide (2a) to generate chiral fluorooxazine derivatives

[0111] The catalytic asymmetric nucleophilic fluorine heterocyclization reaction in this embodiment is carried out according to the following general reaction formula:

[0112]

[0113] The specific operation method is:

[0114] (1) Add 2a (53.5 mg, 0.2 mmol, 1.0 equiv.), catalyst CIC1 (20 mol%) and 8 mL of DCE into a 15 mL reaction tube, cool down to -25 ° C and keep at this temperature for 10 minutes, and then add m-chlorine Peroxybenzoic acid (m-CPBA, 0.24mmol, 1.2equiv.), and slowly drop into BF 3 ·Et 2 O (2 mmol, 10.0 equiv.). After the dropwise addition, the stopper of the reaction tube was tightened, and the stirring was continued at -25°C for 24 hours. After the reaction was completed, the reaction solution was poured into 10 mL of saturated sodium bicarbonate solution, shaken in a separatory funnel a...

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Abstract

The invention discloses a novel asymmetric catalytic fluorine heterocyclization reaction system and application thereof. The novel asymmetric catalytic fluorine heterocyclization reaction system provided by the invention comprises a chiral iodine catalyst and etherified boron trifluoride, and is applied to a catalytic asymmetric nucleophilic fluorine heterocyclization reaction of unsaturated amide; a fluoro oxazine derivative is obtained through treatment after the reaction; and the obtained fluoro oxazine derivative is subjected to hydrolysis and oxidation reaction to obtain the chiral non-natural amino acid. The reaction system provided by the invention has the following advantages: etherified boron trifluoride is used as a fluorine reagent, is cheap and easy to obtain, and has good stability and low toxicity; the reaction conditions are mild; the chiral iodine catalyst is simple to prepare and does not need a complex ligand; the system is environment-friendly and free of heavy metal pollution and precious metal waste; the obtained product is a fluoro oxazine derivative active molecular structure unit with two chiral centers; chiral non-natural amino acid can be obtained through conversion reaction of the product; and the chemical selectivity and stereoselectivity of the reaction are good, and the yield and optical purity are high.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis-asymmetric catalytic fluorination, and specifically relates to a novel asymmetric catalytic nucleophilic fluorine heterocyclization reaction system and its application. Background technique [0002] Introducing one or more fluorine atoms (or fluorine-containing groups) into an organic molecule can greatly change the physical and chemical properties of the molecule. Fluorinated molecules tend to exhibit stronger lipophilicity, higher thermal and metabolic stability, and weakened polarity and intermolecular forces than the original molecules (Petrone, D.A.; Ye, J.; Lautens, M. Modern Transition -metal-catalyzed Carbon–Halogen Bond Formation, Chem. Rev. 2016, 116, 8003-8104). Fluorinated compounds have pivotal applications in biomedicine, materials science, and agricultural chemistry (Champagne, P.A.; Desroches, J.; Hamel, J.D.; Vandamme, M.; Paquin J.F. Monofluorination of Organic Compoun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/08B01J31/02C07C231/00C07C233/73C07C231/12C07C233/87C07C227/04C07C229/36
CPCC07D265/08B01J31/0232B01J31/0231C07C231/00C07C231/12C07C227/04C07C233/73C07C233/87C07C229/36
Inventor 张斌智
Owner SHENZHEN TURIER BIOTECH CO LTD
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