[3+2] Cycloaddition Asymmetric Dearomatization Method for Synthesis of Chiral Nonaromatic Purine Nucleosides

A purine nucleoside, asymmetric technology, applied in the field of synthesis of chiral non-aromatic purine nucleosides, can solve the problems of many reaction steps, high chemical stability, and difficult de-aromatization, etc., to achieve efficient synthesis methods, High stereoselectivity and easy availability of reaction materials

Active Publication Date: 2019-12-20
HENAN NORMAL UNIV
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Problems solved by technology

[0003] At present, the synthetic methods of non-aromatic purine compounds mainly include: 1) Meyers lactamization reaction of diaminopyrimidine and 3-carboxy acid or 4-carboxy acid to construct purine skeleton, and the synthetic product is racemic non-aromatic purine compound; 2) natural nucleus Glycoside chirality induces dearomatization reaction, but the product diversity is limited; 3) The total synthesis method constructs dearomatized purine skeleton, and there are many reaction steps when there are disadvantages; 4) Synthesis of caffeine derivatives by using uracil derivatives
However, the use of purine compounds to directly catalyze the asymmetric dearomatization reaction to synthesize non-aromatic purine compounds has not been reported yet.
It is speculated that the possible reason is that the purine ring, as the genetic material of life, has high chemical stability and is difficult to de-aromatize, especially the corresponding selectivity of the product is more difficult than the external modification, thus limiting the purine compounds. Study on dearomatization reaction

Method used

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  • [3+2] Cycloaddition Asymmetric Dearomatization Method for Synthesis of Chiral Nonaromatic Purine Nucleosides
  • [3+2] Cycloaddition Asymmetric Dearomatization Method for Synthesis of Chiral Nonaromatic Purine Nucleosides
  • [3+2] Cycloaddition Asymmetric Dearomatization Method for Synthesis of Chiral Nonaromatic Purine Nucleosides

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021]

[0022]

[0023]

[0024] [a] The reaction conditions are as follows: Lewis acid (10mol%), ligand (11mol%), β-purine substituted acrylate 1a (0.05mmol), methyl aminocyclopropane dicarboxylate 2a (0.2mmol), Molecular sieves (40mg) were reacted in nitrogen, 1mL solvent at 0°C for 4 days; [b] isolated yield; [c] determined by chiral HPLC analysis.

[0025] In the screening process of reaction conditions, the influence of Lewis acid catalysts on the reaction was firstly investigated (markers 1-5). At the same time, by comparing the influence of different catalysts on the reaction, the catalyst Cu(OTf) was determined 2 The best catalyst.

[0026] Investigation of reaction conditions: In a 10mL vacuum tube, add β-purine-substituted 6-Cl ethyl acrylate 1a (12.6mg, 0.05mmol), copper trifluoromethanesulfonate (3.6mg, 0.01mmol), Molecular sieve (40 mg), ligand L7 (8.0 mg, 0.012 mmol), plugged with a rubber stopper, wrapped with a parafilm, replaced nitrogen with an ...

Embodiment 2

[0041] In a 10 mL vacuum tube, add β-purine-substituted 2,6-Cl 2 Ethyl acrylate 1e (14.3mg, 0.05mmol), copper triflate (3.6mg, 0.02mmol), Molecular sieves (40 mg), ligand L7 (8.0 mg, 0.024 mmol), plugged with a rubber stopper, wrapped with a parafilm, replaced nitrogen with an oil pump three times before filling with nitrogen, added dried chlorobenzene (0.5 mL), and stirred at room temperature for 0.5 hours , Dissolve methyl aminocyclopropanedicarboxylate 2a (51mg, 0.2mmol) in dry chlorobenzene (0.5mL) and inject it into a reaction tube with a syringe, place it in a low-temperature reaction bath at 0°C and stir for 4 days. The end of the reaction was tracked by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3e was obtained by column chromatography with a yield of 53% and an ee value of 96%.

[0042] Representative compound characterization data are as follows:

[0043] 3e colorless oily liquid, 53% yield,...

Embodiment 3

[0045] In a 10mL vacuum tube, add β-purine substituted 2-F / 6-Cl ethyl acrylate 1f (13.5mg, 0.05mmol), copper trifluoromethanesulfonate (3.6mg, 0.02mmol), Molecular sieve (40mg), ligand L7 (8.0mg, 0.024mmol), plugged with a rubber stopper, wrapped with a parafilm, replaced nitrogen three times with an oil pump before filling nitrogen, added dried chlorobenzene (0.5mL), stirred at room temperature for 0.5 After 2 hours, methyl aminocyclopropane dicarboxylate 2a (51 mg, 0.2 mmol) was dissolved in dry chlorobenzene (0.5 mL), injected into the reaction tube with a syringe, placed in a low-temperature reaction bath at 0°C and stirred for 4 days. The reaction was tracked by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3f was obtained by column chromatography with a yield of 86% and an ee value of 98%.

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Abstract

The invention discloses a method for [3+2] cycloaddition asymmetric dearomatization to synthesize chiral non-aromatic purine nucleosides, belonging to the field of asymmetric synthesis in organic chemistry. Using purine and methyl aminocyclopropanedicarboxylate as raw materials, chiral non-aromatic purine nucleosides can be obtained after a Lewis acid-catalyzed reaction. The invention provides a simple, cheap and efficient method for synthesizing chiral cyclopropane carbocyclic purine nucleoside compounds, the reaction raw materials are easy to obtain, the product structure is rich, the reaction enantioselectivity is up to 99%, and the yield is up to 98% %.

Description

technical field [0001] The invention relates to a synthesis method of chiral non-aromatic purine nucleosides, in particular to a method for synthesizing chiral non-aromatic purine nucleosides through [3+2] cycloaddition asymmetric dearomatization, belonging to asymmetric synthesis in organic chemistry field. Background technique [0002] The non-aromatic purine skeleton widely exists in a variety of natural products and bioactive molecules, and has important biological activities. Common non-aromatic purine derivatives such as caffeine have extensive excitatory effects on the central nervous system; theobromine is an important myocardial stimulant, which plays an important role in relaxing smooth muscle and dilating coronary arteries, such as paralytic shellfish toxins (such as Saxitoxin and neosaxitoxin, etc.) and bufotoxin are both non-aromatic fused-ring purine structures; non-aromatic fused-ring purine nucleosides are biosynthetic intermediates of molybdenum protein cof...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/14
CPCC07B2200/07C07D487/14
Inventor 郝二军付丹丹郭海明王东超谢明胜李恭欣
Owner HENAN NORMAL UNIV
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