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A method for the synthesis of chiral five-membered carbocyclic purine nucleosides based on [3+2] cycloaddition of allenoic acid esters

A carbocyclic purine nucleoside and allenoate technology, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of high cost and difficult preparation of chiral substrates, and achieve high-efficiency synthesis methods, rich product structures, and high yields. rate excellent effect

Active Publication Date: 2020-08-04
HENAN NORMAL UNIV
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Problems solved by technology

However, both approaches require equivalent chiral sources, and chiral five-membered carbocyclic nucleosides can be synthesized through multi-step reactions, and chiral substrates are relatively difficult to prepare and costly

Method used

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  • A method for the synthesis of chiral five-membered carbocyclic purine nucleosides based on [3+2] cycloaddition of allenoic acid esters
  • A method for the synthesis of chiral five-membered carbocyclic purine nucleosides based on [3+2] cycloaddition of allenoic acid esters
  • A method for the synthesis of chiral five-membered carbocyclic purine nucleosides based on [3+2] cycloaddition of allenoic acid esters

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Experimental program
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Effect test

Embodiment 1

[0022]

[0023]

[0024] a Unless otherwise noted, the reactions were carried out with 1a(0.05mmol), catalyst(20 mol%), and 2a(0.1 mmol) in solvent(1 mL) under N 2 . b Isolated yield based on1a. c Determined by chiral HPLC analysis. d 2-Naphthol (20mol%) was added. e Catalyst loading: 10mol%. NR=No Reaction.

[0025] During the screening of reaction conditions, the influence of phosphine catalysts on the reaction was first investigated (entries 1-8). At the same time, by comparing the effects of different ligands on the reaction, the ligand C10 was determined to be the best ligand.

[0026] Investigation of reaction conditions: In a 10mL vacuum tube, add α-purine-substituted 6-Cl benzyl acrylate 1a (15.8mg, 0.05mmol), (S)-DTBM-SITCP (4.97mg, 20mmol%) and ethyl naphthol (1.44 mg, 20% mmol). The reaction tube was filled with nitrogen gas by nitrogen replacement 3 times, the reaction tube was sealed, and the reaction tube was placed in a cryopump at 0°C, then allenoa...

Embodiment 2

[0036] In a 10 mL vacuum tube, α-purine substituted 6-Cl benzyl acrylate (16.9 mg, 0.05 mmol), (S)-DTBM-SITCP (4.97 mg, 20 mmol%) and ethyl naphthol (1.44 mg, 20 mmol%). The reaction tube was filled with nitrogen gas by nitrogen replacement 3 times, the reaction tube was sealed, and the reaction tube was placed in a cryopump at 0°C, then benzyl allenoate (17 μL, 0.1 mmol) was dissolved in 1 mL of dichloromethane and injected 18h in the reaction tube. The reaction was tracked by TLC. After the reaction was terminated, dichloromethane / water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo. Then, the target compound 3aa was obtained by column chromatography with a yield of 71%, 96% ee.

Embodiment 3

[0038] In a 10mL vacuum tube, α-purine substituted benzyl 6-methoxyacrylate (15.6mg, 0.05mmol), (S)-DTBM-SITCP (4.97mg, 20mmol%) and ethyl naphthol (1.44mg, 20mmol%) ). The reaction tube was filled with nitrogen gas by nitrogen replacement 3 times, the reaction tube was sealed, and the reaction tube was placed in a cryopump at 0°C, then benzyl allenoate (17 μL, 0.1 mmol) was dissolved in 1 mL of dichloromethane and injected 10h in the reaction tube. The reaction was tracked by TLC. After the reaction was terminated, dichloromethane / water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo. Then, the target compound 3fa was obtained by column chromatography with a yield of 85%, 94% ee. Representative compound characterization data are as follows:

[0039] 3fa Colorless oil, 85% yield, 20.6mg, 94% ee. HPLC CHIRALCEL IA, n-hexane / 2-propanol=60 / 40, flow rate=0.8mL / min, column temperature=25℃, λ=254n...

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Abstract

The invention discloses a method for synthesizing chiral five-membered carbon ring purine nucleoside through [3+2] cycloaddition based on allenoates and belongs to the field of asymmetric synthesis inorganic chemistry. The method takes alpha-purine substituted acrylate 1 and allenoates 2 as raw materials, and chiral STICP as a catalyst; after the raw materials and the catalyst react, chiral five-membered carbon ring nucleoside 3 is obtained; reaction has good enantioselectivity and has moderate to excellent yield. Chiral five-membered carbon ring nucleoside 3 is reduced under the condition ofsodium borohydride to obtain mono-alcohol five-membered carbon ring purine nucleoside 4; then mono-alcohol five-membered carbon ring purine nucleoside 4 is reduced by adopting DIBAL-H to obtain diolfive-membered carbon ring purine nucleoside 5.

Description

technical field [0001] The present invention relates to a synthesis method of chiral carbocyclic purine nucleosides, in particular to a method for synthesizing chiral five-membered carbocyclic purine nucleosides based on [3+2] cycloaddition of allenoic acid esters, which belongs to the field of organic chemistry The field of asymmetric synthesis. Background technique [0002] Chiral five-membered carbocyclic purine nucleoside drugs are an important class of compounds used clinically to treat viral infectious diseases. For example, Abacavir, Entecavir and Carbovir can be used to treat HIV and HBV respectively. Other chiral five-membered carbocyclic nucleosides such as: Noraristeromycin, Aristeromycin, Neplanocin A and HNPA have different pharmaceutical activities. Meanwhile, the absolute configuration of chiral centers in carbocyclic nucleosides has been shown to play a key role in their biological activities. The chiral carbocyclic nucleoside (1R,4S)-kabavir enantiomer is...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/40C07D473/30C07D473/34C07D473/00
CPCC07B2200/07C07D473/00C07D473/30C07D473/34C07D473/40
Inventor 谢明胜郭海明高要伟张齐英王东超王海霞渠桂荣
Owner HENAN NORMAL UNIV
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