Unlock instant, AI-driven research and patent intelligence for your innovation.

Method for Synthesizing Chiral Five-membered Thioheterocyclic Nucleoside Analogs by Asymmetric [3+2] Cyclization

A technology of nucleoside analogs and cyclization reactions, which is applied in the synthesis of chiral five-membered thioheterocyclic nucleosides by asymmetric [3+2] cyclization reactions, and can solve many problems. One-step reaction with low yield, high cost, and difficult preparation of chiral substrates, etc., to achieve high product stereoselectivity, efficient synthesis method, and rich product structures

Active Publication Date: 2021-11-23
HENAN NORMAL UNIV
View PDF0 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these two approaches require an equivalent chiral source, and after multi-step reactions, chiral five-membered heterocyclic nucleosides can be obtained; at the same time, the multi-step reaction yield is low, and the chiral substrate is difficult to prepare, and the cost is high

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for Synthesizing Chiral Five-membered Thioheterocyclic Nucleoside Analogs by Asymmetric [3+2] Cyclization
  • Method for Synthesizing Chiral Five-membered Thioheterocyclic Nucleoside Analogs by Asymmetric [3+2] Cyclization
  • Method for Synthesizing Chiral Five-membered Thioheterocyclic Nucleoside Analogs by Asymmetric [3+2] Cyclization

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028]

[0029]

[0030] a Unless otherwise specified, the steps of the reaction are as follows: under nitrogen atmosphere, Lewis acid (10mol%), ligand (12mol%), 1aa (0.05mmol), 2 (0.03mmol) were reacted for 3 days in a solvent. b Separation yield. c The dr value of the crude product was tested by NMR. d The ee value was separated by high performance liquid chromatography.

[0031] During the screening of reaction conditions, the effect of ligands on the reaction (label 1-8), the influence of Lewis acid on the reaction (label 9-11) and the influence of reaction solvent on the reaction (label 12-14) were investigated. Ni(OTf) was finally determined 2 is the best Lewis acid, and the ligand L7 is the best ligand.

[0032] Investigation of reaction conditions: In a 10mL vacuum tube, add α-6-chloropurine substituted ethyl acrylate 1aa (23.8mg, 0.1mmol), Ni(OTf) 2 (3.5mg, 10mol%) and L7 (3.8mg, 12mol%). Nitrogen was replaced 3 times, then 1 mL of mesitylene was added, st...

Embodiment 2

[0034] In a 10 mL vacuum tube, α-6-propylthiopurine substituted ethyl acrylate 1ia (27.8 mg, 0.1 mmol), Ni(OTf) 2 (3.5mg, 10mol%) and L7 (3.8mg, 12mol%). Replaced with nitrogen 3 times, then added 1 mL of mesitylene, stirred for half an hour, then added 2,5-dihydroxy-1,4-dithiane 2 (10.0 mg, 0.06 mmol), and stirred at room temperature for 3 days. Track the reaction with TLC, after terminating the reaction, add dichloromethane / water for extraction, dry over anhydrous sodium sulfate, concentrate the organic phase in vacuo, column chromatography gives 17.4 mg of white solid 3ia, yield 92%, 20:1dr, 92% ee. HPLC CHIRALCEL IE, n-hexane / isopropanol 70 / 30, flow rate 0.8mL / min, column temperature 25°C, wavelength 254nm, retention time: 11.168min(major), 13.111min(minor). 1 H NMR (600MHz, CDCl 3 ):8.64(s,1H),8.21(s,1H),5.71(s,1H),5.32(t,J=4.8Hz,1H),4.23-4.17(m,2H),3.92(d,J= 12.0Hz, 1H), 3.56(d, J=12.0Hz, 1H), 3.45-3.35(m, 2H), 3.19(dd, J=11.4, 5.4Hz, 1H), 2.87(dd, J=11.4, 4.8 Hz,1H...

Embodiment 3

[0036] In a 10 mL vacuum tube, α-2-chloro-6-hydropurine-substituted ethyl acrylate 1ja (21.4 mg, 0.1 mmol), Ni(OTf) 2(3.5mg, 10mol%) and L7 (3.8mg, 12mol%). Nitrogen was replaced 3 times, then 1 mL of mesitylene was added, and after stirring for half an hour, 2,5-dihydroxy-1,4-dithiane 2 (10.0 mg, 0.06 mmol) was added. The reaction tube was left to react at room temperature for 3 days. The reaction was tracked by TLC. After the reaction was terminated, dichloromethane / water was added for extraction, dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo. Column chromatography gave the target compound 3ja with a yield of 89%, 20:1dr, 91%ee.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a method for synthesizing chiral five-membered sulfur heterocyclic nucleoside analogs through an asymmetric [3+2] cyclization reaction, and belongs to the field of asymmetric synthesis in organic chemistry. Using substituted electron-deficient alkenes and 2,5-dihydroxy-1,4-dithiane as raw materials, using Ni(II) or Fe(II) Lewis acids and oxazoline ligands as catalysts, a chiral five-membered Thiocyclic nucleoside analogs. The method of the invention has high yield, good reaction diastereoselectivity and enantioselectivity, and further derivatization of products can obtain chiral tetrahydrothiophene skeletons substituted by various functional groups in high yield.

Description

technical field [0001] The invention relates to a synthesis method of chiral thioheterocyclic nucleosides, in particular to a method for synthesizing chiral five-membered thioheterocyclic nucleosides through an asymmetric [3+2] cyclization reaction, belonging to the field of asymmetric synthesis in organic chemistry . Background technique [0002] Chiral five-membered thioheterocyclic nucleosides play an important role in biology and medicinal chemistry, such as thionucleosides Lamivudine and Emtricitabine have been used in the treatment of HIV. However, the drug resistance and side effects of drugs are becoming more and more obvious, so it is necessary to develop novel thioheterocyclic nucleoside analogs. Some of the five-membered thioheterocyclic nucleosides that have been discovered so far have shown good antiviral activity, and it is of great significance to further modify their structure in order to change or enhance their antiviral activity. [0003] Traditionally, t...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D409/04C07D471/04C07D335/02
CPCC07D335/02C07D409/04C07D471/04C07D487/04
Inventor 郭海明黄可心谢明胜王东超渠桂荣
Owner HENAN NORMAL UNIV