Thioether Protecting Group for Nucleoside Synthesis
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Solution Overview
Problem
Conventional phosphoramidites such as TOM amidite and ACE amidite are costly and result in low yield and purity during nucleic acid synthesis, while TBDMS amidite's coupling reaction yield and purity are often suboptimal.
Innovation Solution
A glycoside compound represented by a specific chemical formula, produced through coupling reactions involving thioethers and ethers in the presence of halogenating agents and Lewis acids, serves as a low-cost alternative for nucleic acid synthesis, offering improved yield and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional phosphoramidites (TOM amidite, ACE amidite) are used for nucleic acid synthesis, then the synthesis can proceed, but the production cost is high
Solution Approach 1:
The patent changes the chemical structure parameters of the protecting group at the 2'-position of the nucleoside. Specifically, it introduces a new ether-type protecting group with the formula R1-O-CH2-CH2-O-R2, where the structural parameters (molecular weight, steric bulk, electronic properties) are optimized to achieve both low cost and high performance in nucleic acid synthesis
2Productivity
If TBDMS amidite is used for coupling reaction, then the synthesis can proceed, but the yield and purity are not very high
Solution Approach 1:
The protecting group is segmented into two parts: a bulky R1 group (such as tert-butyl or phenyl) that provides steric protection, and a flexible -O-CH2-CH2-O- linker that connects to the nucleoside. This segmentation allows the bulky group to be positioned away from the reaction site, reducing steric hindrance while maintaining protective function
Solution Approach 2:
The patent introduces a flexible ether linker (-O-CH2-CH2-O-) that adds conformational freedom in three-dimensional space. This allows the protecting group to adopt orientations that minimize steric interference with the coupling reaction while maintaining its protective function
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The proposed method allows for the production of phosphoramidites at a lower cost and results in high-yield, high-purity nucleic acid synthesis, comparable to DNA synthesis purity levels, with reduced steric hindrance and easier deprotection.
Implementation Method 1
a coupling reaction of thiol or thioalkoxide represented by the following chemical formulas (101a) and (101b) with a halide represented by the following chemical formula (102) to give a thioether represented by the following chemical formula (103)
Implementation Method 2
a coupling reaction of a thioether represented by the following chemical formula (103) and an alcohol represented by the following chemical formula (105), in the presence of a halogenating agent and a Lewis acid to give the aforementioned ether in the present invention
Implementation Method 3
a coupling step including a coupling reaction of a glycoside compound represented by the following chemical formula (107) and an ether represented by the following chemical formula (106), in the presence of a halogenating agent and a Lewis acid to give a glycoside compound represented by the following chemical formula (1a)
Implementation Method 4
a condensation step for condensing the glycoside compound wherein the glycoside compound represented by the aforementioned chemical formula (1) is the glycoside compound represented by the aforementioned chemical formula (2)
Data Source
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AI summary
An ether is provided which may be used in the production of a glycoside, and method of producing the ether. The ether is represented by the following chemical formula (106): in said chemical formula (106), R4 is a hydrocarbon group, a straight chain or branched alkyl group, a straight chain or branched alkenyl group, a straight chain or branched alkynyl group, an aryl group, a straight chain or branched arylalkyl group, a cycloalkyl group, a cycloalkenyl group, a straight chain or branched cycloalkylalkyl group, a straight chain or branched cyclylalkyl group, or a straight chain or branched alkoxyalkyl group, n is a positive integer, L1 is an ethylene group (-CH2CH2-), wherein hydrogen atoms besides a hydrogen atom bonded to the α-position relative to [D1] are optionally substituted by a straight chain or branched alkyl group, and [D1] is an electron-withdrawing group.