Optically Active Segment Stereocontrolled Oligonucleotide Synthesis
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Solution Overview
Problem
Current methods for synthesizing thiophosphate oligonucleotides face challenges in achieving desired stereochemistry, leading to the use of diastereomeric mixtures as active pharmaceutical ingredients, which can result in side effects and require excessive administration.
Innovation Solution
The use of an optically active segment, represented by formula (I), which incorporates a nucleoside base and a thiophosphate group, allows for the synthesis of stereocontrolled oligonucleotides with fewer steps and improved stereo control, reducing the burden of purification and increasing the yield of the target product.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If a nucleoside monomer-type unit is used as synthesis unit with step by step condensation, then the oligonucleotide can be synthesized base by base, but the number of synthesis steps increases and purification burden becomes heavy
Solution Approach 1:
The invention divides the oligonucleotide synthesis into two distinct segments: (1) synthesis of individually stereocontrolled nucleoside monomers using optically active phosphoramidites, and (2) condensation of these pre-controlled monomers to form the final oligonucleotide. This segmentation allows stereocontrol to be established at the monomer level before assembly, reducing the overall complexity of the synthesis process while maintaining ease of manufacture.
Solution Approach 2:
The invention performs preliminary stereochemical control by introducing optically active phosphoramidites during monomer synthesis before the condensation step. This preliminary establishment of stereochemistry at each phosphorus atom eliminates the need for complex stereocontrol mechanisms during the condensation phase, thereby reducing the total number of synthesis steps required while maintaining manufacturing ease.
2Ease of manufacture
If diastereomeric mixture is used as active pharmaceutical ingredient, then synthesis is simpler, but side effects occur and excessive administration is required
Solution Approach 1:
The invention applies local quality control by using optically active phosphoramidites with specific chirality at each phosphorus atom position. This ensures that each phosphoramidite unit contributes a defined stereochemical configuration (either Rp or Sp) to the final oligonucleotide, achieving high stereochemical purity throughout the molecule while maintaining synthesis simplicity through the use of commercially available chiral building blocks.
Solution Approach 2:
The invention changes the stereochemical parameter of the phosphorus atoms by employing optically active phosphoramidites with controlled configuration. This parameter change from racemic to enantiomerically pure phosphoramidites ensures that the resulting oligonucleotide has defined stereochemistry at each phosphorothioate bond, improving reliability and reducing side effects while keeping the synthesis process relatively simple.
3Manufacturing precision
If purification steps are performed to remove by-products, then product purity increases, but the process becomes more complex and time-consuming
Solution Approach 1:
The invention performs preliminary stereochemical control during monomer synthesis using optically active phosphoramidites, which prevents the formation of unwanted diastereomeric by-products before condensation occurs. This preliminary establishment of stereochemistry significantly reduces the complexity and time required for subsequent purification steps, as the major by-products (N-1)-mer and (N-2)-mer are minimized from the outset.
Solution Approach 2:
By ensuring high stereochemical purity at each phosphorus atom through the use of optically active phosphoramidites, the invention achieves high overall product purity with minimal purification requirements. The local stereochemical control at each monomer unit translates to global purity of the final oligonucleotide product, reducing the need for extensive purification processes.
Data Source
AI summary
An optically active segment for use in synthesis of a stereocontrolled oligonucleotide represented by the following formula (I), a method for producing the same, and a method for synthesizing a stereocontrolled oligonucleotide therefrom are provided. In formula, B is a protected/unprotected nucleoside base; R1 is substituted/unsubstituted aliphatic group; R2, R3 is a DMTr group or —P(R11) (NR12)2; R11 is OCH2CH2CN, SCH2CH2CN, etc.; R12 is a substituted/unsubstituted aliphatic group or aromatic group; X is H, an alkyl, O-alkyl, etc.; Y is H, NHR13, a halogen, etc., or a hydroxyl group protected with an acyl, ether, or silyl, or forms an X—Y bond with X; and n is an integer of 0 or more and 4 or less.