Ionic Tag Linkers for Oligoribonucleotide Synthesis
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Solution Overview
Problem
Current methods for synthesizing oligoribonucleotides face challenges such as difficulty in finding compatible 2'-protecting groups that provide high step-wise coupling yields, stability during chain assembly, and selective removal without phosphodiester bond isomerization or degradation, leading to complex and inefficient RNA synthesis processes.
Innovation Solution
The development of blockmer (dimer, trimer, tetramer, etc.) ribonucleotides for RNA synthesis through block coupling reactions, using ionically tagged linkers that allow longer chain extensions and easier separation of crude oligomers from shorter failure sequences, and the use of ionic tag linkers for orthogonal cleavage, enabling faster and purer synthesis of RNA and DNA oligomers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If stepwise addition of monomeric phosphoramidite units is used for oligoribonucleotide synthesis, then the oligomer can be assembled with controlled sequence, but the number of synthesis steps increases and productivity decreases
Solution Approach 1:
The patent applies segmentation by dividing the oligoribonucleotide synthesis into two distinct phases: (1) assembly phase where monomeric phosphoramidite units are added stepwise to build oligomer chains on solid support, and (2) coupling phase where pre-formed oligomer fragments are joined together. This segmentation allows the high-precision stepwise assembly to be combined with high-speed fragment coupling, resolving the contradiction between sequence control and synthesis speed.
Solution Approach 2:
The patent implements preliminary action by pre-assembling oligomer fragments (e.g., dimers, trimers, tetramers) before the final coupling step. These pre-formed fragments are prepared in advance with protected 5'-hydroxyl groups, allowing them to be stored and then rapidly coupled together in subsequent steps. This preliminary preparation reduces the total number of synthesis steps required while maintaining sequence accuracy.
2Stability of the object's composition
If 2'-protecting groups are used to stabilize ribonucleotides during chain assembly, then stability is improved, but finding compatible protecting groups that provide high coupling yields and selective removal becomes difficult
Solution Approach 1:
The patent applies local quality by using different protecting groups for different positions and functions within the oligoribonucleotide structure. Specifically, the 2'-position uses protecting groups (such as 2'-O-TBDMS or 2'-O-TIPS) that provide stability during chain assembly, while the 5'-position uses orthogonal protecting groups (such as dimethoxytrityl or monomethoxytrityl) that can be selectively removed for coupling reactions. This position-specific protection strategy resolves the contradiction by optimizing each position's properties independently.
Solution Approach 2:
The patent uses orthogonal protecting groups as intermediaries that mediate between the need for stability and the need for selective reactivity. These protecting groups act as temporary masks that can be selectively removed and reinstalled under specific conditions, allowing the synthesis to proceed through multiple stages with different reactivity requirements without compromising overall stability.
3Manufacturing precision
If solid support is used for chain elongation, then the synthesis process can be controlled and purified, but the scale of synthesis is limited and cost effectiveness for large scale production decreases
Solution Approach 1:
The patent applies segmentation by separating the synthesis process into solid-phase oligomer assembly (for precision) and solution-phase fragment coupling (for scale). The solid support is used only for the initial assembly of small oligomer fragments, which are then released and coupled in solution phase using ionic tags. This allows the benefits of solid-phase control to be combined with the scalability of solution-phase chemistry.
Solution Approach 2:
The patent introduces ionic tags as intermediaries that enable the transition from solid-phase to solution-phase chemistry. These ionic tags (such as ammonium or phosphonium salts) are attached to the oligomer fragments during solid-phase synthesis, allowing the fragments to be selectively precipitated and then coupled in solution phase without requiring continuous solid support. This intermediary approach resolves the contradiction between synthesis control and large-scale production capability.
Data Source
AI summary
The invention relates to the chemical synthesis of oligonucleotides, e.g., oligoribonucleotides. In another aspect, the invention relates to compounds of formula (II):processes for making these compounds, and the use thereof in the chemical synthesis of oligonucleotides, e.g., oligoribonucleotides. The invention also relates to methods of synthesis of oligomers, including but not limited to oligopeptides, oligosaccharides and oligonucleotides, particularly oligoribonucleotides and also oligodeoxyribonucleotides, in solution systems, and ionic tag linkers for use in methods provided herein.