Towards DNA‐Encoded Micellar Chemistry: DNA‐Micelle Association and Environment Sensitivity of Catalysis

Abstract

The development of DNA‐compatible reaction methodologies is a central theme to advance DNA‐encoded screening library technology. Recently, we were able to show that sulfonic acid‐functionalized block copolymer micelles facilitated Brønsted acid‐promoted reactions such as the Povarov reaction on DNA‐coupled starting materials with minimal DNA degradation. Here, the impact of polymer composition on micelle shape, and reaction conversion was investigated. A dozen sulfonic acid‐functionalized block copolymers of different molar mass and composition were prepared by RAFT polymerization and were tested in the Povarov reaction, removal of the Boc protective group, and the Biginelli reaction. The results showed trends in the polymer structure‐micellar catalytic activity relationship. For instance, micelles composed of block copolymers with shorter acrylate ester chains formed smaller particles and tended to provide faster reaction kinetics. Moreover, fluorescence quenching experiments as well as circular dichroism spectroscopy showed that DNA‐oligomer‐conjugates, although highly water‐soluble, accumulated very effectively in the micellar compartments, which is a prerequisite for carrying out a DNA‐encoded reaction in the presence of polymer micelles.

Gold(I) NHC Catalysts Immobilized to Amphiphilic Block Copolymers: A Versatile Approach to Micellar Gold Catalysis in Water

“…As can be seen from Figure 4, there is a clear correlation between the type of linker and the resulting activities in a micellar gold catalysis in the following order: pentyl>ethyl>octyl>benzyl. This is in agreement with results published for other block copolymer catalyst systems that showed best activities with a C4 to C6 alkyl linker, whereas too short (ethyl) or too rigid linker (benzyl) led to significant decrease in catalyst activity [19,21] . T 1 /T 2 relaxation studies support this assumption when the catalyst mobility of PC5 (Cat 1+pentyl linker) and PC13 (Cat1+benzyl linker) are compared showing the reduced mobility of the gold(I) NHC catalyst when bound to the polymer by a rather rigid benzyl linker ( PC13 ) compared to the more flexible pentyl linker ( PC5 ) (see also Figure S52).…”

“…Interestingly, all polymeric catalysts that have been prepared with the mesityl functionalized NHC gold(I) ligand showed worm‐like aggregates independent of the linker length ( PC1 , PC5 , PC9 and PC13 , Figure 3). Similar effects of longer hydrophobic side chains on the shape of a micellar aggregate have also been reported in the literature, however, it is not clear so far if the transition from spherical to rod‐like aggregates has any impact on the catalytic activity [19] …”

“…Two strategies have been developed to covalently bind a catalyst to a polymeric support. These are based either on the synthesis of a monomer which already contains the ligand or the ligand‐metal complex and can be polymerised directly into the block copolymer [19,21] or the ligand‐metal complex is coupled to a functionalised block copolymer in a polymer analogue manner [16a,17] . Although the first approach is very elegant and allows excellent control over the amount of catalysts incorporated into the block copolymer, the synthetic effort for such monomers can be significantly higher [21] and some catalysts are not compatible with the respective polymerization mechanism.…”

“…However, the approach of just mixing a gold(III) salt with an amphiphile has some serious drawbacks: Firstly, the catalyst can leach during the reaction which makes catalyst recycling more difficult and secondly, the precise localisation (core, shell or interfaces) of the catalyst within the micelle remains unclear which makes it more difficult to better understand which structural parameters of the amphiphile or the catalyst ligand affect catalyst activity. While the first disadvantage can usually be compensated by adding fresh catalyst for each reaction cycle, the poor catalyst localisation can lead to lower catalyst activities [19] . An important alternative to the usage of gold salts are gold(I) NHC catalysts.…”

Construction of Isocytosine Scaffolds via DNA-Compatible Biginelli-like Reaction

“…In the last few years, an endeavors has been made to introduce this classic multicomponent reaction into DEL synthesis (Scheme ). Controlled pore glass (CPG)-coupled oligonucleotide-aldehyde conjugates incubating with ( R )-(−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, ureas and ethyl acetoacetate at 5 °C for 20 h are able to obtain the target 3,4-dihydropyrimidin-2­(1 H )-ones . Another article involved the DNA-compatible Biginelli reaction of using DNA-conjugated aldehydes to react with ureas and ethyl acetate to obtain pyrimidin-2-ones .…”