Utility Of DNA In Cross-Coupling Reactions

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DNA chemical reactions have found a couple of industrial applications. Targeting protein bound to DNA for manipulation of disease prognosis is gaining a lot of interest among scientists. Due to advancement of in silico technology, thousands of molecules can be search for protein interaction. Molecules with the best docking properties to target proteins can then be synthesized in the lab and used in wet lab setting to affirm their activity. To accelerate this process scientist have set up chemical databases which could be searched for leads identification in drug design and development [1]. DNA modified molecules could also be used as fluorescent probes in sensors, detection of the presence of possible carcinogens and diagnosis of disease [2].

Despite the much success so far attained in this field much more needs to be done to accelerate the drug discovery process. To achieve better results pharmaceutical companies have turned their attention to development of big chemical libraries that are reliable compared to widely used high-through-put screening methods. One such technique gaining interest among scientists is on-DNA encoded library preparation [3]. Generally, DEL approach relies heavily on chemical properties of the functional groups. A major drawback in the coding of DNA-based molecules is sensitivity of the function groups associated on the DNA molecule to various types of chemical reactions. This report will unveil the advancement so achieved and the contribution of various synthetic techniques towards DNA-based substrate cross coupling reactions.

Early ventures into chemical based DNA modification techniques

Use of polymerase chain reaction and solid phase chemical reaction techniques are the earliest known methods in DNA modification. The polymerase chain reaction is known for the use of the enzyme DNA polymerase to in cooperate desired molecules into the bases of the DNA. Small molecules such as amines, methyl group and bromo can easily be in cooperated into short DNA strands. The major problem of this techniques is that large steric inducing molecules cannot be used. On the other hand, solid phase uses acids and oxidants which are not tolerated by the functional groups such as purines present on the DNA strands. To circumvent these challenges Omumi et al., [2], used the Suzuki method in modification of DNA oligonucleotides. Compared to solid phase method this approach gave clean products and could tolerate many functional groups either on the oligonucleotides or from the incoming substrates.

The work of Omumi and colleagues and these polymerase chain biochemists motivated the use of DNA as substrates in cross-coupling reaction. Currently, libraries have been prepared for millions of molecules containing on-DNA coding substrates [4].

How it works

A common approach in the use of DNA in cross coupling is the preparation of the on-DNA linked substrates. Most of the works so far published use substrates such as Head piece-NH2(5’-/5Phos/GAGTCA/_TGACTCCC-3’ which are commercially available. The head piece contains an amine at one end. The amine is mixed with 4-iodo benzoic acid in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM) to form HP-ArI. DMTMM is said to enhance the amine-aryl coupling [5].

Some of the early attempts in on-DNA coupling were from Ding and Clark (2014). Ding used the Suzuki Miyaura reaction in cross coupling of DNA aryl halides to build up a DNA -encoded library. The duo used Pd (PPh3)4 an hydrophilic catalyst for their reaction. The hydrophilicity of the catalyst as well as the solubility of the DNA substrates in water contributed towards better yields through enhancement of catalyst-molecule interaction.

A breakthrough in Ding paper is the ability of their technique to cross-couple challenging heteroaryl molecules in aqueous media. To achieve their objective, they performed a reaction on DNA head piece with a free amine warhead which reacted with 4-iodobenzoic acid to make iodobenzamide. DMT-TM was used to activate the reacting molecules. The iodobenzamide headpiece was then reacted with phenyl boronic acid in the presence of a base and catalyst to produce the desired material. However, when they tried Pd(OAc)2/triphenylphosphine yielded unclean material.

When an electron donating atom such as nitrogen was used the reaction still worked well under the same conditions.

To test the diversity of the substrates used in the cross-coupling reactions, the group used amines and acids as functional groups and the reaction still went well for them. However, for better yield electron-deficient, boronic acid pinacol esters as well as sterically hindered boronic acids where required.

Nitrogen heterocycles such as heteroaryl boronic acids/esters or heterocaryl halides gave low yields of the desired product. However, a tertiary amine side chain or pyrrole did not interfere with the reaction rate.

This method however was somehow functional groups intolerant as observed with hydrolysis of nitriles to give non-desired products. Despite this challenge, Dang and Clark went ahead and used this technique in preparation of a 3.4 million molecule library which they claim to report on a future date. I strongly believe this paper contributes a great chunk of information which has continued to illuminate research in this area.

Lu et al., [5] took a different approach in creating C-N cross coupling. Previous studies had shown that you can do carbon-carbon coupling of DNA aryl halides using Suzuki and Sonogashira coupling reaction [4]. However, based on the observation that amines are easily accessible compared to boronates and alkynes Lu used Buchwald t-butyl-xphos catalyst that effectively helped in coupling of amines and carbon together. Good conversion rates and clean products were obtained. Excess CsCO3 was hypothesized to help in the deprotonation of aromatic amines.

On the other hand, while using the Ullman reaction techniques Lu was able to couple DNA aryl halides to aryl amines. In these experiments the active catalyst was prepared in situ to overcome the solubility challenge experienced in the usual Ullman reaction. Using this technique, they were able to validate 557 amino acids for on-DNA modification. Not only did the amino acids act as ligands for Cu(I) in promoting the reaction rate, their presence also prevents DNA degradation. The use of proline was observed to increase the rate of C-N cross-coupling. However, proline presence accelerated DNA decomposition and competed with aliphatic amines in binding to copper. Standardization of this protocol to prevent DNA decomposition in the presence of various ligands are underway.

Using this procedure 6300 molecules library was prepared in good yields. Alternatively, Cu(I) could be used instead of Pd, however the catalyst was synthesized in situ to improve its solubility both in water and in organic solvents. Amino acids acted as ligands and also prevented DNA decomposition.

Advancements in on-cross coupling reactions

Despite the major works so far done in preparation of DNA modification, the industrial application of the process remains at large. To make the process of DNA modification both economically viable and environmentally friendly recent advancements in on-DNA modification have been done.

Xu et al., [6] instead of using aryl halides used aryl fluorosulfonates. With aryl fluorosulfonates being versatile electrophiles their use in Suzuki, Sonogashira and Buchwald reactions provides economically feasible and an atom-efficient alternative to halide and/or triflate.

Since molecules such as sulfuryl chloride had been proved to react efficiently with many phenols under mild conditions. Replacement of aryl halides which are toxic to the environment and of high cost was the driving force of Xu group. Success in use of such methods will spark the application of this approach in the industry as well accelerating the search for better applications of DNA modified molecules.

To achieve the objectives of their project the Xu first prepared DNA-conjugated 4-hydroxyl benzoic acid which was then mixed 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in borate buffer at pH-7 for 2 hr at room temperature to produce DNA-aryl flourosulfonate (HP-ArOFs-1) at 96% yield. After successful synthesis of HP-ArOFs-1 it was now time to test its utility in to cross-coupling reactions.

Using Palladium acetate as the catalyst the reaction of HP-ArOFs and boronic acids in the triethylamine and N, N-dimthylaniline (DMA) as the co-solvent gave the desired product at 90% yield.

When HP-ArOFs was reacted with phenylacetylene in presence of palladium acetate as the catalyst, xantphos as the ligand and triethylamine as the solvent good yields were observed. The group proved that this reaction unlike in the conventional Sonogashira reaction could be performed in copper free environment. Versatile functional groups and alkynes of different structural orientation could be used.

Cross-coupling of nitrogen and sulfur-containing heteroaryl amines as observed in Suzuki and Sonogashira reactions motivated the group to test the applicability of this approach to Buchwald amination reaction. HP-ArOFs reacted with aniline, sulfur, ester containing aryl amines to give good yields of the desired products. Bulky groups such as t-Butyl attached to the compounds did not significantly affect the reaction rate.

Generally, Xu and his group were able to prove the use of aryl-fluorosulfonates as multipurpose eletrophiles provides a new chemistry in the field of DNA modification using Suzuki, Sonogashira and Buchwald cross-coupling reactions. With optimization of these protocols, economical production of DNA-encoded libraries as needed in the drug design and development could easily be achieved.

Another major advancement in this area has been made by Li and Huang who proved that DNA-encoding using Suzuki reaction could be done in aqueous media. Their research not only proves environmentally friendly reagents but also an economical way for large scale synthesis of these molecules. Li and Huang achieved this by first modifying the catalyst to make it water soluble. The catalyst used in these reactions was sulfonated SPHos-G2. The presence of a base (CsOH) was required for better yields to be observed.

From the articles review, the modification of DNA using classical reactions such as Suzuki, Sonogashira and Ullman is achievable. The protocols so far tested shows high functional groups tolerance and diversity in terms of the molecules to be used in the encoding machinery. Of great importance is ability to economically set systems that can efficiently give desired products at mild conditions. DNA chemistry therefore provides a new tool in the search for novel drugs and sensors among other applications. The establishment of a pool of compounds that can be searched using the available tools in the pharmaceutical is an inevitable endeavor.

Use of DNA as part of a catalyst in cross-coupling reactions

Another utility in the DNA as tool in cross coupling reaction is its as part of the catalyst. The reports Mart et al [7] and others [8,9], have shown that Pd/DNA nanoparticles could be used in the Suzuki-Miyaura coupling reaction. PDA/DNA nanoparticles synthesis using different precursors showed comparable catalytic effect. The size of the nanoparticles didn’t influence the catalytic activity of Pd/DNA nanoparticles. Nanoparticles produced at different temperature (r.t., 80 oC) of Pd (OAC)2 and half Pd (OAC)2 and PdCl2 instead of Pd (OAC)2 had different catalytic activity.

In the Suzuki-Miyaura reaction Pd (0) in the nanoparticles is the active catalytic state of palladium. Mart and his colleagues observed that nanoparticles formed at room temperature had the best conversion rates for 4-bromotoulene and 2-bromoanisole despite it having the least Pd (0) concentration. Based on these findings and their previous observation they concluded that the active catalyst is formed in situ.

Mart also went ahead to search for the catalytic pathway be it homogenous or heterogenous. To prove they filtered the beads from the reaction mixture and tested the conversion rate for the resulting solution. The reaction stopped after 30 minutes giving a clue that the reaction followed the heterogenous pathway. To further ascertain that the reaction was going through the heterogenous pathway the group treated the reaction mixture with Hg (0). The addition of mercury lead to significant decrease in the conversion rate of the catalyst. Scanning electron microscope and EDX analysis of the Pd/DNA – mercury mixture gave evidence on the formation of the Pd/DNA-mercury amalgam alloy. When the solution emanating from the reaction was tested presence of Pd using ICP-MS no detectable amounts was found to be present. All these observation lead to a solid conclusion that the catalytic reaction of Pd/DNA nanoparticles is heterogenous.

Conclusion

The evidence that DNA has various applications in chemical reaction. Taping the potential of the use of DNA molecules in chemistry could provide a cheap reagent source. Since DNA can be harvested from biowaste its industrial use will provide an alternative way in maintaining our environment clean.

References

Ding, Y., DeLorey, J.L. and Clark, M.A. Novel catalyst system for Suzuki-Miyaura coupling of challenging DNA-linked aryl chlorides. Bioconjugate Chemistry, 2016, 27, 11, 2597-2600.
Omumi, A., Beach, D.G., Baker, M., Gabryelski, W. and Manderville, R.A. Postsynthetic guanine arylation of DNA by Suzuki-Miyaura cross-coupling. Journal of Chemical Society, 2011, 133, 42-50.
Lu, X., Roberts, S.E., Franklin, G.J. and Davie, P.C. On-DNA Pd and Cu promoted C-N cross-coupling reactions. Medicinal Chemistry Communications, 2017, 8, 1614-1617.
Ding, Y. and Clark, M.A. Robust Suzuki-Miyaura cross-coupling on DNA-linked substrates. American Chemical Society, Combinatorial Science, 2015, 17, 1-4.
Xu, H., Ma, F., Wang, N., Hou, W., Xiong, H., Lu, F., Li, J., Wang, S., Ma, P., Yang, G. and Lerner, R.A. DNA-encoded libraries: aryl fluorosulfonates as versatile electrophiles enabling facile on-DNA Suzuki, Sonogashira and Buchwald reactions. Advanced Science, 2019, 6, 1901551.
Mart, M., Tylus, W. and Trzeciak, A.M. Pd/DNA as highly active and recyclable catalyst of Suzuki-Miyaura coupling. Catalysts, 2018, 8, 552.
Tang, L., Sun, H., Li, Y., Zha, Z. and Wang, Z. Highly active and selective synthesis of imines from alcohols and amines or nitroarenes catalyzed by Pd/DNA in water with dehydrogenation. Green Chemistry, 2012, 14, 3423.
Wang, Y., Ouyang, G., Zhang, J. and Wang, Z. A DNA-templated catalyst: the preparation of metal-DNA nanohybrids and their application in organic reactions. Chemical Communications, 2010, 46, 7912–7914.

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Utility Of DNA In Cross-Coupling Reactions

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