Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions

Abstract

Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Initiating encoded compound synthesis with solid phase -coupled DNA barcodes does benefi t from choice of organic solvents. Screening of more than 50 metal salts and organic reagents for DNA compatibility suggested reactions for encoded compound synthesis. A ZnCl2-mediated aza-Diels-Alder reaction with Danishefsky's diene and diphenyl phosphate-promoted tetrahydroquinoline and pyrimidinone syntheses by Povarov and Biginelli reactions, respectively, showed a broad substrate scope and were well tolerated by a DNA oligonucleotide.DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Generally, these libraries are synthesized by solution phase combinatorial chemistry requiring aqueous solvent mixtures and reactions that are orthogonal to DNA reactivity. Initiating library synthesis with readily available controlled pore glass-coupled DNA barcodes benefits from enhanced DNA stability due to nucleobase protection and choice of dry organic solvents for encoded compound synthesis. We screened the compatibility of solid-phase coupled DNA sequences with 53 metal salts and organic reagents. This screening experiment suggests design of encoded library synthesis. Here, we show the reaction optimization and scope of three sp 3 -bond containing heterocyclic scaffolds synthesized on controlled pore glass-connected DNA sequences. A ZnCl 2 -promoted aza-Diels-Alder reaction with Danishefsky's diene furnished diverse substituted DNA-tagged pyridones, and a phosphoric acid organocatalyst allowed for synthesis of tetrahydroquinolines by the Povarov reaction and pyrimidinones by the Biginelli reaction, respectively. These three reactions caused low levels of DNA depurination and cover broad and only partially overlapping chemical space though using one set of DNA-coupled starting materials. † Electronic supplementary information (ESI) available: Synthesis and additional tables for screening experiments, reaction optimization experiments and reaction scope. Copies of HPLC traces and MALDI-MS spectra are shown for all discussed DNA conjugates. See a For each: 20 nmol DNA, 200 equiv. (transition) metal salt or organocatalyst A-H, 50 mL dry solvent, r.t., 22 h. b 50 mL of the indicated aqueous acid. c 5 equiv. of metal salt were used. hexT 7 ¼ 5 0 -AcN-(CH 2 ) 6 -TTT TTT-3 0 -CPG, TC 8 ¼ 5 0 -TTC CTC TCC T-3 0 -CPG, ATC 9 ¼ 5 0 -TTA CTA CCT A-3 0 -CPG, ATGC 10 ¼ 5 0 -GTC ATG ATC T-3 0 -CPG, ACN ¼ acetonitrile, MeOH ¼ methanol. This journal is View Article Online c 1000 equiv. of amine 12 were used. d Yb(OTf) 3 was used instead of ZnCl 2 . e The 2 nd step of the reaction was performed overnight at 35 C. 10mer ATGC ¼ 5 0 -GTC ATG ATC T-3 0 , ACN ¼ acetonitrile. This journal isFig. 7 Cheminformatics analysis: A ¼ PCA plot of the DA-1(red), P (blue) and B (green) lib...

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

“…In this reaction we observed that the most lipophilic micelles ( IC a , ID , IID , and IIE ) yielded less of the desired product DNA‐15 , but significantly less DNA‐depurination. To confirm product formation, we compared the micelle‐mediated Biginelli reaction to DNA‐15 with the previously reported Biginelli reaction on a controlled pore glass (CPG) solid support (Figure S110) [10] …”

“…To confirm product formation, we compared the micelle-mediated Biginelli reaction to DNA-15 with the previously reported Biginelli reaction on a controlled pore glass (CPG) solid support (Figure S110). [10] Micelle ID was then selected to perform the Biginelli reaction on a small scope of aldehydes (Figures S112-S115…”

“…DNA‐coupled starting materials are highly diluted, thus high product yields demand reactions with fast kinetics and/or large excess of starting materials. Some of these challenges have been met with fast radical‐based reactions, [4,5] reversible immobilization of DNA on ion‐exchange matrix, [6–8] or solid phase chemistry [9–11] . We and the Waring research group are investigating the potential of micellar catalysis for DNA‐encoded library synthesis [12,13] .…”

“…Some of these challenges have been met with fast radical‐based reactions,[ 4 , 5 ] reversible immobilization of DNA on ion‐exchange matrix,[ 6 , 7 , 8 ] or solid phase chemistry. [ 9 , 10 , 11 ] We and the Waring research group are investigating the potential of micellar catalysis for DNA‐encoded library synthesis. [ 12 , 13 ] Micelles designed as nanoreactors hold much promise for encoded chemistry as they accelerate reactions under mild conditions and in aqueous systems.…”

Diversified strategy for the synthesis of DNA-encoded oxindole libraries

“… 10 One reason for this limitation is that the scope of chemical reactions applicable in solution-phase DEL libraries are constrained to robust reactions that preserve the integrity of the oligonucleotides; few new synthetic methodologies can be applied to DEL library construction. 11 To preserve the integrity of the DNA barcodes, chemists have continued to expand the scope of mild chemical transformations and DNA-protecting strategies (solid-phase DEL, 12 reversible absorption of DNA onto resin, 13 micellar catalyst-promoted reactions 14 ), which provides new opportunities for DEL library synthesis.…”