Synthesis of DNA-coupled isoquinolones and pyrrolidines by solid phase ytterbium- and silver-mediated imine chemistry

Potowski, Marco; Kunig, Verena B. K.; Losch, Florian; Brunschweiger, Andreas

doi:10.1039/c9md00042a

Cited by 38 publications

(58 citation statements)

References 71 publications

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“…† Our chemically very stable adapter oligonucleotide hexT 7 and three different decamer DNA oligonucleotides (TC 8, ATC 9, and ATGC 10) were incubated with three aqueous acids, as well as 33 metal salts and 20 organocatalysts dissolved in dry organic solvents. To reect plausible reaction conditions, 24,25 the catalysts were incubated with DNA strands at a 200-fold reagent excess for 22 hours at ambient temperature. Aer washing steps and standard DNA cleavage from solid support we quantitated and characterized DNA damage by RP-HPLC and MALDI-TOF mass spectrometric analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The latter result is in line with an earlier observation from our group. 24 The transition metal ions Ag(I), 24 Co(II), Cu(II), Fe(III), Ni(II), and Zn(II) were well tolerated, too ( Table 1, entries 11, 13-15, 19, and 27 and Table S1 †).…”

Section: Resultsmentioning

confidence: 99%

“…Initiating DNA-encoded library synthesis on controlled pore glass (CPG)-coupled DNA barcodes [21][22][23][24] benets from free solvent choice and enhanced chemical stability of nucleobaseprotected DNA. Here, we report a systematic analysis of the stability of pyrimidine and purine DNA sequences to 53 metal ions and organic reagents commonly used in preparative organic chemistry.…”

Section: Discussionmentioning

confidence: 99%

“…63 In order to translate this reaction to the barcoded format disclosed in ref. 24 we investigated the DNA-compatible reagents Yb(OTf) 3 , Mg(ClO 4 ) 2 and (R)-(À)-BNDHP A that were all reported in the literature for the Biginelli reaction. CPG-coupled hexT-aldehyde conjugate 11 was reacted with 500 equivalents of urea 24a dissolved in 30 mL tetrahydrofuran and 500 equivalents of ethyl acetoacetate 25 (Table 4).…”

Section: Experiments (mentioning

confidence: 99%

“…Indeed, a few accounts demonstrated DEL synthesis initiated on a CPG solid phase and one of these showed an enlarged scope of amino acid starting materials enabled by facile removal of Boc protecting groups with TFA. [20][21][22][23] We recently reported that CPGcoupled DNA barcodes tolerated Ag(I)-mediated (2 + 3) azomethine ylide cycloadditions, the Yb(III)-mediated Castagnoli-Cushman reaction, 24 and isocyanide multicomponent reactions. 25 Harsher reaction conditions such as the triuoroacetic acid-mediated Pictet-Spengler reaction and Au(I)-mediated pyrazole synthesis were compatible with a chemically very stable, CPG-coupled hexathymidine adapter "hexT".…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Experiments (mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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