DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Abstract

are encoded by unique DNA sequences as identification "barcodes," and are assembled combinatorial using split-andpool strategy or alternative procedures via DNA-compatible reactions. [7][8][9] DELs comprising millions or even billions of DNA-tagged druglike molecules can be effectively synthesized via this technology and screened against various protein targets of interest in a single pooled assay. In a typical affinity-based selection experiment, when non-and low-affinity binders are washed away, the DNA tag of the remaining compounds can be amplified using polymerase chain reaction and the relative frequency of the remaining compounds before and after selection is determined by counting the number of DNA tags in high-throughput DNA sequencing experiments. [10,11] To date, a large number of high-quality hits have been identified by the DEL technology for various therapeutically relevant targets, such as kinases, [12] phosphatases, [13] and G-protein coupled receptors. [14] Several drug candidates derived from their corresponding DEL hits, such as soluble epoxide hydrolase inhibitor GSK2256294, and death domain receptor-associated adaptor kinase RIP1 inhibitor GSK2982772 have progressed to latestage clinical development, [15,16] further emphasizing DEL as a powerful technology for small molecular drug discovery.Despite these successes, the great potential of DEL technology in drug discovery has not yet been fully realized. One of the most fundamental challenges is the synthesis of high-quality libraries with more structural diversity, which in turn depends on the development of new and robust DNA-compatible reactions that allow more flexibility in DEL's design and synthesis. Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. However, the environmental toxicity and high costs of aryl halides have hindered their large-scale applications in industry. Thus, much attention has been paid to phenol-derived electrophiles recently, [27] which, as compared to aryl halides, offer a more sustainable starting material because most of them are readily available from biomass. [28] In addition, phenol modules are also important components of natural products (NPs), bioactive molecules, and pharmaceutical drugs. Coupling reactions with Using (hetero)aryl fluorosulfonates as versatile electrophiles, facile on-DNA cross-coupling reactions of Suzuki, Sonogashira, and Buchwald are reported here. Notably, all of these reactions show excellent functional group tolerance, mild reaction conditions (relative low temperature and open to air), rich heterocyclic coupling partners, and more importantly, DNA-compatibility. Thus, these new reactions based on efficient formation of C(sp 2 )-C(sp 2 ), C(sp 2 )-C(sp), and C(s...

Transition‐Metal‐Mediated Modification of Biomolecules

“…In 2019, Torrado and co‐workers extended the scope of this amination reaction towards aryl bromides in ds DNA using palladium catalysis . The same year, Yang, Lerner and co‐workers, based on their success on Sonogashira reactions (Figure ), investigated the use of arylfluorosulfonates as electrophiles in C−N cross‐coupling and demonstrated its efficient application for the modification of ds DNA with a wide scope of amines.…”

Transition‐Metal‐Mediated Modification of Biomolecules

“…In 2019, Torrado and co‐workers extended the scope of this amination reaction towards aryl bromides in ds DNA using palladium catalysis . The same year, Yang, Lerner and co‐workers, based on their success on Sonogashira reactions (Figure ), investigated the use of arylfluorosulfonates as electrophiles in C−N cross‐coupling and demonstrated its efficient application for the modification of ds DNA with a wide scope of amines.…”

Post‐Synthetic Nucleobase Modification of Oligodeoxynucleotides by Sonogashira Coupling and Influence of Alkynyl Modifications on the Duplex‐Forming Ability

“…Moreover, there are several reports on the synthesis of DNA-encoded library (DEL) via Sonogashira coupling using ONs modified with iodobenzene analogs at the 5'-end; the desired cross-coupling products were obtained in high yields. [56,57] In contrast to these studies, the Sonogashira coupling of ONs in this study afforded cross-coupling products in low yields. These results were attributed to the multi-alkyne functionalization of 5IdU and the low reactivity of 7IdG in the post-synthetic modification by Sonogashira coupling, regardless of the modification position.…”

“…Khan [20] and Beilstein [21] reported the solid‐phase Sonogashira coupling of 5IdU at the 5′‐end of fully protected ONs and the palladium coupling yield was 85–92 % without any side reactions. Moreover, there are several reports on the synthesis of DNA‐encoded library (DEL) via Sonogashira coupling using ONs modified with iodobenzene analogs at the 5′‐end; the desired cross‐coupling products were obtained in high yields [56,57] . In contrast to these studies, the Sonogashira coupling of ONs in this study afforded cross‐coupling products in low yields.…”

Highly selective and AI-predictable Se–N exchange chemistry between benzoselenazolones and boronic acids for programmable, parallel, and DNA-encoded library synthesis

“…62–65 As a result, the development of DNA-compatible reactions is one of the key tasks in DELs. 66–68 Although a set of DNA compatible reactions such as diarylether synthesis, 69 cross-coupling reaction, 70–75 C–H activation and functionalization, 76,77 photo-promoted reaction, 78,79 cycloaddition reaction, 80 and the on-DNA synthesis of privileged heterocycles 81–83 have been developed in the past few years, only a few good reactions have been used in DEL synthesis, 84 due to the highly functionalized and sensitive DNA barcodes, low reaction scale and highly diluted conditions. 75,80,85 Nevertheless, the mild and robust conditions and the excellent functional group tolerance of this Ag( i ) catalyzed SeNEx chemistry indicate its potential for an ideal DNA-compatible reaction development.…”

Transition‐Metal‐Mediated Modification of Biomolecules

“…In 2019, Torrado and co‐workers extended the scope of this amination reaction towards aryl bromides in ds DNA using palladium catalysis . The same year, Yang, Lerner and co‐workers, based on their success on Sonogashira reactions (Figure ), investigated the use of arylfluorosulfonates as electrophiles in C−N cross‐coupling and demonstrated its efficient application for the modification of ds DNA with a wide scope of amines.…”

Post‐Synthetic Nucleobase Modification of Oligodeoxynucleotides by Sonogashira Coupling and Influence of Alkynyl Modifications on the Duplex‐Forming Ability

“…Moreover, there are several reports on the synthesis of DNA-encoded library (DEL) via Sonogashira coupling using ONs modified with iodobenzene analogs at the 5'-end; the desired cross-coupling products were obtained in high yields. [56,57] In contrast to these studies, the Sonogashira coupling of ONs in this study afforded cross-coupling products in low yields. These results were attributed to the multi-alkyne functionalization of 5IdU and the low reactivity of 7IdG in the post-synthetic modification by Sonogashira coupling, regardless of the modification position.…”

“…Khan [20] and Beilstein [21] reported the solid‐phase Sonogashira coupling of 5IdU at the 5′‐end of fully protected ONs and the palladium coupling yield was 85–92 % without any side reactions. Moreover, there are several reports on the synthesis of DNA‐encoded library (DEL) via Sonogashira coupling using ONs modified with iodobenzene analogs at the 5′‐end; the desired cross‐coupling products were obtained in high yields [56,57] . In contrast to these studies, the Sonogashira coupling of ONs in this study afforded cross‐coupling products in low yields.…”

Highly selective and AI-predictable Se–N exchange chemistry between benzoselenazolones and boronic acids for programmable, parallel, and DNA-encoded library synthesis

“…62–65 As a result, the development of DNA-compatible reactions is one of the key tasks in DELs. 66–68 Although a set of DNA compatible reactions such as diarylether synthesis, 69 cross-coupling reaction, 70–75 C–H activation and functionalization, 76,77 photo-promoted reaction, 78,79 cycloaddition reaction, 80 and the on-DNA synthesis of privileged heterocycles 81–83 have been developed in the past few years, only a few good reactions have been used in DEL synthesis, 84 due to the highly functionalized and sensitive DNA barcodes, low reaction scale and highly diluted conditions. 75,80,85 Nevertheless, the mild and robust conditions and the excellent functional group tolerance of this Ag( i ) catalyzed SeNEx chemistry indicate its potential for an ideal DNA-compatible reaction development.…”

Transition‐Metal‐Mediated Modification of Biomolecules

“…In 2019, Torrado and co‐workers extended the scope of this amination reaction towards aryl bromides in ds DNA using palladium catalysis . The same year, Yang, Lerner and co‐workers, based on their success on Sonogashira reactions (Figure ), investigated the use of arylfluorosulfonates as electrophiles in C−N cross‐coupling and demonstrated its efficient application for the modification of ds DNA with a wide scope of amines.…”

Post‐Synthetic Nucleobase Modification of Oligodeoxynucleotides by Sonogashira Coupling and Influence of Alkynyl Modifications on the Duplex‐Forming Ability

“…Moreover, there are several reports on the synthesis of DNA-encoded library (DEL) via Sonogashira coupling using ONs modified with iodobenzene analogs at the 5'-end; the desired cross-coupling products were obtained in high yields. [56,57] In contrast to these studies, the Sonogashira coupling of ONs in this study afforded cross-coupling products in low yields. These results were attributed to the multi-alkyne functionalization of 5IdU and the low reactivity of 7IdG in the post-synthetic modification by Sonogashira coupling, regardless of the modification position.…”

“…Khan [20] and Beilstein [21] reported the solid‐phase Sonogashira coupling of 5IdU at the 5′‐end of fully protected ONs and the palladium coupling yield was 85–92 % without any side reactions. Moreover, there are several reports on the synthesis of DNA‐encoded library (DEL) via Sonogashira coupling using ONs modified with iodobenzene analogs at the 5′‐end; the desired cross‐coupling products were obtained in high yields [56,57] . In contrast to these studies, the Sonogashira coupling of ONs in this study afforded cross‐coupling products in low yields.…”

Highly selective and AI-predictable Se–N exchange chemistry between benzoselenazolones and boronic acids for programmable, parallel, and DNA-encoded library synthesis

“…62–65 As a result, the development of DNA-compatible reactions is one of the key tasks in DELs. 66–68 Although a set of DNA compatible reactions such as diarylether synthesis, 69 cross-coupling reaction, 70–75 C–H activation and functionalization, 76,77 photo-promoted reaction, 78,79 cycloaddition reaction, 80 and the on-DNA synthesis of privileged heterocycles 81–83 have been developed in the past few years, only a few good reactions have been used in DEL synthesis, 84 due to the highly functionalized and sensitive DNA barcodes, low reaction scale and highly diluted conditions. 75,80,85 Nevertheless, the mild and robust conditions and the excellent functional group tolerance of this Ag( i ) catalyzed SeNEx chemistry indicate its potential for an ideal DNA-compatible reaction development.…”