Palladium-Mediated Carbonylative Suzuki Coupling for DNA-Encoded Library Synthesis

Abstract

Developing new DNA-compatible reactions is key to expanding the accessible chemical space of DNA-encoded library (DEL) technology. Here we disclose the first report of a DNA-compatible carbonylative Suzuki coupling of DNA-conjugated (hetero)­aryl iodides with (hetero)­aryl boronic acids to access di­(hetero)­aryl ketones, a valuable structural motif present within several approved or clinically advanced small molecules. The reported DNA-compatible, Pd­(OAc)2-mediated system is mild, uses a robust protocol, has a wide substrate scope for both coupling partners, is suitable for large-scale DEL productions, and provides a source of previously unexplored chemical matter for DEL screens.

Application of DNA‐Conjugated Aryl Diazonium Intermediates in DNA‐Encoded Libraries

“…For instance, Suzuki-Miyaura reaction employs various DNA-tagged aryl halides (X=I, Br or Cl) and boronic acids/esters. [22] Additionally, DNA-compatible Pd-catalyzed Heck coupling reactions have been developed. [23] However, these approaches often involve harsh conditions such as high temperature and strong base, which may lead to DNA damage and instability of functional groups (Scheme 2a).…”

“…Most of them adopt aryl halides as substrates. For instance, Suzuki–Miyaura reaction employs various DNA‐tagged aryl halides (X=I, Br or Cl) and boronic acids/esters [22] . Additionally, DNA‐compatible Pd‐catalyzed Heck coupling reactions have been developed [23] .…”

Aryl diazonium intermediates enable mild DNA-compatible C–C bond formation for medicinally relevant combinatorial library synthesis

“…Previous efforts have generated a few DNA-compatible Pdcatalyzed C-C cross-coupling reactions. [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] A suite of synthetic methodologies realized robust Suzuki-Miyaura coupling between a diverse set of DNA-tethered aryl halides (X = I, Br, or Cl) and boronic acids/esters. [40][41][42][43][44][45][50][51][52][53]55 Besides, efficient Pd-catalyzed DNA-compatible Heck coupling reactions between olens and aryl halides were exploited.…”

Photoredox-Mediated Deoxygenative Alkylation of DNA-Tagged Alkenes with Activated Alcohols

“…Since their inception 30 years ago, DNA-encoded library (DEL) screens have become an indispensable tool for finding small-molecule binders from which to start drug development campaigns. − Typically, DELs consist of a pooled collection of millions (or even billions) of compounds, each covalently appended with a unique DNA tag that encodes the structure of the covalently attached compound. , DELs offer several advantages over conventional screening technologies by enabling hit affinity selection using small amounts of proteins and multiplexed DEL inputs, thereby reducing the cost, effort, and time associated with hit finding. ,, The success of DELs is further corroborated by the growing number of publications from academia and industry reporting the identification of potent and selective hits for diverse biological targets. ,,, Although DEL technology enables the screening of vast collections of compounds, due to the combinatorial nature of DEL synthesis, the diversity of intrinsic DEL chemotypes depends on the development of novel DEL-compatible bond-forming reactions, ideally using widely available building blocks as diversity elements. , For a reaction to be widely useful for producing DELs in solution-phase formats, it should be adapted to fit key constraints such as tolerance to aqueous reaction conditions, amenability to miniaturization, wide substrate scope, high reproducibility and maintain the integrity of DNA tags . To support the Janssen DEL pipeline, we have a continuing interest in developing new DEL chemistries that can address DEL synthetic gaps to essential medicinal chemistry chemotypes or that enable use of under-utilized building block classes. , …”

“…10 To support the Janssen DEL pipeline, we have a continuing interest in developing new DEL chemistries that can address DEL synthetic gaps to essential medicinal chemistry chemotypes or that enable use of under-utilized building block classes. 11,12 Photoredox catalysis has become a powerful technique that enables the synthesis of complex products from simple starting materials and has become an indispensable tool in the organic chemist's toolbox. 13−15 Photoredox methodologies have enabled the formation of C(sp 3 )−C(sp 3 ) bonds by generating alkyl radicals from diverse classes of building blocks under relatively mild reaction conditions.…”