Inverse-Electron-Demand Diels–Alder Reactions for the Synthesis of Pyridazines on DNA

Abstract

The synthesis of pyridazines on DNA has been developed on the basis of inverse-electron-demand Diels−Alder (IEDDA) reactions of 1,2,4,5-tetrazines. The broad substrate scope is explored. Functionalized pyridazine products are selected for subsequent DNA-compatible Suzuki−Miyaura coupling, acylation, and S N Ar substitution reactions, demonstrating the feasibility and versatility of IEDDA reactions for DNA-encoded library synthesis.

Solution-Phase DNA-Compatible Pictet-Spengler Reaction Aided by Machine Learning Building Block Filtering

“…However, no research regarding DEL reaction conversion rate ML Furthermore, applying ML for BB filtering is particularly valuable for challenging DNA-compatible reactions owing to the expected low BB passing rate. Although DEL is successful for hit identification and widely used throughout the academic and industrial small molecule drug discovery community, it still suffers from a limited number of DNA-compatible reactions and thus limited access to desirable drug-like chemical space (Satz et al, 2015;Malone and Paegel, 2016;Lu et al, 2017aLu et al, , 2017bWang et al, 2018aWang et al, , 2018bLi et al, 2018;Flood et al, 2019;Du et al, 2019;Lerner et al, 2019;Liu et al, 2019;Skopic et al, 2019;Xu et al, 2019). More DNA-compatible organic transformations, especially the challenge but highly valuable ones, are strongly desired to improve the chemical diversity of DNA-encoded libraries.…”

Water-Compatible Cycloadditions of Oligonucleotide-Conjugated Strained Allenes for DNA-Encoded Library Synthesis

“…[23,24] Having significantly advanced the field of bioconjugation chemistry, these and related reactions are compatible with water and biopolymers by necessity. [25] With only one recent report on inverse-electron-demand Diels-Alder reactions [26] and reactions of cyclooctyne-DNA conjugates in the solid phase, [27,28] strain-promoted reactivity has not yet found general application in the context of DELs. When contained within 8-membered rings and smaller, cyclic allenes show increased reactivity and readily undergo strain-releasing reactions.…”

Employing Photocatalysis for the Design and Preparation of DNA‐Encoded Libraries: A Case Study

“…Notwithstanding these limitations, a plethora of chemical transformations have been rendered DNA‐compatible in recent years. Among the reactions that have been optimized for DEL are various procedures for the incorporation of valuable heterocyclic scaffolds, [45–49] palladium‐catalyzed coupling reactions, [50–56] inverse‐electron‐demand Diels‐Alder reactions, [57] ruthenium‐promoted C−H activation [43] and ring‐closing metathesis reactions, [58,59] and transition metal‐catalyzed C−N cross‐coupling reactions [38,60–62] . We have sought to enable a particular class of catalytic transformations that is driven by visible light.…”