Multistep Synthesis of 1,2,4-Oxadiazoles via DNA-Conjugated Aryl Nitrile Substrates

Abstract

A multistep protocol for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles on DNA-chemical conjugates has been developed. A set of six DNA-connected aryl nitriles were converted to corresponding amidoximes with hydroxylamine followed by the O-acylation with a series of aryl and aliphatic carboxylic acids. After cyclodehydration of the O-acyl amidoximes by heating at 90 °C in pH 9.5 borate buffer for two hours, the desired oxadiazole products were observed in 51─92% conversion with the cleavage of O-acylamidoximes as the major side-product. The reported protocol paves the way for the synthesis of oxadiazole core-focused DNA-encoded chemical libraries.

DNA-encoded libraries (DELs): a review of on-DNA chemistries and their output

“…Du's group transformed the conventional synthesis of 1,2,4-oxadiazoles to the DNA-compatible reaction via a multistep reaction ( Table 6 entry 9). 77 DNA-conjugated aryl nitrile substrates reacted with hydroxylamine to form amidoxime. The ambient temperature was chosen rather than heating which avoiding the decomposition of DNA conjugates.…”

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.…”

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.…”