DNA-Compatible ortho-Phthalaldehyde (OPA)-Mediated 2-Substituted Isoindole Core Formation and Applications

Abstract

The incorporation of the isoindole core into the DNA-encoded chemical library is highly desirable for the great potential pharmacological characters exampled by molecules like lenalidomide. Herein, we reported a DNA-compatible protocol for the OPA-mediated transformation of amines into drug-like moieties represented by isoindolinone and thio-2-isoindole, respectively. The high conversion and wide substrate-scope property of our protocol render its feasibility in the manipulation of terminal amines on oligonucleotide conjugates, including “cap-and-catch” purification, sequential synthesis during DEL construction, and on-DNA macrocyclization.

DNA-Compatible Suzuki-Miyaura Cross-Coupling Reaction of Aryl Iodides With (Hetero)Aryl Boronic Acids for DNA-Encoded Libraries

“…To expand the chemical space of these DNA-Encoded Libraries, a greater variety of DNA-Compatible reactions is required. Although much progress has been made in this direction ( Potowski et al, 2021 ; Nie et al, 2022 ; Shen et al, 2022 ; Yang et al, 2022 ), the availability of efficient synthetic methods for the synthesis of DELs remains an important challenge.…”

Access to Isoquinolin-2(1H)-yl-acetamides and Isoindolin-2-yl-acetamides from a Common MCR Precursor

“…As for the isoindolin-2-yl-acetamides (Scheme B), Ibrahim synthesized a series of (1-benzylidene-3-oxoisoindolin-2-yl)-acetamide derivatives from 3-benzalphthalide and the corresponding amino acids . Most recently, Li’s group developed an efficient protocol to construct a DNA-encoded, isoindolin-2-yl-acetamide-based chemical library with potential lenalidomide-like pharmacological properties . However, to date, no article has achieved the fast synthesis of both isoquinolin-2­(1 H )-yl-acetamide and isoindolin-2-yl-acetamide derivatives from a common Ugi MCR-based precursor.…”

“… 10 Most recently, Li’s group developed an efficient protocol to construct a DNA-encoded, isoindolin-2-yl-acetamide-based chemical library with potential lenalidomide-like pharmacological properties. 15 However, to date, no article has achieved the fast synthesis of both isoquinolin-2(1 H )-yl-acetamide and isoindolin-2-yl-acetamide derivatives from a common Ugi MCR-based precursor.…”

Vinyl azide as a synthon for DNA-compatible divergent transformations into N-heterocycles

“…44,45 Interestingly, considering that N-heterocycles (imidazole, isoquinoline, etc.) exist widely in bioactive compounds (Scheme 1A), we believe that it is of considerable importance to incorporate N-heterocycles into DELs, [46][47][48][49] supported by recent advances in the DNA-compatible synthesis of N-heterocycles including five-membered, sixmembered, and fused types. 14,50 Inspired by diversity-oriented synthesis, we envision that exploiting an appropriate nitrogencontaining synthon that is already installed on oligomers would achieve N-heterocycle scaffolds, by developing DNAcompatible diversifications.…”