Medium-Sized Ring Expansion Strategies: Enhancing Small-Molecule Library Development

Abstract

The construction of a small molecule library that includes compounds with medium-sized rings is increasingly essential in drug discovery. These compounds are essential for identifying novel therapeutic agents capable of targeting “undruggable” targets through high-throughput and high-content screening, given their structural complexity and diversity. However, synthesizing medium-sized rings presents notable challenges, particularly with direct cyclization methods, due to issues such as transannular strain and reduced degrees of freedom. This review presents an overview of current strategies in synthesizing medium-sized rings, emphasizing innovative approaches like ring-expansion reactions. It highlights the challenges of synthesis and the potential of these compounds to diversify the chemical space for drug discovery, underscoring the importance of medium-sized rings in developing new bioactive compounds.

Synthesis of the first 4-oxobutane-1,1,2,2-tetracarbonitriles containing a phenol fragment and their transformation into cyano-substituted pyrrol-2-ones showing three-position molecular switching

“…Diversity-oriented synthesis (DOS) is one of the effective approaches for preparation of small molecules with various practically useful properties. [1][2][3][4][5][6][7][8][9][10] Thus, based on DOS processes, various biologically active compounds, [1][2][3][4][5][6] luminescent sensors and probes, 8 AIE-luminogens 9 and inaccessible macrocycles 10 have been synthesized. The substrates used in the DOS strategy are quite diverse.…”