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.

Keywords: bioactive compound discovery; diversity-oriented synthesis; medium-sized ring synthesis; natural product mimics; ring-expansion reactions.

Figure 1

(a) Schematic representation of complexity-to-diversity (Ctd) strategy, privileged substructure-based DOS (pDOS), and pseudo-natural products synthesis approach. In Ctd, the rings undergo transformation and are distinguished by various colors. The colored rings in pDOS and pseudo-natural product synthesis refer to privileged structures and fragments derived from natural products, respectively. (b) Representative examples of natural and bioactive compounds with medium-sized rings [48,49,50,51,52,53,54,55].

Scheme 1

(a) Ring-expansion reactions for the synthesis of medium-sized lactones and lactams via the oxidative cleavage of the C=C double bond (highlighted in red). (b) Diversification of the medium-sized ring compound.

Scheme 2

(a) Biomimetic ODRE stepwise sequence for benzannulated medium-ring synthesis. (b) Tandem ODRE reaction for diverse benzannulated medium-ring lactam synthesis. C–C bond cleavage was highlighted in red.

Scheme 3

Electrochemical ring expansion for the synthesis of diverse privileged-structure-embedded medium-sized ring compounds via C–C bond cleavage (highlighted in red).

Scheme 4

pDOS synthetic strategy for pyrimidine-embedded medium-sized ring compounds. (a) Design and synthesis of an N-quaternized key intermediate for the construction of a medium-sized small-molecule library containing a pyrimidine-privileged substructure. (b) Ring-expansion reactions for the synthesis of a medium-sized ring via the cleavage of the N–N bond. (c) Synthesis of a bridged medium-sized ring via the migration of an N–N–C bond to N–C–N. (d) Ring-expansion reactions for the synthesis of a medium-sized ring via internal nucleophile-driven C–N bond cleavage. N–N or C–N bond cleavage sites were highlighted in red.

Scheme 5

(a) Migratory ring-expansion reaction for the synthesis of medium-sized rings with a range of benzo-fused cyclic-urea structures. (b) Acid-promoted cyclic-urea ring contraction. (c) Asymmetric ring expansion for the synthesis of medium-sized rings and the stereochemically retentive recontraction of cyclic ureas. C–N bond cleavage sites were highlighted in red.

Scheme 6

(a) Reaction sequence involving acylation, removal of protecting groups, and ring expansion to synthesize medium-sized lactams and lactones. (b) Strategies for expanding rings in the synthesis of medium-sized and macrocyclic sulfonamides. C–N bond cleavage sites were highlighted in red.

Scheme 7

(a) Pd-catalyzed ring-expansion reaction of trifluoromethyl benzo[d][1,3]oxazinones 59 with vinyl ethylene 57 for the synthesis of nine-membered heterocyclic compounds 62. (b) Synthesis of medium-sized heterocyclic lactones through sequential C–N bond cleavage (highlighted in red) and ring expansion. (c) Sequential catalysis system using gold and palladium to synthesize furan-fused nine-membered heterocycles.

Scheme 8

(a) Diversification strategy through site-selective C–H oxidation and subsequent ring expansion reaction. (b) Electrochemical approach for allylic C–H oxidation combined with Beckmann rearrangement to synthesize lactams with ring expansion. (c) Site-selective Cu-mediated C–H oxidation combined with a Beckmann rearrangement. (d) Complex structural transformations utilizing C–O bonds, featuring ring-expansion reactions, including [2 + 2] cycloaddition/cyclobutene fragmentation and acylation/ring-expansion sequences.