New Synthetic Strategies Create 3D Molecular Architectures for Drug Discovery
New synthetic methods provide access to congested cyclobutanes, bicyclo[2.1.1]hexanes, and housanes for use as 3D scaffolds or bioisosteres in drug discovery. The approaches enable improved solubility and metabolic stability in drug analogues while maintaining biological activity.
Researchers have developed new synthetic strategies to access three-dimensional molecular scaffolds for drug discovery, including congested cyclobutanes, bicyclo[2.1.1]hexanes, and housanes. These methods provide previously difficult-to-access frameworks that can serve as bioisosteres or scaffolds in medicinal chemistry.
A strategy that merges triplet nitrene-mediated ring expansion with titanium-catalysed cyanylation enables the diastereoselective synthesis of vicinal tetrasubstituted cyclobutane amino nitriles. This approach unlocks highly functionalized and congested three-dimensional cyclobutanes that could provide scaffolds for drug discovery but have previously been difficult to access.
Separately, an enantioselective copper-catalysed protoborylation has been developed to obtain 1,3-disubstituted bicyclo[2.1.1]hexanes as suitable mimics of meta-benzenes. The stereocontrolled formation of these bicyclic frameworks, which presents an elusive substitution pattern, was achieved through a desymmetrization of bicyclo[2.1.1]hex-2-enes. The obtained versatile enantioenriched building blocks have been incorporated into the structures of different drug analogues, leading to an improvement in solubility, metabolic stability and permeability in comparison with the parent drugs. The drug analogues showed a retention of biological activity by targeting the same molecular receptors, validating them as suitable meta-benzene bioisosteres.
In another study, a substrate-dependent, divergent strategy accesses a broad family of housanes through an intramolecular-energy-transfer-mediated [2 + 2] cycloaddition of 1,4-dienes. This method rapidly builds up strain while suppressing the di-π-methane rearrangement, expanding the toolkit for efficient exploration of housane chemical space. Substituent engineering enables switching between single and double energy-transfer pathways to deliver 1,3- and 1,2-disubstituted housanes with excellent stereocontrol and broad functional-group tolerance. Mechanistic studies and density functional theory calculations support an energy-transfer pathway and rationalize the observed selectivity.