Synthesis of aryl-fused bicyclo[3.1.1]heptanes and validation as naphthyl bioisosteres

Nature Chemistry, Published online: 06 May 2026; doi:10.1038/s41557-026-02129-2 Naphthalene rings are common in drug candidates but suffer from metabolic liabilities and limited three-dimensionality. Aryl-fused bicyclo[3.1.1]heptanes (BCHeps) have been presented as derivatizable bioisosteres of β-naphthalene. Now it has been shown that aryl-fused BCHeps can be synthesized and validated as viable naphthyl replacements with promising structural and drug-like properties.