Abstract With over 60 of protein–protein interfaces featuring an α‐helix, the use of α‐helix mimetics as inhibitors of these interactions is a prevalent therapeutic strategy. However, methods to control the conformation of mimetics, thus enabling maximum efficacy, can be restrictive. Alternatively, conformation can be controlled through the introduction of destabilizing syn‐pentane interactions. This tactic, which is often adopted by Nature, is not a common feature of lead optimization owing to the significant synthetic effort required. Through assembly‐line synthesis with NMR and computational analysis, we have shown that alternating syn–anti configured contiguously substituted hydrocarbons, by avoiding syn‐pentane interactions, adopt well‐defined conformations that present functional groups in an arrangement that mimics the α‐helix. The design of a p53 mimetic that binds to Mdm2 with moderate to good affinity, demonstrates the therapeutic promise of these scaffolds.
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