Overall, this analysis supported our intention to specifically introduce structural variability at the phenylene core of VHL ligands, by incorporating additional substituents or even replacing it with bicyclic moieties. Synthesis of the first series of VHL inhibitors. Arising from the structure-based analysis, we conceptualized new VHL ligands with different substituents at the phenylene core. In the first series of compounds, the cyanocyclopropyl group on the LHS was maintained to allow comparability of the biodata within the series and with those of the parent compound VH298 (1). The convergent synthetic route to final compounds 1-23 is shown in Scheme 1. Access to such VHL ligands has already been demonstrated by employing readily available 4-bromobenzaldehyde derivatives 40 in a triethylsilane-promoted reductive amination with tert-butyl carbamate (39). Our synthesis pursued this protocol, which differed from synthetic entries applying reagents that are available with limited structural variability, i.e. or 4-bromobenzylamine derivatives. Intermediates 41, obtained by reductive amination, were subjected to a Heck coupling, leading to protected benzylamine derivatives 42. By incorporating one or two residues at different positions of the arene, a broad substitution pattern was realized in order to achieve structural diversity of the first series of VHL ligands (Table ). The set of key building blocks 42 included compounds containing naphthalene or quinoline in place of the benzene moiety, ultimately leading to compounds 22 and 23 harboring a bicyclic aromatic substructure (Table ). For the LHS part of the VHL ligands, benzyl-protected hydroxyproline (43) was converted in two uronium salt-mediated coupling reactions via dipeptide 44 to intermediate 45, followed by hydrogenolytic cleavage of the benzyl ester. The resulting free acid 46 was the sole fragment to be combined through an amide bond with the varying RHS building blocks of type 42, to finally assemble VHL ligands 1-23.