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Updated: Aug 29, 2026
Solid Phase Synthesis of a Functionalized Bis-Peptide Using "Safety Catch" Methodology
Published on: May 15, 2012
Parallel solid-phase synthesis of disubstituted (5-biphenyltetrazolyl) hydantoins and thiohydantoins targeting the
Rune Severinsen1, Jesper F Lau, Kent Bondensgaard
1Medicinal Chemistry, Novo Nordisk A/S, Novo-Nordisk Park 2760, Maaloev, Denmark.
Abstract:
An efficient solid-phase protocol for the synthesis of substituted (5-biphenyltetrazolyl)-hydantoins and -thiohydantoins has been developed. Suzuki cross-coupling between resin-bound 2-(tetrazol-5-yl)-phenylborinane and 4-bromobenzaldehyde gave the corresponding tetrazolylbiphenyl aldehyde. Subsequent reductive amination using amino acid esters gave the pivotal resin bound amino acid esters which were transformed to hydantoins or thiohydantoins via two routes: (i) treatment with isocyanates or isothiocyanates or (ii) successive treatment with triphosgene and primary amines. Using molecular modeling, we were able to jump from L-692,429, a well known non-peptidyl growth hormone secretagogue (GHS), to biphenyltetrazolyl hydantoins, obtaining compounds with IC(50) values below 600 nM after two iterative cycles only.
