title: A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics.
abstract: The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bioactive conformation of a natural peptide has attracted remarkable interest. The frequent occurrence of proline in various turn patterns initiated the design of proline-based reverse turn mimetics. As a structural hybridization of a highly potent type VI beta-turn inducer 1 with saturated spirocyclic lactams 3 efficiently mimicking type II beta turns, we developed a versatile synthetic route towards unsaturated spirocyclic lactams of type 2, when Seebach's self-reproduction of chirality methodology was combined with a peptide coupling reaction and Grubbs' ring-closing metathesis. By this means, a variety of model peptides with six- up to nine-membered lactam rings were accessible following a uniform pathway. Introduction of suitably protected templates into solid-phase peptide synthesis gave rise to unsaturated spirocyclic analogues of the naturally occurring neuropeptide neurotensin. Spectroscopic investigations as well as DFT calculations on a high level of theory revealed a remarkable dependence of the reverse-turn inducing potency on the ring size. While the secondary structure of the unsaturated spirocyclic epsilon-lactam 12 closely agrees with the reference gamma-lactam 3 a, the unsaturated delta-lactam 11 serves as an extraordinarily potent beta-turn inducer which is even superior to beta-lactams of type 3 b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type II beta turn with the highest stability of the whole series. In contrast, the nine-membered spirolactam 14 represents a scaffold with a high conformational flexibility.
authors.affiliation: Department of Medicinal Chemistry, Friedrich Alexander University Erlangen-Nürnberg, Schuhstrasse 19, 91052 Erlangen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Bittermann
authors.forename: Frank
authors.initials: F
authors.lastname: Böckler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Einsiedel
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D040761:Biomimetic Materials / Q000737:chemistry*; D007769:Lactams / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D011392:Proline / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013141:Spiro Compounds / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D007769:Lactams; D013141:Spiro Compounds; D011392:Proline