A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics.
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.
Bittermann
Holger
H
Department of Medicinal Chemistry, Friedrich Alexander University Erlangen-Nürnberg, Schuhstrasse 19, 91052 Erlangen, Germany.
Böckler
Frank
F
Einsiedel
Jürgen
J
Gmeiner
Peter
P
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
D007769:Lactams; D013141:Spiro Compounds; D011392:Proline