Gmeiner P, Einsiedel J (2006)
Publication Type: Journal article
Publication year: 2006
Publisher: Wiley-VCH Verlag
Book Volume: 12
Pages Range: 6315-6322
The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bio-active 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 β-turn inducer 1 with saturated spirocyclic lactams 3 efficiently mimicking type II β 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 ε-lactam 12 closely agrees with the reference γlactam 3a, the unsaturated δ-lactam 11 serves as an extraordinarily potent β-turn inducer which is even superior to β-lactams of type 3b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type II β turn with the highest stability of the whole series. In contrast, the nine-membered spirolactam 14 represents a scaffold with a high conformational flexibility. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA,.
APA:
Gmeiner, P., & Einsiedel, J. (2006). A Highly Practical RCM Approach towards a Molecular Building Kit of Spirocyclic Reverse Turn Mimics. Chemistry - A European Journal, 12, 6315-6322. https://doi.org/10.1002/chem.200600432
MLA:
Gmeiner, Peter, and Jürgen Einsiedel. "A Highly Practical RCM Approach towards a Molecular Building Kit of Spirocyclic Reverse Turn Mimics." Chemistry - A European Journal 12 (2006): 6315-6322.
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