A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics

被引:48
作者
Bittermann, Holger [1 ]
Boeckler, Frank [1 ]
Einsiedel, Hirgen [1 ]
Gmeiner, Peter [1 ]
机构
[1] Univ Erlangen Nurnberg, Dept Med Chem, D-91052 Erlangen, Germany
关键词
metathesis; peptidomimetics; reverse turns; spiro compounds;
D O I
10.1002/chem.200600432
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 I with saturated spirocyclic lactams 3 efficiently mimicking type 11 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-memembered 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 3a, the unsaturated delta-lactam 11 serves as an extraordinarily potent beta-turn inducer which is even superior to beta-lactams of type 3b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type 11 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.
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页码:6315 / 6322
页数:8
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