| Abstract
| - Proline-derived peptide mimetics have become an area of paramount importance in peptide and proteinchemistry. Since protein crystal structures frequently display Ψ angles of 140−170° for prolyl moieties,our intention was to design a completely novel series of 2,3-fused-proline-derived lactams covering thisparticular conformational space. Extending our recently described toolset of spirocyclic reverse-turnmimetics, we synthesized pyrrolidinyl-fused seven-, eight-, and nine-membered unsaturated lactam modelpeptides taking advantage of Grubbs' ring-closing metathesis. Investigating the seven-membered lactam3a by means of IR and NMR spectroscopy and semiempirical molecular dynamics simulations, we couldnot observe a U-turn conformation; however, increasing the ring size to give eight- and nine-memberedcongeners revealed moderate and high type ΙΙ β-turn inducing properties. Interestingly, the conformationalproperties of our model systems depend on both the ring size of the fused dehydro-Freidinger lactam andthe position of the endocyclic double bond. Superior reverse-turn inducing properties could be observedfor the fused azacyclononenone 3e. According to diagnostic transanular NOEs, a discrete folding principleof the lactam ring strongly deviating from the regioisomeric lactams 3c,f explains the conformationalbehavior. Hence, we were able to establish a molecular building kit that allows adjustments of a widerange of naturally occurring proline Ψ angles and thus can be exploited to probe molecular recognitionand functional properties of biological systems.
|
