CONFORMATIONS AND CONFORMATIONAL INTERCONVERSIONS OF DIASTEREOMERIC CYCLIC TETRAPROLINES

Cyclic tetrapeptides exclusively composed of L- and D-Pro have been st udied by theoretical means (conformational searches and molecular mech anics calculations using the CHARMM program) supported by H-1-NMR spec troscopy, X-ray analysis and chiroptical measurements. We explored the entire conformational space of the diastereomers cyclo(LLLL-PrO4) (1) , cyclo(LDLD-Pro4) (11) and cyclo(LLDD-PrO4) (III) including the low-e nergy conformations and the related interconversion paths. The conform ational interconversions were found to be restricted to cis/trans isom erisations of the amide bonds. Owing to the polycyclic nature of cyclo (PrO4) most of the cis/trans transitions are hindered by energy barrie rs higher than 30 kcal/mol (up to 150-200 kcal/mol). A few transitions are characterized by computed energy barriers comparable to those fou nd in linear -Xxx-Pro- sequences (approximately 18 kcal/mol), and are therefore experimentally significant. Experimental evidence has been o btained in the case of cyclo(LDLD-PrO4), where two enantiomers are int erconverted by a series of 4 cis/trans isomerisations ctct --> cttt -- > tttt --> tctt --> tctc. The Eyring activation parameters of this rea ction were determined in H2O and in DMF by chiroptical measurements (D ELTAH(not-equal) = 44 and 28 kcal mol; DELTAS(not-equal) = 59 and 22 c al K-1 mol-1, respectively), and correlated with the calculated barrie rs. In I and III comparable series of four cis/trans isomerisations re late two main conformations with the peptide bond sequences ctct and t ctc. In compound I pseudorotational images are interconverted via ctct --> ccct --> cctt --> cctc --> tctc. The pathway ctct --> ccct --> cc cc --> cctc --> tctc that relates diastereomeric main conformations of III involves exclusively low-energy intermediates; however, the trans itions leading to the all-cis conformation are energetically unfavoura ble, and the conformational space is divided in three insulated domain s. (C) Munksgaard 1993.