Conformation of diastereoisomeric cyclo(neopentylglycyl-prolyls): NMR, X-ray, and CD studies

Abstract

Conformation of diastereoisomeric cyclo(L-neopentylglycyl-L-prolyl) (IV) and cyclo(D-neopentylglycyl-L-prolyl) (VIII) in solution was studied by 1H and 13C NMR spectroscopy. Both compounds have approximately the same conformation of the bicyclic moiety in which the 2,5-piperazinedione ring exists in the boat form with pseudoaxial proline H(α) atom, and the proline ring is in the C(γ)-exo conformation. Rotation of the neopentyl side chain is markedly hindered. In the trans-derivative VIII the side chain occupies a pseudoaxial position with staggered rotamer about the C(α)-C(β) bond, the tert-butyl group pointing from the ring in the direction of the nitrogen atom. The preferred rotamer of the cis-isomer markedly deviates from this staggered conformation in the exo-direction relative to the piperazine ring. X-Ray diffraction analysis shows that crystal conformation of the trans-isomer VIII is very similar to that in solution. According to CD measurements, steric interactions of the acyclic side chain with the dioxopiperazine ring lead to twisted boat conformations of this ring with non-planar amide groups. From comparison with other proline-containing cyclodipeptides it follows that the effect of these interactions depends on the side chain structure. The neopentyl side chain flattens the boat conformation and reduces the deviation of the amide groups from planarity.