Conformationally constrained amino proline

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

The hairpin-like P-turn has recently been examined in more detail from the standpoint of conformational energy (28). This investigation revealed that there are two types of conformation of the L L bend which accomodate the sequences L -> L, L G, G - L, G G, while only one type is possible for the L D bend which accomodates the sequences L - D, L G, G D, G G. The new investigation supported and extended the earlier considerations, and has been successfully compared with the experimental data. These investigations revealed that the formation of the /1-turn is a determining factor in the cyclization of linear peptides and explained why a particular amino acid such as D-amino acid or a constrained amino acid like proline are often found at the comer of the p-tum in thetic and naturally occurring cyclic peptides. 

Based on the findings from an alanine scan, further peptides can be synthesized in which residues involved in the receptor recognition are substituted by homologous amino acids. Interesting in this context is also the use of conformation-ally constrained analogues in which amino acid residues such as the helix breaker proline or the tum-inducing motive alanine-aminoisobutyric acid are introduced into the natural peptide sequence. 

While the previous studies showed that substrate peptides were not found in p turn conformations in solution, they cannot rule out binding of the peptide to the enzyme in this conformation. In order to determine whether this was the case, peptides were synthesized which were constrained into a p turn (79). In the cyclic hexapeptides 2a and 2b, the proline-D-amino acid dipeptide forms a type II p turn. This locks the remaining residues into a type I p turn with the asparagine fixed into either the (i) or (i+1) position of this turn. One and two dimensional NMR confirmed that these peptides were in the predicted conformations with all the predicted NOE connectivities and with the expected intramolecular hydrogen bonding (79). 

---