Amino acids, conformationally constraine

Design, synthesis, conformational analysis, and application of azabicycloalkane amino acids as constrained dipeptide mimics 04SL1499. 

Peptidic p-tum mimetics are generally based on cyclic backbone mimetics (e.g. replacing the turn hydrogen bond by a covalent bond) or by introducing one or several unusual amino acids, which constrain the backbone in P-tum conformations. Synthetic approaches to non-peptidic turn mimetics can be grouped into two classes 1) external P-turn mimetics, and 2) internal P-turn mimetics. ... 

Winkler, M., Knall, A.C., Kulterer, M.R. and Klempier, N. (2007) Nitrilases catalyze key step to conformationally constrained GABA analogous y-amino acids in high optical purity. The Journal of Organic Chemistry, 72, 7423-7426. 

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. 

Antibodies also well catalyze the reactions where a molecule should he forced to adopt a particular and reactive conformation, thanks to privileged interactions with the amino acids of the binding site. For example, ahzymes with a ferrochelatase activity, 7G12, force the mesoporphyrin IX ring to adopt a distorted conformation favorable to the insertion of a Cu ion in the center of the macrocycle,thanks to an interaction with the HlOOc methionine which constrains one of the pyrrole rings to be left outside the plane of porphyrin (Figure 24). 

In removing the oxazoline auxiliary from the products, Richards and coworkers have demonstrated the use of the diastereoselective ferrocenyloxazoline lithiation in the synthesis of conformationally constrained amino acid derivatives (Scheme 146) °. Amination of 305 was achieved by nitration, reducing to the amino group after removal of the oxazoline under standard conditions. Using the trick of silylating the more reactive diastereotopic site, it was possible to make either enantiomer of 321 from the same oxazoline starting material. 

On the other hand, lithium perchlorate catalyzed Diels-Alder reaction between 4-[(ethoxycarbonyloxy)methylene]-2-phenyl-5(47/)-oxazolone 829 and cyclopenta-diene is more efficient and affords a mixture of the corresponding exo-830 and endo-831 cycloadducts. These cycloadducts have been converted to 2-amino-3-hydroxynorbornenecarboxylic acid derivatives 832 and 833 or to 2-amino-3-hydroxynorbornanecarboxylic acids 834 and 835 after a series of careful transformations.In addition, 830 and 831 have been further elaborated to new conformationally constrained serine analogues, the polyhydroxy 2-aminonorbor-nanecarboxylic acids 836-839 as shown in Scheme 7.257. ° ... 

Conotoxins are small (10-30 amino acids), disulphide-rich, conformationally constrained peptides produced by marine mollusks such as cone snails. The fish-hunting snails, in particular Conus geographus, have been extensively studied. Depending upon the arrangement of disulphide bonds and the number of residues between cysteines, five or more classes of conotoxin can be structurally identified ... 

The asymmetric synthesis of conformationally constrained a-amino acids and their incorporation into peptides are currently topics of great interest [47]. Much sought after are fused bicyclic a-amino acids having the N atom incorporated into a ring system [48]. Many of these amino acids display interesting pharmacological activities, and they have served as building blocks for the synthesis of pep-... 

Synthetic Side-Chain Conformationally Constrained a-Amino Acids... 

---