Amino acids, conformationally constrained

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. 

This same strategy has been extended to the synthesis of optically pure conformationally constrained amino acids.450... 

B. Properties of Some Conformationally Constrained Amino Acids. 57... 

Under appropriate circumstances, free-radical methods can also be used to prepare macrocyclic systems. For example, Maillard and coworkers prepared the 12-membered macrocyclic ether (102) by Bu3SnH-mediated intramolecular homolytic addition to a remote, but activated (a, / unsaturated) olefin as depicted in equation 77460. Tozer and coworkers employed 7-, 8- and 9-endo cyclization in their preparations of conformationally constrained amino acids (103), an example of which is provided in equation 78448. 

Hanessian S, McNaughton-Smith G, Lombart HG, Lubell WD. Design and synthesis of conformationally constrained amino acids as versatile scaffolds and peptide mimetics. Tetrahedron (report No. 426) 1997 53 12789-12854. 

Conformationally Constrained Analogs. Local restriction of conformational freedom can be accomplished by incorporating conformationally constrained amino acids (see Refs. 679,680 for reviews). In the case of the enkephalins, incorporation of 2-amino-6-hy-droxy-2-tetralincarboxylic acid (Hat, Fig. 7.43) in place of Tyr in [Leu ]enkephalin methyl ester results in a /u,-selective compound [IC50 ratio (MVD/GPI) = 5.11, whereas the analog containing 2-hydroxy-5-hydroxy-2-indane-carboj rlic acid (Hai) is virtually inactive (681). Incorporation of 2, 6 -dimethyltyrosine (Dmt,... 

In both cases, amino acids that can modulate chemical-physical properties such as lipo-philicity (like 11, present in saquinavir and nelfmavir), can produce supplementary bonds (like 12 and 13 [42]), or can induce stereochemical constraint (like 14 [43]) are frequently used (Fig. 15). The design and synthesis of conformationally constrained amino acids as scaffolds for peptidomimetics synthesis, has been recently reviewed by Hanessian [44]. 

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. 

The restriction of the conformational flexibility of the peptide backbone can also be achieved by the use of constrained amino acids. Thereby, introduction of a single amino acid as structural constraint, if carefully chosen, may have a dramatic effect on the structure of the whole molecifle. Thus, various constrained amino acids can have direct influences on the shape of the peptide [142]. Methylation or even larger alkylation in the N- or C -position causes steric hindrance in the main chain but also in the side chain, resulting in conformational rigidity and also affects the hydrophobicity [143]. 

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. 

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