Conformationally constrained amino

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... 

Another promising conformationally constrained amino alcohol is cis-1 -arnino-2-hydroxy-1,2,3,4-tetrahydronaphthalene. Early studies using the tetrahydronaphthol backbone as a ligand in catalysis often showed that the relative flexibility of the 6-membered ring was highly detrimental to the... 

The explosion of new aminoindanol-derived ligands disclosed in the past few years is the unmistakable mark of recognition and appreciation of the indanyl platform as a valuable backbone in the field of catalytic asymmetric synthesis. The emergence of related and novel structural designs and their success in achieving improved selectivities clearly reveal the continuing interest in the synthetic potential of conformationally constrained amino alcohols. 

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]. 

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