Peptides conformational restriction

Another similar application was in the production of bicyclic lactams 357 that might serve as building blocks for the synthesis of conformationally restricted peptides (equation 137). 

Moeller has more recently contributed a series of reports describing the further use of this reaction in synthesis. Oxidation of the unsaturated amide 71 in methanolic acetonitrile afforded a substance 72 (equation 37) which could subsequently be converted into conformationally restricted peptide mimics99. Further, anodic oxidation of 73 resulted in intramolecular cyclization to afford 74 (equation 38), which could be converted into bicyclic reverse-turn peptidomimetics100. A similar intramolecular anodic cyclization of 75 into 76 (equation 39) was employed as the key step in total syntheses of the natural products (—)-A58365A and (+)-A58365B101. 

Toniolo C. Conformationally restricted peptides through short-range cyclizations. Int. J. Pept. Protein Res. 1990 35 287-300. 

Moeller and coworkers have made extensive use of the anodic a-alkoxylation of amides [27-31]. Much of their work has focused upon the synthesis of conformationally restricted peptide mimetics in an effort to ascertain the relationship between the bioactivity of the parent peptide and a specific conformer of it. The example illustrated in Scheme 8 portrays an exceptionally clever synthesis of 94, a key substance en route to the Phe-Pro building block 95 [28]. Both the electrooxidation and ring-forming metathesis (93 to 94) reactions are of special note. 

Cyclopropane amino acids are extremely interesting compounds, which have been found in nature. They present tremendous interest because of their biological activity and potential use in conformationally restricted peptides (peptide mimics)... 

There has been increased use of acrylate reagents with an a-nitrogen substituent, and the corresponding aza-annulation reaction products were a-amido 6-lactams, which represented an interesting class of conformationally restricted peptide analogs. Oxidation of the dihydropyridones that resulted from aza-annulation led to the corresponding pyridones. 

The copper (I) catalyzed cyclopropanation of amino acid protected pyrroles 37 with methyl diazoacetate proceeds smoothly to afford exclusively the exo-isomers 38 and 39, which were utilized as precursors to conformationally restricted peptides having a aminocyclopropane carboxylic acid <97SL202>. 

Calvo JC, Choconta KC, Diaz D et al. (2003) An alpha helix conformationally restricted peptide is recognized by cervical carcinoma patients sera. J Med Chem 46(25) 5389-5394 Cao L, van Rantwijk F, Sheldon R (2000) Cross-linked enzyme aggregates a simple and effective method for the immobilization of penidllin acylase. Otg Lett 2 1361—1364 Cao L, van Langen L, Sheldon R (2003) Immobilised enzymes carrier-bound or carrier free Curr Opin Biotech 14 387-394... 

S. F. Martin, C. J. Oalmann, and S. Liras, Tetrahedron, 49, 3521 (1993). Cyclopropanes as Conformationally Restricted Peptide Isosteres. Design and Synthesis of Novel Collagenase Inhibitors. 

Binding and Information Transfer in Conformationally Restricted Peptides (V. J. Hruby). 269... 

Binding and Information Transfer in Conformationally Restricted Peptides... 

An asymmetric approach to differentially substituted cw-1,2-diamino cyclohexanes also utilized the Curtius rearrangement. The chiral diamine products are components of biologically active small molecules and useful as conformationally restricted peptide-like scaffolds. y Amino acid 54 was prepared in enantiomerically pure form using asymmetric reductive amination and converted to phthaloyl-protected y -amino acyl azide 56. Curtius rearrangement, followed by addition of benzyl alcohol and further heating provided chiral c/5-1,2-diamine 57 with orthogonal A-protection. 

In this chapter the versatility of this amino acid resolution technology is further illustrated by some examples of recent resolutions and further synthetic transformations. Examples include the resolution of a-methyl-substituted amino acids, e.g., a-methylvaline, and their incorporation into a number of conformationally restricted peptides that tend to adopt P-bend or 3io-helix conformations. a-Methylphenylglycine was used to syntiiesize semisynthetic antibiotics. a-Methylphenylalanine was used as a building block for more stable aspartame-like sweeteners. a-Methyl-3,4-dichlorophenylalanine served as a building block for the antidepressant cericlamine, whereas a-phenylproline is a structural element of a nonpeptide substance P antagonist, selective for the NKj receptor. 

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