Conformationally constrained amino 8-substituted

The conjugate addition of activated nitrogen nucleophiles, such as hydroxylamine and hydrazine derivatives, to a,/3-unsaturated bicyclic lactam 284 gave the corresponding /3-amino product 285 in good yield and excellent diastereoselectivity. These products can be manipulated to afford enantiopure /3-aminopyrrolidinones of potential application as conformationally constrained, substituted glutamate templates (Equation 45) <2001J(P1)2997>. 

Potent inhibitors of aspartyl proteases have been prepared by incorporating hydroxy-methylene transition-state analogues modified in the a-position. The a-methylene moiety is either functionalized by a heteroatom 16,71 72 or it is dihalogenated)15,73,74 Alkyl substituents in that position are found in several residues present in compounds of natural origin, such as dolaproine (8) in dolastatin 10 and 4-amino-3-hydroxy-2-methylpentanoic acid (9) in bleomycin D (Scheme 1). This position is also substituted in synthetic, conformationally constrained six-membered-ring analogues)75 77 ... 

Microwave-assisted Diels-Alder reactions of 9-substituted anthracenes with 2-acetamidoacrylate in DMF generate conformationally constrained bicyclic bisaryl a-amino acid derivatives with high regioselectivity.138 The Sc(OTf)3-catalysed Diels-Alder reaction of anthracenes with methyl vinyl ketone does not proceed via an electron-transfer process from anthracenes to the MVK-Sc(OTf)3 complex.139 (-)-(/ )-9-(l,2-Dimethoxyethyl)anthracene has been used as a chiral template in the Diels-Alder/retro-Diels-Alder sequence for the synthesis of a,j3-unsaturated lactams.140... 

Ornstein, P.L., Augenstein, N.K., and Arnold, M.B., Stereoselective synthesis of 6-substituted decahy-droisoquinoline-3-carboxylates. Intermediates for the preparation of conformationally constrained acidic amino acids, J. Org. Chem., 59, 7862, 1994. 

Topham, C.M., McLeod, A., Eiserunenger, F., Overington, J.P., Johnson, M.S., et al. (1993) Fragment ranking in modelling of protein structure. Conformationally constrained environmental amino acid substitution tables. J. Mol. Biol. 229 194-220. 

Blundell,/. Mol. Biol.,229,194 (1993). Fragment Ranking in Modeling of Protein Structure Conformationally Constrained Environmental Amino Acid Substitution Tables. 

The P-tetralin amino acid induces the a-helical conformation by fixing the torsional angles along the peptide backbone at about -60° (< >) and -50° ( p).109 P-Tetralin amino acids may be regarded as cyclic-constrained phenylalanine analogues. As shown in Section II.A, this class of unnatural amino acids is known to stabilize distinct conformations in peptides since the two substituents at the a-cen-ter restrict the available conformational space. Cyclic a,a-dialkylated glycines and a-substituted alanines preferentially adopt a-helical conformations.205... 

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. 

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