Conformationally Constrained Structures

Insertion of two overlapping i, i + 4 lactam bridges in the terminally protected hexa-peptide Boc-Lys-Lys-Ala-Ala-Asp-Asp-OPac results in a highly conformationally constrained structure 27 (Scheme 16).[l52 CD spectra showed a rigid structure that exhibited only partial melting at high temperature, while NMR studies in TFE-d3/H20 revealed a predominantly a-helical structure, as judged by observed NOEs. 

CM Topham, A McLeod, E Eisenmenger, JP Overmgton, MS Johnson, TL Blundell. Erag-ment ranking in modelling of protein structure. Conformationally constrained environmental ammo acid substitution tables. J Mol Biol 229 194-220, 1993. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

The hemispherands, spherands, calixarenes, and related derivatives. A number of hosts for which the pre-organization criterion is half met (the hemispherands) (Cram et al., 1982) or fully met (the spherands) (Cram, Kaneda, Helgeson Lein, 1979) have been synthesized. An example of each of these is given by (251) and (252), respectively. In (251), the three methoxyl groups are conformationally constrained whereas the remaining ether donors are not fixed but can either point in or out of the ring. This system binds well to alkali metal ions such as sodium and potassium as well as to alkylammonium ions. The crystal structure of the 1 1 adduct with the f-butyl ammonium cation indicates that two linear +N-H - 0... 

Being conformationally constrained their popularity to determine three-dimensional structure and biological relationships has increased. " ... 

The design of our conformationally constrained aminoglycosides is based on the structural information available for the RNA-paromomycin complex [21-26]. It is known that positions 05m and N2i are hydrogen bonded within the ribosome bound state. Thus, in our analogs, this interaction has been replaced by either a direct covalent bond, as in 2, a two-methylene bridge, as in 3, or by a salt bridge, as in 4 (see Fig. 9). 

The transformation from spheres to cyhnders is a peculiar example for the self-adjustment of the molecular conformation. The switching shape can be regarded as an example for the principle of quasi equivalency established by A. Klug for the self-assembly of biomolecules and viruses [145] for the sake of an improved intermolecular packing, the molecules adopt a conformation different from the minimum energy one. This also demonstrates that shape control does not mean a fully constrained structure. Similar to biomolecules, the combination of flexible macromolecules and self-assembly principles is a powerful strategy for preparation of molecules with well-defined but switchable shape [23]. 

Unfortunately, direct Ugi reaction of 85 predominantly led to the formation of DHOPs (87) [172]. However, by applying a MCR-alkylation-MCR strategy, the Ugi products (88) could be isolated in high yields [173]. The obtained conformationally constrained peptidomimetics allow for unprecedented diversification and were ultimately evaluated for their turn-inducing properties, indicating an open turn structure for 88a (Fig. 27). 

This conformational preference in conjunction with the preference of the terminal amides to exist in an i-trans conformation constrains the system such that the terminal anthranilamide substituents are positioned above and below the plane of the molecule, resulting in a local helical structure. The helical antipodes experience a... 

The constrained bis(oxazolines) 9a and 9b can be constructed beginning with malononitrile 32 as shown by Ghosh and co-workers. Thus, treatment of 32 with anhydrous hydrochloric acid in dioxane, as shown by Lehn and co-workers, yielded imidate salt 33 (Fig. 9.9). Condensation of the imidate salt with commercially available (15,2/ )-l-aminoindan-2-ol afforded the conformationally constrained bis(oxazoline) inda-box 9a. Alkylation at the bridging methylene of 9a was carried out by Davies and co-workers.Treatment of 9a with lithium diisopropylamide followed by alkylation with methyl iodide afforded 9b. Alternatively, alkylation with diiodoalkanes incorporated ring systems at the bridging position (structures 34a-d). 

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 discovery of the norcardicins and monobactams demonstrated for the first time that a conformationally constrained bicyclic structure was not necessary for antibacterial activity of (3-lactams [12, 13]. In recent years, various natural and unnatural monocyclic-(3-lactams have been shown to exhibit high biological activity, suggesting that the biological activity of the particular ring is influenced by the type of substitution attached to the azetidin-2-one ring (Fig. 2). 

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