Conformational restriction steric effects

Textbook discussions of the steric effects of side chains on backbone conformation convey the impression that, except for glycine and proline, all side chains restrict the allowed range of phi and psi to approximately the same extent. If this were true, encoding of long-range structure by local steric repulsion would seem unlikely. 

Various diastereomeric di-, tri-, and tetrapeptides that carry the sterically demanding trifluoromethyl group instead of the natural a-proton at different positions within these short peptide sequences have been designed, and their stability towards enzymatic hydrolysis has been investigated. The structures of the a-trifluoromethyl (aTfm)-substituted amino acids are shown in Scheme 1. From these studies we gained valuable information on how a-trifluoromethyl-substi-tuted peptides may interact with proteins. The aTfm amino acids used in this study combine the conformational restrictions [49-52] of C -dialkylation with the unique stereoelectronic properties of the fluorine atom and have shown interesting effects on peptide-enzyme interactions [53,54]. 

Bond angle constraint aided by solvophobic effect Fig. 15.1. Examples of polymers with conformational restriction due to steric and bond angle constraints. 

The fZj-selectivity has been attributed to be due to a propeller-like conformation of the stationary phenyl groups which, in the transition state, favours cw-oxaphosphetane formation [51]. Introducing 6>rr/io-substituents in the phenyl groups increases the steric pressure in the transition state and thus the fZj-selectivity. However, the sterically less restricting tris-furyl substituted phosphorus ylides also lead to high fZj-selectivities (see Section C.2.a) obviously, in addition to purely steric effects, polarity effects are also important. 

The observed high diastereofacial selectivity is attributable to conformational restriction at the allylic center in dienophile 20. The steric bulk of the sugar chain and the acetyl group effectively limit the C-3—C-4 rotamers to a single conformer, as shown in the following scheme. The diene attacks almost exclusively from the same side as the allylic oxygen atom fsi-face for the D-enonate 20), where the steric hindrance is lowest. 

The meso and dl forms of 9 were isolated with no stereochemical preference. Their structures were assigned through the study of the dynamic nuclear magnetic resonance spectra of the two compounds at various temperatures. The bond between the two moieties is only partially restricted at room temperature for one isomer (the dl), but is completely restricted at low temperature for both. The dimers are an interesting example of a situation where the normally favored conformation, anti, is forbidden by steric effects. Rotation in 50 was completely restricted at room temperature, but the rotational isomers could not be separated the C-13 N.M.R. spectrum of the mixture has 8 peaks. It is of interest that the bonding found in 7 (dotted line) has been observed in the alkaloid cimiciphytine, 8 (f 5) and that the bonding found in 9is present in the alkaloid chimonanthine, 51 ( t6). 

While the reaction is somewhat insensitive to the electronic effect of the substituent on the aryl group, it is very sensitive to any steric effects. The reaction of 2-o-tolylpyridine is very slow and yields little product due to restricted conformation. Nitrogen-containing heterocycles other than pyridine also undergo this ary-lation reaction. Some examples are shown above. In this interesting case of iron... 

More than 30 years ago Warshel proposed, on the basis of semiempirical simulations, an isomerization mechanism that could explain how this process can occur in the restricted space of the Rh binding pocket (Warshel 1976). Since two adjacent double bonds were found to isomerize simultaneously the mechanism reveal a so-called bicycle pedal motion. Due to the concerted rotation of two double bonds in opposite directions the overall conformational change is minimized and hence this mechanism was found to be space-saving. The empirical valence bond (EVB) method (Warshel and Levitt 1976) was used to compute the excited state potential energy surface of the chromophore during a trajectory calculation where the steric effects of the protein matrix were modeled by specific restraints on the retinal atoms. Since then, Warshel and his coworkers have improved the model employing better structural data and new computational developments (Warshel and Barboy 1982 Warshel and Chu 2001 Warshel et al. 1991). The main refinement of the bicycle pedal mechanism was that the simultaneous rotation of the adjacent double bonds is aborted at a twist of 40° and leads to the isomerization of only one bond (Warshel and Barboy 1982). 

Within the limits of experimental error PPG-L presents practically the same complex formation constants as the racemic PPG. From the table it can be seen that log 2 > equal to log p2 log/ i, is usually much smaller than logA i it very likely results from chain conformation restrictions and steric effects, as well as from variation of the electrostatic potential due to the binding of the metal ion on the neighboring unit. 

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