Steric blocking model explained

The effects of improved wettability, entropic repulsion, and sterical hindrance undoubtedly play a role in stabilizing dispersed solid particles by block or graft copolymers. However, since the dispersions of titanium dioxide in toluene stabilized by carboxylated styrene-butadiene block copolymers are so much more stable than dispersions stabilized by carboxylated homopolymers under otherwise identical conditions, we must assume that an additional factor comes into play when block copolymers are used. The model in Figure 1 is an attempt to explain this additional... 

The model in Scheme 11 explains the regioselectivity, enantioselectivity and diastereoselectivity of the reaction. In the radical cyclisation step the endo radical 28 is formed exclusively due to the high stability of the resulting benzyl radical. The approach of the alkyl radical in the complex 27 (+)-12 occurs from the sterically unhindered re face whereas the attack of the radical from the si face is blocked by the tetrahydronaphthalene shield. For the same reason the hydrogen abstraction step in the complex 28 (+)-12 takes place at the same face to form product trans-29 predominantly with high enantioselectivity. 

Moreover, a final 3D-QSAR model vahdation was done using a prospective study with an external test set. The 82 compounds from the data set were used in a lead optimization project. A CoMFA model gave an (cross validated) value of 0.698 for four relevant PLS components and a conventional of 0.938 were obtained for those 82 compounds. The steric descriptors contributed 54% to the total variance, whereas the electrostatic field explained 46%. The CoMSIA model led to an (cross vahdated) value of 0.660 for five PLS components and a conventional of 0.933. The contributions for steric, electrostatic, and hydrophobic fields were 25, 44, and 31%. As a result, it was proved that the basic S4-directed substituents should be replaced against more hydrophobic building blocks to improve pharmacokinetic properties. The structural and chemical interpretation of CoMFA and CoMSIA contour maps directly pointed to those regions in the Factor Xa binding site, where steric, electronic, or hydrophobic effects play a dominant role in ligand-receptor interactions. 

The regiospecificity of the lipoxygenase reaction may also be explained by assuming that the substrate is bound in one orientation and the free electron of the enzyme-bound fatty acid radical is localized on either C-1 or C-5 of the (1Z,4Z)-pentadienyl moiety. For the linoleyl radical this would be achieved if rotation around the C-ll-C-12 or C-lO-C-11 blocks delocalization of the free electron over the C-12-C-13 or C-9-C-10 -n-orbital respectively [41]. In yet another model the regiospecificity is achieved by the specific approach of dioxygen through steric interference of the enzyme such that a regio- (and stereo-) selective reaction takes place [62]. 

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