Stereochemical interactions

Only the S-enantiomer, the teratogenic form, fits properly into the major groove of the double helix and binds to the polyG sequences. It seems that a very specific stereochemical interaction may be necessary for this toxic effect to occur. 

Two distinct tendencies can be recognized in the literature dealing with diastereo-selective reactions on metal complexes. On one side, stability differences are determined on the base of equilibrium data or product ratios. Inert cobalt(III)-complexes play a large part in this investigation. The procedures and the methods used in these investigations correspond to those already known in coordination chemistry. The aim of these studies is a better understanding of stereochemical interactions in the coordination sphere of metal complexes. The nature of ligand molecules is not modified in the systems studied. These reactions correspond to the first step of the scheme shown in Fig. 1. 

First of all, the reaction of the enantiomeric 1,2-propanediols will be discussed because, quite apart from their unique stereochemical interaction with the enzyme, two important discoveries were made during a detailed investigation of the way they are transformed. 

With 1,4-diketones the distribution of the reduction products is dependent on the stereochemical situation of the two carbonyl functions. In acyclic derivatives, with no stereochemical interaction between the two carbonyl functions, the ketone groups are independently reduced to give methylene products in the usual manner. On the other hand, cyclic 1,4-diketones react differently. For example, cyclohexane-1,4-dione (22) suffers ring opening to give hexane-2,5-dione and hex-5-en-2-one derivatives, and products of further reduction are also detectable (equation 11). A 1,4-diketone (23) in which the two carbonyls are stereochemically close, gave the diketone (24) under relatively mild conditions (Zn/AcOH, 25 C), formed by the same C—C bond cleavage as seen in cyclohexane-1,4-dione. Under Clemmensen conditions this derivative was then converted to cyclobutane-1,4-diol (25 equation 12) in 98% yield, which is closely related to the aforementioned cyclopropanediol intermediate. ... 

Stereochemical interactions in ammonium dications, hypervalent diammonium cation-radicals and ammonium radicals. A B3-MP2 computational study74... 

Enzymes frequently require coenzymes for optimum activity. The coenzymes are usually vitamins and cofactors, invariably—electrolytes such as mono- and divalent metallic ions (e.g., K+, Na+, Ca+2, Mg+2, Zn+2, and Fe+2). These coenzymes activate different enzymes by various means of complexation and stereochemical interactions. A detailed consideration of the mechanisms involved is not within the scope of this discussion. It can be stated, however, that such ions may affect enzymes in one of two ways. Either direct interaction induces changes in the conformation or a charge on the enzyme, or interaction of the cation with an enzyme-inhibiting substance, prevents or minimizes the deactivation. 

The stereochemical interaction of the classical ion 159 with the solvent should not be determined by the ion geometry since it is symmetrical. The participation of the solvent and the shielding by the leaving group should lead to some net inversion of the configuration if the solvolysis proceeds via the classical ion 159. 

To these requirements the alkaloids of the cinchona group correspond moderately well owing to the their peculiar structure. The quinoline group of the Cnd molecule provides strong adsorption of the modifier on the surface of Pt while the stereochemically important part of molecule provides energetic and stereochemical interactions with the pyruvate molecule through the N- atom of quinuclidine ring. 

In the future, the choice between developing the racemate of a chiral drug versus single enantiomers will largely depend on a critical evaluation of their chiral characteristics with respect to their pharmacodynamic, pharmacokinetic, and toxicological effects. The potential for stereoselectivity in skin permeation due to stereochemical interactions between chiral drug, chiral excipients, and the biomembranes has generally been overlooked. Nevertheless, extrapolation of enantioselectivity in the permeation of enantiomers from in vitro data to in vivo behavior (permeation, disposition, and efficacy) is important and should be carried out carefully. 

Fig. 23.9 Distribution analysis of the entries contributing to the estimation of the methyl groups at position 4 of podocarpane. Bottom trace stereochemical effects are ignored leading to a useless mean value around 28 ppm (small triangle) a total number of 34 reference data contribute to this mean value. Trace A and B Utilization of stereochemical interactions separates the 34 reference data into two distinct sets of chemical shift values leading to a correct prediction for the axial and equatorial methyl group.

Although the free-radical polymerization of MMA typically exhibits a syndiotactic bias (rr triad content = 60%-70%), it has long been known that the stereochemical interactions between the chain-end radical and vinyl monomers in free-radical polymerization can be modified by using chiral protecting groups. For example, the 80 °C AIBN-initiated polymerization (AIBN = 2,2 -azobisisobutyronitrile) of oxazolidine acrylamides based on valine and t rt-leucine ultimately yields highly isotactic (92% m dyad content) poly(acrylic acid) and PMA after chemical modification (Scheme 23.23). " ... 

The 3D conformation also creates binding site for affinity interactions [85]. Affinity results from the same basic physico-chemical interactions (ionic, hydrophobic, hydrogen bonding), but only when certain functional groups are arranged in a particular stereochemical interaction (fig. 7). The arrayed... 

When a chiral solute dissolves in a chiral solvent then a stereochemical interaction must be involved. The expense of using a chiral material as a bulk solvent for NMR determination of enantiomeric purity is rarely justified. A solvating agent is added in between 1 to 10 mole equivalents to a solution of the solute enantiomers in an achiral bulk... 

This effect is attributed to the increased microenvironmental polarity around the sensitizer chro-mophore that stabilizes the exciplex or contact ion pair in nonpolar solvents. As a result of this effect, the stereochemical interaction between the sensitizer and the substrate is more intimate. Because significant enantioselectivities were only observed for dimer 44, an independent cyclodimerization pathway to 44 via an exciplex or contact ion pair of cyclohexadiene and the chiral sensitizer was suggested. Dimer 45 gave much lower ee values even at low temperatures, but the product chirality was inverted within the tested temperature range in favor of enantiomer ent-A5. Similar temperature switching of product chirality has been reported in the enantiodifferentiating photoisomerization of cycloalkenes and in the polar addition of alcohols to 1,1-diphenylalkenes. This effect has been rationalized by a non-zero differential activation entropy of the same sign as the differential activation enthalpy. 

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