Chiral environments

Before leaving this biosynthetic scheme notice that PGE2 has four chirality cen ters Even though arachidomc acid is achiral only the stereoisomer shown m the equa tion IS formed Moreover it is formed as a single enantiomer The stereochemistry is controlled by the interaction of the substrate with the enzymes that act on it Enzymes offer a chiral environment m which biochemical transformations occur and enzyme catalyzed reactions almost always lead to a single stereoisomer Many more examples will be seen m this chapter... 

Although scientists have known since the time of Louis Pasteur (1) that optical isomers can behave differentiy in a chiral environment (eg, in the presence of polarized light), it has only been since about 1980 that there has been a growing awareness of the implications arising from the fact that many dmgs are chiral and that living systems constitute chiral environments. Hence, the optical isomers of chiral dmgs may exhibit different bioactivities and/or biotoxicities. 

Traditionally, chiral separations have been considered among the most difficult of all separations. Conventional separation techniques, such as distillation, Hquid—Hquid extraction, or even some forms of chromatography, are usually based on differences in analyte solubiUties or vapor pressures. However, in an achiral environment, enantiomers or optical isomers have identical physical and chemical properties. The general approach, then, is to create a "chiral environment" to achieve the desired chiral separation and requires chiral analyte—chiral selector interactions with more specificity than is obtainable with conventional techniques. 

Preparation of enantiomerically enriched materials by use of chiral catalysts is also based on differences in transition-state energies. While the reactant is part of a complex or intermediate containing a chiral catalyst, it is in a chiral environment. The intermediates and complexes containing each enantiomeric reactant and a homochiral catalyst are diastereomeric and differ in energy. This energy difference can then control selection between the stereoisomeric products of the reaction. If the reaction creates a new stereogenic center in the reactant molecule, there can be a preference for formation of one enantiomer over the other. 

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

Chiral cystallization of achiral N-heterocycles—generation of chirality without chiral environment 98YGK268. 

To achieve catalytic enantioselective cycloaddition reactions of carbonyl compounds, coordination of a chiral Lewis acid to the carbonyl functionality is necessary. This coordination activates the substrate and provides the chiral environment that forces the approach of a diene to the substrate from the less sterically hindered face, introducing enantioselectivity into the reaction. 

In another example of enantioselective distillation, it was the enantiomeric mixture to resolve itself which contributed to create a chiral environment. Thus, non-racemic mixtures of a-phenylethylamine were enantiomerically enriched by submitting to distillation different salts of this amine with achiral acids [199]. 

All enantioselective separation techniques are based on submitting the enantiomeric mixture to be resolved to a chiral environment. This environment is usually created by the presence of a chiral selector able to interact with both enantiomers of the mixture, albeit with different affinities. These differences in the enantiomer-selector association will finally result in the separation that is sought. 

We describe the situation by saying that the receptor provides a chiral environment for the substrate. In the absence of a chiral environment, the two red substituents are chemically identical, but in the presence of the chiral environment, they are chemically distinctive (Figure 9.18a). The situation is similar to what happens when you pick up a coffee mug. By itself, the mug has a plane of symmetry and is achiral. You could, if you wanted, drink from on either side of the handle. When you pick up the mug, however, your hand provides a chiral environment so one side becomes much more accessible and easier to drink from than the other (Figure 9.18b). 

Figure 9.18 (a) When a prochiral molecule is held in a chiral environment, the two seemingly identical substituents (red) are distinguishable, (b) Similarly, when an achiral coffee mug is held in the chiral environment of your hand, it s much easier to drink from one side than the other because the two sides of the mug are now distinguishable. 

Two methods are used in practice to obtain enantiomerically pure amino acids. One way is to resolve the racemic mixture into its pure enantiomers (Section 9.8). A more direct approach, however, is to use an enantioselective synthesis to prepare only the desired 5 enantiomer directly. As discussed in the Chapter 19 Focus Oil, the idea behind enantioselective synthesis is to find a chiral reaction catalyst that will temporarily hold a substrate molecule in an unsymmetrical environment. While in that chiral environment, the substrate may be more... 

Chiral environment (Section 9.14) Chiral surroundings or conditions in which a molecule resides. 

Chapter 9, Stereochemistry —A discussion of chirality at phosphorus and sulfur has been added to Section 9.12, and a discussion of chiral environments has been added to Section 9.14. 

Of course, the most practical and synthetically elegant approach to the asymmetric Darzens reaction would be to use a sub-stoichiometric amount of a chiral catalyst. The most notable approach has been the use of chiral phase-transfer catalysts. By rendering the intermediate etiolate 86 (Scheme 1.24) soluble in the reaction solvent, the phase-transfer catalyst can effectively provide the enolate with a chiral environment in which to react with carbonyl compounds. 

The two ways of introducing a chiral environment into the reaction medium are ... 

Provided electron transfer between the electrode and solute species is not interrupted by the coating, even electroinactive films can offer interesting applications. Thus, a chiral environment in the surface layer may impose stereoselectivity in the follow-up reactions of organic or organometallic intermediates. Furthermore, polymer layers may be used to obtain diffusional permeation selectivity for certain substrates, or as a preconcentration medium for analyzing low concentration species. 

Enantioselective electron transfer reactions are not possible in principle because the electron cannot possess chirality. Whenever the choice of enantiodifferentiation becomes apparent, it will occur in chemical steps subsequent (or prior) to electron transfer. Thus, enantioselectivities require a chiral environment in the reaction layer of electrochemical intermediates although asymmetric induction was report-... 

The enantioselective 1,4-addition addition of organometaUic reagents to a,p-unsaturated carbonyl compounds, the so-called Michael reaction, provides a powerful method for the synthesis of optically active compounds by carbon-carbon bond formation [129]. Therefore, symmetrical and unsymmetrical MiniPHOS phosphines were used for in situ preparation of copper-catalysts, and employed in an optimization study on Cu(I)-catalyzed Michael reactions of di-ethylzinc to a, -unsaturated ketones (Scheme 31) [29,30]. In most cases, complete conversion and good enantioselectivity were obtained and no 1,2-addition product was detected, showing complete regioselectivity. Of interest, the enantioselectivity observed using Cu(I) directly in place of Cu(II) allowed enhanced enantioselectivity, implying that the chiral environment of the Cu(I) complex produced by in situ reduction of Cu(II) may be less selective than the one with preformed Cu(I). 

SP Sephadex C-25 cation exchangers whose dextran support, itself composed of propane-sulfonate-functionalized cross-hnked a-o-glucopyra-noside units, provides the chiral environment. Thus chiral eluents are not always necessary and achiral solvents can be used for separation. However, in some cases, separation is improved using an eluent containing a chiral ion [13]. 

The carbon-carbon double bond that undergoes hydrogenation is remote from the modifier and no rate enhancement for the enantioselective process is to be expected. None was observed. Moreover, since the rate at the enantioselective sites is the same as that at other sites on the surface that experience no chiral environment and so give racemic product, the overall enantiomeric excess should be modest, as is the case To obtain higher... 

The pioneering work on enantioselective ruthenium olefin metathesis was carried out by Grubbs and co-workers in 2001 [69] (Fig. 3.23). Catalysts 55a-b and 56a-b were designed and prepared from C -symmetric NHC hgands with a combination of chiral backbone and mono-ortfto-substituted aryl side chains, a motif that was expected to form a chiral environment around the metal centre. 

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