Introducing Stereoisomers

Characteristically, metal ions form complexes that can exist as several isomers. This is a consequence of the stereochemistry, resulting from high numbers of ligands, adopted by most metal complexes. The best known examples of isomerism in complexes are geometrical isomers (such as cis and trans isomers), but these are not the sole type. We can, following a traditional approach, divide the area into two classes constitutional (or structural) isomerism and stereoisomerism. 

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In Chapter 3 another type of isomerism called stereoisomerism, will be introduced Stereoisomers have the same constitution but differ m the arrangement of atoms m space... 

At this point, it is worth introducing stereoisomers. These are isomeric molecules that have the same molecular formula and hence the same sequence of bonded atoms. However, they differ in the three-dimensional orientation of their constituent atoms. For example, consider the example of the antiarrhythmic drug sotalol. Both d-sotalol and I-sotalol isomers affect 4, that influences cardiac repolarization, but only the I-isomer has beta-blocking effect. Another example is warfarin. The S-isomer is three to five times more potent than the R-isomer, and they are metabolized by different cytochrome pathways, an influence that contributes to variable response and toxicity between batches of the drug and ethnic populations. 

When a bidentate phosphine is used as a ligand for the reaction of J-keto esters or /i-diketones, no dimerization takes place. Only a 2-butenyl group is introduced to give 68[49,62], Substituted dienes such as isoprene, 1,3-cyclohexa-diene, and ocimene react with carbon nucleophiles to give a mixture of possible regio- and stereoisomers of 1 1 adducts when dppp is used as a ligand[63,64]. 

Disubstituted cyclopropanes exemplify one of the simplest cases involving stabil ity differences between stereoisomers A three membered ring has no conformational mobility so the ring cannot therefore reduce the van der Waals strain between cis sub stituents on adjacent carbons without introducing other strain The situation is different m disubstituted derivatives of cyclohexane... 

It is possible to introduce substituents that can influence the conformational equilibria to favor a particular product. In the reactions shown below, the addition of the trimethylsilyl substituent leads to a single stereoisomer in 85% yield, whereas in the unsubstituted system two stereoisomers are formed in ratios from 4 1 to 8 1.124... 

Similarly, the 2,8,10-triene 3a gives a mixture of four isomers, but introduction of a TMS group as in 3b gives a single stereoisomer in 89% yield. The reason for the improved stereoselectivity is that the steric effect introduced by the TMS substituent favors a single conformer. 

In Entry 4 the silyl group appears to introduce a controlling steric factor, leading to the observed stereoisomer. The unsubstituted terminal alkyne, which reacts through the dianion, gives the alternate isomer. 

The synthesis in Scheme 13.49 features use of an enantioselective allylic boronate reagent derived from diisopropyl tartrate to establish the C(4) and C(5) stereochemistry. The ring is closed by an olefin metathesis reaction. The C(2) methyl group was introduced by alkylation of the lactone enolate. The alkylation is not stereoselective, but base-catalyzed epimerization favors the desired stereoisomer by 4 1. 

Information about the stereochemical course followed by a particular reaction can also provide useful insight into its mechanism, and may well introduce stringent criteria that any suggested mechanistic scheme will have to meet. Thus the fact that the base-catalysed bromination of an optically active stereoisomer of the ketone (13)... 

The dissection of a molecular model into those components that are deemed to be essential for the understanding of the stereochemistry of the whole may be termed factorization (9). The first and most important step toward this goal was taken by van t Hoff and Le Bel when they introduced the concept of the asymmetric carbon atom (10a, 1 la) and discussed the achiral stereoisomerism of the olefins (10b,lib). We need such factorization not only for the enumeration and description of possible stereoisomers, important as these objectives are, but also, as we have seen, for the understanding of stereoselective reactions. More subtle differences also giving rise to differences in reactivity with chiral reagents, but referable to products of a different factorization, will be taken up in Sect. IX. 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

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