Chiral molecules stereoselective reactions

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

It is not easy to control the steric course of photoreactions in solution. Since molelcules are ordered regularly in a crystal, it is rather easy to control the reaction by carrying out the photoreaction in a crystal. However, molecules are not always arranged at an appropriate position for efficient and stereoselective reaction in their crystals. In these cases inclusion chemistry is a useful technique, as it can be employed to position molecules appropriately in the host-guest structure. Chiral host compounds are especially useful in placing prochiral and achiral molecules in suitable positions to yield the desired product upon photoirradiation. Some controls of the steric course of intramolecular and intermolelcular photoreactions in inclusion complexes with a host compound are described. 

As we have seen a stereoselective reaction is one in which there is a preponderance of one isomer irrespective of the stereochemistry of the reactant. The enzymatic reduction of pyruvic acid is stereoselective when the chiral molecules of the enzyme complexes with achiral pyruvic acid, they given a preponderance of one form of pyruvic acid-enzyme complex which then gives a single form of lactic acid. 

Another aspect of the chemical properties of mixmres of enantiomers has been reported by Wynberg and Feringa in 1976. These authors have smdied some dia-stereoselective reactions on chiral molecules (such as the LiAlH4 reduction of camphor) in the absence of chiral auxiliaries. They found that the product distribution was significantly different if the substrate was enantiopure or racemic. Similarly, it is known that reduction of enantiopure or racemic camphor by K/liquid NH3 gives rise to different isobomeol/bomeol ratios, a detailed mechanistic analysis has been done by Rautenstrauch. °... 

In retrospect, it seems unfortunate that in 1971 Morrison and Mosher8 generalized the definition, while keeping the term, an asymmetric synthesis is a reaction in which an achiral unit in an ensemble of substrate molecules is converted by a reactant into a chiral unit in such a manner that the stereoisomeric products arc produced in unequal amounts ( Footnote The substrate molecule must have either enantiotopic or diastereotopic groups or faces) . Obviously the phrase "an achiral unit in an ensemble of substrate molecules is too inexact and requires a great deal of additional explanation, which was partially given by the footnote (note that molecule, i.e., singular, was used ). Currently, the Morrison-Mosher term appears to be equivalent to stereoselective reaction. Unfortunately, this term was only defined in the modem sense by Izumi in 1971, i.e., in the same year the Morrison-Mosher definition was published. 

Stereoselective catalysis using biocatalysts (e.g. enzymes) and also of rationally designed small chiral molecules, deals essentially with the same principle the spatial and selective docking of guest molecules to a chiral host molecule to form complementary interactions to form reversible transient molecule associates (see the specific sections in this volume). The enantiomeric excess of a certain reaction and hence the result will be determined by the degree of chiral discrimination. Along the same theoretical lines the concepts of protein (enzyme, antibody, etc.) mimicks via imprinted" synthetic polymers should be mentioned and will be discussed further. 

Stereospecificitv. Rate accelerations are only one aspect of enzyme catalyzed reactions. More important for practical applications are the exacting regio- and stereoselectivity displayed by biocatalysts. Since antibodies are chiral molecules, they might be expected to exert considerable control over reactions they promote. In fact, an antibody-catalyzed lactonization reaction was recently reported to be stereospecific (19). Not surprisingly, experiments with racemic chorismate establish that the antibodies with chorismate mutase activity also exhibit high enantioselectivity Q7). 

A chiral substance is enantiopure or homochiral when only one of two possible enantiomers is present. A chiral substance is enantioenriched or heterochiral when an excess of one enantiomer is present but not to the exclusion of the other. If the desired product is an enantiomer, the reaction needs to be sufficiently stereoselective even when atom economy is 100%. For the biological usage we almost need one enantiomer and in high purity. This is because when biologically active chiral compounds interact with its receptor site which is chiral, the two enantiomers of the chiral molecule interact differently and can lead to different chemistry. For example, one enantiomer of asparagines (1.37) is bitter while the other is sweet. As far as medicinal applications are concerned, a given enantiomer of a drug may be effective while the other is inactive or potentially harmful. For example, one enantiomer of ethanbutol (1.38) is used as antibiotic and the other causes blindness. 

There must be enantiopure chiral information in the stereoselective step. This can be achieved either by using covalent attachment to one of the substrates (stereoselective auxiliary-based methods) or by creating a complex that is cleaved after the stereoselective elementary step under the reaction conditions and reused for the next molecule (stereoselective catalytic methods). Substrate control is observed when the substrates themselves are chiral,... 

CCCs may obtain chiral compounds by classical resolution, kinetic resolution using chemical or enzymatic metlrods, biocatalysis (enzyme systems, whole cells, or cell isolates), fermentation (from growing whole microorganisms), and stereoselective chemistry (e.g., asymmetric reduction, low-temperature reactions, use of chiral auxiliaries). CCCs may also be CCEs by capitalizing on a key raw material position and going downstream. Along with companies manufacturing chiral molecules primarily for other purposes, such as amino acid producers, these will be the key sources for the asymmetric center. 

For the purposes of this treatise, the definition of asymmetric synthesis is a modification of that proposed by Morrison and Mosher [1] and as such will be applied to stereospecific reactions in which a prochiral unit in either an achiral or a chiral molecule is converted, by utility of other reagents and/or a catalytic antibody, into a chiral unit in such a manner that the stereoisomeric products are produced in an unequal manner. As such, the considerable body of work devoted to antibody-catalysis of stereoselective reactions including chiral resolutions, isomerizations and rearrangements are considered to be beyond the scope of this discussion. For information regarding these specific topics and more general information regarding the catalytic antibody field the following papers... 

In addition to the physicochemical factors that affect xenobiotic metabolism, stereochemical factors play an important role in the biotransformation of drugs. This involvement is not unexpected, because the xenobiotic-metabolizing enzymes also are the same enzymes that metabolize certain endogenous substrates, which for the most part are chiral molecules. Most of these enzymes show stereoselectivity but not stereospecificity in other words, one stereoisomer enters into biotransformation pathways preferentially but not exclusively. Metabolic stereochemical reactions can be categorized as follows substrate stereoselectivity, in which two enantiomers of a chiral substrate are metabolized at different rates product stereoselectivity, in which a new chiral center is created in a symmetric molecule and one enantiomer is metabolized preferentially and substrate-product stereoelectivity, in which a new chiral center of a chiral molecule is metabolized preferentially to one of two possible diastereomers (87). An example of substrate stereoselectivity is the preferred decarboxylation of S-a-methyIdopa to S-a-methyIdopamine, with almost no reaction for R-a-methyIdopa. The reduction of ketones to stereoisomeric... 

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