Synthesis of chiral molecules

Fluoxetine, commonly known as Prozac , as a racemic mixture is an antidepressant drug, but has no effect on migraine. The pure 5-enantiomer works remarkably well in the prevention of migraine and is now under clinical evaluation. 

On many occasions, a reaction carried out with achiral reactants results in the formation of a chiral product. In the absence of any chiral influence, the outcome of such reactions is the formation of a racemic form. For example, hydrogenation of ethylmethylketone yields a racemic mixture of 2-hydro-xybutane. 

Similarly, the addition of HBr to 1-butene produces a racemic mixture of 2-bromobutane. 

A reaction that produces a predominance of one enantiomer over other is known as enantioselective synthesis. To carry out an enantioselective reaction, a chiral reagent, solvent, or catalyst must assert an influence on the course of the reaction. In nature, most of the organic or bioorganic reactions are enantioselective, and the chiral influence generally comes from various enzymes. Enzymes are chiral molecules, and they possess an active site where the reactant molecules are bound momentarily during the 

Lipase catalyses a reaction called hydrolysis, where esters react with a molecule of water and are converted to a carboxylic acid and an alcohol. 

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The pharmaceutical industry has been giving increased attention to homogeneous asymmetric hydrogenation for the synthesis of chiral molecules due to significant improvements in this technology (1). We recendy synthesized a chiral a-amino acid intermediate using Et-DuPhos-Rh catalyst, obtaining enantiomeric pmities (EP) of... 

Oxidoreductases, which catalyze oxidation-reduction reactions and are acting, for example, on aldehyde or keto groups. An important application is the synthesis of chiral molecules, especially chiral PFCs (22 out of 38 chiral products produced on large industrial scale are already made using biocatalysis). 

Enantioselective synthesis is a topic of undisputable importance in current chemical research and there is a steady flow of articles, reviews and books on almost every aspect involved. The present overview will concentrate on the application of solid chiral catalysts for the enantioselective synthesis of chiral molecules which are a special class of fine chemicals. Included is an account on our own work with the cinchona-modified Pt catalysts. Excluded is the wide field of immobilized versions of active homogeneous complexes or of bio-catalysts. During the preparation of this survey, several reviews have been found to be very informative [1-14]. 

One of the most exciting features of these intermolecular C-H insertions is that the functionalization of unactivated C-H bonds can be efficiently achieved, leading to new strategies for the synthesis of chiral molecules. An example of this is the asymmetric synthesis of (+)-indatraline (13) shown in Eq. (6) [19]. Rh2(S-DOSP)4 catalyzed reaction of 11 with 1,4-cydohexadiene generated 12 in 93% ee, which was then readily converted to (+)-indatraline (13). 

Enzymes provide catalytic pathways which are often superior to non-enzymic routes. The advantage of enzymes can overcome their disadvantages as relatively unstable species which workbest in aqueous solution. In synthetic processes, the selectivity of the enzyme-catalysed process is not approached by chemical catalysis particularly regarding the enantioselective synthesis of chiral molecules. Furthermore, protective group chemistry is often not required in enzyme-catalysed reactions. 

The biggest impact of homogeneous catalysis is in the synthesis of chiral molecules, especially of enantiomerically pure products. Most natural products are chiral, and in many cases different enantiomers exhibit radically different properties. Moreover,... 

Asymmetric synthesis using nonchiral crystals was also performed. See [lb] and (a) Chenchaiah, P. C., Holland, H. L., and Richardson, M. F. (1982) A new approach to the synthesis of chiral molecules from nonchiral reactants. Asymmetric induction by reaction at one surface of a single (nonchiral) crystal, J. Chem. Soc. Chem. Commun., 436-437. (b) Chenchaiah, P. C., Holland, H. L., Munoz, B., and Richardson, M. F. (1986) Synthesis of chiral molecules from non-chiral crystals by controlled reaction at a single surface, J. Chem. Soc. Perkin Trans. 2, 1775-1777. 

Enzymes often prove to be the catalyst of choice for numerous transformations, and their prowess is particularly noteworthy for the synthesis of chiral molecules. The ability of biocatalysts to impart chirality through conversion of prochiral molecules or by transformation of only one stereoisomer of a racemic mixture stems from the inherent chirality of enzymes. As noted in the introduction to this book (Chapter 1), the chiral drug market is increasing, partly as a result of the need to produce single enantiomers as advocated by the U.S. Food and Drag Administration.1 The ability to extend the patent life of a drug through a racemic switch also plays a role in this increase. An example of a racemic switch is Astra Zeneca s Esomeprazole, a proton pump inhibitor (see Chapter 31).2... 

A wide variety of substituted y-butyrolactones can be prepared directly from olefins and aliphatic carboxylic acids by treatment with manganic acetate. This procedure is illustrated in the preparation of 7-( -OCTYL)-y-BUTYROLACTONE. Methods for the synthesis of chiral molecules are presently the target of intensive investigation. One such general method developed recently is the employment of certain chiral solvents as auxiliary agents in asymmetric synthesis. The preparation of (S.SM+H, 4-BIS(DIMETHYLAMINO)-2,3-DIMETHOXY-BUTANE FROM TARTARIC ACID DIETHYL ESTER provides a detailed procedure for the production of this useful chiral media an example of its utility in the synthesis of (+)-(/ )-l-PHENYL-l-PEN-TANOL from benzaldehyde and butyllithium is provided. 

L-dopa has one chiral center. Until the 1970s, only enzymes could produce chiral molecules. In the 1970s, workers at Monsanto developed the first nonbiological cataly.st for the synthesis of chiral molecules. The Monsanto group shnv etl tluit catalj sis of the type ... 

Many biotransformations are difficult to achieve by conventional synthesis. A classical example is the synthesis of chiral molecules. 

We highlight here a few studies in which the synthesis of chiral molecules has been achieved through the use of organic crystals in the hopes that this will prove a useful incentive and review. The reported studies fall into two natural categories. In the one case one starts with racemic mixtures or optically inactive compounds, crystallize these materials into chiral crystals and finally by subsequent reactions, trap this chirality in the final chemical products. In the second category one forms host-guest inclusion compounds in which the host is already an optically resolved compound. This in turn leads to the formation of optically active guest molecules. 

The synthesis of chiral molecules in laboratories results in the formation of a racemic mixture, an equal percentage mixture of both enantiomers. The extraction of enantiomers from racemic mixtures is almost impossible because of the identical physical and chemical properties of the enantiomers. Racemic mixtures are optically inactive, as they contain equal amounts of the D and L isomers. Some big organic molecules may contain more than one asymmetric carbon atom in their structure. An increasing number of asymmetric carbon atoms (n) increases the number of enantiomers by a factor of 2n. 

The examples given above show that biocatalysis is used on an industrial scale (100 kg to ton amounts) for the synthesis of chiral molecules. Both true asymmetric synthesis and the resolution of racemates are employed to produce compounds that are difficult or ineffident to synthesize by purely chemical means. All of the processes described use both chemical steps and one or more biocatalyt-... 

Asymmetric synthesis of chiral molecules by any type of technology has always been a central theme in organic chemistry and is, furthermore, of vital and fundamental interest for understanding chiral biology in the life sciences. In addition chirality is a key factor in the interaction of man-made new molecules with biopolymers from nature and therefore the mode of action of each enantiomer in a racemic mixture is of enormous practical importance. 

When it became clear that the two IS-enantiomers of metolachlor were responsible fijr most of the biological activity (see Fig. 1), there was the obvious challenge of finding a chemically and economically feasible production process for the active stereoisomers. Many methods allow the enantioselective synthesis of chiral molecules (that is the preferential formation of one enantiomer instead of the usual racemate). However, the selective preparation of S-metolachlor was a formidable task, due to the very special structure and properties of this molecule and also because of the extremely efficient production process for the racemic product as described above. During the course of the development efforts, the following minimal requirements evolved for a technically viable catalytic system ee S80%, substrate to catalyst ratio (s/c) >50 000 and turnover fi-equency (tof) >10 000 h" . 

Desymmetrization is the modification of a symmetric object that results in the loss of symmetry elements. When coupled with the catalytic asymmetric process, it provides an efficient method for enantioselective synthesis of chiral molecules with multiple stereogenic centers [116]. 

The synthesis of chiral molecules is a real challenge. There are, at least, three different approaches. 

Tartaric acid is an inexpensive and readily available chiral starting material for the synthesis of chiral molecules. In a well-known prostaglandin synthesis, the (S,S)-tartaric acid enantiomer was used to prepare the chiral diol in several steps. The chiral diol was isolated as a synthetic intermediate, and the following reagents are used. Draw the structures of synthetic intermediates A and B. 

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