Asymmetric synthesis enantiomers

You will notice that the reaction products 23 and 24 are diastereomers, not enantiomers. Asymmetric synthesis can be achieved only when the possible transition states for reaction are diastereomeric because they then will have different energies and will lead to products at different rates. The larger the energy difference between diastereomeric transition states, the more stereochemical preference there will be for one chirality over the other. 

There are two different approaches for the production of enantiomers asymmetric synthesis and racemate resolution. The first, in special cases, allows a favourable production as costs are concerned, e.g. in case of the asymmetric hydrogenation of double bonds by use of optimized chiral transition metal complexes. In most cases, however, asymmetric syntheses, especially multi-step ones, are restricted to the laboratory scale. 

Enzyme-Catalyzed Asymmetric Synthesis. The extent of kinetic resolution of racemates is determined by differences in the reaction rates for the two enantiomers. At the end of the reaction the faster reacting enantiomer is transformed, leaving the slower reacting enantiomer unchanged. It is apparent that the maximum product yield of any kinetic resolution caimot exceed 50%. 

Kinetic Resolutions. From a practical standpoint the principal difference between formation of a chiral molecule by kinetic resolution of a racemate and formation by asymmetric synthesis is that in the former case the maximum theoretical yield of the chiral product is 50% based on a racemic starting material. In the latter case a maximum yield of 100% is possible. If the reactivity of two enantiomers is substantially different the reaction virtually stops at 50% conversion, and enantiomericaHy pure substrate and product may be obtained ia close to 50% yield. Convenientiy, the enantiomeric purity of the substrate and the product depends strongly on the degree of conversion so that even ia those instances where reactivity of enantiomers is not substantially different, a high purity material may be obtained by sacrificing the overall yield. 

The variety of enzyme-catalyzed kinetic resolutions of enantiomers reported ia recent years is enormous. Similar to asymmetric synthesis, enantioselective resolutions are carried out ia either hydrolytic or esterification—transesterification modes. Both modes have advantages and disadvantages. Hydrolytic resolutions that are carried out ia a predominantiy aqueous medium are usually faster and, as a consequence, require smaller quantities of enzymes. On the other hand, esterifications ia organic solvents are experimentally simpler procedures, aHowiag easy product isolation and reuse of the enzyme without immobilization. 

The importance of chemical syntheses of a-amino acids on industrial scale is limited by the fact that the standard procedure always yields the racemic mixture (except for the achiral glycine H2N-CH2-COOH and the corresponding amino acid from symmetrical ketones R-CO-R). A subsequent separation of the enantiomers then is a major cost factor. Various methods for the asymmetric synthesis of a-amino acids on laboratory scale have been developed, and among these are asymmetric Strecker syntheses as well. ... 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

A different approach to making chiral drugs is asymmetric synthesis. An optically inactive precursor is converted to the drug by a reaction that uses a special catalyst, usually an enzyme (Chapter 11). If all goes well, the product is a single enantiomer with the desired physiological effect In 2001, William S. Knowles, Ryogi Noyori, and K. Barry Sharpless won the Nobel Prize in chemistry for work in this area. 

In a special case of this type of asymmetric synthesis, a compound (47) with achiral molecules, but whose crystals are chiral, was converted by UV light to a single enantiomer of a chiral product (48). ... 

It is often possible to convert an achiral compound to a chiral compound by (1) addition of a chiral group (2) running an asymmetric synthesis, and (3) cleavage of the original chiral group. An example is conversion of the achiral 2-pentanone to the chiral 4-methyl-3-heptanone (50). In this case, >99% of the product was the (5) enantiomer. Compound 49 is called a chiral auxiliary because it is used to induce asymmetry and then is removed. 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

Valentine DJ (1984) Preparation of the enantiomers of compounds containing chiral phosphorus centers. In Morrison JD, Scott JW (eds) Asymmetric synthesis, vol 4. Academic Press, New York, chap 3... 

To date, direct asymmetric synthesis of optically active chiral-at-metal complexes, which by definition leads to a mixture of enantiomers in unequal amounts thanks to an external chiral auxiUary, has never been achieved. The most studied strategy is currently indirect asymmetric synthesis, which involves (i) the stereoselective formation of the chiral-at-metal complex thanks to a chiral inductor located either on the ligand or on the counterion and then (ii) removal of this internal chiral auxiliary (Fig. 4). Indeed, when the isomerization of the stereogenic metal center is possible in solution, in-... 

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

The novel phenomenon of converting racemic substrates into a single enantiomer of the product hy dynamic kinetic resolution (DKR) via racemization of the substrates has been a formidable challenge in asymmetric synthesis. Recently, DKR has been receiving increasing attention since it can overcome the limitations... 

Hong, C.Y, Kado, N., Overman, L.E. (1993) Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (—)- and (-f)-Dihydrocodeinone and (—)- and (-F)-Morphine. Journal of the American Chemical Society, 115, 11028-11029. 

The cyclooctapyrroles shown in Figure 55 appear predestined to form binuclear metal complexes since the loop-shaped conformation of these macrocycles exhibits two structurally identical, helical N4 cavities. Enantiomers of such complexes, which are presumably generally very stable towards racemization owing to the rigidity of the molecule imposed by the incorporation of the metal, are of interest as possible models for binuclear metalloenzymes and as potential catalysts in asymmetric synthesis. The first two ligands as well as their recently obtained palladium complexes601 were... 

The sequence detailed here provides 3-(S)-((tert-butyldiphenylsilyl)oxy)-2-butanone in high purity and on a preparative scale from inexpensive (S)-ethyl lactate. This optically active ketone should be a useful intermediate for the preparation of a variety of enantiomerically pure materials. It has been used in our laboratory for an asymmetric synthesis of (+)-muscarine3 and in the preparation of various other optically active tetrahydrofurans.4 Mitsunobu inversion of (S)-ethyl lactate followed by protection to provide 2-(R)-((tert-butyldiphenylsilyl)oxy)propanoate5 affords, by this method, ready access to the enantiomer of the title compound. 

As mentioned in Section 1.2, the presence of an asymmetric carbon is neither a necessary nor a sufficient condition for optical activity. Each enantiomer of a chiral molecule rotates the plane of polarized light to an equal degree but in opposite directions. A chiral compound is optically active only if the amount of one enantiomer is in excess of the other. Measuring the enantiomer composition is very important in asymmetric synthesis, as chemists working in this area need the information to evaluate the asymmetric induction efficiency of asymmetric reactions. 

Naturally occurring chiral compounds provide an enormous range and diversity of possible starting materials. To be useful in asymmetric synthesis, they should be readily available in high enantiomeric purity. For many applications, the availability of both enantiomers is desirable. Many chiral molecules can be synthesized from natural carbohydrates or amino acids. The syntheses of (+)-exo-brevicomin (66) and negamycin (67) illustrate the application of such naturally occurring materials. 

This chapter has provided a general introduction to stereochemistry, the nomenclature for chiral systems, the determination of enantiomer composition and the determination of absolute configuration. As the focus of this volume is asymmetric synthesis, the coming chapters provide details of the asymmetric syntheses of different chiral molecules. 

The previous section discussed chelation enforced intra-annular chirality transfer in the asymmetric synthesis of substituted carbonyl compounds. These compounds can be used as building blocks in the asymmetric synthesis of important chiral ligands or biologically active natural compounds. Asymmetric synthesis of chiral quaternary carbon centers has been of significant interest because several types of natural products with bioactivity possess a quaternary stereocenter, so the synthesis of such compounds raises the challenge of enantiomer construction. This applies especially to the asymmetric synthesis of amino group-substituted carboxylic acids with quaternary chiral centers. 

The study of Fuji et al. shows that the addition of lithium enolate 75 to ni-troamine 74 is readily reversible quenching conditions are thus essential for getting a good yield of product 76. An equilibrium mixture of the adducts exists in the reaction mixture, and the elimination of either the prolinol or lactone moiety can take place depending on the workup condition (Scheme 2-34). A feature of this asymmetric synthesis is the direct one pot formation of the enantiomer with a high ee value. One application of this reaction is the asymmetric synthesis of a key intermediate for indole type Aspidosperma and Hun-teria alkaloids.68 Fuji69 has reviewed the asymmetric creation of quaternary carbon atoms. 

The modes of addition shown in Figure 6.3 are similar to those shown in Figure 6.2 and are consistent with extant mechanistic work [6,9] they accurately predict the identity of the slower reacting enantiomer. It should be noted, however, that variations in the observed levels of selectivity as a function of the steric and electronic nature of substituents and the ring size cannot be predicted based on these models alone more subtle factors are clearly at work. In spite of such mechanistic questions, the metal-catalyzed resolution protocol provides an attractive option in asymmetric synthesis. This is because, although the maximum possible yield is 40 %, catalytic resolution requires easily accessible racemic starting materials and conversion levels can be manipulated so that truly pure samples of substrate enantiomers are obtained. 

Before conducting an asymmetric synthesis, one needs to ensure that one is able to separate both enantiomers of the desired compound. The racemate (RS, 50% of each enantiomer) needs to be synthesized in order to study the different possibilities of differentiating each enantiomer. 

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