The Synthesis of Chiral Molecules

In a racemic mixture the effect of each molecule of one enantiomer on the circularly-polarized beam cancels the effect of molecules of the other enantiomer, resulting in no net optical activity. 

The racemic form of a sample is often designated as being ( ). A racemic mixture of (/ )-(—)-2-butanol and ( S )-(+)-2-butanol might be indicated as 

A sample of an optically active substance that consists of a single enantiomer is said to be enantiomerically pure or to have an enantiomeric excess of 100%. An enantiomerically pure sample of (5)-(+)-2-butanol shows a specific rotation of +13.52 ([a]o +13.52). On the other hand, a sample of (5)-(+)-2-butanol that contains less than an equimolar amount of (/ )-(—)-2-butanol will show a specific rotation that is less than +13.52 but greater than zero. Such a sample is said to have an enantiomeric excess less than 100%. The enantiomeric excess (ee), also known as the optical purity, is defined as follows  

The enantiomeric excess can be calculated from optical rotations  

Let us suppose, for example, that a mixture of the 2-butanol enantiomers showed a specific rotation of +6.76. We would then say that the enantiomeric excess of the (5)-(+)-2-butanol is 50%  

---

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). 

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). 

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-... 

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. 

Mario Betti, a highly skilled chemist in organic synthesis, possessed great familiarity with the synthesis of chiral molecules, a field that he had cultivated since... 

Recent developments in o-aminopeptidases, racemases, and oxidases and their application in the synthesis of chiral molecules, microbial transformations of pentacyclic triterpenes, and yeast-mediated enantioselective biocatalysis are described. 

---