Chiral molecules synthesis

There are two possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials kinetic resolution and asymmetric synthesis [44,87], For both types of reactions there is one principle in order to make an optically active compound we need another optically active compound. A kinetic resolution depends on the fact that two enantiomers of a racemate react at different rates with a chiral reagent or catalyst. Accordingly, an asymmetric synthesis involves the creation of an asymmetric center that occurs by chiral discrimination of equivalent groups in an achiral starting material. This can be done either by enan-tioselective (which involves the reaction of a prochiral molecule with a chiral substance) or diastereoselective (which involves the preferential formation of a single diastereomer by the creation of a new asymmetric center in a chiral molecule) synthesis. 

G. M. Coppola andH. F. Asymmetric Synthesis Construction of Chiral Molecules Using Amino Acids, oBis N d y dn Sons, Inc., New York, 1987. 

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 introduction of a THP ether onto a chiral molecule results in the formation of diastereomers because of the additional stereogenic center present in the tetrahy-dropyran ring (which can make the interpretation of NMR spectra somewhat troublesome at times). Even so, this is one of the most widely used protective groups employed in chemical synthesis because of its low cost, the ease of its installation, its general stability to most nonacidic reagents, and the ease with which it can be removed. 

The use of carbohydrates as SM s has greatly expanded in recent years, and many cases have been summarized in a text by Hanessian.33 Several examples of such syntheses are indicated in Chart 15. Other commercially available chiral molecules such as a-amino acids or a-hydroxy acids have also been applied widely to the synthesis of chiral targets as illustrated by the last two cases in Chart 15. 

In the case of chiral molecules that are biologically active the desired activity almost always resides in only one of the enantiomers. The other enantiomer constitutes isomeric ballast that does not contribute towards the desired activity and may even exhibit unwanted side effects. Hence, there is a marked trend in pharmaceuticals, agrochemicals and flavours and fragrances towards the marketing of products as enantiomerically pure compounds. This, in turn, has generated a demand for economical methods for the synthesis of pure enantiomers (Sheldon, 1993a). 

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... 

In conclusion, we have learned a lot from studying chiral dendrimers, about the behavior of such large chiral molecules and about the contributions of the different building blocks to the whole structure. It remains a great challenge to rationalize the origin of the dramatic diastereoselectivity effects observed in the synthesis of certain chiral dendrimers. 

Scott, J. W., Enantioselective Synthesis of Non-Racemic Chiral Molecules on an Industrial Scale, 19, 209. 

Axial Chirality. For a system with four groups arranged out of the plane in pairs about an axis, the system is asymmetric when the groups on each side of the axis are different. Such a system is referred to as an axial chiral system. This structure can be considered a variant of central chirality. Some axial chiral molecules are allenes, alkylidene cyclohexanes, spiranes, and biaryls (along with their respective isomorphs). For example, compound 7a (binaphthol), which belongs to the class of biaryl-type axial chiral compounds, is extensively used in asymmetric synthesis. Examples of axial chiral compounds are given in Figure 1-5. 

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. 

Asymmetric synthesis refers to the conversion of an achiral starting material to a chiral product in a chiral environment. It is presently the most powerful and commonly used method for chiral molecule preparation. Thus far, most of the best asymmetric syntheses are catalyzed by enzymes, and the challenge before us today is to develop chemical systems as efficient as the enzymatic ones. 

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. 

In summary, asymmetric cycloadditions are powerful methods for the synthesis of complex chiral molecules because multiple asymmetric centers can be constructed in one-step transformations. Among them, reactions using chiral catalysts are the most effective and promising, and fruitful results have been reported in asymmetric Diels-Alder reactions. 

Hetero Diels-Alder reactions are very useful for constructing heterocyclic compounds, and many important chiral molecules have thus been synthesized. Although the retro Diels-Alder reaction does not itself involve the asymmetric formation of chiral centers, this reaction can still be used as an important tool in organic synthesis, especially in the synthesis of some thermodynamically less stable compounds. The temporarily formed Diels-Alder adduct can be considered as a protected active olefin moiety. Cyclopentadiene dimer was initially used, but it proved difficult to carry out the pyrrolytic process. Pentamethyl cyclopentadiene was then used, and it was found that a retro Diels-Alder reaction could easily be carried out under mild conditions. 

In 1997, the synthesis of 1,3-dideuteroallene 116, the lightest chiral molecule composed of stable elements, was reported utilizing enzymatic deuteration of 113 and thermal rearrangement of 115 to 116 (Scheme 4.30) [48]. 

That chiral molecules can be produced in a CPL field, either from achiral precursors by photo-activated synthesis or by preferential chiral photodestruction of a racemic mixture, is now well demonstrated and has been reviewed. [46] In all cases currently known, however, such processes have proved very inefficient. For example, asymmetric photochemical ring-closures of achiral helicene precursors induced by CPL have produced only about 0.2% e.e. in the products. Likewise, the CPL-induced photolysis of racemic camphor produced about 20 % e.e., but only after 99% photodestruction, and photolysis of D.L-glutamic acid produced only 0.22 % e.e. after 52 % photodecomposition. [71]... 

Until now I have discussed the methods of synthesis of optically active polymers from chiral monomers. As is well known in organic chemistry, it is also possible to produce chiral molecules with one preferred configuration by reaction of achiral molecules in the presence of some chiral influence. These reactions are known as asymmetric syntheses (36, 323-325) when an unsatuiated compound is involved, the term enantioface-differenriating reaction is often used (281). 

Richardson s synthesis of ( )-pentenomycin I displayed similar levels of conceptual elegance and was also very well received. In the mid-1970s, synthetic organic chemistry was far less refined that it is currently, and the synthesis of such chiral molecules as (—)-pentenomycin looked extremely formidable. However, Richardson was never put off by the degree of difficulty of any problem he faced he was always determined to overcome that problem. His account of the (—)-pentenomycin I synthesis reveals the many traps and snares in which he was successively caught during that synthetic endeavor, before the successful synthesis shown in Scheme 36 was eventually accomplished. 

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). 

The second aspect has already been addressed in relation to the term EPC synthesis. The meaning of the term enantiomerically pure compound is self-evident, i.e., a compound which consists only of superimposable chiral molecules. Unfortunately, such a compound is not likely to exist except as a concept. Realistically, the label pure, hence enantiomerically pure, can only be given according to the analytical tools available or applied. Thus, two terms are required one to describe the abstract concept, enantiomerically pure as defined above, the other to describe a real compound, as enantiopure according to the available or applied analytical methods. The term enantiopure has already been used by the Fluka Chemical Company, and was also recommended in one of the letters mentioned previously20. One consequence of this distinction is a re-interpretation of the term EPC synthesis to mean enantiopure compound synthesis. 

G. M. Coppola, H. F. Schuster, Asymmetric Synthesis, Construction of Chiral Molecules using Amino Adds, pp 32.42,96-98. 106,207,217, 278, 304, Wiley, New York 1987. 

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