Homochiral compounds

Different optical enantiomers of amino acids also have different properties. L-asparagine, for example, tastes bitter while D-asparagine tastes sweet (see Figure 8.3). L-Phenylalanine is a constituent of the artificial sweetener aspartame (Figure 8.3). When one uses D-phenylalanine the same compound tastes bitter. These examples clearly demonstrate the importance of the use of homochiral compounds. 

Racemic mixtures of sulfoxides have often been separated completely or partially into the enantiomers. Various resolution techniques have been used, but the most important method has been via diastereomeric salt formation. Recently, resolution via complex formation between sulfoxides and homochiral compounds has been demonstrated and will likely prove of increasing importance as a method of separating enantiomers. Preparative liquid chromatography on chiral columns may also prove increasingly important it already is very useful on an analytical scale for the determination of enantiomeric purity. 

Asymmetric synthesis [2] [3], which involves the conversion of prochiral precursors into homochiral compounds, can be attained by means of ... 

An ingenious experimental example for the reverse of the socalled la coupe de Roi (i.e. the dividing of finite geometric objects into isometric segments) — namely the assembly of two homochiral compounds into an achiral one — was provided by making use of appropriate [2.2]metacyclophanes. Whereas self-coupling of (+)-4-(bromomethyl)-6-(mercaptomethyl)[2.2]metacyclophane (cf. formulas 55 to 60 for... 

M. L. Sinnott, Catalytic mechanisms of enzymic glycosyl transfer, Chem. Rev. 90 1171 (1990). G. W. J. Fleet, Homochiral compounds from sugars, Chem. Br. 25 287 (1989). 

Synthetic pathways towards the dimethylene isosteres comprise several disconnections, indicated by the essential bond forming reactions (Scheme 2). Several methods yield racemic dipeptide analogues. These are usually incorporated into the peptide sequence and the resulting epimeric peptides are separated. When either R1 or R2 = H, asymmetric syntheses towards the required enantiomer are available. When both R1 and R2 H, only the reduction of the i )[CH=CH] precursor yields homochiral compounds. As many co-amino acids (R1 = R2 = H) are commercially available, their synthesis needs not be discussed here. 

Resolution Methods. Chiral pharmaceuticals of high enantiomeric purity may be produced by resolution methodologies, asymmetric synthesis, or the use of commercially available optically pure starting materials. Resolution refers to the separation of a racemic mixture. Classical resolutions involve the construction of a diastcrcomcr by reaction of the racemic substrate with an enantiomerically pure compound. The two diastereomers formed possess different physical properties and may be separated by crystallization, chromatography, or distillation. A disadvantage of the use of resolutions is that the best yield obtainable is. 50%, which is rarely approached. However, the yield may he improved by repeated raccmization of the undcsired enantiomer and subsequent resolution of the racemate. Resolutions are commonly used in industrial preparations of homochiral compounds. 

When Michael additions of chiral enolates to nitroalkenes were studied, it was found that lithium enolates (132) of l,3-dioxolan-4-ones (131), derived from the corresponding a-hydroxy acids, afford the adducts (133) with high diastereoselectivity (Scheme 50).144 Recrystallization leads, in general, to diastereomerically pure products, which in turn can efficiently be converted to homochiral compounds like (134), (135) or (136). A number of other chiral enolates (137M140) were also shown to undergo highly selective additions to nitroalkenes however, product configurations were not determined in these cases. 

Many of the custom synthesis and research and development contracts tackled at Ultraflne have required the preparation of homochiral compounds, so it has been necessary to build up expertise in the whole range of available methodology. Some of the most interesting examples remain confidential, but the selection that follows illustrates how some of the challenges were tackled. 

Synthesis of Homochiral Compounds A Small Company s Role... 

The preparation of homochiral compounds by formation and separation of diastereoisomers or by kinetic resolution of racemates, at or near the end of a total synthesis, has been a method of choice. This avoids the possibility of racemization should chirality be introduced earlier. However, the costs are high because only half by weight of the homochiral compound is theoretically possible from the racemate unless the optical antipode can also be easily inverted to the desired product. Indeed, previous methods for producing levomethadone based on the classical resolution at the end, or at the penultimate stage of the synthesis, were costly and not very effective. Levomethadone hydrochloride has previously been marketed as L-Polamidon and Levadone16 but was subsequently withdrawn because of the high cost of production. 

Optical Networks crystallize in chiral (enantiomorphic) space groups and can therefore be related to homochiral compounds. 

Process options for the production of homochiral compounds are summarized in Fig. 2. The three basic routes are separation of racemic mixture, synthesis using a naturally occurring chiral synthon, and asymmetric synthesis using a prochiral intermediate. Historically, the efficiency of asymmetric synthesis has been capricious in terms of chemical and optical yield. Hence, from a practical, commercial process perspective, resolution via diastereomer crystallization has remained important for many commercial scale processes, for example, diltiazem. 

D. I. Stirling, The use of aminotransferase for the production of chiral amino acids and amines. The Industrial Production of Homochiral Compounds (A. N. Collins and G. N. Sheldrake, eds.), WEey, Chichester, 1992. 

The term homochiral was introduced by Kelvin in the 1904 publication of his Baltimore Lecture of 1884 and represented a relationship between molecules (see Mislow10). Molecules are homochiral if they possess the same sense of chirality. For example, the right hands of a group of people are homochiral (or alike). More recently, and unfortunately, homochiral has been used in the sense of enantiomerically pure, i.e. one reads of a homochiral compound , which clearly violates the original definition. Since some journals permit the latter usage, readers should be aware of the potential for confusion. 

The selectivity of a chemical reaction is a very important criterion. Besides the chemo- and regioselectivity, the stereoselectivity, i.e. the favored or excluded formation of one or several stereoisomers in the course of a chemical reaction, plays an important role. If there is a formation of (S)- and (K)-enantiomers from a prochiral compound, an enantioselective reaction takes place. What are the reasons for the growing interest in enantioselective reactions and preparation of homochiral compounds Firstly, it is certainly the wish of the chemist to imitate the ability of nature by stereospecific synthesis in the laboratory. Secondly, there are some practical and economic reasons many natural products and a great number of synthetic drugs have a chiral structure and the enantiomers can differ markedly in their biological activity. Sometimes only one of the enantiomers exhibits the wanted optimal activity, while the other is less active or totally inactive, or even toxic. 

Casiraghi, G., Rassu, G., Spanu, P and Pinna, L., J. Org. Chem., 1992, 57, 3760 idem, Tetrahedron Lett, 1994, 35, 2423 Furan-, pyrrole-, and thiophene-based siloxydienes for synthesis of densely functionalised homochiral compounds , Casiraghi, G. and Rassu, G., Synthesis, 1995, 607. 

---