Enantiomer-selective synthesis

The aforementioned polymer-supported bis-pyridyl ligand has also been applied in microwave-assisted asymmetric allylic alkylation [140], a key step in the enantio-selective synthesis of (R)-baclofen (Scheme 7.118), as reported by Moberg and coworkers. The ( (-enantiomer is a useful agonist of the GABAb (y-aminobutyric acid) receptor, and the racemic form is used as a muscle relaxant (antispasmodic). Under microwave heating, the enantioselectivity could be improved to 89% when using toluene as solvent (see also Scheme 6.52) [140],... 

Ketorolac 132, a nonstereoidal anti-inflammatory drug with cyclooxygenase (COX) inhibitory activity, was marketed as a racemic mixture. It is now well established that (V)-ketorolac is the active enantiomer <1999MI382>. Therefore, efforts were devoted to the selective synthesis of this active stereomer, either by enzymatic kinetic resolution <2001TA1865> or by enantioselective synthesis <2005AGE609>. 

The enantiomers of the naturally occurring lignans, schizandrin (5) and isoschizandrin (6), have been prepared from oxazoline 10 in 11 steps with 0.7% and 5.5% overall yield, respectively. Although both natural products are accessible by this strategy, the reported synthetic approach is basically a route to isoschizandrin (6). Schizandrin (5) was obtained only as minor congener and a selective synthesis of 5 has not been accomplished by the authors. 

The selective synthesis of the enantiomer of 48 started with the allyl alcohol... 

Recker, J., Muller, W.M., Muller, U., Kubota, T., Okamoto, Y., Nieger, M., Vogtle, F. Dendronized molecular knots selective synthesis of various generations, enantiomer separation, circular dichroism, Chem. Eur. J. 8 (2002), 4434-4442. 

Kallenborn, R. Oehme, M. Vetter, W. Parlar, H., Enantiomer selective separation of toxaphene congeners isolated from seal blubber and obtained by synthesis Chemosphere 1994,28, 89-98. Vetter, W. Klobes, U. Krock, B. Luckas, B. Glotz, D. Scherer, G., Isolation, structure elucidation, and identihcation of a further major toxaphene compound in environmental samples Environ. Sci. TechnoL 1997, 31, 3023-3028. 

Enantiomers are stereoisomers structured like rnirror-images (see Fig. 1). A main problem related to producing a pure single enantiomer is that selective synthesis is often not feasible or too expensive. In contrast, conventional synthetic procedures are less expensive but non-selective (they deliver the racemic 1 1 mixture). Since usually only one enantiomer has the desired physiological effect (the other might be ineffective or harmful), such mixtures need to be separated for example, by kinetic resolution, crystallisation, or chromatography. However, the yield achievable by this approach is inherently limited to 50% only. 

The Sn(OTf)2-based chiral promoter system enables highly selective synthesis of both enantiomers of the aldol adducts by using similar types of chiral diamines derived from L-proline (Scheme 10.47). Diamines 50d and 50h are highly effective chiral sources for the synthesis of (2S,3K) and 2R,3S) adducts, respectively, from 52a [135]. In the aldol reaction of 52b, diamines 50f and 50g realize the selective synthesis of both enantiomers of the syn adducts [136]. The sense of diastereoselectivity can also be controlled by choice of the diamine ligands. The use of 50 g... 

Vanden Bossche, H., G. Willemsens, I. Roels, D. Bellens, H. Moereels, M.-C. Coene et al. (1990). R 76713 and enantiomers Selective, nonsteroidal inhibitors of the cytochrome P450-dependent oestrogen synthesis. Biochem. Pharmacol. 40, 1707-1718. 

A classical method for the preparation of enantiopure compounds is the resolution of racemate. However, it is much more effective to use the selective synthesis of the desired enantiopure substance via enantioselective approach. Stereoselective methods of synthesis have been widely developed in organic chemistry. The method of asymmetric synthesis has been known since the nineteenth century and asymmetric catalysis has witnessed an enormous amount of development in recent decades as shown in Chapter 3. In contrast, the asymmetric synthesis of coordination compounds has only recently become a subject of systematic investigation. This is no doubt related to the fact that the chirality of coordination compounds is a much more complex phenomenon than that of organic compounds, because of higher coordination and the multitude of possible central atoms. Furthermore, while in organic chemistry the chiral tetrahedral carbon centres can be prepared without racemization, in contrast T-4 metal centres are very often labile. In fact it is even difficult to prepare compounds with a metal centre coordinated to four different monodentate ligands, and thus the possibility of obtaining one enantiomer is excluded in most cases. 

Recently, the potential of bacterial enzymes for the synthesis of aromatic, optically active amides, and carboxylic acids firom racemic nitriles was evaluated. An enantiomer-selective amidase, active on several 2-aryl and 2-aryloxy propionamides, was identifided and purified from Brevibacterium sp. strain R312 [145]. A nitrilase, found in Acinetobacter sp. strain AK226 and able to hydrolyze efihciently both aromatic and aliphatic nitriles, was reported to hydrolyze racemic nitriles to optically active 2-aryl propionic acids [146]. Enzyme system of Rhodococcus butanica could be successfully adapted for the kinetic resolution of a-arylpropionitriles resulting in the formation of (R)-... 

Polymers having configurational chirality in the side chain or the main chain can be prepared by asymmetric synthesis polymerization or enantiomer-selective polymerization. As for the main-chain chiral polymers, it is difficult to determine a definite chiral structure and rationally connect observed chiroptical properties with the structure for most polymers. Improved analytical techniques need to be evolved to address this issue. 

This stereoselective synthesis of the required enantiomer from a simple achiral precursor such as an alkene would be a preferred route for any chiral product. Even if a racemisation, such as that which accompanies the synthesis of L-methionine and L-cysteine, is practical, there are likely to be fewer steps in a selective synthesis fi om a carefully chosen achiral compound. In this instance the manufacture is very efficient. It is catalysed either by whole E. coli cells or by an enzyme preparation extracted from them. In... 

DKR is defined as an enantiomer-selective reaction accompanying racemization of a chiral substrate as shown in Figure 5.1. The basic pattern of DKR, where each enantiomer of Sjj and S5 is transferred to the corresponding enantiomeric product ( and P5) with the different rate constants fejj and fej, respectively, is illustrated in Figure 5.1a. The simplest of these cases involves the stereoselective synthesis of the enantiomeric products, Pj, or P, when the rate of the stereomutation of S is sufficiently high with respect to the rate of the reaction (i.e. > kjj or k ) in... 

In Sj reactions, substrate and reagent combine to form a diastereomeric transition state. In the case of auxiliary-controlled reactions, the asymmetric induction is promoted by a chiral element temporarily linked to the arene or the nucleophile. The ideal chiral auxiliary has to fulfill several requirements (i) it must be easily available in both enantiomeric forms to permit selective synthesis of both enantiomers, (ii) it must induce good stereoselectivity, (iii) the diastereomeric products must be easily separated, and (iv) cleavage of the chiral auxiliary must provide the requisite enantiomer in high yield without racanization. Additionally, an efficient work-up to allow easy recovay of expensive chiral auxiliaries is highly desirable. Most chiral auxiliaries are either natural products (alcohols, amino acids, carbohydrates, etc.) or derived from natural products. 

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