Chirally enantioselectivity

Fig. 23. Prototypical receptor molecules for chiral (enantioselective) substrate recognition.

Section 2 discusses the syntheses of different classes of concave acids and bases. Convergent synthetic strategies were chosen for an easy structural variation of the reagents (modular assembly). Section 3 characterizes the concave acids and concave bases and checks whether the acid/base properties of the parent compounds benzoic acid, pyridine and 1,10-phenanthroline are conserved in the bimacrocyclic structures. In Section 4, the influence of the concave shielding on the reactivity and selectivity of the concave reagents is measured in model reactions. In principle, the concave shielding should be able to influence inter- and intramolecular competitions as well as chemoselectivity and (dia)stereoselectivity. If the reagent is chiral, enantioselectivity should also be observable. 

If the transition metal could exist in two different oxidation states in the complex 87, one would have a concave redox reagent which could be useful for instance in epoxidation reactions [56]. The concave shielding of the metal ion should influence the regio-, stereo- and, if the concave 1,10-phenanthroline 21 is chiral, enantioselectivity of an epoxidation. 

SCHEME 102. Memory of chirality enantioselective methylation of a phenylalanine derivative lithium enolate in the presence of no external source of chirality501... 

Brassinosteroids, Brevicomin, Chirality, Enantioselective Synthesis, Gibberellins, Glycinoeclepin A, Juvenile Hormones, Minamata Disease, Pheromones, Phytoalexins, Strigolactones... 

Keywords Chiral, Enantioselectivity, Heterogeneous catalysis, Metal-organic frameworks. Porous, Size selectivity... 

In chemoinformatics, chirality is taken into account by many structural representation schemes, in order that a specific enantiomer can be imambiguously specified. A challenging task is the automatic detection of chirality in a molecular structure, which was solved for the case of chiral atoms, but not for chirality arising from other stereogenic units. Beyond labeling, quantitative descriptors of molecular chirahty are required for the prediction of chiral properties such as biological activity or enantioselectivity in chemical reactions) from the molecular structure. These descriptors, and how chemoinformatics can be used to automatically detect, specify, and represent molecular chirality, are described in more detail in Chapter 8. 

Neural networks were trained on the basis of these codes to predict chiralit> -dependent properties in enantioselective reactions [42] and in chiral chromatography [43]. A detailed description of the chirality codes is given in the Tutorial in Section 8,6,... 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

The first example of enantioselective catalysis of a Diels-Alder reaction was reported in 1979 . Since then, an extensive set of successful chiral Lewis-acid catalysts has been prepared. Some selected examples will be presented here together with their mechanistic interpretation. For a more complete... 

To the best of our knowledge the data in Table 3.2 constitute the first example of enantio selectivity in a chiral Lewis-acid catalysed organic transformation in aqueous solution. Note that for the majority of enantioselective Lewis-acid catalysed reactions, all traces of water have to be removed from the... 

Most importantly, enantioselectivity benefits considerably from the use of water. This effect could be a result of water exerting a favourable influence on the cisoid - transoid equilibrium. Unfortunately, little is known of the factors that affect this equilibrium. Alternatively, and more likely, water enhances the efficiency of the arene - arene interactions. There is support for this observation"" . Since arene-arene interactions are held responsible for the enantioselectivify in many reactions involving chiral catalysts, we suggest that the enhancement of enantioselectivity by water might well be a general phenomenon. 

Giovanni Boocaletti is gratefully acknowledged for the large number of experiments that paved the way to enantioselective Lewis-acid catalysis in water. Furthermore, we kindly thank the Syncom company for the use of the chiral HPLC column. 

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

The enantioselective introduction of chiral centres into an achiral molecule can nowadays be achieved most easily using chiral reductants or oxidants. 

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

The target molecule above contains a chiral center. An enantioselective synthesis can therefore be developed We use this opportunity to summarize our knowledge of enantioselective reactions. They are either alkylations of carbanions or addition reactions to C = C or C = 0 double bonds ... 

Table 17. Some enantioselective reactions to produce chiral monofunctional products.

This target molecule again contains a chiral center and we inspect Table 18 for help. Table 18. Some enantioselective reactions that produce difunctional products... 

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