Enantioselectivity enantiomeric excess

In 2008 Brimble and coworkers examined the effect of a-substitution in proline-based catalysts for the asymmetric aldol addition of acetone to aromatic aldehydes. In the benchmark aldol reaction between acetone and p-nitro-benzaldehyde they observed a remarkable improvement of stereoselectivity using (5 )-a-methyl-tetrazole 9, albeit with longer reaction times caused by the a-geminal disubstitution. Surprisingly 7a afforded a completely racemic product (Scheme 11.7). Using 9 the scope of this reaction was extended efficiently to several other aromatic aldehydes with excellent enantioselectivities (enantiomeric excess — 70-91%). 

The extension of the titanium-catalysed asymmetric allylation to ketones was first reported in 1999 by Tagliavini et al. using tetraallylstannane (2 equivalents) as nucleophile to afford tertiary homoallylic alcohols in good yields, but with modest enantioselectivities (enantiomeric excesses <81%). ° An enhancement of enantioselectivity was observed by Walsh et al. when isopropanol was introduced in excess in the reaction media. Several ketones and enones were used with high yield and enantioselectivities (Conditions A, Scheme 7.36). ° ... 

The model gives changes of the coverage with time being in agreement with experimental observations, showing changes of enantioselectivity (enantiomeric excess) with... 

Likewise, the influence of the ligand catalyst ratio has been investigated. Increase of this ratio up to 1.75 1 resulted in a slight improvement of the enantioselectivity of the copper(L-tryptophan)-catalysed Diels-Alder reaction. Interestingly, reducing the ligand catalyst ratio from 1 1 to 0.5 1 resulted in a drop of the enantiomeric excess from 25 to 18 % instead of the expected 12.5 %. Hence, as anticipated, ligand accelerated catalysis is operative. 

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 ratio of yy -epoxide (shown above) to ant -eipoxide is 10—25 1 with TYZORTPT catalysis, whereas vanadjdacetylacetonate is less selective and y -chloroperoxybenzoic acid gives the reverse 1 25 ratio. It is supposed that TYZOR TPT esterifies the free hydroxyl, then coordinates with the peroxide to favor yy -epoxidation (135). This procedure is related to that for enantioselective epoxidation of other allyflc alcohols in 9—95% enantiomeric excess (135). 

Quantitative Analysis of Selectivity. One of the principal synthetic values of enzymes stems from their unique enantioselectivity, ie, abihty to discriminate between enantiomers of a racemic pair. Detailed quantitative analysis of kinetic resolutions of enantiomers relating the extent of conversion of racemic substrate (c), enantiomeric excess (ee), and the enantiomeric ratio (E) has been described in an excellent series of articles (7,15,16). 

Because ketones are generally less reactive than aldehydes, cycloaddition reaction of ketones should be expected to be more difficult to achieve. This is well reflected in the few reported catalytic enantioselective cycloaddition reactions of ketones compared with the many successful examples on the enantioselective reaction of aldehydes. Before our investigations of catalytic enantioselective cycloaddition reactions of activated ketones [43] there was probably only one example reported of such a reaction by Jankowski et al. using the menthoxyaluminum catalyst 34 and the chiral lanthanide catalyst 16, where the highest enantiomeric excess of the cycloaddition product 33 was 15% for the reaction of ketomalonate 32 with 1-methoxy-l,3-butadiene 5e catalyzed by 34, as outlined in Scheme 4.26 [16]. 

The effect of the metals used was then examined (Table 5.4). When the group 4 metals, titanium, zirconium, and hafnium, were screened it was found that a chiral hafnium catalyst gave high yields and enantioselectivity in the model reaction of aldimine lb with 7a, while lower yields and enantiomeric excesses were obtained using a chiral titanium catalyst [17]. 

For imines, a-imino esters with an N-p-methoxyphenyl substituent (21b) also reacted with Danishefsky s diene in the presence of 10 mol% of CUCIO4-T0I-BINAP to give the corresponding adduct in high yield with good enantiomeric excess (Scheme 5.10). Remarkably, reverse enantioselectivity was observed when the a-imino esters 21a and 21b were used. This notable selectivity was explained by as-... 

This reagent can be used for the enantioselective hydroboration of Z-alkenes with enantiomeric excess of up to 98%. Other chiral hydroboration reagents have been developed. ... 

The asymmetric epoxidation of an allylic alcohol 1 to yield a 2,3-epoxy alcohol 2 with high enantiomeric excess, has been developed by Sharpless and Katsuki. This enantioselective reaction is carried out in the presence of tetraisopropoxyti-tanium and an enantiomerically pure dialkyl tartrate—e.g. (-1-)- or (-)-diethyl tartrate (DET)—using tcrt-butyl hydroperoxide as the oxidizing agent. 

The synthesis of 4-alkyl-y-butyrolactones 13 and 5-alkyl-<5-valerolactones 14 can be achieved in high enantiomeric excess by alkylation of ethyl 4-oxobutanoate and ethyl 5-oxopentanoate (11, n = 2, 3). The addition of diethylzinc, as well as dimethylzinc, leads to hydroxy esters 12 in high optical purity. When methyl esters instead of ethyl esters are used as substrates, the enantioselectivity of the addition reaction is somewhat lower. Alkaline hydrolysis of the hydroxy esters 12, followed by spontaneous cyclization upon acidification, leads to the corresponding y-butyro- and -valerolactones32. 

When /V-arenesulfonyl-a-amino acid derived boranes 13 and 14 are used in substoichiometric amounts in order to mediate enantioselective aldol additions of a,a-dimethyl substituted ketcnc acetal 15, /J-hydroxycarboxylic esters 16 are obtained in enantiomeric excess of 84 to > 99 %3fi. 

Enantioselective synthesis of Hantzsch 1,4-dihydropyridines was developed based on similar 1,4-additions of /1-oxoester derivatives to 2-(arylmethylene)-3-oxopropanoates. High enantiomeric excess (84-98%) was achieved when (5 )-l-amino-2-(l-methoxy-l-methylethyl)pyrrolidine was used at the auxiliary202. 

The enantioselectivity of biocatalytic reactions is normally expressed as the enantiomeric ratio or the E value [la], a biochemical constant intrinsic to each enzyme that, contrary to enantiomeric excess, is independent of the extent of conversion. In an enzymatic resolution of a racemic substrate, the E value can be considered equal to the ratio of the rates of reaction for the two enantiomers, when the conversion is close to zero. More precisely, the value is defined as the ratio between the specificity constants (k st/Ku) for tho two enantiomers and can be obtained by determination of the k<-at and Km of a given enzyme for the two individual enantiomers. 

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