Deprotonation prochiral substrates

A much more efficient procedure consists in the deprotonation of prochiral substrates 4 by chiral base 5 (equation 2). The removal of the enantiotopic protons in 4 proceeds through diastereotopic transition states having different energies AG and thus yielding the diastereomeric carbanions 6 and epi-6 in unequal amounts (equation 2). 

Asymmetric induction in these reactions occurs either in the first deprotonation step [Eq. (la)] or in a postdeprotonation step [1] [(Eq. (lb)]. When the enantioselection occms in the deprotonation step, a proton is stereoselectively removed by a chiral base from a prochiral substrate to provide a configuration-ally stable enantioemiched carbanion, which reacts with an electrophile giving an enantioenriched product. This enantiodetermining pathway is termed asymmetric deprotonation . In fact, reactions of a-oxy and a-amino carban-ions are often controlled through an asynunetric deprotonation pathway (Fig. 2) [1,2]. 

The methods described in this chapter are based on the enantioselective deprotonation of alkyl groups in - usually achiral - phosphine derivatives, which provide highly enantioenriched a-carbanions that are versatile precursors of a variety of mono- and diphosphines. This method was developed by combining two known facts firstly, that the methyl group in methylphosphines and their oxides, boranes and sulfides can be deprotonated with strong bases and secondly common organolithium reagents ( -, s- or r-BuLi) can exert enantioselective deprotonations in prochiral substrates in the presence of certain chiral auxiliaries. ... 

Thus, the role of zinc in the dehydrogenation reaction is to promote deprotonation of the alcohol, thereby enhancing hydride transfer from the zinc alkoxide intermediate. Conversely, in the reverse hydrogenation reaction, its role is to enhance the electrophilicity of the carbonyl carbon atom. Alcohol dehydrogenases are exquisitely stereo specific and by binding their substrate via a three-point attachment site (Figure 12.7), they can distinguish between the two-methylene protons of the prochiral ethanol molecule. 

In a series of reports between 1991 and 1997 Yamaguchi showed that rubidium salts of L-proline (9) catalysed the conjugate addition of both nitroalkanes [29, 30] andmalonates [31-33] to prochiral a,p-unsaturated carbonyl compounds in up to 88% ee (Scheme 1). Rationalisation of the selectivities observed involved initial formation of an iminium ion between the secondary amine of the catalyst and the a,p-unsaturated carbonyl substrate. Subsequent deprotonation of the nucleophile by the carboxylate and selective delivery using ion pair... 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

Asymmetric protonations of prochiral enolates or enaroines by enantiopure carboxylic acids typically occur with low enantioselectivity, but there are some exceptions. P. Duhamel, L. Duhamel and coworkers accomplished the " deracemi-zation of Schiff bases of a-aminoesters [552], The best selectivities (ee 70%) are obtained when the substrates are deprotonated by Li (ify-A -ethylphene-thylamide, and then reprotonated at -70°C by (fy )-diacyltartaric add 2.2 (R = fert-BuCO) [154] (Figure 4.4). In another successful application, asymmetric protonation of the potassium enolale of racemic benzoin 4.7 by (RJR) 2.2 (R = terf-BuCO) gjves the (S)-enantiomer with a good enantiomeric excess [552] (Figure 4.4). 

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