Chiral ion pair

Short-lived chiral ion pairs are intermediates in the Haller-Bauer cleavage 14 15 of enantiomer-ically enriched 2,2-disubstituted 1,2-diphenylethanones, which give optically active phenylalka-nes on in situ protonation with partial retention of the configuration. 

Another historically important reaction is the reorganization of chiral ion pair intermediates of solvolysis of a chiral substrate that leads to racemization of substrate during solvolysis. This reorganization competes with other reactions of the ion pair intermediate of solvolysis of a chiral substrate, so that the relative rate constant for ion-pair racemization can be obtained by determining the relative rates of formation of products from partitioning of the ion pair reaction intermediate, including the enantiomer of substrate (Scheme 14). 

Based on the theory, the separation of enantiomers requires a chiral additive to the CE separation buffer, while diastereomers can also be separated without the chiral selector. The majority of chiral CE separations are based on simple or chemically modified cyclodextrins. However, also other additives such as chiral crown ethers, linear oligo- and polysaccharides, macrocyclic antibiotics, chiral calixarenes, chiral ion-pairing agents, and chiral surfactants can be used. Eew non-chiral separation examples for the separation of diastereomers can be found. 

This review will concentrate on metal-free Lewis acids, which incorporate a Lewis acidic cation or a hypervalent center. Lewis acids are considered to be species with a vacant orbital [6,7]. Nevertheless, there are two successful classes of organocatalysts, which may be referred to as Lewis acids and are presented in other chapter. The first type is the proton of a Brpnsted acid catalyst, which is the simplest Lewis acid. The enantioselectivities obtained are due to the formation of a chiral ion pair. The other type are hydrogen bond activating organocatalysts, which can be considered to be Lewis acids or pseudo-Lewis acids. 

The asymmetric (—)-sparteine-mediated deprotonation of alkyl carbamates was unprecedented until discovered in 1990 °. For the first time, protected 1-alkanols could be transformed generally to the corresponding carbanionic species by a simple deprotonation protocol. Moreover, an efficient differentiation between enantiotopic protons in the substrate took place and the extent of stereoselection could be stored in a chiral ion pair, bearing the chiral information at the carbanionic centre. 

Shortly thereafter, Terada demonstrated that the Mannich reaction between several N-Boc aryl imines and acetoacetone was effectively catalyzed by only 2 mol% of le (Scheme 5.2) [4]. In view of AMyama s work, this study is particularly significant because it suggested that le may act as a bifunctional catalyst [9] not only to form a chiral ion pair with the electrophile but also to activate the nucelo-phile through hydrogen bonding of the a-proton with Lewis basic phosphoryl oxygen. 

Two other strategies for producing separations of enantiomers involve the addition of chiral modifiers to the mobile phase (e.g. chiral ion-pairing reagents), which can bring about separation on for instance an ordinary ODS column and the formation of derivatives with chirally pure reagents that produce different diastereoisomers when reacted with opposite enantiomers of a particular compound (see GC example, Ch. II p. 219). 

Deracemization. Results from Michael additions described earlier (Scheme 10.8) led Toke and co-workers to an interesting deracemization study. When racemic Michael adduct 106 was reacted with a catalytic amount of base in the presence of the chiral crown 12 for 8 min, the resulting product was optically active (40% ee). The authors propose that a deprotonation followed by reprotonation of the resulting chiral ion-pair accounts for the asymmetric induction [39]. 

Enantioselective catalytic alkylation is a versatile method for construction of stereo-genic carbon centers. Typically, phase-transfer catalysts are used and form a chiral ion pair of type 4 as an key intermediate. In a first step, an anion, 2, is formed via deprotonation with an achiral base this is followed by extraction in the organic phase via formation of a salt complex of type 4 with the phase-transfer organocata-lyst, 3. Subsequently, a nucleophilic substitution reaction furnishes the optically active alkylated products of type 6, with recovery of the catalyst 3. An overview of this reaction concept is given in Scheme 3.1 [1],... 

In the Michael-addition, a nucleophile Nu is added to the / -position of an a,fi-unsaturated acceptor A (Scheme 4.1) [1], The active nucleophile Nu is usually generated by deprotonation of the precursor NuH. Addition of Nu to a prochiral acceptor A generates a center of chirality at the / -carbon atom of the acceptor A. Furthermore, the reaction of the intermediate enolate anion with the electrophile E+ may generate a second center of chirality at the a-carbon atom of the acceptor. This mechanistic scheme implies that enantioface-differentiation in the addition to the yfi-carbon atom of the acceptor can be achieved in two ways (i) deprotonation of NuH with a chiral base results in the chiral ion pair I which can be expected to add to the acceptor asymmetrically and (ii) phase-transfer catalysis (PTC) in which deprotonation of NuH is achieved in one phase with an achiral base and the anion... 

Nu is transported into the organic phase by a chiral phase-transfer catalyst, again resulting in a chiral ion pair from which asymmetric / -addition may proceed. 

Clearly, the outcome of such processes is determined by a diastereoisomerism existing somewhere along the reaction pathway. This could, for example, be in the approach of two materials to each other, in a transition state or reaction intermediate, or in the properties of the final product. The nature of the approach, interaction or bonding, is immaterial. For example, it has been shown recently that there are real and significant differences in the energetics of aggregation of chiral ions in solution to make diastereoisomeric ion pairs [31]. As shown in Table 1, even very simple chiral ion pairs can differ by 200-500 cal/mol in their heats of formation from the free ions. Such a difference can account for the difference between a reaction yield of 50 50 and 60 40. 

New Developments in Enantioselective Bronsted Acid Catalysis Chiral Ion Pair Catalysis and Beyond... 

With regard to the mechanism we assume that, similar to the dehydrogenase (Fig. 1), the ketimine 1 will be activated by protonation through Brpnsted acid 5 which results in the formation of a chiral ion-pair, an iminium ion A. Subsequent hydrogen transfer from the dihy-... 

First Highly Enantioselective Br0nsted Acid Catalyzed Strecker Reaction Use of C-Nucleophiles in Chiral Ion Pair Catalysis... 

BINOL-phosphates as efficient Brpnsted acid catalysts in the enantios-elective Strecker reaction shows that C-nucleophiles can be applied in the chiral ion-pair catalysis procedure. This, in turn, not only increases the diversity of possible transformations of this catalyst but also shows the great potential chiral Brpnsted acids in asymmetric catalysis. 

The possibility of using C-nucleophiles in chiral ion pair catalysis encouraged us to investigate an enantioselective Brpnsted acid catalyzed imino ene reaction (Rueping et al. 2007a Scheme 5). The reaction consists of a new BINOL-phosphate catalyzed addition of methylene-hydrazines 22 to A-Boc-protected aldimines 23 to afford chiral amino-hydrazones 24. 

Within the field of chiral ion pair catalysis only aldimines and keto-imines had been activated so far. However, we have recently been successful in the activation of both the electrophile, as well as the nucleophile in a new double Brpnsted acid catalyzed reaction. 

Karlsson, A. and Charron, C. Reversed phase chiral ion-pair chromatography at a column temperature below 0°C using three generations of Hypercarb as solid phase. J. Chromatogr. A. 1996, 732, 245-253. 

Karlsson, A. and Karlsson, O. Chiral ion-pair chromatography on porous graphitized carbon using N-blocked dipeptides as counter ions. J. Chromatogr. A. 2001, 905, 329-335. 

Another approach is electrochromatography with capillary columns packed with an achiral stationary phase, preferentially a reversed-phase type material. The chiral SO is added to the background electrolyte, and may be adsorbed onto the stationary phase by a secondary equilibration process. Enantioseparations in this additive mode have been reported with cyclodextrin type SOs )504-507) and with a chiral ion-pair agent derived from quinine 1508) as mobile phase additives. 

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