Pseudo-enantiomers

Both quinine and dihydroquinine favored the required (S)-enantiomer. A small ee difference of the product might be due to inconsistent purity of the naturally obtained cinchona alkaloids. It was noted that quinidine (the pseudo-enantiomer of quinine) gave the (R)-enantiomer with a similar 55% ee. Since quinine was... 

An isotopic labeling scheme based on pseudo-enantiomers that enabled the diastereomeric receptors to be individually addressed (by LC-MS) was also examined. This methodology enabled the direct identification of the amplified diastereomer and the measurement of its selectivity over the competing stereoisomers (Fig. 5.12). 

Reetz and coworkers developed a highly efficient method for screening of enantioselectivity of asymmetrically catalyzed reactions of chiral or prochiral substrates using ESI-MS [60]. This method is based on the use of isotopically labeled substrates in the form of pseudo-enantiomers or pseudo-prochiral compounds. Pseudo-enantiomers are chiral compounds which are characterized by different absolute configurations and one of them is isotopically labeled. With these labeled compounds two different stereochemical processes are possible. The first is a kinetic separation of a racemic mixture, the second the asymmetric conversion of prochiral substrates with enantiotopic groups. The conversion can be monitored by measuring the relative amounts of substrates or products by electrospray mass spectrometry. Since only small amounts of sample are required for this method, reactions are easily carried out in microtiter plates. The combination of MS and the use of pseudo-enantiomers can be used for the investigation of different kinds of asymmetric conversion as shown in Fig. 3 [60]. 

The second MS-based approach does not require any derivatization reaction and has in fact been applied several times in the area of directed evolution [20,33-36]. It makes use of deuterium-labeled pseudo enantiomers or pseudo meso compounds. This practical method is restricted to studies involving kinetic resolution of race-mates and desymmetrization of prochiral compounds bearing reactive enantiotopic groups (Figure 9.2) [20]. 

The products of these transformations are pseudo enantiomers differing in absolute configuration and in mass, integration of the MS peaks and data processing affording the ee or E values. Any type of ionization can be employed, but electrospray ionization (ESI) is used most commonly [20,33-35]. An internal standard is advisable if it is necessary to determine percent conversion. The uncertainty in the ee value is less than 5%. In the original version about 1000 ee values could be measured per day [20a], but this has recently been increased to about 10 000 sam-... 

The exact ratio of the two pseudo enantiomers is accessible by simple integration of the respective peaks, which provides the ee value. Quantitative analysis can be accomplished automatically by suitable software such as AMIX (Bruker Biospin). The presence of naturally occurring 13C in the nonlabeled (R) substrate is automatically considered in the dataprocessing step. As demonstrated in control experiments, the agreement with the corresponding ee values obtained by independent GC analysis is excellent, the correlation coefficient amounting to 0.9998 [21]. 

The concept of isotopic labeling for distinguishing pseudo enantiomers in the kinetic resolution of chiral compounds and in the desymmetrization of prochiral substrates bearing reactive enantiotopic groups (Sections 9.2 and 9.3) can also be applied when Fourier transform infrared spectroscopy (FTIR) is used as the detec-... 

A specific example concerns the kinetic resolution of 1-phenylethyl acetate, previously used to illustrate the NMR-based ee assay (see Section 9.3.2). The optimal way to proceed is to apply 13C labeling in the carbonyl moiety, i. e., to prepare a pseudo racemate comprising a 1 1 mixture of (.S)-13C-4 and (R)-4 (Section 9.3). Figure 9.7 shows part of the FTIR spectrum of a 1 1 mixture of (R)-4 and (.S)-13C-4, illustrating the anticipated shift of the respective carbonyl-stretching vibration, which allows quantification of the pseudo enantiomers [22]. 

After preparation of a stock solution (0.200 M) of (R)- 1-phenylethyl acetate ((i )-4) and (S)-( 1 -phenylethyl)-1 -13C-acetate ((b1)-l3C-4) in cyclohexane, the solutions are diluted with cyclohexane to concentrations of 0.180, 0.160, 0.140, 0.120, 0.100, 0.080, 0.060, 0.040, and 0.020M (total volume lmL). The absorbance of the resulting samples is measured with a FTIR spectrometer at the corresponding absorption maxima of the carbonyl-stretching vibration ((i )-4 1751 cm-1 (S)-13C-4 1699 cm-1) with a thickness of the layers of 25.0 pm, performing 32 scans at a resolution of 4 cm-1. The molar coefficients of absorbance are determined by linear regression, with correlation coefficients >0.995. Analysis of synthetic mixtures of the pseudo enantiomers of 1-phenylethyl acetate is performed under the same conditions at a concentration of 0.10 M. 

In particular, it is not only the cinchona alkaloids that are suitable chiral sources for asymmetric organocatalysis [6], but also the corresponding ammonium salts. Indeed, the latter are particularly useful for chiral PTCs because (1) both pseudo enantiomers of the starting amines are inexpensive and available commercially (2) various quaternary ammonium salts can be easily prepared by the use of alkyl halides in a single step and (3) the olefin and hydroxyl functions are beneficial for further modification of the catalyst. In this chapter, the details of recent progress on asymmetric phase-transfer catalysis are described, with special focus on cinchona-derived ammonium salts, except for asymmetric alkylation in a-amino acid synthesis. 

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

Kinetic resolution of chiral, racemic anhydrides In this process the racemic mixture of a chiral anhydride is exposed to the alcohol nucleophile in the presence of a chiral catalyst such as A (Scheme 13.2, middle). Under these conditions, one substrate enantiomer is converted to a mono-ester whereas the other remains unchanged. Application of catalyst B (usually the enantiomer or a pseudo-enantiomer of A) results in transformation/non-transformation of the enantiomeric starting anhydride ). As usual for kinetic resolution, substrate conversion/product yield(s) are intrinsically limited to a maximum of 50%. For normal anhydrides (X = CR2), both carbonyl groups can engage in ester formation, and the product formulas in Scheme 13.1 are drawn arbitrarily. This section also covers the catalytic asymmetric alcoholysis of a-hydroxy acid O-carboxy anhydrides (X = O) and of a-amino acid N-carboxy anhydrides (X = NR). In these reactions the electrophilicity of the carbonyl groups flanking X is reduced and regioselective attack of the alcohol nucleophile on the other carbonyl function results. 

The chiral ligand consists of a diphenylpyrimidine (PYR) 39, which is connected to two dihydroquinidine (DHQD) molecules 40. Dihydroquinidine (DHQD) 40 and dihydroquinine (DHQ) 41 are diastereomers. However, in the asymmetric dihydroxylation, they behave like pseudo-enantiomers, giving diols of opposite configuration. 

Fig. 11.4. MS-based ee-screening of isotopically labeled substrates [50]. a) Asymmetric transformation of a mixture of pseudo-enantiomers involving cleavage of the functional groups FG and labeled functional groups FG. b) Asymmetric transformation of a mixture of pseudo-enantiomers involving either cleavage or bond formation at the functional group FG isotopic labeling at R2...

These nitrogen-containing natural products, often with powerful biological properties, are not usually incorporated into target molecules. However, they are important in asymmetric syntheses as the foundations of many reagents and catalysts. Quinine 119 is familiar as an anti-malarial and an ingredient in tonic water. Quinine and its twin cinchona alkaloid quinidine 118 are referred to as pseudo enantiomers. Each occurs naturally as one enantiomer only but the two structures are nearly enantiomeric only the vinyl side-chains disturb the symmetry and they act as enantiomers. The vinyl side-chains are reduced and two molecules of, say, dihydroquinine (DHQ) are joined... 

Bolm51 was able to improve matters by piling in the quinine (so that over an equivalent was used -110 %) which enabled the reaction of anhydride 223 to be done at a lower temperature (giving a better ee) in a mere 1.5 days. The pseudo-enantiomer quinidine could also be used to give ester 224. A range of rings 225 to 229 works. 

However, (DHQD)2PYR, the pseudo-enantiomer of (DHQ)2PYR (see chapter 25), would prefer to form two R chiral centres. The substrate and reagent are in competition here—the mismatched case. The selectivity is turned over to 75 25 in favour of the C2 symmetric product 91 this time. So the reagent wins but not outright there is still much of the meso diastereomer formed. Now we can return to the original question which concerns the reaction of triene 89. 

Fig. 8. The use of diamines derived from (Jl)-proline as pseudo-enantiomers...

Racemic diacid 79 was imprinted at an elevated temperature with an alkaloid. Quinine and quinidine that are pseudo enantiomers led to opposite enantiomers. The guest-induced chirality was preserved on cooling to rt, which was maintained even in the absence of a guest (fi/2 = 14 years). The chiral enrichment process was also reversible, allowing the diacid to be used as a chiral switch (09OL2599). 

The lithium compound 256 can react from two conformations 256a and 256b. In an a-substitution, products 258 or enf-258 are formed from both conformers, their ratio depends on the stereospecificity of the appropriate Sg reaction, which may occur with retention or inversion, depending on the electrophile. Electrophilic y-substitution of 256a and 256b can lead, depending on the stereospecificity of the substitution step, to four different stereoisomers with two pairs of enantiomers (257 and ent-257,259 and enf-259) 257 and enf-259 and as well, ent-257 and 259 can be regarded as pseudo-enantiomers . Since the latter pairs are diastereomers, in principle, these can be easily separated before deprotection. 

The hgands used by the Sharpless group are based on dihydroquinidine (DHQD) (5.01) and dihydroquinine (DHQ) (5.02). Dihydroquinidine and dihydro quinine are diastereomers, although their derivatives behave as pseudo-enantiomers in... 

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