Ammonium salt enantiomers

The analytical capability of these matrices has been demonstrated for chiral amines [12, 13]. The procedure is illustrated in Fig. 8-4 for the separation of NapEtNH " CIO . Concentrated methanol/dichloromethane solutions of the racemic mixture were placed on a column containing the chiral macrocycle host. The enantiomers of the ammonium salts were resolved chromatographically with mixtures of methanol and dichloromethane as the mobile phase. The amounts of R and S salts in each fraction were determined by polarimetry. Because the chiral supported macrocycle interacts more strongly with S salts, the R salt passes through the column first and the S salt last, as seen in Fig. 8-4. 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

An overall efficiency of TRISPHAT 8 and BINPHAT 15 anions as NMR chiral shift agents for chiral cations has been demonstrated over the last few years. Additions of ammonium salts of the A or A enantiomers of 8 and 15 to solutions of racemic or enantioenriched chiral cationic substrates have generally led to efficient NMR enantiodifferentiations [112-121]. Well-separated signals are usually observed on the spectra of the diastereomeric salts generated in situ. 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

A young Louis Pasteur observed that many salts of tartaric acid formed chiral crystals (which he knew was related to their ability to rotate the plane of polarization of plane-polarized light). He succeeded in solving the mystery of racemic acid when he found that the sodium ammonium salt of racemic acid could be crystallized to produce a crystal conglomerate. After physical separation of the macroscopic enantiomers with a dissecting needle, Pasteur... 

Amines with three different substituents are potentially chiral because of the pseudotetrahedral arrangement of the three groups and the lone-pair electrons. Under normal conditions, however, these enantiomers are not separable because of the rapid inversion at the nitrogen center. As soon as the lone-pair electrons are fixed by the formation of quaternary ammonium salts, tertiary amide N-oxide, or any other fixed bonding, the inversion is prohibited, and consequently the enantiomers of chiral nitrogen compounds can be separated. 

The maximum observed free energy difference between two enantiomeric host-guest complexes in which one 1,1 -dinaphthyl element is the only source of chirality in the crown ether is about 0.3 kcal mol-1. Improvement of the free energy difference can be achieved by introduction of two such elements. Unfortunately crown ethers with three 1,1 -dinaphthyl groups did not form complexes with primary ammonium salts (de Jong et al., 1975). The dilocular chiral crown ether [294] forms complexes of different stability with R- and 5-cr-phenylethylammonium hexafluorophosphate. The (J )-J J -[284] complex was the more stable by 0.3 kcal mol-1 at 0°C (EDC value 1.77) (Kyba et al., 1973b). Crown ether [284] also discriminates between the two enantiomers of phenylglycine methyl ester hexafluorophosphate and valine methyl ester... 

Carnitine is a vitamin-like quaternary ammonium salt, playing an important role in the human energy metabolism by facilitating the transport of long-chained fatty acids across the mitochondrial membranes. An easy, fast, and convenient procedure for the separation of the enantiomers of carnitine and 0-acylcarnitines has been reported on a lab-made teicoplanin-containing CSP [61]. The enantioresolution of carnitine and acetyl carnitine was enhanced when tested on a TAG CSP, prepared in an identical way [45]. Higher a values were reached also in the case of A-40,926 CSP [41]. 

An elegant four-enzyme cascade process was described by Nakajima et al. [28] for the deracemization of an a-amino acid (Scheme 6.13). It involved amine oxidase-catalyzed, (i )-selective oxidation of the amino acid to afford the ammonium salt of the a-keto acid and the unreacted (S)-enantiomer of the substrate. The keto acid then undergoes reductive amination, catalyzed by leucine dehydrogenase, to afford the (S)-amino acid. NADH cofactor regeneration is achieved with formate/FDH. The overall process affords the (S)-enantiomer in 95% yield and 99% e.e. from racemic starting material, formate and molecular oxygen, and the help of three enzymes in concert. A fourth enzyme, catalase, is added to decompose the hydrogen peroxide formed in the first step which otherwise would have a detrimental effect on the enzymes. 

The enantioselective binding properties of certain chiral crown ethers have been employed in the resolution of amino add racemates. The racemic amino ester is adsorbed onto silica gel as its ammonium salt and eluted by a chloroform solution of the chiral crown ether. An excellent separation of the two enantiomers is achieved by this method (74JA7100). 

Through luck, in 1848, Louis Pasteur was able to separate or resolve racemic tartaric acid into its (+) and (—) forms by crystallization. Two enantiomers of the sodium ammonium salt of tartaric acid give rise to two distinctly different types of chiral crystal that can then be separated easily. However, only a very few organic compounds crystallize into separate crystals (of two enantiomeric forms) that are visibly chiral as are the crystals of the sodium ammonium salt of tartaric acid. Therefore, Pasteur s method of separation of enantiomers is not generally applicable to the separation of enantiomers. 

The first method, resolution, is unattractive unless both enantiomers are useful in synthesis. In some cases, such as the resolution of dienecarboxylic acid derivatives mentioned earlier (via the phenylethyl-ammonium salt), the resolution is efficient and provides optically pure materials in good yield.39 60,63 In certain cases, the dienyliron complex can be treated with a chiral nucleophile to give a mixture of dia-stereomers which are separated and then reconverted to enantiomerically pure dienyl complex.64 An example of this method is the resolution of complex (27 Scheme 33), via the menthyl ethers (195) and... 

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. 

A similar approach was reported by Lygo and co-workers who applied comparable anthracenylmethyl-based ammonium salts of type 26 in combination with 50% aqueous potassium hydroxide as a basic system at room temperature [26, 27a], Under these conditions the required O-alkylation at the alkaloid catalyst s hydroxyl group occurs in situ. The enantioselective alkylation reactions proceeded with somewhat lower enantioselectivity (up to 91% ee) compared with the results obtained with the Corey catalyst 25. The overall yields of esters of type 27 (obtained after imine hydrolysis) were in the range 40 to 86% [26]. A selected example is shown in Scheme 3.7. Because the pseudo-enantiomeric catalyst pairs 25 and 26 led to opposite enantiomers with comparable enantioselectivity, this procedure enables convenient access to both enantiomers. Recently, the Lygo group reported an in situ-preparation of the alkaloid-based phase transfer catalyst [27b] as well as the application of a new, highly effective phase-transfer catalyst derived from a-methyl-naphthylamine, which was found by screening of a catalyst library [27c],... 

Some other optical resolution procedures of rac-BNO (14a) by complexation with various chiral ammonium salts are summarized in the section 6 of this chapter as an example of the progress on novel enantiomer separation technique. 

The R and S enantiomers of ammonium salt A can interconvert only by processes that involve breaking a carbon-nitrogen bond. This does not occur easily, and thus, the enantiomers can be separated by formation of diastereomeric salts. 

Although the enantiomers of chiral amines cannot be separated, such amines can be alkylated to form quaternary ammonium salts where the enantiomers can be separated. Once the lone pair of electrons is locked up in a a bond, pyramidal inversion becomes impossible and the enantiomers can no longer interconvert. 

Of course, any tetrahedral atom, not just caibon, that has four different groups bonded to it is a chirality center, and compounds containing such atoms will exist as a pair of enantiomers. Many such compounds have been prepared and resolved, including the following quaternary ammonium salt and the silicon compound ... 

Quaternary ammonium salts with asymmetric nitrogen atoms. Inversion of configuration is not possible because there is no lone pair to undergo nitrogen inversion. For example, the methyl ethyl isopropyl anilinium salts can be resolved into enantiomers. 

Form Supplied in both enantiomers are commercially available as ammonium salts. 

Quaternary ammonium salts of alkaloids have been used for the synthesis of optically active oxiranes from electron-poor olefins under phase-transfer conditions. The enantiomer yield is inversely proportional to the dielectric constant of the solvent,Asymmetric epoxidation in the presence of catalytic amounts of poly-(S)-amino-acids in a triphase system has been described with optical yields up to 96% ... 

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