Diastereomers salt formation

Sulfoxides were first prepared in optically active form in 1926 by the classical technique of diastereomeric salt formation followed by separation of the diastereomers by recrystallization16 17. Sulfoxides 1 and 2 were treated with d-camphorsulfonic acid and brucine, respectively, to form the diastereomeric salts. These salts were separated by crystallization after which the sulfoxides were regenerated from the diastereomers by treatment with acid or base, as appropriate. Since then numerous sulfoxides, especially those bearing carboxyl groups, have been resolved using this general technique. 

Alternative synthetic approaches include enantioselective addition of the organometallic reagent to quinoline in the first step of the synthesis [16], the resolution of the racemic amines resulting from simple protonation of anions 1 (Scheme 2.1.5.1, Method C) by diastereomeric salts formation [17] or by enzymatic kinetic resolution [18], and the iridium-catalyzed enantioselective hydrogenation of 2-substituted quinolines [19]. All these methodologies would avoid the need for diastereomer separation later on, and give direct access to enantio-enriched QUINAPHOS derivatives bearing achiral or tropoisomeric diols. Current work in our laboratories is directed to the evaluation of these methods. 

Enantiomerically pure mandelic acid has also been prepared by resolution of the racemic substance through the formation of a dissociable diastereomer with ephedrine [5]. In a typical preparation, 12 g of (L)-ephedrine and 12 g of racemic mandelic acid are heated together in 40 mL of 90% ethanol. The diastereomer salt is obtained upon cooling of the solution, and may be purified by recrystallization from a small volume of alcohol. )-... 

Compounds other than organic bases, acids, or alcohols can also be resolved. Although the particular chemistry may differ from the salt formation just described, the principle remains the same a racemic modification is converted by an optically active reagent into a mixture of diastereomers which can then be separated. 

Approaches for resolution by crystallizing0 Entrainment Generate diastereomers by salt formation or covalent modification NA... 

In the case of the salt of a racemic acid and a racemic amine, six crystal modifications are possible (Table 5.7), while there are three crystal modifications for the salt of a racemic acid or amine with an enantiopure amine or acid (Table 5.8). If the successful enantioseparation of an amine with an enantiopure acid by diastereomeric salt formation is assumed, the diastereomers in Table 5.8 should obviously be more stable than the double salt and pseudo-diastereomer. Then, the diastereomers in Table 5.7 should be more stable than the other crystal modifications. On the other hand, this assumption leads to the conclusion that the solubilities of the diastereomers in Table 5.8 are largely different from each other. This... 

Diastereomeric relationships provide the basis on which a number of important processes depend. Resolution is the separation of a mixture containing equal quantities of enantiomers (termed a racemate or racemic mixture) into its components. Separation is ordinarily effected by converting the mixture of enantiomers into a mixture of diastereomers by treatment with an optically active reagent (the resolving agent). Since the diastereomers will have different physical and chemical properties, they can be separated by conventional methods and the enantiomers regenerated in a subsequent step. An example of this method is shown in Scheme 2.2 for the resolution of a racemic carboxylic acid by way of diastereomeric salt formation using an optically active amine. The / -acid-/ -amine and S-acid-/ -amine salts are separated by fractional recrystallization, and the resolved carboxylic acid is freed from its amine salt by acidification. 

It can be frequent observed at the fractionated crystallization of diastereomeiic salts that the crystalline diastereomer forms solvate with the solvent. As an example can be mentioned the first ever resolution by salt formation accomplished by Pasteur wher the "d-quinotoxine-d-tartrate" obtained was a hexahydrate. Of course it can be foimd numerous similar examples in the literature. s... 

The authors developed a scalable route for the synthesis of the intermediate core 45 in 12 steps and 0.4% yield and successfully implemented at a pilot plant scale. In this multistep synthesis, racemic hydantoin 43 was obtained after crystallization in 4 1 mixture of diastereomers. Separation of enantiomers by diastereomeric salt formation with (/ )-2-phenylglycerol and further crystallization followed by salt break gave single isomer (-)-44, with the targeted l-glutamic acid configuration. 

Of the methods to prepare single enantiomers, resolution by preparation of the diastereomers from the racemic mixture and then separation of the diastereomers followed by regeneration of the single enantiomer might be the most common. If the racemic mixture has either acidic or basic functionality, this can be accomplished by salt formation. For example, in the synthesis of levothyroxine, used to treat hypothyroidism, the chiral center is resolved at an intermediate stage. The intermediate is a racemic mixture and has a carboxylic acid fimctionality. When the racemic mixture is treated with a chiral amine to form the ammonium carboxylate, two diastereomers are formed. These can be separated and then the carboxylic acid of the single enantiomer regenerated by treatment with acid. 

Some chiral resolving agents have been developed for the derivatization of racemic carboxylic acids to form pairs of diastereomers, which can be separated by conventional methods such as recrystallization. However, in some cases, this process requires several repetitions of salt formation between a carboxylic acid and an amine followed by recrystallization and subsequent separation of the chiral auxiliaries from the acid component to obtain a pure enantiomer. On the other hand, the conversion of a racemic substrate to enantioenriched products, commonly referred to as a kinetic resolution, is also an established method with broad applications [30, 31]. 

Chiral amines have been attracting attention as an important composition, particularly for pharmaceutical products. The organic synthetic methods of optically active amine compounds have been developed through the traditional resolution of racemic amines with the formation of diastereomer salts using an optically active mandelic acid or tartaric acid. Enzymatic synthesis has mainly used lipase and S- or R-stereoselective amine transaminase (AT) [29-31] (Figure 19.7). Turner et al. successfully synthesized chiral (R)- and (S)-amines by kinetic resolution using a combination of stereoselective AT and d- or L-amino acid oxidase (AAOx) [32] (Figure 19.7). However, the theoretical yield of the products has been limited to 50% in the kinetic resolution. 

Racemate resolution methods via diastereomeric salt formation may be classified into the following categories 1) resolution by formation of noncovalent diastereomers (diastereomeric salt formation, diastereomeric complex formation, etc.) and 2) resolution by formation of covalent diastereomers. 

Probably the most popular and the most preferred method for the resolution of organic acids or bases is a chiral resolution via diastereomeric salt formation. Ionic salts are easily formed and easily crystallized, and after the separation process, an enantiomerically pure separated compound may be easily isolated, and the resolving agent can be recovered and reused (Figure 1.37). Resolution via diastereomeric salt formation involves the acid-base reaction of a racemate with an enantiomerically pure resolving agent. The resulting two diastereomers have different physical properties e.g., the difference in solubility is used to separate them by crystallization. 

FIGURE 56.7. Samples with varying diastereomer composition display similar XRPD pattern to that of major diastereomer, indicating that the low ratio of resulting diastereomers after diastereo-mer salt formation crystallization is the result of incorporation of minor diastereomer into the crystal lattice as a solid solution. 

A very attractive approach to produce optically pure compounds economically is to combine diastereomeric salt formation and racemization into a single process. Thus, the overall yield of desired diastereomer can be significantly increased. Kato et al. described a practical synthesis of a... 

Reaction of labeled aryl halomethyl ketones with amines furnishes j8-amino[ C] ketones. If e.p. amines are employed, subsequent reduction of the keto group with achiral reducing agents produces diastereomeric mixtures of )8-amino alcohols. The individual diastereomers can usually be separated by achiral chromatographic methods, or if these fail chiral HPLC procedures or salt formation with a chiral acid (e.g. dibenzoyl-L-tartaric acid) may prove successful. This pathway was followed for the preparation of [ C]dilevalol (12), an antihypertensive agent (Figure 6.8). Within this synthetic sequence the reaction of the a-bromomethyl ketone 8 with e.p. (7 )-Wbenzyl-(l-methyl-3-phenyl)propylamine (2)... 

Thus, in comparison to the situation in most conventional, ground state asymmetric induction reactions, where the chiral auxiliary is intimately involved in the enantiodifferentiating step through its stereoelectronic effects or coordinating ability, the role of the ionic chiral auxiliary in solid state cyclobutanol formation is a relatively passive one. For example, the ionic chiral auxiliary does not need to be located close to the site of reaction and all that is required is that its attachment to the reactant via salt formation does not give rise to diastereomers. In addition, there is no direct correlation between the size and structure of the ionic chiral auxiliary and the extent of ee, nor is it possible to predict which enantiomer of the photoproduct will be favored. This would be akin to making an a priori prediction of crystal and molecular structure, a feat that is currently beyond the scope of modem crj tal engineering. 

When one needs to determine the optical purity of a compound that is not amenable to salt formation (i.e., not a carboxylic acid or amine), analysis by NMR becomes slightly more difficult. It is frequently necessary to determine the enantiomeric excesses of chiral secondary alcohols, for example. In these cases, derivatization of the alcohol through covalent attachment of an optically pure auxiliary provides the mixture of diastereomers for analysis. This requires reacting a (usually small, a few milligrams) sample of sample alcohol with the optically pure derivatizing agent. Sometimes, purification of the products is necessary. In the example shown below, a chiral secondary alcohol is reacted with (5)-2-methoxyphenylacetic acid [(5)-MPA] using dicyclohexylcarbodiimide (DCC) to form diastereomeric esters. After workup, the NMR spectrum of product mixture is acquired, and the res-... 

This encouraging precedent led us to develop new asymmetric syntheses of haiothane (27) and desflurane plus the desflurane analogue "Hoechst s ether" (22). The cornerstone of the second-generation syntheses is stereoselective decarboxylation. In both cases, a chiral halogenated acid derivative was prepared which had the carboxyl group attached directly to the chiral center. Rather than use salt formation and repeated crystallization for resolution of the acids, we chose to form secondary amides and use chromatography for separation of the resulting diastereomers. The diastereomerically enriched amides would then he converted to enantiomerically enriched acids to be used as decarboxylation substrates. 

Since electron-donating substituents at the phosphorus atom favor addition reactions over olefination reactions, addition of 9 to aldehydes leads to the exclusive formation of the silyl-pro-tected allylic alcohols 10. No reaction products arising from Wittig alkenylation could be detected. The ylides (R,S)-9 and (S.S)-9 and their enantiomers were prepared from the corresponding optically pure l-[2-(diphenylphosphino)ferrocenyl]-A,A -dimethylethanamine diastereomers 7 via the phosphonium salts 8. 

D-mannopyranoside [41]. All these anions were isolated as their dimethylam-monium salts in good yields and chemical purity. The presence of the stereo-genic centers of the chiral ligands induces the formation of diastereomers. In essentially all cases, the initial salts are obtained in high diastereomeric purity. Figure 20 shows the diastereomeric ratios and, when known, the relative configuration of the major isolated compounds. 

After identifying the optimal etherification conditions, our attention turned to isolation of 18 in diastereomerically pure form. Diastereomers 18 and 19 were not crystalline, but, fortunately, the corresponding carboxylic acid 71 was crystalline. Saponification of the crude etherification reaction mixture of 18 and 19 with NaOH in MeOH resulted in the quantitative formation of carboxylic acids 71 and 72 (17 1) (Scheme 7.22). Since the etherification reaction only proceeded to 75-80% conversion, there still remained starting alcohol 10. Unfortunately, all attempts to fractionally crystallize the desired diastereomer 71 from the crude mixture proved unfruitful. It was reasoned that crystallization and purification of 71 would be possible via an appropriate salt. A screen of a variety of amines was then undertaken. During the screening process it was discovered that when NEt3 was added... 

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