Methylbenzylamine, resolution

As 29 had been recognized as the most accessible starting-material for the synthesis of racemic carba-sugars, its resolution was successfully achieved with optically active a-methylbenzylamine as chiral reagent. Reaction of 29 with (-l-)-a-methylbenzylamine gave a mixture of two diastereoisomeric salts [(+)-amine, (—)-29 and (+)-amine, (-l-)-29], which were well separated, and the former salt was converted into (—)-29, [a] -111.8° (ethanol). Analogously, (+)-29, [a] +110.7° (ethanol), was obtained. ... 

All sixteen of the racemic carba-sugars predicted are known, as well as fifteen of the enantiomers. The most accessible starting-material for the synthesis of racemic carba-sugars is the Diels-Alder adduct of furan and acrylic acid, namely, e i o7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylicacid (29). Furthermore, adduct 29 is readily resolved into the antipodes, (—)-29 and (+)-29, by use of optically active a-methylbenzylamine as the resolution agent. The antipodes were used for the synthesis of enantiomeric carba-sugars by reactions analogous to those adopted in the preparation of the racemates. 

The use of dissociable diastereomers for enantiomer resolution may be illustrated by the case where racemic mandelic acid is resolved using en-antiomerically pure a-methylbenzylamine. The n and p salts of a-methylbenzyl-amine mandelate have aqueous solubilities of 49.1 and 180 g/L, respectively, at 25°C [153], A more recent example, which focuses on the crystallographic origin of the solubility differences, is provided by the resolution of ( )-mandelic acid with (-)-ephedrine in water or methanol solution [154], In general, the relative solubilities of the n and p salt pairs are strongly influenced by the choice of solvent medium and temperature, which provide considerable flexiblity in optimizing the crystallization conditions and the efficiency of resolution. This process may be facilitated by the development of a full solubility phase diagram. 

A similar sequence was reported where the asymmetry was introduced by the reaction of weio-3-substituted glutanc anhydrides and (S)-methylbenzylamines to give diastereomeric hemiamides that could be separated by recrystallization The asymmetnc desymmetrization of certain 4-aryl substituted glutanmides has also been accomplished with high levels of selectivity (up to 97% ee) by enolization with a chiral bis-lithium amide base. The selectivity of the reaction was shown to be the result of asymmetric enolization, followed by a kinetic resolution." ... 

The integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100% yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz, in 1996, first reported the DKR of rac-2-methylbenzylamine using Candida antarctica lipase B and vinyl acetate with palladium on carbon as the racemization catalyst [20]. The reaction was carried out at 50°C over 8 days to give the (S)-amide in 99% ee and 64% yield. Rather surpris-... 

As the Diels-Alder cyclic adduct 33 has been recognized as the most accessible starting compound for the synthesis of racemic pseudo-sugars, a resolution of 33 has been attempted to prepare enantiomeric pseudo-sugars, starting from an optically active antipode of 33. It has been revealed that 33 was readily separated into the enantiomers by using optically active a-methylbenzylamines as resolution reagents. 

More recently, a facile synthesis of 126 and pseudo-a-L-glucopyranose (137) has been described [32], When the bromolactone 38 was heated with glacial acetic containing hydrogen bromide and subsequently acetylated, DL-(l,3,5/2,4)-2,3-diacetoxy-4,5-dibromocyclohexane-l-carboxylic acid (130) was obtained [31], Resolution of 130 with optically active a-methylbenzylamines provided the enantiomer (131), m.p. 

J.-S. Shin and B.-G. Kim, Kinetic modeling of cotransamination for enzymic kinetic resolution of a-methylbenzylamine,... 

Table 2 shows the result of examinations for the derivatives of a-methylbenzylamine. As can be seen, the salt of a-methylbenzylamine with cinnamic acid forms the crystals of a racemic mixture (Figure 5), and optical resolution by preferential crystallization can be possible in the form of this salt.8 Jacques and his co-authors have listed up 248 examples of organic conglomerates.1... 

Nohira, H., Kai, M., Nohira, M., Nishikawa, J., Hoshiko, T. and Saigo, K. (1981) Optical resolution of a-methylbenzylamine and l-phenyl-2-(/ -tolyl)ethylamine by preferential crystallization, Chem. Lett., 1981, 951-952. 

Another classic resolution process developed by Ethyl Corp. for (S)-ibuprofen production uses (S)-(-)-a-methylbenzylamine (MAB) as the chiral base for diastereomeric salt formation 49 The difference in solubility between (S)- and (ft)-ibuprofen MAB salts is so substantial that only half an equivalent of MAB is used for each mole of racemic ibuprofen, and no seeding is needed. The process can also be performed in a wide range of solvents, and the unwanted (ft)-ibuprofen can be recycled conveniently by heating the mother liquor in sodium hydroxide or hydrochloric acid. Other designer amines have been developed for resolution of ibuprofen with good stereoselectivities,50 but these chiral amines were prepared specifically for ibuprofen resolution and are thus unlikely to be economical for industrial production. 

Although the earliest syntheses of the Corey lactone, using a cyclopentadienyl-thallium species, were not very attractive, it was soon found that the lactone could be usefully generated by a Baeyer-Villiger reaction on a bicycloheptenone.8 In turn, this derives from an easy [2 + 2] cycloaddition reaction between dichloroketene and cyclopentadiene (Scheme 30.2).9 Additionally, an intermediate of the lactone could be resolved by way of the a-methylbenzylamine salt of its opened hydroxyacid, bringing the resolution step earlier in the synthesis than previously.10... 

Reagent for the Resolution of Carboxylic Acids. Reagent (1) and its enantiomer have been used, although not as extensively as the more common (S)-a-Methylbenzylamine, as resolving agents for carboxylic acids via fractional crystallization of the corresponding diastereomeric salts. Examples of acids resolved this way include (2)-(6). Additional examples, such as man-delic, hydratopic, and a-aryloxypropionic acids, can be found in the literature. ... 

Resolution of Asymmetric Aldehydes. The resolution of the aldehyde-containing natural product ( )-gossypol has been accomplished by chromatographic separation of (7), the diastereomeric condensation product between (1) and gossypol hexaacetate. Other chiral primary amines commonly used for the resolution of aldehydes and ketones by physical separation of diastereomeric imines include 2-amino-1-butanol, a-methylbenzylamine, and Betti s base (8). ... 

Write out a scheme for the resolution of the two enantiomers of racemio lactic acid [CH3CH(OH)COOH] using (R)-a-methylbenzylamine as resolving agent. 

Based on chiral functional monomers such as (15) in Table 5.6C MIPs capable of chiral resolution can be prepared using a racemic template. Thus, using racemic N-(3,5-dinitrobenzoyl)-a-methylbenzylamine (16 in Table 5.6C) as template, a polymer capable of racemic resolution of the template was obtained [86]. Another chiral monomer based on L-valine (17) was used to prepare MIPs for the separation of dipeptide diastereomers [94]. In these cases, the configurational chirality inherent in the pendant groups of the polymer are to some extent themselves chiral selectors and the effect of imprinting is merely to enhance the selectivity. Alternative approaches to imprint peptides via strong monomer-template association have recently been... 

Figure 9 Kinetic resolution of a-methylbenzylamine using an w-aminotrans-ferase.

Resolution of diastereomeric amides by preparative HPLC has been developed for a-branched alkanoic acids, and has been employed to prepare dimethyl branched alkanes implicated in tsetse fly sexual communication (6). In much of our own work we have made use of fractional crystallization whereby racemic acids are converted to amides of either (R)- or (S)-ot-methylbenzylamine. These amines are available from Hexcel Corp., Zeeland, MI, and the diastereomeric amides can be analyzed for purity chromato-graphically. 

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