Diastereomers Diastereomeric amides, separation

Diastereomeric amides of l,12-dioxa[12]paracyclophanedicarboxylic acid (20, as the first example of diastereomers with a plane of pseudo-asymmetry) could be separated by chromatography on silicagel on the basis of their 1H-NMR spectra tentative configurations were assigned to the amides 38). 

The use of covalent diastereomeric derivatives (e g. amides) is generally precluded by the strong conditions required for their cleavage to obtain the resolved enantiomers, but recently the resolution of 3-amino-l,4 benzodiazepines has been achieved by means of the preparation and separation of diastereomeric phenylalanyl amides [20]. This procedure, which is based upon the reaction of the racemic amine with N-Boc protected phenylalanine, followed by separation of the two diastereomeric amides and subsequent Edman degradation, was also applied to our series [21] and the desired enantiomers were obtained with excellent enantiomeric excess. However the total yield of the process was quite low due to a difficult chromatographic separation of the two diastereomers and the low conversion during the Edman degradation step. 

The imidazolidine-4-one 29, obtained by heating the methanol solution of an a-aminoamide and a 4-substituted benzaldehyde, is a mixture of two diastereomers which can be separated by chromatography. They are oxidized by MCPBA, separately or as a mixture, into the two diastereomeric l-hydroxyimidazolidine-4-ones 30. Hydrolysis of 30 by ethanolic HC1 and hydroxylamine hydrochloride gives the optically pure TV-hydroxyamino acid amide 31 (Scheme 9).[12]... 

The use of a cationic aza-Cope rearrangement in concert with a Mannich cyclization has also been applied to the total synthesis of enantiomerically pure (—)-crinine (359) (205). In the event, nucleophilic opening of cyclopentenoxide with the aluminum amide that was formed on reaction of (/ )-a-methylbenzyl-amine and trimethylaluminum gave the amino alcohol 485 together with its (15,25) diastereomer. Although there was essentially no asymmetric induction in this process, the diastereomeric amino alcohols were readily separated by chromatography, and the overall procedure therefore constitutes an efficient means for the preparation of enantiomerically pure 2-amino alcohols from epoxides. When the hydrochloride salt derived from 485 was treated with paraformaldehyde and potassium cyanide, the amino nitrile 486 was formed. Subsequent Swem oxida-... 

Moreover, it is possible to lead these compounds into the diastereomeric esters or amides using of optically active acid anhydrides. In this case, the diastereomers with a covalent bond need not always necessarily be a crystalline compound because there are still some other methods left to separate these diastereomers, such as thin layer chromatography, high-performance liquid chromatography, etc. 

The knots based on neutral, purely organic molecules are obviously not prone to classical diastereomer resolution, and, while chromatographic methods were not suitable for the separation of the two enantiomers of the metal-templated trefoil knot, they have been proved successful in the amide-containing knots. As far as these knotted molecules are concerned, it must be noted that they incorporate classical stereogenic centers (carbon atoms), which makes them very different from the copper-based systems in terms of chirality. In the first instance, the separation of the two enantiomers of six different knots was achieved with a colunm that was not conunercially available (chiral-AD type). Trichloromethane was needed to obtain an optimal separation. The silica gel and the chiral stationary phase were covalently bound so that the material did not bleed out when the lipophilic eluent was used. Moreover, comparison of the experimental CD of the pure enantiomers of a knot with a theoretically calculated CD (based on X-ray structure and a fiiUy optimized AMI geometry) permitted assignment of the absolute configuration of this knot. The latter preparation of soluble knots based on substitution of the 5-position of the pyridine moieties in 13 afforded molecules that were soluble in solvents which could be used in commercially available chiral columns." On the other hand, the substitution of a racemic mixture of knots with chiral auxiliaries allows the separation of the diastereomeric product." ... 

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. 

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