Diastereomers crystallization

Cleavage of the acetals 9 provides crystalline amino diol hydrochlorides. Remarkably, the (S.S.S)-diastereomer crystallized preferentially leading to a considerable enhancement of d.r. values. 

If one of two equilibrating diastereomers crystallizes out of solution, shifting the equilibrium in one direction, the process is referred to as an asymmetric transformation of the second kind lUPAC Compendium of Chemical Technology, 2nd Edition, Mc-Naught, A. D., Wilkinson, A., Eds. Blackwell Science, 1997. 

A second method requires the formation of diastereomeric salts or covalent derivatives, which are in a mobile equilibrium in solution ( First-Order Asymmetric Transformation"). Again, one of the diastereomers crystallizes ( Second-Order Asymmetric Transformation ). 

Remarkably, in the equilibrium mixtures, the less abundant diastereomer crystallizes (Tabic 12). A more recent example for a configurationally labile organolithium derivative has been reported49. A conceptually different approach starts with a meso-compound containing two enantiotopic functional units (A). 

In case the racemate is a true racemic mixture, this cannot be separated by preferential crystallization, but can be resolved using the diastereomer crystallization developed by Pasteur in 1848. A solution of the racemic mixture in water or methanol is allowed to react with a pure enantiomer (resolving agent), thereby forming a mixture of diastereomers that can be separated by crystallization. 

What about the (17 S,3S7 )-epimeric diastereomers that contain a C(3)-methyl cis to the phenyl group Like their irons analogs discussed above, a solution of the cis compound should contain the two TV-methyl diastereomers as a (17 , 3 7 ,57 r) racemic mixture (see 26 in Fig. 9) and a (17 S,3S7 ,5S7 ) racemic mixture (see 27 in Fig. 10). The mixture of two racemic diastereomers crystallizes as a racemic compound of only 27 in an achiral crystal. Torsion angles for the (IS,37 ,57 )-enantiomer are given in X-ray structure 27. X-ray crystallographic structure analysis of these crystals shows them to have two symmetry unrelated molecules in... 

Process options for the production of homochiral compounds are summarized in Fig. 2. The three basic routes are separation of racemic mixture, synthesis using a naturally occurring chiral synthon, and asymmetric synthesis using a prochiral intermediate. Historically, the efficiency of asymmetric synthesis has been capricious in terms of chemical and optical yield. Hence, from a practical, commercial process perspective, resolution via diastereomer crystallization has remained important for many commercial scale processes, for example, diltiazem. 

At present, the resolution of racemates via dassical diastereomer crystallization as a method of chiral target production is somewhat hampered by a rapid development of other methods, mainly asymmetric synthesis, including biocatalysis [9] and enantioselective chromatography [11], Diastereomer crystallization remains, however, an important technique because of its two fundamental advantages, especially attradive for industry. First, process development (practical know-how and accessibility to wide libraries of the resolving agents) is usually fast and easy. Second, the cost is often low compared to other methods. 

As with ephedrine, chiral resolution can be achieved for 2,2 -ninaphthy 1-1,1 -diamine (DABN) (29) through diastereomer crystallization. Equal molar quantities (0.19mmol) of (i )-DABN, (5)-DABN, and (R)-camphorsulfonic acid (CSA) were first dissolved in methanol (40 mL). The resulting solution was pumped at low flow rates together with CO2 (10 mL/... 

The atropisomers of 336 were resolved by diastereomer crystallization with (S)-a-phenethylamine. The ee of the process can be monitored by chiral HPLC after methylation of the acids. X-ray structure analysis allowed the assignment the R configuration to the (+) enantiomer. The absolute configuration was also confirmed by comparison of the experimental CD spectra using ethanol with the ZINDO calculated one. 

The next laboratory period (4th day of lab experiment), collect the (S, R) diastereomer crystals (some of the (R, R) diastereomer is also present) by vacuum filtration using a Buchner funnel or Hirsch funnel. Rinse the solid in the funnel with about 1 mL of ice-cold methanol. Dry the solid on the Buchner funnel or Hirsch funnel, under vacuum, for several minutes. Pour the remaining filtrate into a bottle that... 

Conversely, when A-alkyl tryptophan methyl esters were condensed with aldehydes, the trans diastereomers were observed as the major products." X-ray-crystal structures of 1,2,3-trisubstituted tetrahydro-P-carbolines revealed that the Cl substituent preferentially adopted a pseudo-axial position, forcing the C3 substituent into a pseudo-equatorial orientation to give the kinetically and thermodynamically preferred trans isomer." As the steric size of the Cl and N2 substituents increased, the selectivity for the trans isomer became greater. A-alkyl-L-tryptophan methyl ester 42 was condensed with various aliphatic aldehydes in the presence of trifluoroacetic acid to give predominantly the trans isomers. ... 

A -sulfinyl chiral auxiliaries have been used to prepare enantiopure tetrahydro-P-carbolines and tetrahydroisoquinolines in good yields under mild reaction conditions. Both enantiomers of V-p-toluenesulfinyltryptamine 46 could be readily prepared from the commercially available Andersen reagents.Compound 46 reacted with various aliphatic aldehydes in the presence of camphorsulfonic acid at -78 °C to give the A-sulfinyl tetrahydro-P-carbolines 47 in good yields. The major diastereomers were obtained after a single crystallization. Removal of the sulfinyl auxiliaries under mildly acidic conditions produced the tetrahydro-P-carbolines 48 as single enantiomers. 

In the third sequence, the diastereomer with a /i-epoxide at the C2-C3 site was targeted (compound 1, Scheme 6). As we have seen, intermediate 11 is not a viable starting substrate to achieve this objective because it rests comfortably in a conformation that enforces a peripheral attack by an oxidant to give the undesired C2-C3 epoxide (Scheme 4). If, on the other hand, the exocyclic methylene at C-5 was to be introduced before the oxidation reaction, then given the known preference for an s-trans diene conformation, conformer 18a (Scheme 6) would be more populated at equilibrium. The A2 3 olefin diastereoface that is interior and hindered in the context of 18b is exterior and accessible in 18a. Subjection of intermediate 11 to the established three-step olefination sequence gives intermediate 18 in 54% overall yield. On the basis of the rationale put forth above, 18 should exist mainly in conformation 18a. Selective epoxidation of the C2-C3 enone double bond with potassium tm-butylperoxide furnishes a 4 1 mixture of diastereomeric epoxides favoring the desired isomer 19 19 arises from a peripheral attack on the enone double bond by er/-butylper-oxide, and it is easily purified by crystallization. A second peripheral attack on the ketone function of 19 by dimethylsulfonium methylide gives intermediate 20 exclusively, in a yield of 69%. 

Oxidation of the methyl substituent in compounds 4 to the corresponding aldehydes and subsequent reaction with ephedrine leads to (V.O-acetals, which can be separated by crystallization into the two diastereomers. Treatment with silica gel then gives the enantiomerically pure aldehydes.17... 

Even acetophenone reacts with the magnesium compound 17 (R1 = R2 = H) to yield the w-diastereomer 18 with 90 % de 22 24. The structure of the metal-organic precursor and, as well, of the major product was determined by an X-ray crystal structure analysis23. 

Another route to enantiomcrically pure iron-acyl complexes depends on a resolution of diastereomeric substituted iron-alkyl complexes16,17. Reaction of enantiomerically pure chloromethyl menthyl ether (6) with the anion of 5 provides the menthyloxymethyl complex 7. Photolysis of 7 in the presence of triphenylphosphane induces migratory insertion of carbon monoxide to provide a racemic mixture of the diastereomeric phosphane-substituted menthyloxymethyl complexes (-)-(/ )-8 and ( + )-( )-8 which are resolved by fractional crystallization. Treatment of either diastereomer (—)-(/J)-8 or ( I )-(.V)-8 with gaseous hydrogen chloride (see also Houben-Weyl, Vol 13/9a, p437) affords the enantiomeric chloromethyl complexes (-)-(R)-9 or (+ )-(S)-9 without epimerization of the iron center. 

Although it is claimed that the Strecker reaction of 2 results in the exclusive formation of one isomer of 3 and that selective elimination of the minor isomer during isolation of the intermediate compound 4 is not possible, it is apparent that during the workup of the hydrolysis product 4, fractional precipitation or crystallization or other separation of the diastereomers may... 

Interestingly, when R1 and R2 are hydrogens, the -configurated amino nitriles 1 arc obtained, whereas one or two methoxy substituents on the aromatic ring leads to (S)-diastereomers. This surprising effect is caused by the preferential crystallization of the (R)- or the (.S )-diastereomers, respectively. If the pure diastereomers of 1 are dissolved in methanol, equilibration occurs. On concentration, the optically pure diastereomer again crystallizes from the solution45. 

Usually, the reaction is carried out at 60 °C in methanol. After addition of acetic acid and on cooling, the diastereomerically pure amino nitrile crystallizes from the reaction mixture. If crystallization docs not occur, the mixture is stirred in the open vessel until precipitation of the pure diastereomer takes place. 

The method is very useful for the synthesis of physiologically interesting a-mcthylamino acids, e.g., methyl dopa from the 3,4-dimethoxybenzyl derivative. The excellent stereoselection achieved in the process, however, is caused by the preferential crystallization of one pure diastereomerfrom the equilibrium mixture formed in the reversible Strecker reaction. Thus, the pure diastcrcomers with benzyl substituents, dissolved in chloroform or acetonitrile, give equilibrium mixtures of both diastereomers in a ratio of about 7 347. This effect has also been found for other s-methylamino nitriles of quite different structure49. If the amino nitrile (R1 = Bn) is synthesized in acetonitrile solution, the diastereomers do not crystallize while immediate hydrolysis indicates a ratio of the diastereomeric amino nitriles (S)I(R) of 86 1447. 

The shielding effect of the vicinal phenyl substituent accounts for the favored attack of the cyanide from the opposite direction, giving rise to the (S)-diastereomers. However, it should be noted that imines of aliphatic aldehydes which bear an odd number of carbons in the main side chain surprisingly give (/ )-diastereomcrs, concluded from ORD data48. This opposite stereochemical course in the formation of these compounds has not been explained48. It might simply be due to crystallization of the (R)-diastereomer which continuously shifts the equilibrium (vide supra). 

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