Crystallization-induced diastereomer

Diastereoselective Slrecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an In situ crystallization-induced asymmetric transformation, whereby one diastereomer selecliveiy precipitates and can be isolated in 76-33% yield and dr > gsti. The diastereomeilcaily pure a-amino nitrtie obtained from pivaidehyde (R, = t-Bu, Rj = H) was converted in three steps to (S)-tert-leucine in 73% yieid and >98% ee. 

The observed diastereoselectivity in the asymmetric Strecker step via the crystallization-induced asymmetric transformation can be explained as shown in Figure 2. Apparently, the re face addition of CN to the intermediate imine 4 is preferred at room temperature in methanol and results in a dr 65/35. At elevated temperatures in water, the diastereomeric outcome and yield of the process are controlled by the reversible reaction of the amino nitriles 3 to the intermediate imine and by the difference in solubilities of both diastereomers under the applied conditions. . .. 

Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and... 

Overview. To solve these problems, we present the first example of a crystallization-induced asymmetric transformation using optically pure (R)-phenylglycine amide 1 as a chiral auxiliary. The (R,S)-3 diastereomer precipitates out of solution in 76-93% yield with a diastereomeric ratio (dr) > 99/1. (106 words)... 

As mentioned, asymmetrically pure compounds are important for many applications, and many different strategies are pursued. However, in spite of many methods being developed, the classic resolution technique of diastereomeric crystallization is still preferentially used to prepare optically active pure compounds in bulk quantity. Crystallization is commonly used in the last purification steps for solid compounds because it is the most economic technique for purification and resolution. Attempts to achieve crystallization after completed reaction without workup and extraction is called a direct isolation process. This technique can be cost-effective even though the product yield obtained is lower. Special conditions may be needed in this case, and the diastereomers can be classified into two types diastereomeric salts and covalent diastereomeric compounds, respectively. Diastereomeric salts can, for example, be used in the crystallization of a desired amine from its racemic mixture using a chiral acid. Covalent diastereomers can, on the other hand, be separated by chromatography, but are more difficult to prepare. Another advantage of crystallization is the possibility of combining in situ racemi-zation reactions and diastereomeric formation reactions to get the desired pure compounds. This crystallization-induced resolution technique is still under development because of its requirements for optimized conditions [55, 56],... 

The dynamic crystallization-induced diastereomeric resolution was further investigated in order to develop practical approaches to obtain one diastereomer by exploiting more diversity of the diastereomeric nitroaldol adducts in the dynamic system [77]. A larger and more diverse dynamic nitroaldol system (CDS-5C) was generated by equimolar amounts of nine different benzaldehydes, nitroethane 38, and triethylamine was used as catalyst as shown in Scheme 15. A total of 36 nitroaldol diastereomers were formed under thermodynamic control in chloroform-d, and the reaction was followed by H-NMR spectroscopy. 

The desired oxazinone was created by the condensation of 4-fluorophenylglyoxal hydrate 59 with amino alcohol 58. The initial diastereoselectivity of this condensation was 2 1 (60 61). A number of crystallization-induced resolution conditions were examined. The 2 1 mixture could be treated with HCl in IPAC at 70 °C to selectively crystallize the desired diastereomeric hydrochloride salt 61-HCI and concomitantly epimerize the undesired oxazinone diastereomer 60. Overall, the process afforded a 90% yield of oxazinone hydrochloride 61-HCI (98% de). 

Our attempts to obtain a crystalline oxazolidinone were eventually successful with the (L)-iV-i-butoxycarbonyl derivatives and 4 -biphenylcarboxaldehyde, leading to 29d,[26] In solution, flie typical 85 15 equilibrium ratio of cis and trans diastereomers is observed (Table I, entry 4), When the solvent was partially removed and the residue suspended in teft-butyl methyl ether, an off-white solid precipitated, which consists of pure cw-29d in 88% yield. Analysis of the mother liquors shows very minor amounts of cis and trans product in a 85 15 ratio, along with some unreacted carbamate and a,a-dichloro biphenyl. The presence of both cis and trans isomers in the mother liquor is clear evidence that a crystallization-induced asymmetric transformation is responsible for the high selectivity. 

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. 

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