Hydroxy amines from amino esters

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

The formation of tluorinated Q -hydroxy-jS-imino esters (180) by treatment of fluorinated imino ethers (179) with lithium 2,2,6,6-tetramethylpiperidide has been reported. A possible explanation for this interesting intramolecular rearrangement is proposed in Scheme 64. Acyclic imides derived from primary benzylic amines and amino acid esters have been found to undergo a novel nitrogen to carbon acyl migration via a base-generated carbanion to yield the corresponding a-amino... 

Therefore, in principal, condensation of a primary amine with an enantiomerically pure ketone should allow asymmetric synthesis of a-substituted primary amines. This approach has been applied to the synthesis of a-amino acids, for example, using the imine prepared from a-amino esters and (l.S, 2,S ,5,S )-2-hydroxy-3-pinanone, via an amino-substituted ester enolate anion with some success39 40. Application of this approach to simple primary amines has seldom been reported. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

In addition to the mobile phase composition, the effect of other parameters such as temperature, flow rate, pH, and structure of the analytes were also studied, but only a few reports were available in the literature. In 1995, Lin and Maddox [66] studied the effect of temperature on the chiral resolution of amino acids and esters. The temperature was varied from 5°C to 25°C and it was reported that the resolution improved at low temperature. Hyun et al. [48-50,67] carried out the effect of temperature on the chiral resolution of amino alcohols, amines, fluoroquinolones, and other drugs. Again, lowering of temperature resulted in better resolution. The effect of temperature on the chiral resolution of phenylalanine, phenylglycine, and 2-hydroxy-2-(4-hydroxy-phenyl)-ethyl amine is shown in Table 5 [50], which indicates an increase in retention factors at lower temperature, but the best separation occurred at 20°C. These experiments indicated the exothermic nature of chiral resolution on CCE-based CSPs. Lin and Maddox [66] also studied the effect of flow rate on the chiral resolution of... 

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