Enantioenriched chiral substance

We thought that when i-Pr2Zn was treated with pyrimidine-5-carbaldehyde without adding any chiral substance, extremely slight enantioenrichment would be induced statistically in the initially formed zinc alkoxide of the pyrimidyl aUca-nol, and that the subsequent amplification of chirality by asymmetric autocatalysis would afford the pyrimidyl alkanol with detectable enantioenrichment [Eq. (9.11)]. Indeed, we found that pyrimidyl alkanol with an ee that is above the detection level was formed.Pyrimidine-5-carbaldehyde was reacted with /-Pr2Zn, and the resulting pyrimidyl alkanol was used as an asymmetric autocatalyst for the subsequent asymmetric autocatalysis. The consecutive asymmetric autocatalysis afforded pyrimidyl alkanol of either 5 or 7 configuration with enantiomeric enrichment above the detection level. °... 

The reaction of pyrimidine-5-carbaldehyde 7 and 2-methylpyrimidine-5-carbaldehyde 9 with z-P Zn without adding a chiral substance produced enantioenriched (S)- or ( )-pyrimidyl alkanol 8 and 2-methylpyrimidyl alkanol 10, respectively [102]. 

A chiral substance is enantiopure or homochiral when only one of two possible enantiomers is present. A chiral substance is enantioenriched or heterochiral when an excess of one enantiomer is present but not to the exclusion of the other. If the desired product is an enantiomer, the reaction needs to be sufficiently stereoselective even when atom economy is 100%. For the biological usage we almost need one enantiomer and in high purity. This is because when biologically active chiral compounds interact with its receptor site which is chiral, the two enantiomers of the chiral molecule interact differently and can lead to different chemistry. For example, one enantiomer of asparagines (1.37) is bitter while the other is sweet. As far as medicinal applications are concerned, a given enantiomer of a drug may be effective while the other is inactive or potentially harmful. For example, one enantiomer of ethanbutol (1.38) is used as antibiotic and the other causes blindness. 

A chiral substance is enantioenriched or heterochiral when an excess of one enantiomer is present but not to the exclusion of the other. 

The reaction of pyrimidine-5-carbaldehyde 2 and 2-methylpyrimidine-5-carbaldehyde with t-Pr2Zn without adding a chiral substance produced enantioenriched (S)- or (/ )-pyrimidyl alkanol 2 and 2-methylpyrimidyl alkanol, respectively [49]. When 2-alkynylpyrimidine-5-carbaldehyde 2 reacted with j-Pr2Zn in a mixed solvent of ether and toluene, the subsequent raie-pot asynunetric autocatalysis with amplification of ee gave enantiomerically enriched pyrimidyl alkanol 1 whose ee was well above the detection level [50], The absolute configurations of the pyrimidyl alkanol 1 exhibit an approximate stochastic distribution of S and R enantiomers (formation of S 19 times and / 18 times). 

In November 1997, the Department of Health and Human Services along with the International Conference on Harmonisation (ICH) released a draft guidance for the selection of test procedures, which included chiral drugs. For the development of an enantiopure drug substance, acceptable criteria shall include, if possible, an enan-tioselective assay. This assay should be part of the specification for the identification of an enantiopure drug substance and related enantioenriched impurities [16]. 

The discovery of chirality, during the last century, necessitated that chemists concern themselves with developing methods to obtain enantioenriched substances. The importance of chirality is underscored by the fact that nearly all natural products are chiral and that their physiological or pharmacological properties depend upon their recognition by chiral receptors. These chiral receptors will interact only with molecules of the proper absolute configuration. 

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