Proton abstraction from chiral carbon atoms

Each act of proton abstraction from the a-carbon atom converts a chiral molecule to an achiral enol or enolate anion. Careful kinetic studies have established that the rate of loss... 

The presence of a second nucleophile in the reaction mixture reduces the concentration of the O-acylisourea and thereby the extent of racemization. Also, HOBt, a weak acid, prevents proton abstraction from the chiral carbon atom and thus contributes to the conservation of chiral purity in a second manner as well. Last, but not least the availability of the auxiliary nucleophile (HOBt) efficiently shortens the lifetime of the overactivated O-acyl-isourea intermediate and thus diminishes the extent of O N acyl-migration leading to... 

Various side chains affect the extent of racemization in different ways. Thus, the benzyl side chain in phenylalanine contributes to the stabilization of a carbanion and can thereby facilitate proton abstraction from the a-carbon atom. This effect is much more pronounced in phenylglycine (which is not a protein constituent but occurs in microbial peptides) because its chiral carbon atom is benzylic ... 

Proton abstraction from the chiral carbon atom can be suppressed by the addition of weakly acidic materials to the reaction mixture. From the numerous additives tested 1-hydroxybenzotriazole (Konig and Geiger 1970 a) and N-hy-droxysuccinimide (Weygand et al. 1966) are routinely used in the practical execution of coupling. These compounds are not acidic enough to protonate the amino group... 

When the humulinic acids are formed either from humulone or from the isohumulones, the ratio of (+) cis (-) trans is 7 3 (35). The percentage of cis humulinic acid decreases as a function of time to ca. 10% of the mixture. Conversion of cis to trans humulinic acid may occur via proton abstraction or via enolizatlon at both chiral centres. This means that the four stereo-isomers may be interconverted. When only one chiral carbon atom is epimerized, isomerization is the result. There is no loss of optical activity when the epimerization occurs at C-4, while inversion at C-5 causes racemization. Isomerization at both centres will be accompanied by racemization. Humulone must be converted first to the isohumulones, which further may be deacylated to the humulinic acids (36). In principle, this reaction can start from both epimeric isohumulones, but cis isohumulone is hydrolyzed much faster than trans isohumulone. In fact, hydrolysis of trans isohumulone is only observed in conditions, whereby trans isohumulone is epimerized to cis isohumulone. This phenomenon does not exclude direct hydrolysis, but the fraction of trans isohumulone, that is converted via the cis epimer, will probably be much higher. Up to pH 12 hydrolysis is slower than epimerization, while above pH 12 the formation of humulinic acids increases much faster than epimerization. As a consequence, it is possible to obtain a rather high conversion rate of trans to cis isohumulone without appreciable degradation. 

The central event in an epimerization reaction is the removal of a proton from the chiral a-carbon of an amino acid residue. This event generates an enolate with a trigonal planar carbon atom. Replacement of the proton on the face opposite from which it was abstracted results in the inversion of the configuration of the a-carbon. In theory, this event can occur at any stage of peptide synthesis. In practice, however, epimerization is observed almost exclusively during the amide-bond-formation step. This discussion will be confined to that type of epimerization. 

Now when the proton gets attached to the same carbon centre, it can attach itself from the front as well as from the back thereby losing optical activity. Hence racemizes. In the case of ketone (B) there is a group CH2 in between the chiral centre and the carbonyl group. Hence such racemization in basic solution is ruled out as the hydrogen atom at the chiral centre in (B) is not acidic enough to be abstracted. 

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