Putative racemization mechanism

Scheme S.10 Putative racemization mechanism and resolution of XU305 thiopropyl ester.

Gas-phase intracomplex substitution in (R)-(- -)-l-arylethanol/CHs OH2 adducts. It is well established that bimolecular Sn2 reactions generally involve predominant inversion of configuration of the reaction center. Unimolecular SnI displacements instead proceed through the intermediacy of free carbocations and, therefore, usually lead to racemates. However, many alleged SnI solvolyses do not give fully racemized products. The enantiomer in excess often, but not always, corresponds to inversion. Furthermore, the stereochemical distribution of products may be highly sensitive to the solvolytic conditions.These observations have led to the concept of competing ° or mixed SNl-SN2 mechanisms. More recently, the existence itself of SnI reactions has been put into question. ... 

Put another way, epimerization is the mechanistic event, racemization is the observation. True racemization, the actual production of a racemic mixture, is rarely seen in peptide synthesis. Instead, it is the extent of epimerization that defines the stereochemical outcome of a peptide-bond-forming reaction. In order to assess the probability of epimerization under a given set of conditions, one must be aware of the mechanisms of epimerization, as well as the thermodynamic and kinetic factors that affect this process. 

The salts (-l-)-[AsAmylBnEtPh]Br, (-)-[AsBn(n-Bu)EtPh]Cl and (-l-)-[AsBnEt(n-Pentyl)Ph]Br were reported to completely racemize over ca 1 h at 20 °C in chloroform. A dissociation-equilibrium between the salt and the tertiary arsine and alkyl halide was put forward as the mechanism of the racemization, where the alkyl halide was considered to attack the tertiary arsine from the side of the lone-pair (preferred) or from the side of the plane of the three substituents . It was stated that the racemization would be facilitated by raising the temperature due to inversion of the tertiary arsine in line with earlier calculations . This notion of facile dissociation-equilibrium in arsonium salts, first suggested in 1921 and carried through until 1964 , was finally put to rest in 1965, however, when it was shown that the salts (—)-[AsBn( -Bu)EtPh]X (where X = Cl or Br) in chloroform or ethyl acetate were completely stable for days . Moreover,... 

A somewhat different mechanism for the exchange of secondary alcohols and water was put forward by Grunwald et al. (1957) on the basis of results for the exchange and racemization of optically active 1-phenyl-ethanol (2). In OOlN perchloric acid they found exch/ rac = 0 82 004 at two different temperatures. The result is interpreted in terms of the ion pair hypothesis of Winstein and co-workers (1956). It is assumed that the protonated alcohol ionizes to give a planar carbonium ion, but the leaving water molecule does not equilibrate immediately with the solvent. Instead it is held for some finite time in the solvent shell of the carbonium ion, and therefore has a greater chance of being recaptured by the carbonium ion than the water molecules in the bulk of the solution. The chances of return, as compared to escape from the solvent shell, depend... 

Dwyer (2) and Kirschner (3) have attributed this change in rotation to a shift in the equilibrium between the dextro- and /ev -enantiomers of the complex, a shift that occurs because of the presence of an optically active "environment" (the /evo-malic acid) around the complex. Such an equilibrium shift is not possible in the case of optically stable complexes because no equilibrium exists between such enantiomers, as evidenced by the tendency of enantiomers of such complexes to resist racemization in solution for very long periods of time. Other proposals have also been put forth for the mechanism of this Effect, which are described in excellent reviews by Gillard and Williams (4) and Schipper (5), but space does not permit discussing these here. 

Developing this idea, we arrive at the conclusion that the succession of interrupted syntheses and degradations occurring continuously in biological systems may be added to the list of mechanisms which help such systems to evade or correct the racemization process. As Gause (43) puts it, the incessant reconstruction of living matter should.. ., perhaps, be considered as an indispensable condition for the maintenance of the optical purity of stereo-autonomic substances. ... 

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