Chirality leakage

This procednre prodnced crude pyrrolidine acid 3 that was >99.6% trans with an optical purity of 99.5% ee, indicating that there was no chirality leakage in the cyclization-hydrolysis-epimer-ization process. This 3 was isolated by crystallization from IPA/MTBE in 95% yield with 99.97 LCAP purity and >99.9% ee on multi-kg scale. Thns, an efficient direct one-step basic epimeriza-tion-hydrolysis of the pyrrolidine nitrile mixtnre to the trani-pyrrolidine acid 3 was achieved (Scheme 5.28). 

In the case of 1,2-disubstituted alkenes, the nonstereospecificity of the epoxidation reaction results in formation of diastereomeric epoxides. In contrast, for terminal alkenes the trans pathway results in partitioning to enantiomers. Thus, diminished enantiose-lectivity observed in the epoxidation of terminal alkenes such as styrene (50-70% ee) relative to sterically similar cis-disuhstituted alkenes can be attributed to enantiomeric leakage due to the trans pathway. Suppression of this pathway has not been accomplished successfully, and synthetically useful enantioselectivities with terminal alkenes have not yet been achieved using the chiral (salen)Mn systems. 

In both techniques, leakage of the chiral selector into the elute can be completely eliminated by filling the outlet of the column with a proper amount of the CS-free stationary phase so as to absorb the chiral selector leaking into the flowing mobile phase. 

With a parallel kinetic resolution, the two reactions should not interfere with one another. In the example above, both reactions were acylations but the use of stoichiometric reagents meant that the right acylating group was attached to the right enantiomer. Even here, Vedejs does not rule out a small amount of leakage between the paths (once the chiral DMAP is liberated it can get in on the act with the other pathway). A PKR becomes more difficult if, in addition to the reactions being related, they are also catalytic. 

Perhaps there is scope for further developments in CSP in order to more frequently achieve high enough enantioselectivity for facile preparative isolation to be carried out. However, most of the current developments in terms of preparative chiral separations seems to be in developing technolgies for SFC and SMB and, to a lesser extent, CSP in which there is not even an ultra-trace leakage of the chiral selector. 

Over the years, many protocols for the stereoselective reduction of C-C, C-N, and C-0 double bonds have been developed and optimized, providing excellent yields and selectivities. Most of these protocols are based on transition metal catalysts carrying chiral ligands for stereo-induction. Besides the fact that preparation and handling of transition metal catalysts can be challenging and costly, their environmental effect must be taken into account as well. Metal leakage can be problematic, as well as the disposal of toxic waste. In the synthesis of pharmaceuticals, product contamination by traces of catalyst is critical and has to be avoided. ... 

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