A Potential Widely Applicable Solution for Resolving Chiral Bases

kilomentor | 28 April, 2009 14:41

The Problem of Resolving Enantiomers of Chiral Basic Compounds does not have a general solution. There is no chiral acidic substance that that quite dependably will form diastereomeric salts that can be separated at useful synthetic scale .

There will probably never be a reagent that will work for resolving every enantiomeric pair but a solution might be closer than is commonly apparent. TABA which is (2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid has been available by an Organic synthesis preparation since 1973. The compound was developed initially to resolve chiral polycyclic aromatic molecules with neither acidic nor basic functional groups. It works by forming diastereomeric charge transfer complexes between the pi donor rings of the chiral polycyclic aromatic racemate and the pi acceptor, electron deficient rings of the TABA reagent.

Subsequently, the enantiomeric TAPA reagents were used to resolve chiral antimalarial agents that had large hydrophobic amine groups that formed salts poorly. [F. Ivy Carroll, Bertold Berrang and C.P. Linn. Resolution of Antimalarial Agents via Complex formation with alpha-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid. J. Med. Chem.. 1978, 21(4) 326-330.]

When the structure of the enantiomers to be resolved has both a primary, secondary or tertiary amine and a potential electron donating ring there are two points of attachment between the enantiomers and the chiral resolving agent increasing the potential for success. In the paper referenced above 5 different compounds were successfully resolved using this pair of (+)-TAPA and (-)-TAPA. No compounds are reported to have failed resolution.

Even when there is no polycyclic aromatic pi donor in the racemic basic material that you are trying to resolve a solution may be possible if the amine is primary or secondary. Introduction of a benzylic protecting group that incorporates such a pi donor might provide a new compound that can be easily resolved. Removal of the benzylic group by hydrogenolysis for example would return the resolved material that is sought.