Resolution without resolving agents by use of preferential enrichment and attrition induced grinding
Two techniques for separation of racemateswithout aid of external chiral sources are discussed.The techniques are based on the natural occurrenceof conglomerates. The first is very well known, namelypreferential crystallization. We suggest methods to makeconglomerates more accessible in order to improve theattractiveness of this method. The second method is entirelynew and involves attrition induced grinding of racemizableconglomerates as solids in contact with solution whereinracemization occurs, with a theoretical 100 percent yieldand 100 percent enantiomeric excess. This technique hasrecently been applied to the synthesis of two popular drugs,Clopidogrel and Naproxen.The separation of racemates intothe individual enantiomers requires chiral recognition in someform. This may be accomplished, for example, by means ofseparation of diastereomeric salts, chiral chromatography orkinetic resolution with enzymes. A special case is formed byconglomerates in which the symmetry breaking, essential toany separation of the enantiomers, has already been carriedout by Nature. Textbooks report that some 5-10 percent ofchiral organic compounds crystallize as conglomerates.How can optimal use be made of this advantage providedby Nature in an as inexpensive way as possible to separatethe enantiomers, namely without resolving agents?Wediscuss briefly here two techniques to do this together withconsiderations of a) how to identify conglomerates, b) howto increase the chance of finding a suitable conglomerate,c) how the chemistry of the compounds can be employedin their resolution and d) the role of previously underappreciated physical phenomena such as Ostwald ripening.