Total spontaneous resolutions

In 1969 Calvin [64] proposed a scheme for autocatalytic symmetry breaking, which he called stereospecific autocatalysis . Calvin s mechanism has been validated experimentally in the context of the total spontaneous resolution during the crystallization of racemic mixtures. During crystallization, crystals of one enantiomer may spontaneously separate, leaving the other enantiomer in solution. If the possibility of the equilibration of the enantiomers in solution exists and if the enantiomer in solution can convert rapidly to the enantiomer that is crystallizing before crystallization is complete, then the entire racemate may deposit as a single enantiomer. At least half a dozen examples of Calvin s stereospecific autocatalysis involving such... 

A practical and total spontaneous resolution process for the asymmetric transformation of ( )-narwedine (269) into either of its enantiomers, depending on which enantiomer is used as the seeds, and a highly stereospecific conversion of (-)-narwedine (269) into (-)-galanthamine (261) by reduc-... 

Shieh WC, Carlson JA (1994) Asymmetric transformation of either enantiomer of narwedine via total spontaneous resolution process, a concise solution to the synthesis of (—)-galantha-mine. J Org Chem 59 5463-5465... 

Another important but non-synthetic method involves harvesting crops of enan-tioenriched crystals by seeding a supersaturated racemate and is known as resolution by entrainment, or preferential crystallization. These approaches have been well reviewed and will not be covered here [8]. Rare (but spectacular) examples where crystallizations of conglomerates are observed combined with racemization events in solution, leading to total spontaneous resolutions [9], are briefly mentioned in Chapter 7 as there have been interesting recent developments on that front. Included therein are special cases where diastereomeric interactions in solution combined with racemization may yield more than a 50% yield of one enantiomer. 

Bonner concluded that efficient polymerization mechanisms that involve enantiose-lective enrichment via a-helix or /3-sheet secondary structures during polypeptide growth, are applicable to prebiotic environments. Total spontaneous resolution of racemates during crystallization involving secondary asymmetric transformations can also be important. The polymerization amplification concept involves the partial polymerization of a slightly enriched amino acid mixture, followed by an autocatalytic sequence of additional partial hydrolysis and polymerization steps. These amplification reactions occur because reactions of one enantiomer with another to form two diastereomeric products occur at different rates for each diastereomer. 

But what about stereoisomers Not too long ago the question was considered largely theoretical, since many synthetic drugs were racemates for which there were no practical means of resolution. Efforts to prepare and isolate pure enantiomorphs were generally perceived as interesting chemical exercises of little practical pharmaceutical importance because it was presumed that both enantiomorphs were equally active, or one of the pair was totally inert, or the enantiomorphs would spontaneously race-mize in solution. Now we know better. The d versus I forms of amphetamine are perhaps one of our best and oldest examples of important pharmacological differences between enantiomorphs of the same agent. 

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