Switching product chirality

Figure 1 Temperature switching of product chirality in enantiodifferentiating phot...

The dramatic switching of product chirality by temperature is entropic i origin, for which the different degrees of conformational changes induced by thj rotational relaxation to the enantiomeric twisted cyclooctene singlets (/ )- am (S)-lp within the exciplex are thought to be responsible [30,31]. This idea w supported experimentally by using chiral pyromellitate sensitizers 45g-j. C ing chiral auxiliaries with an electron-rich aromatic substituent as a donor moiel... 

Figure 2 Pressure switching of product chirality in enantiodifferentiating photoisomerization of cyclooctene 47 sensitized by (— )-menthyl pyromellitate 45a in pentane at 25°C.

As a consequence of the extensive efforts devoted to this attractive and intriguing area of asymmetrical photochemistry, the chirality transfer mechanisms operating in both uni- and bimolecular enantiodifferentiating photosensitizations have been understood in considerable detail, which in turn enabled us not only to obtain optical yields much higher than those achieved in earlier studies but also to utilize a variety of internal and external, or electronic, structural, and environmental, factors in the critical control of enantioselectivity in the excited state. From a wider chemical viewpoint, it should be emphasized that the entropy-related environmental factors, such as temperature, pressure, and solvent, play much more important roles than previously expected, and in typical cases even the product chirality may be switched by these apparently supplementary factors. 

However, this is not always the case. Since the temperature dependence of the product s op. is quite tricky in these enantiodifferentiating photoisomerization sensitized by optically active polyalkyl benzenepolycarboxylates, one should use special caution in changing irradiation temperature. For instance, (-)-tetramenthyl 1,2,4,5-benzenetetracarboxylate gives (-)-4.1d of 9.6% op. at 25 °C, but produces the antipode (+)-4.1d of 28.5% op at -90 °C. Thus, the product chirality is often switched by the irradiation temperature see reference l for full detail. 

This effect is attributed to the increased microenvironmental polarity around the sensitizer chro-mophore that stabilizes the exciplex or contact ion pair in nonpolar solvents. As a result of this effect, the stereochemical interaction between the sensitizer and the substrate is more intimate. Because significant enantioselectivities were only observed for dimer 44, an independent cyclodimerization pathway to 44 via an exciplex or contact ion pair of cyclohexadiene and the chiral sensitizer was suggested. Dimer 45 gave much lower ee values even at low temperatures, but the product chirality was inverted within the tested temperature range in favor of enantiomer ent-A5. Similar temperature switching of product chirality has been reported in the enantiodifferentiating photoisomerization of cycloalkenes and in the polar addition of alcohols to 1,1-diphenylalkenes. This effect has been rationalized by a non-zero differential activation entropy of the same sign as the differential activation enthalpy. 

These policy decisions by the FDA were the driving force for chiral switches and the commercial development of chromatographic processes such as simulated moving bed (SMB) technology. Due to technological advances such as SMB and the commercial availability of CSPs in bulk quantities for process-scale purification of enantiopure drugs, the production of many single enantiomers now exists on a commercial scale. 

C in a TH F-toluene-hexane mixture. After the mixture was cooled below —50 °C, ketone 41 was added. After 60min, the reaction was quenched with aqueous citric acid. The organic layer was then solvent switched into toluene, and the product 50 was crystallized by the addition of heptane (91-93% isolated yield, >99.5% ee). The chiral modifier 46 is easily recycled from the aqueous layer by basification with NaOH and extraction into toluene to recover 46 (>99% purity, 98% recovery yield). The modifier has been recycled up to nine times in subsequent chiral addition reactions without any problem. 

Fairly recently, an increase in the use of allenyl amides bearing chiral auxiliaries could be observed. Many interesting and synthetically useful results can be expected in this area. Sulfur- and selenium-substituted allenes have rarely been employed, although many of their subsequent products would feature unique properties. Hence it should be possible to switch the donor property of a sulfur substituent to an electron-accepting group by various oxidation methods. 

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