Prochiral compounds, asymmetric desymmetrization

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

Asymmetric synthesis with lipases and esterases can basically be performed by two different approaches - the desymmetrization of prochiral or meso compounds and the enzymatic kinetic resolution of racemic mixtures. The main bottleneck of kinetic resolutions, product yields of maximum 50%, can be overcome if an in situ racemization of the starting material is possible. In this case all starting material can theoretically be converted to the desired product [34],... 

The proper stereochemistry was achieved by enzyme catalyzed desymmetrization of the prochiral 1,3-diol 30. Candida antarctica lipase (CAL)-catalyzed transesterification yielded the monoacetate 31, which gave rise to the methyl with the proper stereochemistry 32. The generation of the desired chiral epoxide 35 was achieved by asymmetric dihydroxylation employing AD-mix-a,42 followed by epoxide formation. Base-catalyzed etherification yielded the mixture of the enantiopure (+)-heliannuol A and (-)-heliannuol D. Unfortunately these compounds correspond to the opposite d/l series and correspond to the enantiomers of the natural products (-)-heliannuol A and (+)-heliannuol D (Fig. 5.6.A). 

As mentioned above, the enantioselective desymmetrization of prochiral, as well as meso compounds, by using a Mizoroki-Heck coupling represents another pos-sibiUty to effect asymmetric transformations [81-84]. Therefore, the plane of symmetry in these precursors must be broken by differentiation of enantiotopic alkene-containing groups with a chiral palladium complex. 

Bruckner and coworkers reported on the asymmetric halogen/metal exchange to desymme-trize prochiral bis(bromoaryl)alcohols using iPr Mg in the presence of stoichiometric amounts of enantiopure lithium alkoxides or phenoxides. The desymmetrized arylmagnesium compounds were quenched with electrophiles. The best ee/yield combination was (52% ee, 58% yield) (Scheme 28.9) [60]. 

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