Chiral Alcohols Through Enantioselective Reduction

On the other hand a direct hydrogen transfer through a Meerwein-Ponndorf mechanism, involving coordination of both the donor alcohol and the ketone to the copper site may also be considered. In this case, by using alcohols other than 2-propanol, we could expect some difference in stereochemistry. This would also imply the possibility of carrying out the enantioselective reduction of a prochiral ketone with a chiral alcohol as donor. 

In addition, Giacomini et al. have shown that the asymmetric synthesis of (25)-2-phenylpropanol and (25)-2-(4- o-butylphenyl)propanol ((5)-ibuprofenol) could be achieved by means of horse liver alcohol dehydrogenase (HLADH) in buffered aqueous solution or buffered organic solvent mixtures. Indeed, the reduction through DKR of the corresponding aldehydes occurred with both excellent yields and enantioselectivities, as shown in Scheme 3.13. The value of these results resided in the appKcation of these two chiral alcohols as intermediates for the synthesis of optically active pharmaceutical products of the profen class (ibuprofen) and fragrances. 

Among substituents, electron-withdrawing o-Cl and o-Br substituents appear to induce better enantioselectivities. Besides, they represent a convenient handle for further synthetic modification, e.g. through coupling reactions [25]. Chiral benz-hydryl fragment can be found in a variety of pharmaceutically relevant molecules. Synthetic application of the reduction of prochiral diaryl ketones was illustrated by enantioselective synthesis of antihistamine agents (I )-orphenadrine (37) and (5)-neobenodine (38) [26]. The former was synthesized in two easy steps from alcohol 35, whereas synthesis of 38 from 36 also included debromination step. 

Nicolaou and coworkers completed the enantioselective synthesis of these two natural products molecules through a short and equally efficient route (12 steps from commercially available material with the 4% overall yield) involving a series of cascade reactions and novel skeletal rearrangements [107b]. This unique route commenced with a CBS asymmetric reduction of ketone 288 that is easily generated from the resveratrol monomer (Scheme 10.55). The chiral benzylic alcohol 289 was obtained in 85% yield and 95% ee in the presence of one equivalent of catecholborane and catalytic amount of (/ )-(+)-2-methyl-CBS-oxazaborolidine. This newly formed C8a center would be served as a chiral source by which other stereocenters within the architectnre... 

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