Reduction of Ketones Using Enantioselective Borohydride Reagents

5 Reduction of Ketones Using Enantioselective Borohydride Reagents 

Enantiomerically pure boranes have a long history in the reduction of prochiral ketones/ Amongst the early results using stoichiometric oxazaborolidines, the work of Itsuno is of particular interest. For example, acetophenone (3.32) could be reduced with the oxazaborohdines (3.113) or (3.114) where the ratio of amino alcohol to borane was 1 2, implying that one equivalent of oxazaborolidine and one equivalent of borane were present in the transition state. Itsuno also reported that the oxazaborohdine reagent (3.114) could be used catalytically in the reduction of prochiral ketoxime ethers.  

In 1987, Corey, Bakshi and Shibata demonstrated that the enantioselective reduction of ketones could be catalysed by oxazaborolidines. They showed that acetophenone was reduced only slowly by BHs-THF alone, and that oxazaborohdine (3.114) alone did not cause reduction. However, in combination they reduced acetophenone in one minute at room temperature. Using just 2.5 mol% of oxazaborolidine, and stoichiometric BHs-THF still provided excellent enantios-electivity. In the same initial commimication, proline-derived oxazaborolidine (3.115) was identified as a catalyst that was suitable for the reduction of a range of ketones, including acetophenone (3.32) and ketones (3.116) and (3.117). 

The reduction product (3.128) serves as a precursor for ct-amino acids (3.129) and a-hydroxy esters (3.130) while the reduction product (3.131) is a precursor to the anti-depressive drug fluoxetine (3.132). 

A great many other amino alcohols have been examined for their abihty to provide good oxazaborolidine catalysts. It is difficult to know which amino alcohol provides the very best enantioselectivity over a range of ketone reductions, since not all amino alcohols have been tried with aU ketones. As an example, the four-membered ring analogue (3.134) gives high enantioselectivity in the catalytic reduction of acetophenone (3.32).  

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