Diaryl ketone enantioselective reduction

The asymmetric formation of industrially useful diaryl methanols can be realized through either the addition of aryl nucleophiles to aromatic aldehydes or the reduction of diaryl ketones. The latter route is frequently the more desirable, as the starting materials are often inexpensive and readily available and nonselective background reactions are not as common. For good enantioselectivity, chemical catalysts of diaryl ketone reductions require large steric or electronic differentiation between the two aryl components of the substrate and, as a result, have substantially limited applicability. In contrast, recent work has shown commercially available ketoreductase enzymes to have excellent results with a much broader range of substrates in reactions that are very easy to operate (Figure 9.6). ... 

Truppo, M. D., Pollard, D. and Devine, P., Enz3Tne-catalyzed enantioselective diaryl ketone reductions. Org. Lett., 2007, 9, 335. 

Two strategies for the synthesis of enantiomerically enriched diaryl methanols 27 are apparent first, asymmetric reductions of the corresponding diaryl ketones 36 [33], and, second, enantioselective aryl transfer reactions to the respective benzaldehyde derivatives 37 (Scheme 2.1.2.5) [34, 35]. 

The Corey-Bakshi-Shibata reduction (CBS reduction) is a highly enantioselective method for arylketones, diaryl ketones, and dialkylketones. In addition, cyclic a,p-unsaturated ketones, acyclic a,p-unsaturated ketones, and a,p-ynones are reduced enantioselectively in a 1,2-fashion. The high enantioselective nature of this reduction relies on the chiral oxazaborolidine catalyst, shown in the reaction scheme, in the presence of borane or a dialkylborane. Reviews (a) Singh, V. K. Synthesis 1992, 605-617. (b) Deloux, L. Srebnik M. Chem. Rev. 1993,93,163-1. (c) Corey, E. J. Helal, C. J. Angew. Chem. Int. Ed. 1998, 37. 1986-2012. 

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. 

Li, H., Zhu, D., Hua, L., and Biehl, E.R. (2009) Enantioselective reduction of diaryl ketones catalyzed by a carbonyl reductase from Sporobolomyces salmonicolor and its mutant enzymes. Adv. Synth. Catal., 351, 583-588. 

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