DOI: 10.1021/jo101530f Published on Web 10/29/2010 J. Org. Chem. 2010, 75, 7717–7725 7717 r 2010 American Chemical Society pubs.acs.org/joc Mild and Expedient Asymmetric Reductions of r,β-Unsaturated Alkenyl and Alkynyl Ketones by TarB-NO 2 and Mechanistic Investigations of Ketone Reduction Scott Eagon, Cassandra DeLieto, William J. McDonald, Dustin Haddenham, Jaime Saavedra, Jinsoo Kim, and Bakthan Singaram* Department of Chemistry and Biochemistry, University of California at Santa Cruz, Santa Cruz, California 94086, United States singaram@chemistry.ucsc.edu Received August 17, 2010 A facile and mild reduction procedure is reported for the preparation of chiral allylic and propargyl alcohols in high enantiomeric purity. Under optimized conditions, alkynyl and alkenyl ketones were reduced by TarB-NO 2 and NaBH 4 at 25 °C in 1 h to produce chiral propargyl and allylic alcohols with enantiomeric excesses and yields up to 99%. In the case of R,β-unsaturated alkenyl ketones, R-substituted cycloalkenones were reduced with up to 99% ee, while more substituted and acyclic derivatives exhibited lower induction. For R,β-ynones, it was found that highly branched aliphatic ynones were reduced with optimal induction up to 90% ee, while reduction of aromatic and linear aliphatic derivatives resulted in more modest enantioselectivity. Using the (L)-TarB-NO 2 reagent derived from (L)-tartaric acid, we routinely obtained highly enantioenriched chiral allylic and propargyl alcohols with (R) configuration. Since previous models and a reduction of a saturated analogue predicted propargyl products of (S) configuration, a series of new mechanistic studies were conducted to determine the likely orientation of aromatic, alkenyl, and alkynyl ketones in the transition state. Introduction The asymmetric reduction of prochiral alkenyl and alkynyl ketones is one of the most expedient methods to synthesize chiral allylic and propargyl alcohols. These chiral alcohols are present in a myriad of bioactive compounds and can be converted into a variety of synthetic intermediates due to the unique reactivities of the carbon-carbon double and triple bond. A handful of methods for the regiospecific 1,2-reduction of R,β-unsaturated alkenyl ketones have been reported, with one of the most popular being the cerium trichloride/sodium borohydride mediated Luche reduction. 1 Though the Luche reduction is not enantioselective, it has been used as a diaster- eoselective reduction agent for several recent compounds with modest success. 2 Modern enantioselective 1,2-reductions of R,β-unsaturated alkenyl ketones have been reported using several methods including ruthenium catalysts, 3 enzymes, 4 and the boron-containing DIP-Cl 5 and CBS 6 reagents. In the (1) Luche, J. J. Am. Chem. Soc. 1978, 100, 2226. (2) (a) Pragani, R.; Roush, W. Org. Lett. 2008, 70, 4613. (b) Gollner, A.; Mulzer, J. Org. Lett. 2008, 70, 4701. (c) Westermann, J.; Schneider, M.; Platzek, J.; Petrov, O. Org. Process Res. Dev. 2007, 11, 200. (d) Tsegay, S.; Huegal, H.; Rizzacasa, M. Aust. J. Chem. 2009, 62, 676. (e) Taber, D.; Gu, P.; Li, R. J. Org. Chem. 2009, 74, 5516. (3) (a) Van Innis, L.; Plancher, J.; Marko, I. Org. Lett. 2006, 8, 6111. (b) Hannedouche, J.; Kenny, J.; Walsgrove, T.; Wills, M. Synlett 2002, 263. (c) Peach, P.; Cross, D.; Kenny, J.; Mann, I.; Houson, I.; Campbell, L; Walsgrove, T.; Wills, M. Tetrahedron 2006, 62, 1864.