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Monday, November 15, 2004
Douglass Taber
University of Delaware

Best Synthetic Methods: Enantioselective Oxidation and Reduction

Usually, only a single enantiomer of a pharmaceutical is the useful drug. Often, the synthesis of the single enantiomer depends on the ability to form C-O or C-N bonds with high asymmetric induction. In the ideal asymmetric synthesis, both enantiomers of the starting material would be converted to the same enantiomer of the product. Mahn-Joo Kim and Jaiwook Park of Pohang University of Science and Technology, Korea report (J. Org. Chem. 2004, 69, 1972. ) an example of a simple solution to this problem. Selective acylation by a lipase is limited, because the increasing relative concentation of the less reactive residual enantiomer makes the esterification progressively less enantioselective. If the enantiomers of the starting alcohol could be interconverted, there would be no relative build-up of the less reactive enantiomer, and the enantioselectivity would be maintained. The authors report the development of an efficient Ru catalyst for the interconversion of the two enantiomers of 1 by in situ oxidation and reduction.

When the substrate is readily epimerizable, as with 3, the problem is even easier. Xumu Zhang of Pennsylvania State University reports (J. Am. Chem. Soc. 2004, 126, 1626. ) the development of a chiral Ru complex (derived from C3-Tunephos) that selectively hydrogenates one of the two interconverting enantiomers of 3, delivering 4 with high enantioselectivity and diastereoselectivity.

The Sharpless asymmetric dihydroxylation has played a prominent role in enantioselecitve organic synthesis. Two groups have recently reported improvements in the procedure. Osmo E.O. Horni of the University of Oulu, Finland has found (J. Org. Chem. 2004, 69, 4816. ) that sodium chlorite is a more efficient reoxidant than is the usual K3[Fe(CN)6]. Carlos A.M. Alfonso of the Instituto Superior Técnico, Lisbon has reported (J. Org. Chem. 2004, 69, 4381. ) that the asymmetric dihydroxylation can be carried out using an ionic liquid as the solvent. The product can be extracted with ether, leaving the osmium catalyst in the ionic liquid to be used again. Note that even monosubstituted alkenes such as 5 are dihydroxylated with high enantioselectivity with these systems.

Alcohol oxidation can also be enantioselective. The best systems reported to date for the selective oxidation of one enantiomer of 7 to 9 depend on the naturally-occurring alkaloid sparteine as a source of chirality. Unfortunately, only one enantiomer of sparteine is available. Peter O'Brien of the University of York has developed (J. Org. Chem. 2004, 69, 5789. ) an alternative tricyclic amine 8 that is complementary to sparteine, directing oxidation toward R-7.

D. F. Taber, Org. Chem. Highlights 2004, November 15.