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Monday, May 14, 2007
Douglass Taber
University of Delaware

Oxidation and Reduction in Organic Synthesis

The enantioselective reduction of ketones by alcohol dehydrogenases is a valuable synthetic procedure, but the required co-factors are expensive. If the reduction can be carried out with intact cells, the expense of added co-factors can be avoided. Harald Gröger and Oliver May of Degussa AG, Hanau, Germany have demonstrated (Angew. Chem. Int. Ed. 2006, 45, 5677. ) reductions on a substantial scale, using an E. coli strain into which both an alcohol dehydrogenase and a glucose dehydrogenase had been incorporated. The reduction of ketone 1, for instance, used 40 mmol of the ketone in a total buffer plus glucose (1.5 eq) volume of 40 mL. This delivered 2 in 88% yield and 99.4% ee. This procedure should be easily scaled, particularly if the investigators are willing to share their engineered microorganisms.

The Openauer oxidation has the advantage of using the inexpensive and environmentally-innocuous aluminum. The disadvantage, until recently, has been that the Al was used in stoichiometric quantities. SonBinh T. Nguyen of Northwestern University has now found (J. Am. Chem. Soc. 2006, 128, 12596. ) that 10 mol % of AlMe3 in toluene serves well to catalyze this reduction. They found it convenient to use m-nitrobenzaldehyde as the hydride acceptor. Primary alcohols were oxidized to the corresponding aldehdyes, and secondary alcohols such as 3 to the ketones.

Commercial bleach (5% aqueous NaOCl) is an inexpensive oxidant. Stephen A. Miller of Texas A&M University has shown (J. Org. Chem. 2006, 71, 9291. ) that 2.5 mol % of NiCl2 or Ni(OAc)2 in the presence of bleach oxidizes primary alcohols such as 5 efficiently to the corresponding carboxylic acid. Secondary alcohols are oxidized to ketones, and 1,2-diols are cleaved to the bis carboxylic acid. The Ni can presumably be recovered and recycled.

Selective oxidation is not limited to simple systems. René Csuk of Martin-Luther-Universität Halle-Wittenberg has developed (Tetrahedron Lett. 2006, 47, 8769. ) conditions for the selective oxidation of betulin 7 to betulinic acid 8. If the oxidation is carried out at 35°C, the aldehyde corresponding to 8 can be isolated in good yield.

The direct oxidative esterification of aldehydes is also a useful synthetic conversion. This has usually been effected with stoichiometric Cr reagents. Christian Wolf of Georgetown University has now shown (J. Am. Chem. Soc. 2006, 128, 13052. ) that a Pd catalyst in the presence of (CH3O)4Si effects this transformation. Other tetra-alkyl orthosilicates work as well.

For exacting coupling of the acid with an expensive partner, it would be desirable to be able to isolate an activated ester intermediate. Two research groups have introducted strategies for doing this. Xinmiao Liang of the Dalian Institute of Chemical Physics has found (Chem. Lett. 2006, 35, 566. ) that N-hydroxysuccinimide 12 activates PhI(OAc)2, and that the combination converts a primary alcohol 11 or the intermediate aldehyde into the activated O-Su ester 13. In a complementary approach, Chao-Jun Li of McGill University, Montreal, has demonstrated (J. Org. Chem. 2006, 71, 6266. ) that an aldehyde 14 will undergo oxidative coupling with a β-dicarbonyl compound 15, to give the activated ester 16. Both 13 and 16 are stable enough to purify, and are expected to efficiently acylate alcohols and amines.

D. F. Taber, Org. Chem. Highlights 2007, May 14.