Stereoselective Reductions of Carbonyl Groups

Thermophilic bacteria, growing in hot springs like these at Yellowstone National Park, produce heat-stable enzymes called extremozymes that have proven useful for a variety of chemical processes. 

The two faces of a trigonal planar center are designated re and si, according to the direction of Cahn-Ingold-Prelog priorities (Section 5.7) for the groups bonded at the trigonal center when viewed from one face or the other (re is clockwise, si is counterclockwise)  

The preference of many NADH-dependent enzymes for either the re or si face of their respective substrates is known. This knowledge has allowed some of these enzymes to become exceptionally useful stereoselective reagents for synthesis. One of the most widely used is yeast alcohol dehydrogenase. Others that have become important are enzymes from thermophilic bacteria (bacteria that grow at elevated temperatures). Use of heat-stable enzymes (called extremozymes) allows reactions to be completed faster due to the rate-enhancing factor of elevated temp erature (over 100 °C in some cases), although greater enantioselectivity is achieved at lower temperatures. 

Often it is necessary to test several reaction conditions in order to achieve optimal stereoselectivity. 

4A Oxidation of Primary Alcohols to Aldehydes RCHgOH-------- RCHO 

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A MECHANISM FOR THE REACTION ] Reduction of Aldehydes and Ketones by Hydride Transfer 548 THE CHEMISTRY OF... Alcohol Dehydrogenase—A Biochemical Hydride Reagent 548 THE CHEMISTRY OF... Stereoselective Reductions of Carbonyl Groups 550... 

Enzyme catalyzed reductions of carbonyl groups are more often than not com pletely stereoselective Pyruvic acid for example is converted exclusively to (5) (+) lactic acid by the lactate dehydrogenase NADH system (Section 15 11) The enantiomer... 

The well-known reduction of carbonyl groups to alcohols has been refined in recent studies to render the reaction more regioselective and more stereoselective Per-fluorodiketones are reduced by lithium aluminum hydride to the corresponding diols, but the use of potassium or sodium borohydride allows isolation of the ketoalcohol Similarly, a perfluoroketo acid fluonde yields diol with lithium aluminum hydnde, but the related hydroxy acid is obtainable with potassium borohydnde [i f] (equations 46 and 47)... 

Chelation Control. The stereoselectivity of reduction of carbonyl groups can be controlled by chelation when there is a nearby donor substituent. In the presence of such a group, specific complexation among the substituent, the carbonyl oxygen, and the Lewis acid can establish a preferred conformation for the reactant. Usually hydride is then delivered from the less sterically hindered face of the chelate so the hydroxy group is anti to the chelating substituent. 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

Conjugate reduction.1 This stable copper(I) hydride cluster can effect conjugate hydride addition to a,p-unsaturated carbonyl compounds, with apparent utilization of all six hydride equivalents per cluster. No 1,2-reduction of carbonyl groups or reduction of isolated double bonds is observed. Undesirable side reactions such as aldol condensation can be suppressed by addition of water. Reactions in the presence of chlorotrimethylsilane result in silyl enol ethers. The reduction is stereoselective, resulting in hydride delivery to the less-hindered face of the substrate. 

The stereoselectivity of reduction of carbonyl groups is effected by the same combination of steric and stereoelectronic factors which control the addition of other nucleophiles, such as enolates and organometallic reagents to carbonyl groups. A general discussion of these factors on addition of hydride is given in Section 3.10 of Part A. 

A. P. Davis, M. M. Midland, L. A. Morell, Formation of C-H Bonds by Reduction of Carbonyl Groups (C=H), Reduction of Carbonyl Groups with Metal Hydrides, in Methoden Org. Chem. (Houben-Weyl) 4th ed., 1952-, Stereoselective Synthesis (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schau-mann, Eds.), Vol. E21d, 3988, Georg Thieme Verlag, Stuttgart, 1995. 

In the enzyme-catalysed reduction of carbonyl groups to alcohols, hydrogen is delivered exclusively to one face. The reverse oxidation of ethanol to ethanal is also completely stereoselective, and involves sole removal of a particular prochiral hydrogen,... 

All syntheses involving C - H bond formation by the reduction of carbonyl groups that achieve stereoselectivities greater than 70% ee are collected in this section. If there are three or more such syntheses within a subsection they are organized in a table. In addition, optical inductions lower than, but close to. 70% ee are included in the text. However, low stereoselectivities are considered unimportant with respect to application in organic synthesis. Their results can be found in recent reviews of the field 5. 

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