Enantioselective Carbonyl Reductions

Recall from Section 9.15 that an achiral starting material gives a racemic mixture when a new stereogenic center is formed. 

The stereochemistiy of carbonyl reduction follows the same principles we have previously learned. Reduction converts a planar sp hybridized carbonyl carbon to a tetrahedral sp hybridized carbon. What happens when a new stereogenic center is formed in this process With an achiral reagent like NaBITt or LiAlHi. a racemic product is obtained. For example, NaBH4 in CH3OH solution reduces 2-butanone, an achiral ketone, to 2-butanol, an alcohol that contains a new stereogenic center. Both enantiomers of 2-butanol are formed in equal amounts. 

Why is a racemic mixture formed Because the carbonyl carbon is sp hybridized and planar, hydride can approach the double bond with equal probability from both sides of the plane, forming two alkoxides, which are enantiomers of each other. Protonation of the alkoxides gives an equal amount of two alcohols, which are also enantiomers. 

Problem 20.8 Draw the products formed (including stereoisomers) when each compound is reduced with NaBH4 in CH3OH. 

One enantiomer can be formed selectively from the reduction of a carbonyl group, provided a chiral reducing agent is used. This strategy is identical to that employed in the Sharpless asymmetric epoxidation reaction (Section 12.15). A reduction that forms one enantiomer predominantly or exclusively is an enantioselective or asymmetric reduction. 

Many different chiral reducing agents have now been prepared for this purpose. One such reagent, formed by reacting borane (BH3) with a heterocycle called an oxazaborolidine, has one stereo-genic center (and thus two enantiomers). 

Chapter 20 Introduction to Carbonyl Chemistry Organometallic Reagents Oxidation and Reduction 

Problem 20.10 What reagel iR flclPo reSuSfito iJi ife iSyS lh ynthesis of the antidepressant 

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Even more highly selective ketone reductions are earned out with baker s yeast [61, 62] (equations 50 and 51) Chiral dihydronicotinamides give carbonyl reductions of high enantioselectivity [63] (equation 52), and a crown ether containing a chiral 1,4-dihydropyridine moiety is also effective [64] (equation 52). 

Scheme 13 Enantioselective carbonyl (Z)-dienylation via reductive coupling of acetylene to aldehydes and imines mediated by hydrogen...

Zhu, D. and Hua, L. (2006) Enantioselective enzymatic reductions of sterically bulky aryl alkyl ketones catalyzed by a NADPH-dependent carbonyl reductase. The Journal of Organic Chemistry, 71 (25), 9484—9486. 

Asymmetric transfer hydrogenation of imines catalyzed by chiral arene-Ru complexes achieves high enantioselectivity (Figure 1.34). Formic acid in aprotic dipolar solvent should be used as a hydride source. The reaction proceeds through the metal-ligand bifunctional mechanism as shown in the carbonyl reduction (Figure 1.24). 

The most common oxidation states and corresponding electronic configurations of rhodium are +1 (tf8), which is usually square planar although some five coordinate complexes are known, and +3 (T) which is usually octahedral. Dimeric rhodium carboxylates are +2 (oxidation states —1 (industrial applications include rhodium-catalyzed carbonylation of methanol to acetic acid and acetic anhydride, and hydroformylation of propene to tf-butyraldehyde. Enantioselective catalytic reduction has also been demonstrated. 

Control of enantioselectivity will be discussed in the corresponding sections on carbonyl reduction (Chapter 4) alkene hydrogenation, epoxidation, and dihydroxylation (Chapter 5) aldol condensation (Chapter 6) allylation and crotylation (Chapter 7) Claisen rearrangement (Chapter 8) and the Diels-Alder reaction (Chapter 9). 

Carbonyl reduction. Many substrates have been reduced enantioselectively to give alcohols trifluoromethyl ketones, a-acetoxyketones, pyridinophenones, ethyl a-methylacetoacetate, a-keto acid derivatives," and 3-chloro-2-oxoaIkanoic esters a,/3-Epoxy ketones undergo reduction and hydrolytic ring opening/... 

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