The Stereochemistry of Carbonyl Reduction

The net result of adding Hr (from NaBH4 or LiAIH4) and H (from H2O) is the addition of the elements of H2 to the carbonyl n bond. 

Catalytic hydrogenation also reduces aldehydes and ketones to 1° and 2° alcohols, respectively, using H2 and Pd-C (or another metal catalyst). H2 adds to the C=0 in much the same way that it adds to the C=C of an alkene (Section 12.3). The metal catalyst (Pd-C) provides a surface that binds the carbonyl starting material and H2, and two H atoms are sequentially transferred with cleavage of the n bond. 

When a compound contains both a carbonyl group and a carbon-carbon double bond, selective reduction of one functional group can be achieved by proper choice of reagent. 

2-cyclohexenone, a compound that contains both a carbon-carbon double bond and a carbonyl group, can be reduced to three different compounds— an allylic alcohol, a carbonyl compound, or an alcohol—depending on the reagent. 

NaBH4 reduces the C=0 selectively to form an allylic alcohol. 

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The stereochemistry 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 NaBH4 or LiAlH4, 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. 

C=X bonds The stereochemistry of the reduction of carbonyl compounds has been intensely studied with regard to synthetic and mechanistic aspects. The reduction of 1,2-diphenyl-l-propanone at a Hg cathode in aqueous EtOH and pH 8 affords the erythro alcohol as the major diastereomer (erythro threo = 5 to 1.4 1) [332]. This selectivity is in accord with a protonation of the intermediate anion, formed in an ECE sequence, from the least hindered side (Fig. 61). 

The stereochemistry of 338 and 339 in each case results from initial conjugate addition of MeO" at position 2 of the chromone ring. Ensuing attack of the formed enolate 342 upon PhI(OMe)2 occurs in an anti manner because of steric interaction. Sequential addition of MeO to the carbonyl group of 343 gives 344, and intramolecular reductive elimination of C6H5I then occurs with inversion of configuration, 344 345. The reaction is... 

It is known that electrochemical reduction of oximes in protic media occurs in two steps the N—O bond is first reduced to form an imine and the latter is then reduced to afford a primary amine1,29. Tallec has shown that the amine from oxime 33 can be trapped intramolecularly (equation 16)35. Interestingly, the SS diastereomer predominates the chiral pyrrolidine ring derivative serves to control the stereochemistry of formation of the new benzylic chiral center. Electrochemical reductive cross-coupling of O-methyl oximes with carbonyl compounds in isopropanol at a tin cathode affords adducts (equation 17) which can be reduced further to 2-amino alcohols36. In this fashion, menthone could... 

We shall start the discussion with a classical experiment related to the stereochemistry of oxidation of ethanol and reduction of acetaldehyde mediated by the enzyme yeast alcohol dehydrogenase in the presence of the oxidized (NAD+) and reduced (NADH) forms, respectively, of the coenzyme nicotinamide adenine dinucleotide (Fig. 54). The stereochemically interesting feature of this reaction stems from the fact that the methylene hydrogens in CH3CH2OH and the faces of the carbonyl in CH3CH = 0 are enantiotopic. The question thus arises which of the CH2-hydrogens... 

Procter has suggested that a study of the dependence of reaction outcome on the stereochemistry of the alkene in the substrate can be used to gain information on the mechanistic direction of reductive couplings.42,43 In cases where the alkene stereochemistry has a marked effect on the reaction outcome, a traditional carbonyl first mechanism may be in operation, whereas in reactions where alkene stereochemistry has little effect, an alternative mechanism in which the alkene is reduced first and a common reactive intermediate is formed, regardless of the geometry of the starting alkene, may operate (Scheme 5.20).42,43... 

In a somewhat related example, case (e), the stereochemistry of the product is determined by the direction of approach of the hydride reagent to the carbonyl group, which can occur either from above or from below the plane of the ring. The steric course of hydride reductions can easily be controlled by a careful choice of the reagent. Related examples will be considered in Section 2.12. 

Many experimental procedures have been developed in order to influence the enantioselectivity and the stereochemistry of the products use of organic media, the addition of various compounds to the incubation mixture, or enclosure in a dialysis tube can be helpful. Immobilized BY can be used in water or in organic solvents for the same purpose. Slight modifications of the substrate can obtain the same result and many examples are available. Several other groups can be present in the carbonyl-containing substrate. For instance, the asymmetric reduction of keto groups in compounds containing a cyclopropyl moiety has been achieved (eq 5). ... 

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