Stereochemistry of reduction

Although the nature of the general polar effect suggested by Kamernitzsky and Akhrem " to account for axial attack in unhindered ketones is not clear, several groups have reported electrostatic interactions affect the course of borohydride reductions. Thus the keto acid (5a) is not reduced by boro-hydride but its ester (5b) is reduced rapidly further, the reduction of the ester (6b) takes place much more rapidly than that of the acid (6a). Spectroscopic data eliminate the possibility that in (5a) there is an interaction between the acid and ketone groups (e.g. formation of a lactol). The results have been attributed to a direct repulsion by the carboxylate ion as the borohydride ion approaches. " By contrast, House and co-workers observed no electrostatic effect on the stereochemistry of reduction of the keto acid (7). However, in this compound the acid group may occupy conformations in which it does not shield the ketone. Henbest reported that substituting chlorine... 

The data available on the stereochemistry of reduction of steroidal ketones have been obtained largely in the course of synthetic work, rather than in studies devoted specifically to stereochemical problems. As discussed in an earlier section, the proportion of epimers depends on the steric environment of the ketone, the reagent, the solvent and the temperature. These factors will be discussed below. 

The stereochemistry of reduction of 20-ketones with LiAlH4 is more influenced by substituents than that of other ketones. Usually reduction of the 20-ketone gives the more hindered -alcohol.208 stated that when C-17 has a substituent, the reduction yields almost quantitatively the 20)5-ol. However, the evidence on this point is conflicting Fukushima and Meyer claim that with a 17a-hydroxy present the 20a-ol is the predominant product except when an 11-ketone is being reduced simultaneously. Other results appear to support this conclusion, but... 

The stereochemistry of reductions with diborane has been little studied. 

The success of the halo ketone route depends on the stereo- and regio-selectivity in the halo ketone synthesis, as well as on the stereochemistry of reduction of the bromo ketone. Lithium aluminum hydride or sodium borohydride are commonly used to reduce halo ketones to the /mm-halohydrins. However, carefully controlled reaction conditions or alternate reducing reagents, e.g., lithium borohydride, are often required to avoid reductive elimination of the halogen. 

The stereochemistry of reduction by homogeneous catalysts is often controlled by functional groups in the reactant. Delivery of hydrogen occurs cis to a polar functional group. This behavior has been found to be particularly characteristic of an iridium-based catalyst that contains cyclooctadiene, pyridine, and tricyclohexylphosphine as ligands, known as the Crabtree catalyst 6 Homogeneous iridium catalysts have been found to be influenced not only by hydroxy groups, but also by amide, ester, and ether substituents.17... 

As was indicated previously, several other parameters can affect the stereochemistry of reduction of cyclopropyl halides 20>. For example the optical purity of 59 produced from the electrochemical reduction of 58 in acetonitrile... 

Fry and Newberg 1,2> examined the electrochemical reduction of nor-camphor oxime (109) and camphor oxime (110) to the corresponding amines. The results of this study are shown in Table 3. It is clear from a comparison of these data with those in Table 2 that the electrochemical reduction of oximes 109 and 110 takes a very different stereochemical course from reduction of the corresponding anils 103 and 104. Reduction of oximes apparently proceeds under kinetic control, affords products corresponding to protonation at carbon from the less hindered side of the carbon-nitrogen double bond, and affords the less stable epimeric amine in each case. It is not evident why the stereochemistry of reduction of anils and oximes should differ, however. 

The concept that the stereochemistry of reduction of an unsaturated hydrocarbon is determined at the adsorption stage of the reaction is evident in each of the above accounts, and others could be cited. However, the development of techniques which permit the identification of different product-controlling reactions directs one to consider the stereochemical consequences of various postulated reaction sequences and this will be discussed in Section IV. 

Mechanism, Stoichiometry and Stereochemistry of Reductions with Hydrides... 

In many cases also the reduction agent itself influences the result of the reduction, especially if it is bulky and the environment of the function to be reduced is crowded. A more detailed discussion of stereochemistry of reduction with hydrides is found in the section on ketones (p. 114). 

A large amount of data has been accumulated on the stereoselectivity of reduction of cyclic ketones.81 Table 5.4 compares the stereochemistry of reduction of several ketones by hydride donors of increasing seric bulk. The trends in the table illustrate the increasing importance of steric approach control as both the hydride reagent and the ketone become more highly substituted. The alkyl-substituted borohydrides have especially high selectivity for the least hindered direction of approach. 

The stereochemistry of reduction of acylic aldehydes and ketones is a function of the substitution on the adjacent carbon atom and can be predicted on the basis of a conformational model of the transition state.78... 

Mechanism and stereochemistry of reductions of ketones, 66 Mechanism of dehydrohalogenation, 292 Mechanism of hydrogenation, 111 Mechanism of reduction of aromatic compounds, 12... 

Stereochemistry of reduction, 34 Stereochemistry of reductions with diborane, 90... 

Saturated Ketones and Ketol Acetates. Reductive Alkylation / 27 Mechanism of reduction / 27 Stereochemistry of reduction / 34 Side reactions in reductions / 37... 

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