Stereochemistry ketones, acid effect

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... 

Reduction of ketones. Reduction of ketones with metals in an alcohol is one of the earliest methods for effecting reduction of ketones, and is still useful since it can proceed with stereoselectivity opposite to that obtained with metal hydrides.1 An example is the reduction of the 3a-hydroxy-7-ketocholanic acid 1 to the diols 2 and 3. The former, ursodesoxycholic acid, a rare bile acid found in bear bile, is used in medicine for dissolution of gallstones. The stereochemistry is strongly dependent on the nature of the reducing agent (equation I).2 Sodium dithionite and sodium borohydride reductions result mainly in the 7a-alcohol, whereas reductions with sodium or potassium in an alcohol favor reduction to the 7p-alcohol. More recently3 reduction of 1 to 2 and 3 in the ratio 96 4 has been achieved with K, Rb, and Cs in f-amyl alcohol. Almost the same stereoselectivity can be obtained by addition of potassium, rubidium, or cesium salts to reductions of sodium in t-amyl alcohol. This cation effect has not been observed previously. 

Fig. 13.68. Michael addition to an tt,/kunsaturated ketone. A sequence of reactions is shown that effects the 1,4-addition of acetic acid to the unsaturated ketone. See Figure 17.51 regarding step 2 and Figure 13.37 for the mechanism of step 3. The stereochemistry of reaction steps 1 and 2 has not been discussed in the literature. The third step consists of a decarboxylation as well as an acid-catalyzed epimerization of the carbon in the position a to the carbonyl group. This epimerization allows for an equilibration between the cis,trans-isomeric cyclohexanones and causes the trans-configuration of the major product.

Rules 1 and 2 may be accepted as a generalization based primarily on the results obtained over platinum catalysts. However, there have been known many examples of the exception to this rule,153 since the stereochemistry of hydrogenation may be influenced by many factors, such as the solvent, the temperature, the hydrogen pressure, and the basic or acidic impurity associated with catalyst preparation, as well as the activity of the catalyst, and since the effects of these factors may differ sensitively with the catalyst employed and by the structure of the ketone hydrogenated. 

The high diastereoselectivity attending the spirocyclisation of ketene dithioacetals provides an effective means for controlling the stereochemistry of a methyl substituent at the a-position on a 6-lactone ring,244 The method was applied to the synthesis of the polyether antibiotic Salinomycin [Scheme 2.120].242 Condensation of the methyl ketone 120 1 with the lithiated l,3-dithian-2-yl-phospho-nic acid diethyl ester 120.2 gave the ketene dithioacetal 1203 in 76% yield. After hydrolysis of the two benzoate ester groups, cyclisation of diol 120.4 was... 

The ease and the stereochemical course of hydrogenation of a,p-unsaturated ketones are particularly influenced by the nature of the solvent and the acidity or basicity of the reaction mixture. Some efforts have been made to rationalize the effect of the various parameters on the relative proportions of 1,2- to 1,4-addition, as well as on the stereochemistry of reduction. For example, the product distribution in -octalone hydrogenation in neutral media is related to the polarity of the solvent if the solvents are divided into aprotic and protic groups. The relative amount of cis- -decalone decreases steadily with decreasing dielectric constant in aprotic solvents, and increases with dielectric constant in protic solvents, as exemplified in Scheme 21 (dielectric constants of the solvents are indicated in parentheses). Similar results were observed in the hydrogenation of cholestenone and of testosterone. In polar aprotic solvents 1,4-addition predominates, whereas in a nonpolar aprotic solvent hydrogenation occurs mainly in the 1,2-addition mode. 

---