Trimethylcyclohexanones, reduction

Coleman, Kobylecki, and Utley studied the electrochemical reduction of the conformationally fixed ketones 4-tert-butylcyclohexanone and 3,3,5-tri-methylcyclohexanone 82>. Stereochemically, the cleanest reductions took place at a platinum cathode in a mixture of hexamethylphosphoramide and ethanol containing lithium chloride. Under these conditions the equatorial alcohol predominated heavily (95% from 4-fer/-butylcyclohexane and 91% from 3,3,5-trimethylcyclohexanone).In acidic media roughly equal quantities of axial and equatorial alcohol were produced. It was suggested that organo-lead intermediates are involved in the reductions in aqueous media. This is reasonable, based upon the probable mechanism of reduction in acid 83F Reductions in acid at mercury cathodes in fact do result in the formation of... 

A study of the stereoselectivity of reduction of 3,3,5-trimethylcyclohexanone (5) with TIBA in benzene showed that under kinetically controlled conditions (excess reagent and short reaction time) 96% of trans-3,3,5-trimethylcyclo-hexanol (trans-6) was formed (148). This high degree of stereoselectivity was explained by proposing a cyclic 6-center transition state with hydride transfer occurring preferentially from the less hindered side (Scheme 17). 

Different stereoselectivities caused by solvent effects are demonstrated in the reduction of dihydroisophorone (3,3,5-trimethylcyclohexanone) with sodium borohydride which gave less stable tranj-3,3,5-trimethylcyclohexanol (with axial hydroxyl) by reduction in anhydrous isopropyl alcohol (55-56%), in anhydrous tert-butyl alcohol (55%), in 65% aqeuous isopropyl alcohol (59.5%), in anhydrous ethanol (67%), and in 71% aqueous methanol (73%) (the balance to 100% being the more stable cis isomer with equatorial hydroxyl) [849]. 

Hydride reduction of 3,3,5-trimethylcyclohexanone and its 5-substituted analogues exhibits a rate dependence on the substituent [268]. There is rate enhancement and rate retardation, respectively, with an acceptor and a donor. Enhancement is due to the existence of a destabilizing d-d bonding situation between the a- and p-carbon atoms, retardation might reflect a reluctance of the molecule to diminish a polarity alternating sequence. 

The method is useful in the preparation of other axial alcohols. Henbest6 has reported the reductions of 3-bbutylcyclohexanone, 3,3,5-trimethylcyclohexanone, and cholestanone to the axial alcohols by this procedure, although for the preparation of 3 a-cholestanol the procedure of Edward7 is preferred by the checkers. Recently8 2,4,4-trimethylcyclohexanone has been reduced to the pure axial alcohol by this method in 90% yield. 

A technical synthesis of (4i ,6/ )-4-hydroxy-2,2,6-trimethylcyclohexanone (85) starting from the readily available oxo-isophorone (86) has been described. (85) is an ideal precursor for the synthesis of optically active hydroxylated carotenoids (e.g. zeaxanthin). Chirality was introduced at C-6 (C-3, carotene numbering) by a stereoselective reduction of the double bond by baker s yeast." ... 

Haubenstock and Davidson found that reduction of 3,3,5-trimethylcyclohexanone (dihydroisophorone) with the reagent is highly stereospecific but dependent upon the reaction conditions. When a solution of the ketone in benzene is added to excess reagent the product consists of 96% of the axial /rans-aicohol in this kinetic-ally controlled reduction the reagent approaches on the less hindered a-face to give... 

Similar yields of p-heterosubstituted alcohols have been observed 35) with deoxybenzoin and 2,2,6-trimethylcyclohexanone for all three heterosubstituted lithio derivatives if the reactions are performed at — 78 °C in THF (Scheme 34 g, i), whereas the best results are obtained when (methylseIeno)eyclopropyllithium is reacted at the same temperature but in ether instead of THF (Scheme 34 h, j)). This is probably due to a reduction of the degree of enolisation of the starting ketone when ether is used 87). This is a tendency which proved to be general for other a-selenoalkyl-lithiums 7 8-9-12)... 

Adsorption of the ketone on montmorillonite clay enhances the axial attack of NaBH reduction to >99% for 4-t-butylcyclohexanone 3.26 and 78% for 3,3,5-trimethylcyclohexanone 3.29 [SRI], Other hindered substituted borohydrides also give higher levels of equatorial attack [CYl]. From the numerous studies to date, it appears that torsional and steric factors are very often predominant, as illustrated by the reduction of eight-membered cyclic taxane derivatives [SH7]. An interesting solvent effect in the reduction of a sugar derivative has been recently shown. The reduction of a substituted rigid six-membered ketone with DIBAH in CH2CI2 or... 

Compared with many other reagents, the amount of axial alcohol is very small (2-11 %) using isobornyloxyaluminum dichloride (1 a) (see Table 1, p 4101) as the reducing agent. The proportion of axial attack, yielding the equatorial alcohol, is also decreased in the reduction of sterically more hindered carbonyl compounds such as 3,3,5-trimethylcyclohexanone and men-thone79. 

Table 13. Reduction of 3,3,5-Trimethylcyclohexanone Dependance of Stereochemistry on Reaction Time by Equilibrium with Triisobutylaluminum164...

Predominant attack of the reagent from the equatorial direction is observed even in the case of a simple cyclohexanone containing a single substituent in the 3- or 4-position. Thus, 3-t-butylcyclo-hexanone gives 72% of the trans isomer as compared to only 15% with LiAlH4. From 3,3,5-trimethylcyclohexanone, trans alcohol (99%) is obtained. In all cases, even in the reduction of the highly hindered camphor structure, the reaction is 100% complete within 0.5 h at 0°C <70JA709>. 

In Figure 10.3, we illustrate nonselective and aselective morpholytic processes. The reductions of ( )-3,3,5-trimethylcyclohexanone, ( )-37, with triisobutylaluminum, and of ( )-2-methylcyclohexanone, ( )-40, with Alpine-borane are morpholytononselective processes in each reaction, the two enantiomers are consumed at equal rates. Thus, the two enanhomers in racemate ( )-37 react with achiral triisobutylaluminum (36), at expectedly-equal rates, to give racemic cis-38 plus racemic trans-39 (cis/trans = 4.8 1). In contradistinction, the two enantiomers in racemate ( )-40 react at accidentally-equal rates to give nonracemic ds-41 (68% ee) and nonracemic trans-M (68% ee) cis/trans = 1 1). No kinetic resolution of either ( )-37 or ( )-40 takes place. 

With other less-rigid cyclohexanones, the stereochemical course of the reduction is less easy to predict. In general, a mixture of products is obtained in which, with comparatively unhindered ketones, the more stable equatorial alcohol predominates with hindered ketones, the axial alcohol is often the main product. Thus, reduction of 4-tert-butylcyclohexanone 84 with lithium aluminium hydride gives predominantly the equatorial trans-4-/ crt-butylcyclohexanol, whereas the hindered 3,3,5-trimethylcyclohexanone 85 gives a mixture containing mainly the axial alcohol 86 (7.69,7.70). The latter is almost the only product when a more hindered and hence more selective reducing agent such as L-selectride [LiBH( Bu)3] or lithium hydrido-tri-tert-butoxyaluminate [LiAlH(0 Bu)3] is employed. 

Oxoisophorone 68 can be converted into trimethylcyclohexanone (74), in a series of reduction and elimination steps [82], opening up a new route to p,p-carotene (3) and vitamin A [85,86]. The Cio-epoxide 75 can be obtained by Wittig olefination of 73 with methylene-triphenylphosphorane, isomerization and reaction with peracids. Lewis acid-catalysed rearrangement to give the five-membered ring yields the capsorubin synthon 76 [9]. 

Table 6. Enantiomeric excess in 3,3,5-trimethylcyclohexanone from the reduction of iminium salts with 1,4-dihydronicotinamide sugar...

The effects of changes in solvent and reducing agent are also profound. This is illustrated in Equation 9.19, where reduction of 3,3,5-trimethylcyclohexanone to the corresponding axial alcohol (from equatorial hydride addition) and equatorial alcohol (from axial hydride addition) is shown. 

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