2,2,6-Trimethylcyclohexanone

The high importance of the steric interaction of the incoming nucleophile with the axial groups at C-3 and C-5 of the cyclohexanone is impressively demonstrated by addition reactions to 3,3,5-trimethylcyclohexanone (14). The presence of an axial methyl substituent intensifies the steric interaction in such a way that the nucleophile is forced to enter the carbonyl group exclusively from the less hindered equatorial side6,7,21. Exclusive formation of the axial... 

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]. 

Ashby and coworkers reported in 1974 stereochemical studies on addition of lithium trimethyhnagnesate to several ketones . The reactions of 4-ferf-butylcyclohexanone with methyllithium, with dimethylmagnesium and with lithium trimethyhnagnesate in ether afforded mixtures of the corresponding axial and equatorial alcohols in ratios of 65 35, 70 30 and 69 31, respectively (equation 11). Reaction of 3,3,5-trimethylcyclohexanone with lithium trimethylmagnesate yielded exclusively the axial alcohol (equation 12). Reaction of norcamphor provided 95% of the endo alcohol and 5% of the exo alcohol (equation 13). In contrast, reaction of camphor yielded the exo alcohol with high stereoselectivity (equation 14). Among the methylmetals examined, no difference in the stereoselectivity was virtually observed. 

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. 

Other cyclic imines also show enhanced stereoselectivities compared to ketones. Thus, 3,3,5-tri-methylcyclohexyl imine (17) afforded a 94 6 transxis ratio with NaBH4 compared to 58 42 with 3,3,5-trimethylcyclohexanone," again suggesting increased steric interference from N-substituents. 

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... 

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... 

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