3.3.5- Trimethylcyclohexanone: reaction with

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). 

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... 

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. 

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]. 

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... 

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. 

Using a Stille s reaction, De Lera et al. connected a tetraenic stannate with a triflate derived from the trimethylcyclohexanone [19,20]. First, the tetraenylstannate was prepared by Homer-Wadsworth-Emmons... 

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)... 

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>. 

Rearrangement of a-acetylenic alcohols. The key step in a stereospecific synthesis of vitamin A from 2,2,6-trimethylcyclohexanone is the rearrangement of (1) to (2). This reaction was carried out with the vanadate in the presence of additional triphcnylsilanol. The yield of crude (2) was 96% purification was accompanied by considerable decomposition, but still the yield of pure (2) was 40%. This vanadate-catalyzed rearrangement appears to be general. 

Enol triflates are also excellent substrates in the Heck reaction. They may be prepared by the reaction of enolizable ketones with trifluoromethanesulphonic anhydride or the crystalline A, A -bis(trifluoromethanesulphonyl)anilide (A/ -phenyltriflide) [46]. The enol triflates derived from 2,2,6-trimethylcyclohexanone (90), from the r-butyldi methyl si lyl ether of 3-hydroxy-2,2,6-trimethylcyclohexanone (91), and from 2,2,5-trimethylcyclopentanone (92) couple in excellent yields (88-93%) to methyl vinyl ketone (10) in the presence of bis(triphenyl-phosphine)palladium(n) dichloride [PdCl2(PPh2)2l, to give p-ionone (2) [47], the 3-hydroxy-P-ionone derivative 93 [48], and the 5-membered-ring P-ionone analogue 94 [49], respectively (Scheme 22). 

Carbonyl Reactivity.—A new reagent, lithium tri-s-butylborohydride, is claimed to exhibit enzyme-like stereoselectivity in reduction of cyclic (and bicyclic) ketones. Reduction of 2-methylcyclohexanone at 0°C in THF for 30 min occurred quantitatively to give the less stable cis-alcohol with an epimeric purity of 99.3%. 3,3,5-Trimethylcyclohexanone was reduced to the trans-alcohol with 99.8% stereoselectivity and 3-methylcyclohexanone likewise with 85% stereoselectivity. Reduction of 4-methylcyclohexanone to the cis-alcohol occurs with 80.5% stereoselectivity correspondingly cis-4-t-butyl-cyclohexanol is produced with 93% isomeric purity, much higher than in previous cited procedures, and this figure rises to 96.5% when reaction is... 

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