Cyclohexanones 2,2-disubstituted, chiral

The regio- and diastereo-selectivity of the Michael addition of 2-phenylcyclo-hexanone with a,p-unsaturated ketones are dependent on the reaction conditions. Mixtures of all six diastereoisomers resulting from reaction at either the 2- or 6-position of the cyclohexanone ring can be obtained using solid potassium hydroxide with tetra-n-butylammonium or A-benzylephcdrinium bromide catalysts. At 20°C with tetra-n-butylammonium bromide, the ratio of the 2,2- and 2,6-disubstituted cyclohexanones is ca. 3 2, but at higher temperatures with solid potassium f-butoxide the kinetically formed 2,6-isomer predominates (ca. 5 1) with the (2S,6R, R )-stereoisomer dominant, whereas greater amounts of the thermodynamically preferred 2,2-(2S,lR )-isomer are obtained with the chiral catalyst [61]. 

The first asymmetric procedure consists of the addition of R2Zn to a mixture of aldehyde and enone in the presence of the chiral copper catalyst (Scheme 7.14) [38, 52]. For instance, the tandem addition of Me2Zn and propanal to 2-cyclohexenone in the presence of 1.2 mol% chiral catalyst (S, R, R)-1S gave, after oxidation of the alcohol 51, the diketone 52 in 81% yield and with an ee of 97%. The formation of erythro and threo isomers is due to poor stereocontrol in the aldol step. A variety of trans-2,3-disubstituted cyclohexanones are obtained in this regioselective and enantioselective three-component organozinc reagent coupling. 

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

The creation of all-carbon quaternary chiral centers by asymmetric conjugate addition is a challenging task. A chiral heterocyclic carbene 199 has been used as a ligand for this reaction. Chiral 3,3-disubstituted cyclohexanones 200 were obtained by this method with up to 85% ee (equation 126) . ... 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

Whitesell and Felman therefore concluded that an amine with a C2 axis of symmetry was required in order to ensure that the same side of the cyclohexene ring was shielded from attack whichever conformation of the enamine underwent alkylation. The en-antioselectivity was thereby considerably increased, but in the opposite chiral sense, by using the cyclohexanone enamine derived from ( + )-/mnj-2,5-dimethylpyrrolidine. This was assumed to have the S, S-configuration based on the results of the alkylation (Scheme 70). Optical yields of 82-93% ee were obtained. Also noteworthy was the low level of dialkylation observed (4-7%) and the fact that formation of enamine 77 was at least ten times faster using type 3A molecular sieves compared to 4A molecular sieves. Similar methodology has been applied to the alkylation of 4-substituted cyclohexanone enamines to give mainly the less stable trans disubstituted cyclohexanone s . 

Asymmetric conjugate addition reactions of carbonyl compounds with a, -unsaturated systems are known. The simple amine a-methylbenzylamine 68 acts as both the activator (to give the imine and hence the enamine required for alkylation) and as the chiral auxiliary to effect neutral asymmetric conjugate-addition reactions. " Thus, condensation of (5)-a-methylbenzylamine 68 with 2-methylcyclohexanone, followed by addition of methyl acrylate (and hydrolysis of the product imine), gave the 2,2-disubstituted cyclohexanone 69 with high enantiomeric purity (1.78). 

The Horner-Wadsworth-Emmons (HWE) reaction of a carbonyl compound with an a-lithiated phosphonate is an extremely useful method for introducing a double bond. In order to create a chiral compound having a double bond, 4-substituted cyclohexanones, 3-substituted cyclohexanones, 2,2-disubstituted cyclohexane-l,3-diones, or ketenes would be potential carbonyl substrates for the enantioselective HWE reaction, as Rein and coworker proposed [Fig. (15)] [69]. Only 4-substituted cyclohexanones have so far been applied to the enantioselective HWE reaction. 

Analogous isomerization occurred with 1-alkenylcyclobutanol 51 to afford chiral 3,3-disubstituted cyclohexanone 52 (Scheme 3.29). 

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