Cyclohexanone prochiral 4-substituted

Substituted 1-hydroxy cyclohexane-1-carboxyhc acids, which could be prepared from the corresponding cyanohydrins by acid hydrolysis as described above, are important as pharmaceuticals and plant-protective agents. Although the compounds derived from 2- and 3-cyclohexanones have two stereogenic centers, stereoselective syntheses of these interesting products have been published only very recently. " Completely unexpected are the results of HNL-catalyzed additions to 4-substituted cyclohexanones, which do not possess a prochiral center. The (R)-PaHNL-catalyzed addition affords almost exclusively fran -isomers, whereas with (5 )-MeHNL cA-addition is favored (Table 4). ... 

Such enantioselective deprotonations depend upon kinetic selection between prochiral or enantiomeric hydrogens and the chiral base, resulting from differences in diastere-omeric TSs.27 For example, transition structure E has been proposed for deprotonation of 4-substituted cyclohexanones by base D.28 This structure includes a chloride generated from trimethylsilyl chloride. 

Deprotonation of carbonyl compounds by chiral amide bases followed by trapping with silylating agents or aldehydes has become a common method for de-symmetrizing prochiral and conformationally locked 4-substituted cyclohexanones and bicyclic ketones. The literature through 1997 has been reviewed [45]. 

Chen et al. have further applied the TFA salt of 9-amino-9-deoxyepiquinine lo as chiral organocatalyst to the desymmetrization of prochiral a,a-dicyanoalkenes from 4-substituted cyclohexanones via domino Michael-Michael addition reactions with a, 3-unsaturated ketones. These reactions exhibited high synthetic efficacy and bicyclic products 16 with two new C—C bonds, and four stereogenic centers... 

Research activities on heterogeneously-catalyzed stereoselective reductions have generally increased during the past years[l]. Among various functionalities the stereoselective aromatic ring reduction is of importance in the synthesis of fine chemicals such as pharmaceuticals, herbicides, fragrances and liquid crystals. Particularly, substituted phenol derivatives offer the possibility to control the product selectivity via reduction of the prochiral intermediate cyclohexanone [2,3]. 

Using purified CHMO from A. calcoaceticus NCIMB 9871, Taschner and coworkers[96, 971 showed that several prochiral substrates including some 4-substituted cyclohexanones were efficiently converted into their corresponding lactones, each of them showing very high enantiomeric purities (Fig. 16.5-20). Thus, CHMO prove to... 

Recently, 4-substituted prochiral cyclohexanones (10 equiv.) have been efficiently desymmetrized by their reaction with aromatic aldehydes catalyzed by (5)-prohne (1, 20 mol%) in the presence of 3,5-dimethylphenyl 3,5-bisfluoromethylphenyl thiourea as co-catalyst (20 mol%) in toluene at 25°C [53], affording the corresponding aldol products in good yields (68-87%), diastereoselectivities up to 78% de and in high enantioselectivities (94-99% ee). 

Besides the use of chiral bases or catalysts in solution, a rather interesting and unique approach that belongs to the present category involves the utilization of inclusion complexes of the stabilized ylides [104]. In the solid state, an achiral stabilized ylide such as 190 is reacted with a symmetrically substituted prochiral cyclohexanone such as 189 in the presence of a chiral host molecule. The best result was obtained using the chiral host molecule 191, which gave the dissymmetric alkene 192 with up to 57% ee. 

The cation fragment nature exerts negligible impact on selectivity of the Michael reactions that involve enamine intermediates and commonly the stereochemical outcome remains high. Indeed, pyrrolidine derivatives (Figure 22.6) containing pyridinium 87a,b [98], isoquinolinium 88a,b [99], 1,2,3-triazolium 89a,b [100], benzimidazolium 90 [101], and linear 91 [102] or cyclic 92 [103] quaternary ammonium cations in combination with various anions proved efficient catalysts of asymmetric additions of carbonyl compounds to a-nitro alkenes. Desymmetriza-tion of prochiral 4-substituted cyclohexanones can be achieved by analogy [101]. The reaction efficacy was similar under neat conditions in the presence of acidic additives (catalysts 87, 89, 90, 91) or in the IL medium (commonly in [bmim]BF4) (catalysts 88a,b, 92). 

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