C6 -OH cinchona alkaloids

In 2006 Deng and coworkers reported that C6 -OH cinchona alkaloids catalyze the reaction of nitromethane with a-ketoesters to afford the corresponding nitroaldol products with excellent yields and enantioselectivities. The enantiose-lectivities obtained with C6 -OH cinchona alkaloids were found to be considerably higher than those displayed by C6 -OMe catalyst (Table 29.2, 11 versus 12) [17]. 

Recently, Wang et al. reported the reaction of isatins with nitromethane using C6 -OH cinchona alkaloid catalyst 15 (Scheme 29.8). 3-Substituted 3-hydroxy-oxindoles are obtained in excellent yields and enantioselectivities albeit long reaction times are required [22]. For the 4,7-dichloroisatin and N-benzyl-isatin, only moderate enantioselectivities were obtained (71% and 76%, respectively). The methodology was applied to the total synthesis of (R)-(+)-dioxibrassinin (20) and the formal synthesis of (S)-(-)-spirobrassinin (21). 

The usefulness of these types of catalysts for the asymmetric nitroaldol reaction of a-ketophosphonates and nitromethane has also been demonstrated [20]. The enantioselectivity achieved with the C6 -OH catalyst was found again to be considerably higher than that displayed by C6 -OMe cinchona alkaloid (14 97% ee versus 16 33% ee). No effects in terms of yield and selectivity were observed on modifying the C9 position of the catalyst (14 versus 17). Screening of the solvents revealed that THF is the best one in terms of both reactivity and enantioselectivity. Unfortunately, the absolute configuration of the major enantiomer was not determined. 

The organocatalyzed condensation of arenes (i.e., phenols) with a model carbonyl compound, 3,3,3-trifluoropyruvate 6a, was first described in 2008 in the presence of Cinchona alkaloid 42a (10mol%). Crucial aspect to guarantee high levels of stereoinductions (ee up to 94%) Ued on blocking the C9—OH with a hindered group (i.e., phenanthrene, PHEN) and leaving unprotected the C6 —OH function (Scheme 5.13) [23]. 

A dual activation mode based on a network of hydrogen bond interactions is assumed being active in all these methodologies. In particular, the C6 —OH group could activate the carbonyl derivatives, while the quinuclidine tertiary nitrogen atom could modulate the reactivity of the hydroxybenzene (the case of Cinchona alkaloids is reported in Fig. 5.3). 

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