Organocatalytic Addition of Nitroalkanes to Ketones

The enantioselective Henry reaction with ketones is challenging, owing to the attenuated reactivity of the ketone carbonyl group compared to the aldehyde carbonyl moiety and the high tendency of tertiary nitro-aldol adducts to undergo a retro-addition reaction under basic conditions [15], Stereoselective construction of 

To date, few examples of organocatalytic asymmetric addition of nitromethane to ketones have been reported and all of them involve activated ketones, mainly ketoesters and ketoamides. 

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]. 

Notably, the selectivity and yields achieved with pseudoenantiomeric catalysts 11 and 13 are similar albeit with opposite sense of stereoinduction. Starting from both aliphatic and aromatic a-ketoesters and also from a, 5-unsaturated ketoesters enantioselectivities in the range of 93-96% ee were obtained. 

Fluorinated amino acids and amino alcohols have shown extensive biological activity [18]. In 2008, the Bandini and Umani-Ronchi group developed an efficient Henry reaction between nitromethane and fluoromethyl ketones catalyzed by cinchona alkaloids [19]. They showed that benzoylcupreines bearing electron-withdrawing substituents at the C9 position of the catalyst structure are essential for good results (Table 29.2,14 versus 15). Remarkably, comparable levels of asymmetric induction could be obtained with both aromatic and aliphatic ketones. 

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