Asymmetric bifunctional cinchona alkaloids

Despite the obvious potential of cinchona alkaloids as bifunctional chiral catalysts of the nucleophilic addition/enantioselective protonation on prochiral ketenes, no further contribution has appeared to date and only a few papers described this asymmetric reaction with other catalysts [13], When the reaction is carried out with soft nucleophiles, the catalyst, often a chiral tertiary amine, adding first on ketene, is covalently linked to the enolate during the protonation. Thus, we can expect an optimal control of the stereochemical outcome of the protonation. This seems perfectly well suited for cinchona analogues and we can therefore anticipate successful applications of these compounds for this reaction in the near future. 

Natural cinchona alkaloids are bifunctional aminoalcohol compounds. They can catalyze some asymmetric reactions through concerted activation modes, which could generally provide better stereocontrol. In 1996, Nakatani and coworkers... 

Scheme 6.146 Representative adducts obtained from the asymmetric Henry reaction between nitromethane and (hetero)aromatic aldehydes under bifunctional catalysis of C6 -thiourea-functionalized cinchona alkaloid 131.

The role of some chiral bifunctional amines and optically active cinchona alkaloid derivatives (Figure 3) as catalysts has been explored in catalytic asymmetric Staudinger reactions. Bicarbonate salts have been used as viable alternatives to... 

Asymmetric Cycloadditions Catalyzed by Bifunctional Cinchona Alkaloids 309... 

Recently, more efforts have been devoted to the design of novel bifunctional organocatalysts derived from natural cinchona alkaloids, which have been successfully applied in a number of asymmetric reactions. Deng et al. promoted the extensive... 

Zhang et al. investigated the asymmetric 1,3-dipolar cycloaddition of tert-butyl 2-(diphenylmethyleneamino)acetate and nitroalkenes promoted by bifunctional thiourea compounds derived from cinchona alkaloids, affording chiral pyrrolidine derivatives 13 with multisubstitutions. Catalyst lm delivered the best results in terms of catalytic activity, diastereoselectivity and enantioselectivity. Nevertheless, only moderate ee values could be obtained while the diastereoselectivities were generally good (Scheme 10.18) [22]. 

Shortly afterwards, asymmetric addition of indoles to isatins catalyzed by bifunctional cinchona alkaloid catalysts was reported by the groups of Wang and Li (Scheme 6.6, eqn (1)) and Chimni (Scheme 6.6, eqn (2)) independently. Comparable yields and enantioselectivity were obtained by employing slightly different catalytic systems. The 6 -OH group of catalyst 18 and 19 was found to play an important role in controlling the stereochemical outcome and tuning activity of catalysts in these reactions. 

High yields of 2-substituted chromans are readily attained from the asymmetric intramolecular oxa-Michael addition reaction of phenols bearing an (f -a,P-unsaturated ketone or thioester moiety mediated by a cinchona-alkaloid-urea-based bifunctional organocatalyst (140BC119). Molecular iodine-catalyzed reaction of phenols with a,P-unsaturated alcohols affords a wide range of 2,2-disubstituted chromans (14T5221). Chiral derivatives result from the intramolecular allylic alkylation of phenols bearing an... 

An asymmetric Diels-Alder reaction of 2-pyrones 57 and a,P-unsaturated ketones 34 with a bifunctional organic catalyst, e.g., cinchona alkaloid derivative 58, was reported by Deng, et al. Scheme 3.23. [37]. 

In 2005, Sons and coworkers introduced a novel bifunctional thiourea organocatalyst based on a Cinchona alkaloid for the asymmetric conjugate addition of nitromethane to tra s-chalcones. Using 10 mol% of thiourea 17, various electron-rich and electron-poor chalcones were well tolerated providing the desired adducts in high yields (80-94%) and very high enan-tioselectivities (95-96%) (Scheme 19.24). It has to be highlighted that... 

S. Oxindole Derivatives. Most recently, Curti et al. [140] disclosed the first example of a direct, organocatalytic asymmetric vinylogous Michael addition of 3-alkylidene oxindole to nitroalkenes. Bifunctional cinchona alkaloid/thiourea catalyst 69 could effectively promote the reaction, solely aHbrding the 7-substituted 3-alkylidene oxindoles 146 with excellent regio-, diastereo-, and enantioselectivities (Scheme 5.71). Importantly, both aromatic and aliphatic substituted nitroalkenes were applicable for such a reaction. 

Wu EH, Hong R, Khan JH, Liu XF, Deng L (2006) Asymmetric Synthesis of Chiral Aldehydes by Conjugate Additions with Bifunctional Organocatalysis by Cinchona Alkaloids. Angew Chem Int Ed 45 4301... 

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