Asymmetric organocatalysts alkaloid derivatives

Currently, the chiral phase-transfer catalyst category remains dominated by cinchona alkaloid-derived quaternary ammonium salts that provide impressive enantioselec-tivity for a range of asymmetric reactions (see Chapter 1 to 4). In addition, Maruoka s binaphthyl-derived spiro ammonium salt provides the best results for a variety of asymmetric reactions (see Chapters 5 and 6). Recently, some other quaternary ammonium salts, including Shibasaki s two-center catalyst, have demonstrated promising results in asymmetric syntheses (see Chapter 6), while chiral crown ethers and other organocatalysts, including TADDOL or NOBIN, have also found important places within the chiral phase-transfer catalyst list (see Chapter 8). 

The use of Merrifield resin-bound alkaloid-based organocatalysts has also been reported [66-67]. The best results were obtained when attachment to the Merrifield resin was made via the hydroxy moiety of a (cinchonidine) alkaloid derivative [67]. The immobilization of alkaloid-derived catalysts on poly(ethylenglycol) (and modifications thereof) was also developed [68a, b]. Furthermore, asymmetric catalytic alkylations under micellar conditions were reported [68c],... 

With respect to the use of Cinchona alkaloid-derived organocatalysts, the first example of asymmetric Michel addition of ketones to enones appeared in 1979 when Trost illustrated, during the total synthesis of the sesquiterpene ( )-hirsutic acid C [101], a stereoselective (30% ee) quinine (59)-catalyzed intramolecular conjugate addition of an intermediate functionalized cyclohexanone (Scheme 2.32). 

Nonquatemised Cinchona Alkaloid Derivatives as Asymmetric Organocatalysts for Carbon-Carbon Bond-forming Reactions... 

An enamine-catalyzed asymmetric a-fluorination of ketones, which are notoriously challenging substrates for this reaction, was reported by MacMillan and coworkers in 2011 [27]. After exhaustive automated screening of over 250 organo-catalysts, a Cinchona alkaloid-derived primary amine organocatalyst was identified as the optimal catalyst for this transformation (Scheme 13.11). Only cyclic ketones provided fluorinated products in high yields and enantiomeric excesses. 

On the other hand, several cinchona alkaloid-derived primary amines have been successfully investigated as organocatalysts for asymmetric Michael additions of ketones to Michael acceptors. As an example, Lu et al. have described the first Michael addition of cyclic ketones to vinyl sulfone catalysed by a catalyst of this type, providing an easy access to chiral a-alkylated carbonyl compounds with high yields and enantioselectivities of up to 96% ee, albeit with moderate diastereoselectivities (<72% de), as shown in Scheme 1.21. This novel methodology was apphed to the synthesis of sodium cyclamate, an important compound in the artificial sweeteners industry. 

These authors also reported the first catalytic asymmetric 1,3-dipolar cycloaddition between a-substituted isocyanoesters and nitroolefins by using a cinchona alkaloid derivative as the organocatalyst to afford chiral 2,3-dihy-dropyrroles with high diastereo- and enantioselectivities of up to > 90% de and >99% ee, respectively. The best results are collected in Scheme 6.17. 

Wang and co-workers reported a novel class of organocatalysts for the asymmetric Michael addition of 2,4-pentandiones to nitro-olefms [131]. A screen of catalyst types showed that the binaphthol-derived amine thiourea promoted the enantiose-lective addition in high yield and selectivity, unlike the cyclohexane-diamine catalysts and Cinchona alkaloids (Scheme 77, Table 5). 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

Together with cinchona-PTC-mediated a-alkylations, the asymmetric nucleophilic a-substitution of carbonyl derivatives by using cinchona alkaloids as organocatalysts in nonbiphasic homogeneous conditions also have been extensively studied (e.g., arylation, hydroxylation, amination, hydroxyamination, and sulfenylation). 

The naturally occurring cinchona alkaloids (Figure 8.1), as described in other chapters of this book, have proven to be powerful organocatalysts in most major chemical reactions. They possess diverse chiral skeletons and are easily tunable for diverse catalytic reactions through different mechanisms, which make them privileged organocatalysts. The vast synthetic potential of cinchona alkaloids and their derivatives in the asymmetric nucleophilic addition of prochiral C=0 and C=N bonds has also been well demonstrated over the last decade. 

In the presence of cinchona derivatives as catalysts, peroxides or hypochlorites as Michael donors react with electron-deficient olefins to give epoxides via conjugate addition-intramolecular cyclization sequence reactions. Two complementary methodologies have been developed for the asymmetric epoxidation of electron-poor olefins, in which either cinchona-based phase-transfer catalysts or 9-amino-9(deoxy)-epi-dnchona alkaloids are used as organocatalysts. Mechanistically, in these two... 

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