Cinchona substrate scope

Significant progress in the substrate scope of the Pt-cinchona systems has been made in the last 5 years. Besides a-keto acids and esters, a-keto acetals, a-keto ethers, and some trifluoromethyl ketones have been shown to give high ee s. It is now possible to classify ketones concerning their suitability as substrates for the Pt-cinchona catalyst system, as depicted in Figure 18.6. Nevertheless, for the synthetic chemist, the substrate scope is still relatively narrow, and it is not expected that new important substrate classes will be found in the near future. However, the chemoselectivity of this system has not yet been exploited to its full value, and this might be a potential for future synthetically useful applications. 

The development of the first highly enantioselective cyanocarbonation of prochiral ketones promoted by a chiral base catalyst, such as a cinchona alkaloid derivative, was reported by Tian and Deng in 2006. " Importantly, the reaction complemented known enzyme- and transition metal based methods in substrate scope via its unique ability to promote highly enantioselective cyanocarbonation of sterically hindered simple dialkyl ketones. Mechanistic studies provided experimental evidence to shed significant light on the asymmetric induction step in which the modified cinchona alkaloid acted as a chiral nucleophilic catalyst. Moreover, experimental evidence supported the mechanistic proposal that the enantioselectivity determination step in the cyanocarbonation was a DKR of the putative intermediates G and H via asymmetric transfer of the alkoxycarbonyl group (Scheme 2.105). 

Catalytic asymmetric nitroaldol (Henry) reactions of ketones lead to synthetically versatile chiral tertiary nitroaldols. Enantioselective nitroaldol reactions of a-keto esters have been achieved using chiral Cu and Mg complexes, and cinchona alkaloids [140]. However, there are no reports on the asymmetric synthesis of tertiary nitroaldols derived from simple ketones. Even for a racemic version, only a few methodologies with limited substrate scope are available. The difficulty arises from the attenuated reactivity of ketones and their strong tendency toward a retro-nitroaldol reaction under basic conditions. (S)-LLB catalyst was found suitable to promote retro-nitroaldol reaction and a kinetic resolution of racemic tert-nitroaldols was realized. (S)-LLB preferentially converted the matched (R)-enantiomer into ketone and nitromethane, whereas the mismatched (S)-enantiomer remained unchanged and was recovered in an enantiomerically... 

Deng and co-workers developed the first asymmetric Diels-Alder reactions of a,p-unsaturated ketones and 2-pyrones (Scheme 5.36) [65] with cinchona-based primary amine catalysts 38 or 39. The substrate scopes are substantial and in most cases excellent diastereoselectivity and enantioselectivity were obtained. 

In 1982, Wynberg and coworkers discovered the cinchona alkaloid catalyzed enantioselective aldol lactonization of ketenes with chloral or trichloroacetone [35], in which the zwitterionic acyl ammonium enolate provides the carbon nucleophile. This work is probably one of the most important early contributions to enantioselective organocatalysis [36], One drawback associated with this process is the severe substrate limitations. The aldehydes should be highly reactive, presumably due to the relatively limited nudeophilicity of ammonium enolates. Nelson and coworkers first addressed the scope and reactivity problems associated with Wynberg s original protocol by combining a cinchona alkaloid derivative (O-trimethylsilylquinine (12) or O-trimethylsilylquinidine (13)) with a metal Lewis acid as a cocatalyst to... 

This group continuously enlarged the scope of substrate to allylsilane, silyl enol ether 113 and oxindoles 115 for enantioselective catalytic a-fluorination (Scheme 6.34) [62]. They employed N-fluorobenzenesulfonimide (NFSI) as a fluorinating reagent with bis-cinchona alkaloid catalysts and excess base to provide the corresponding fluorinated compounds 114,115 in excellent enantioselectivities up to 95% ee. 

Jew and Park have also utilized the dimerization effect, as observed in the development of Sharpless asymmetric dihydroxylation, where ligands with two independent cinchona alkaloid units attached to heterocyclic spacers led to a considerable increase in both the enantioselectivity and scope of the substrates, to design dimeric and trimeric cinchona alkaloid-derived phase-transfer catalysts 12 [12] and 13 [13]. These authors investigated the ideal aromatic spacer for optimal dimeric catalysts, and found that the catalyst 14 with a 2,7-bis(bromomethyl) naphthalene spacer and two cinchona alkaloid units exhibited remarkable catalytic and chiral efficiency (Scheme 11.3) [14]. 

Encouraged by our success with these cyclizatirais, and recognizing that symmetric dienone substrates contain enantiotopic olefins, we then explored the possibility of performing desymmetrization reactions with chiral phase-transfer catalysts. This is somewhat outside the scope of this account, so a detailed description of these efforts will not be given. Nevertheless, we were successful in using cinchona alkaloid-derived catalyst A to desymmetrize a number of dienone substrates with moderate levels of enantiocontrol (Scheme 11). ... 

The conceptually different activation of carbonyl substrates through the formation of a nucleophilic enamine or an electrophilic iminium ion is achieved by use of 9-deo>q -ep/-9-amino Cinchona catalysts. In contrast to typical secondary amine-based catalysts i.e. derived from proline), the primary amine of these modified Cinchona alkaloids can combine also with sterically biased substrates, such as ketones and hindered aldehydes. This class of catalyst has thus allowed the scope of aminocatalysis to be extended beyond unhindered aldehydes/enals, and has proved to be remarkably powerful and general. 

Although considerable improvements have been made for endo-selective cycloadditions of azomethine imines, methods for exo and enantioselective cycloaddition of azomethine imines were relatively scarce. By employing novel, multifunctional primary amine catalysts 145 derived from cinchona alkaloids in the presence of triisopropylbenzene sulfonic acid (TIPBA) 146 as cocatalyst, Chen and coworkers developed the first organocatalytic, highly exo-selective, and enantioselective 1,3-DC reaction of cyclic enones 142 and azomethine imines 143 in 2007 [53]. The additional and synergistic hydrogen-bonding interaction of catalyst and 1,3-dipole is essential for enantiocontrol, and excellent stereoselectivities were achieved for a broad scope of substrates (dr > 99 1, up to 95% ee) (Scheme 2.37). 

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