Organocatalytic reactions, enantioselection Cinchona alkaloids

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

The direct enantioselective organocatalytic a-fluorination can also be performed with cinchona alkaloid derivatives as catalyst under phase-transfer reaction conditions [25]. The fluorination reaction by NFSI of / -ketoesters 21, readily enolizable substrates, generated a stereogenic quaternary C-F bond in high yields and with enantioselectivities up to 69% ee for the optically active products 26 (Eq. 6). 

Catalytic enantioselective Mannich reactions provide one of the most versatile approaches for the synthesis of optically active chiral amines. Recently, several organocatalytic protocols have been developed using the parent cinchona alkaloids or their derivatives. 

Few examples have been reported for the organocatalytic asymmetric conjugate addition of sulfur nucleophiles other than thiols. The reaction of thiocarboxylic acids to cyclohex-2-enones [390] and a,p-nnsatnrated esters [391] was initially studied by Wynberg et al. employing Cinchona alkaloid catalysts with limited success in terms of selectivity (up to 54% ee). Slightly better enantioselectivities have been recently obtained by Wang et al. in the 1,4-addition of thioacetic acid to P-nitrostyrenes (up to 78% ee) [392] and trani-chalcones (up to 65% ee) [393], using Takemoto s thiourea 142 as catalyst (2-10 mol%). 

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

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. 

Gouverneur and co-workers [18] have described an organocatalytic enantioselective fluorocyclization (Scheme 13.7). In most cases, enantiomeric excesses were slightly improved when stoichiometric quantities of (DH(5)2PHAL were used. Preliminary mechanistic studies suggest that when stoichiometric quantities of Cinchona alkaloid are employed, the reaction proceeds via a transfer fluorination process, whereas another mechanism may be operative when catalytic quantities of Cinchona alkaloid are used. 

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). 

An enantioselective organocatalytic cyclopropanation reaction via chiral ammonium ylides was also developed. The reaction operates under an 8 2 process of a-halocarbonyl compounds by means of cinchona alkaloid catalysts, allowing the... 

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