Cinchona alkaloid-based catalysts thiourea

In the next few years, the use of isobutyraldehyde as the nucleophile in conjugate additions to aromatic nitroalkenes received a lot of attention. He and coworkers reported a chiral thiourea that could efficiently catalyse this transformation, while Chen and coworkers employed a catalyst combining the 1,2-diaminocyclohexane moiety with the privileged Cinchona alkaloid scaffold. A more sustainable protocol was provided by Ma and coworkers, where catalyst 40, based on a beyerane skeleton, was found to promote the same transformation both in organic solvents (up to 92% yield and 98%... 

More recently, it has been reported that primary amines derived from cinchona alkaloids [75] as well as proline derivatives [76], combined with achiral Brpnsted or Lewis acids, may also efficiently catalyze the enantioselective Biginelli reaction. Alternatively, a carbohydrate-based bifnnctional primary amine-thiourea catalyst was developed for this transformation, with similar enantiocontrol [77]. 

The catalytic potential of base functionalities has been referred to in the previous chapter (see Sect. 7.4), wherein the interplay between an acidic (thio-)urea and a basic amine separated by a chiral linker was shown to enable the simultaneous activation of both the electrophile and nucleophile. In addition to such brfunctional thiourea-containing acid-base catalysts, chiral catalysts containing Lewis or Br0nsted-) base functionality as the sole catalyticaUy active group as weU as those having another H-bond donor like a hydroxy group e.g. Cinchona alkaloids) have found widespread applications in asymmetric catalysis (443-449). 

Chiral H-bond donors and acids have proven their potential many times over several decades. Some useful apphcations in natural product synthesis have been reported, using either hydrogen bonding activation as the sole catalytically active principle, or utilizing bifunctional catalysts. With respect to the catalytic moiety of choice, the considerable potential of thioureas can be emphasized, especially those based on Cinchona alkaloids (Table 6). 

On the other hand, Zhao s group achieved remarkable results with bifunctional cinchona alkaloid and thiourea catalysts [35], which, over the years, have been broadly employed as catalysts in Mannich reaction. Indeed, as Brpnsted bases, the preferred bifunctional catalyst 46 can lead to the Mannich three-component product 47 with extranely high diastereo- and... 

This challenging problem was addressed by Deng and coworkers [51] by the use of 9-thiourea cinchona alkaloids as acid-base bifunctional catalysts. As shown in Scheme 10.30, the enantioselective aza-Friedel-Crafts reaction proceeded through a network of hydrogen bonding interactions between indoles 145 and A-Ts aldimines 149... 

The dual activation mode of the aforementioned cinchona alkaloid-derived thiourea catalysts proved to be highly effective in catalyzing the asynunetric Mannich reaction, among other transformations. These findings prompted the development of new, more simple bifunctional chiral catalysts that are predominately based on tra 5 -l,2-diaminocy-clohexane. For example, the application of the thiourea catalyst 120, which was developed by Takemoto and coworkers, afforded upon the reaction of Af-Boc-protected imines with diethyl malonate the desired chiral amines in good chemical yields (up to 91%) and enantioselectivities (98% ee) (Scheme 11.23) [81]. The catalytic mechanism presumably involves deprotonation and coordination of the active carbonyl compound by the chiral tertiary amine moiety. The formed enolate then attacks the si-face of the... 

This gives chapter an overview of natural cinchona alkaloids and synthetic derivatives together with examples of their use in asymmetric organocatalysis. In recent years, the emphasis has been on the development of cinchona-based bifunctional catalysts, in particular species with a thiourea moiety. The search for new cinchona-based organocatalysts continues and new derivatives are relentlessly being prepared and applied for specific enantioselective reactions. The design of these new... 

The synthetic utility of the bifunctional catalysts in various organic transformations with chiral cyclohexane-diamine derived thioureas was estabhshed through the works of Jacobsen, Takemoto, Johnston, Li, Wang, and Tsogoeva. In the last decade, asymmetric conjugate-type reactions have become popular with cinchona alkaloid derived thioureas. The next section presents non-traditional asymmetric reactions of nitroolefins, enones, imines, and cycloadditions to highhght the role of chiral Br0nsted base derived thiourea catalysts. 

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