Cinchona alkaloid-based catalysts bifunctional

In the same year, Connon and coworkers [63] reported that the chiral bifunctional cinchona alkaloid-based thiouea 81a is also able to catalyze the addition of dimethyl chloromalonate 196 to nitroolefins 124, leading to the Michael adduct that cyclizes to form the cyclopropane 197 in the presence of DBU. Almost single diastereomeric nitrocyclopropanes (>98% de) were obtained in good yields. However, the enantios-electivity obtained with this type of catalyst was poor (<47% ee) (Scheme 9.69). 

In 2003, Rawal reported the use of TADDOLs 177 as chiral H-bonding catalysts to facilitate highly enantioselec-tive hetero-Diels-Alder reactions between dienes 181 and different aldehydes 86 (Scheme 6.29A) [82], and also BINOL-based catalysts 178 were found to facilitate this reaction with excellent selectivities [83]. TADDOLs were also successfully used as organocatalysts for other asymmetric transformations like Mukaiyama aldol reactions, nitroso aldol reactions, or Strecker reactions to mention a few examples only [84]. In addition, also BINOL derivatives have been employed as efficient chiral H-bonding activators as exemplified in the Morita-Baylis-Hilhnan reaction of enone 184 with different carbaldehydes 86 [85]. The use of chiral squaramides for asymmetric reactions dates back to 2005 when Xie et al. first used camphor-derived squaric amino alcohols as ligands in borane reductions [86]. The first truly organocatalytic application was described by Rawal et al. in 2008 who found that minute amounts of the bifunctional cinchona alkaloid-based squaramide 180 are... 

Addition of CH2(CN)2 to -substituted 2-enoylpyridines RCH=CHCO(2-Py), catalysed by the cinchona alkaloid-based bifunctional ureas, such as (345) (10mol%), has been reported to proceed with <97% ee in m-xylene at room temperature. Squaramide (346) proved to be even more efficient for the addition of the same nucleophile to enones R CH=CHCOR, which required only 0.5 mol% catalyst loading to attain <96% ee (in CHCI3 at room temperature), ... 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

In this chapter, we review the enantioselective proto nation of enols/enolates where the asymmetry is brought by cinchona alkaloids, either the natural products or some analogues. The cinchona alkaloids may act as a direct protonating agent of enolates or as an acid-base bifunctional catalyst by first deprotonating the substrate to generate the enolate and then, as an acid, by reprotonating the carbanion. 

The reversibility problem in 1,2-additions is alleviated when imines bearing an electron-poor protecting group at nitrogen (sulfonyl, aeyl, ear-bamoyl) are employed as aeceptor partners, rendering possible even the use of 1,3-dicarbonyl compounds as donors. For example, Sehaus and eoworkers reported the highly enantioselective Mannich reaction of acetoacetates and cyclic 1,3-dicarbonyl compounds with N-carbamoyl imines derived from benzaldehydes and cinnamaldehydes catalysed by the natural Cinchona alkaloid cinchonine (CN) (Scheme 14.15). On the basis of the obtained results they developed a model that accounts for the observed diastereo- and enantioselectivity based on the bifunctional nature of the catalyst, which acts simultaneously as a hydrogen-bond donor and acceptor. 

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... 

Finally, the methanolytic desymmetrisation of a variety of cyclic anhydrides was also achieved by using a thermally robust sulfonamide-based bifunctional cinchona alkaloid as the organocatalyst. Under these conditions, an unprecedented catalytic activity combined with an excellent level of enantioselectivity of up to 98% ee were obtained at a catalyst loading of 5 mol %, as shown in Scheme 9.5. No appreciable effects of the concentration and temperature on the reactivity and enantioselectivity were observed with this catalyst. 

In 2012, Maikov and coworkers reported a similar strategy for the synthesis of spirocyclopropanes bearing two quaternary centers. In this approach, 2-chloroacetoacetates (49) reacted with 17c via a Michael/a-alkylation domino reaction (Scheme 10.16) [22]. The reaction was catalyzed by bifunctional Brpnsted Acid-Lewis base X. The final spirocyclopropanes 50 were obtained under optimized conditions in good yields and excellent diastereo and enantioselectivities. A similar approach was developed by the same research group using 3-chlorooxindoles (51) instead of 2-chloroacetoacetates [23]. This time, the catalyst was a bifiinctional squaramide-tertiary amine XI derived from cinchona alkaloids, rendering the final spirocyclopropanes 52 in good yields and excellent enantioselectivities. 

In 1981, Hiemstra and Wynberg reported a thorough investigation of the cinchona alkaloid-catalyzed addition of thiols to a,p-unsaturated enones [24] (Scheme 6.30). Mechanistic studies revealed that the free OH group is ctu-cial in this reaction and thus cinchona alkaloids most likely act as bifunctional catalysts herein. This report may now be considered as one of the major breakthroughs in asymmetric organocatalysis and has inspired a lot of further research toward the development of asymmetric Lewis or Brpnsted base catalysts. 

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... 

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