Cinchona alkaloid-based catalysts

Uozumi has explored a series of (25, 4/ )-4-hydroxyproline-derived 2-aryl-6-hydroxy-hexahydro-lFf-pyrrolo[l,2-c]imidazolones as potential alternatives to cinchona alkaloid-based catalysts for the alcoholative ASD of meio-anhydrides (Fig. 16) [226]. Uozumi screened a small library of catalysts prepared by a four-step, two-pot reaction sequence from 4-hydroxyproline in combination with an aldehyde and an aniline. The most selective member, compound 67, mediated the methanolytic ASD of cw-hexahydrophthalic anhydride in 89% ee when employed at the 10 mol% level for 20 h at -25 °C in toluene [226]. 

These reports have accelerated research investigations into improving the asymmetric alkylation of 1 in terms of catalytic activity and stereoselectivity, the result being the emergence of a series of appropriately modified cinchona alkaloid-based catalysts. The performance of the representative monomeric catalysts in the asymmetric benzylation and allylation of 1 are summarized in Table 2.1, in order to provide an overview of the relationship between the structure, activity and enantioselectivity. 

Scheme 4.74 The catalytic enantioselective phospha-Michael reactions using cinchona alkaloid-based catalysts.

Nitroaldol (Henry) reactions of nitroalkanes and a carbonyl were investigated by Hiemstra [76], Based on their earlier studies with Cinchona alkaloid derived catalysts, they were able to achieve moderate enantioselectivities between aromatic aldehydes and nitromethane. Until then, organocatalyzed nitroaldol reactions displayed poor selectivities. Based on prior reports by Sods [77], an activated thionrea tethered to a Cinchona alkaloid at the quinoline position seemed like a good catalyst candidate. Hiemstra incorporated that same moiety to their catalyst. Snbsequently, catalyst 121 was used in the nitroaldol reaction of aromatic aldehydes to generate P-amino alcohols in high yield and high enantioselectivities (Scheme 27). 

Esters 16b,c are used in reactions catalyzed by cinchona alkaloid-based phase-transfer catalysts, since the size of the ester is important for efficient asymmetric induction in these reactions [35], However, the syntheses of esters 16b,c adds considerable cost to any attempt to exploit this chemistry on a commercial basis. Fortunately, it was possible to develop reaction conditions which allowed the readily available and inexpensive substrate 16a to be alkylated with high enantios-electivity using catalyst 33 and sodium hydroxide, as shown in Scheme 8.18 [36]. The key feature of this modified process is the introduction of a re-esterification step following alkylation of the enolate of compound 16a. It appears that under... 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

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). 

One of our simplest attempts at overriding the inherent diastereoselectivity was inspired by our success with using Cinchona alkaloid-based phase-transfer catalysts to promote the enantioselective desymmetrization of achiral malonate-tethered cyclohexadienones (Scheme 27). When catalyst B was... 

General principles applied on the design of chiral cinchona alkaloid-based chiral ammonium salt PTC catalysts. 

Continuing with the use of cinchona alkaloid-based quaternary ammonium salts as catalysts, phenyl vinyl sulfones have also been employed as Michael acceptors in the reaction with glycine imines using cinchonidinium salt 103a as catalyst both in solution or in a solid-supported version (Scheme 5.33), furnishing similar results to those provided by the corresponding vinyl ketones and acrylates shown in Schemes 5.8 and 5.23. ... 

Figure 6.1 Two examples of dimeric cinchona alkaloid-based Bronsted base catalysts.

Two examples of hetero-Michael reactions have been reported using these kinds of bis-cinchona alkaloid-based chiral Bronsted bases as catalysts. One of them refers to a sulfa-Michael reaction and the other is a case of an aza-Michael reaction. 

Phase-transfer catalysis is one of the most practical synthetic methodologies because of its operational simplicity and mild reaction conditions, which enable applications in industrial syntheses as a sustainable green chemical process. As reviewed in this chapter, diverse Cinchona alkaloid-derived quaternaiy ammonium salts have been developed via the modification of Cinchona alkaloids based on steric or electronic factors as highly efficient chiral PTC catalysts and successfully applied in various asymmetric organic reactions. Despite the successful development and application of these catalysts, some problems remain to be addressed. Although Cinchona alkaloids have unique structural features, resulting in the availability of four... 

After the first successful application of Cinchona alkaloid-based quaternary amo-nium salts as chiral phase-transfer catalysts in 1984 [187], the use of chiral quaternary ammonium salts in asymmetric catalysis has experienced a notable growth [177a, 188]. In particular, the asymmetric alkylation of glycine-derived Schiff bases by means of phase-transfer organocatalysis, pioneered by O Donnell et al. [ 189] and further improved by Lygo and Wainwright [190] and by Maruoka and co-workers [191], among others, has become one of the most reliable procedures for... 

Asymmetric phase-transfer catalysis is a method that has for almost three decades proven its high utility. Although its typical application is for (non-natural) amino acid synthesis, over the years other types of applications have been reported. The unique capability of quaternary ammonium salts to form chiral ion pairs with anionic intermediates gives access to stereoselective transformations that are otherwise very difficult to conduct using metal catalysts or other organocatalysts. Thus, this catalytic principle has created its own very powerful niche within the field of asymmetric catalysis. As can be seen in Table 5 below, the privileged catalyst structures are mostly Cinchona alkaloid-based, whereas the highly potent Maruoka-type catalysts have so far not been applied routinely to complex natural product total synthesis. 

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