Cinchona alkaloid-based

The first silica-supported CSP with a cinchona alkaloid-derived chromatographic ligand was described by Rosini et al. [20]. The native cinchona alkaloids quinine and quinidine were immobilized via a spacer at the vinyl group of the quinuclidine ring. A number of distinct cinchona alkaloid-based CSPs were subsequently developed by various groups, including derivatives with free C9-hydroxyl group [17,21-27] or esterified C9-hydroxyl [28,29]. All of these CSPs suffered from low enantiose-lectivities, narrow application spectra, and partly limited stability (e.g., acetylated phases). 

CINCHONA ALKALOID-BASED CHIRAL STATIONARY PHASES... 

The cinchona alkaloid-based CSPs are actually mixed-mode RP/weak anion-exchange phases and HILICAVAX phases, respectively. The surface layer of these... 

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]. 

Scheme 3. Cinchona alkaloid-based methodology for cyanation of ketones developed by Deng and Tian...

TABLE 1 Chiral Resolution of Amino Acid Derivatives on Cinchona Alkaloid-Based CSPs... 

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. 

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 cinchona alkaloid-based stationary phases are chiral stationary phases where quinine/ quinidine are chemically bonded to a silica gel matrix. The interaction between the selectand and selector is based on charge transfer n-n interactions as well as ion pairing with the selector. They operate under aqueous-organic mobile phases or mixtures of organic solvents such as hexane-alcohols. 

The Sharpless asymmetric epoxidation of allyl alcohol gives the glycidol derivative 61 in 90% ee after in situ tosylation of 60 [63]. This process is working on a multiton-a-year scale (Arco Co., USA), facilitating the synthesis of a variety of /0-blockers. Asymmetric dihydroxylation of the allyl ether 63 catalyzed by a combined system of OSO4 and the cinchona alkaloid-based ligand 65 allows the commercial synthesis of the propranolol intermediate 64 in 91 % (Sepracor Co., USA) [64]. 

As mentioned briefly in Chapter 2, very few publications describing cinchona alkaloid-based asymmetric reduction systems have appeared, despite the importance of this reaction, and they are restricted to the reduction of aromatic ketones. 

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). 

Fig. 32. Postulated ion pairing of hydroxy pyrone 71 with Cinchona alkaloid base...

Dihydroxylation. Besides the enormously popular and effective cinchona alkaloid-based chiral auxiliaries several C2-symmetrical diamines (13), (14) and (15) have been developed to direct alkene dihydroxylation with OSO4. These efforts are probably overwhelmed by the Sharpless protocols because the approaches are not catalytic with respect to the most expensive and toxic reagent. 

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... 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

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

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... 

Recently, Ma and co-workers [41] reported a related Michael-acetalization sequence between (S,7-unsaturated a-ketoesters and cyclic 2-oxo aldehydes with a cinchona alkaloid-based organocatalyst (Scheme 16.20). The lactol intermediates were oxidized to the desired spirolactones obtained in good yields and excellent stereoselectivities. Hong et al. [42] used 2-hydroxynitrostyrenes instead of unsaturated ketoesters exploiting the same strategy for the synthesis of spirolactones with similar efficiency. 

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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