Cinchona Bronsted bases

Studies of different cinchona alkaloids as the chiral Bronsted bases and a metal salt showed that hydrocinchonine lh (Scheme 10.13) and AgF were the most effective combination. The scope of the [3 + 2] cydoaddition of azomethine ylides and alkenes was investigated. Selected examples are shown in Scheme 10.14. High yields and moderate enantioselectivities were obtained from a variety of a-imino esters. It was worth mentioning that most of the pyrrolidine derivatives 11 obtained from tert-butyl acrylate were solids that could be enantiomerically enriched by crystallization. 

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. ... 

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. 

Under a different manner of cinchona alkaloid activation, azodicarboxylates were utilized as substrates for enantioselective aUylic aminations. The electrophilic addition of nucleophiles to electron-withdrawing aUyUc C-H bonds (21) was feasible via activation by a chiral Bronsted base, DHQ(2PYR) (Scheme 13.6) [15]. This discovery, from Jorgensen s group, highUghts the first enantioselective, metal-free allylic amination using alkyUdene cyanoacetates with dialkyl azodicarboxylates. 

Chiral Bronsted base catalysis began with the recognition of a natural product class of compounds in the cinchona alkaloid family [2]. Cinchona alkaloids are templates for Bronsted bases when their quinuclidine nitrogen is protonated by nucleophilic substrates, resulting in a stabihzed chiral intermediate for stereochemical attack of an electrophile. Systematic evaluation of structural variants to the scaffold... 

Michael donors and acceptors are common components in Bronsted base-mediated catalysis. Such transformations offer an uncomplicated route towards all-carbon quaternary stereocenters. In the most basic form, a, 5-unsaturated aldehydes are highly reactive templates towards nucleophilic reactions. Under such conditions, mechanistic studies show no polymerization of the unsaturated aldehydes under cinchona alkaloid catalysis [10]. This absence of polymerization is a key mechanistic indicator that the quinucUdine nitrogen of the catalyst does not act as a nucleophilic promoter. Rather, the quinucUdine nitrogen acts, as predicted, in a Bronsted basic deprotonation-activation of various cycUc and acyclic... 

The synthetic utility of the bifunctional catalysts in various organic transformations with chiral cyclohexane-diamine derived thioureas was established 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 highlight the role of chiral Bronsted base derived thiourea catalysts. 

Apart from acting as effective Lewis base catalysts, the quinuclidine structure of cinchona alkaloids can also participate in the other cycloaddition reaction by a different catalytic mechanism. Calter et al. described an interesting asymmetric interrupted Feist-Benary reaction between ethyl bromopyruvates and cyclohexadione. They proposed that the protonated cinchona alkaloid would perform as a Bronsted acid to form hydrogen-bonding interaction with a-ketoester moiety, rendering it more electrophilic toward attack by either the enol or enolate of cydohexandione. Then intramolecular alkylation would afford the formal [3 + 2] cycloadduct (Scheme 10.12) [16]. 

Taking the advantage of the reactivity of alkylideneindolones, Bencivenni and Bartoli developed the nitrocyclopropanation of oxindoles (Scheme 10.15) [21]. The reaction of 1-bromonitromethane (47) with 17c was catalyzed by the bifunctional Bronsted acid-Lewis base cinchona derivative IX. The reaction required 1 equiv of Na2C03 to trap the bromhydric acid released during the last cyclization step. The reaction started with Michael addition of the nitromethane, which was followed by intramolecular alkylation to afford the spirocyclic nitropropanes 48. 

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