Catalytic Asymmetric Synthesis. Группа авторов
alt="Schematic illustration of the structures of nucleophilicity and electrophilicity of enamines and iminium ions."/>
Figure 1.3. Nucleophilicity and electrophilicity of enamines and iminium ions.
Source: Based on [11].
1.2.3. Cinchona Amine‐Based Catalysts
Some secondary amine catalysts, such as diphenylprolinol silyl ether, are effective catalysts in Michael reactions using an aldehyde as a Michael donor (see Scheme 1.1), but these catalysts are not effective in Michael reactions using a ketone as a Michael donor because generation of an enamine from a ketone using diphenylprolinol silyl ether is hindered by its steric bulk. On the other hand, a primary amine can easily generate an enamine from a ketone. Primary amine catalysts derived from cinchona alkaloids have enabled the stereoselective functionalization of a variety of sterically hindered carbonyl compounds, which cannot be realized by secondary amine catalysts (Scheme 1.1) [10]. Moreover, primary amine catalysts can activate structurally substituted substrates such as α‐branched substituted aldehydes and ketones. They also activate α‐substituted α,β‐unsaturated aldehydes and ketones. The reactions of these substrates using chiral cyclic secondary amine catalysts are difficult.
Scheme 1.1. Reactions of cinchona alkaloid catalysts.
Source: Based on [10].
Cinchona alkaloid catalysts act as efficient bifunctional catalysts. They possess a primary amine moiety that can react with aldehydes, ketones, and α,β‐unsaturated carbonyl compounds to generate enamines and imines. The catalysts have a basic quinuclidine moiety, which acts as a base, and a hydroxy or alkoxy group on C9, which can make a hydrogen‐bonding interaction. Thus, they can simultaneously activate both electrophilic and nucleophilic reagents in a reaction.
1.3. ENAMINE
1.3.1. Aldol Reaction
Aldol reaction is one of the most important carbon–carbon bond‐forming reactions in synthetic organic chemistry, and the application of organocatalysts in this reaction has been investigated intensively [12]. The basic design of catalysts for aldol reactions is a bifunctional catalyst such as proline, with acid and basic moieties (Figure 1.4) [13]. The amine moiety reacts with a carbonyl group to generate an enamine, while the acid moiety activates the electrophile. Based on this concept, many bifunctional aldol catalysts have been developed.
Although proline is an effective and inexpensive organocatalyst, its solubility in organic solvents is poor; rather large loading of the catalyst is necessary, and applicable aldol reactions are limited. This has driven the development of organocatalysts that are more reactive and selective than proline, and the substrate scope has been expanded greatly. These developments have been nicely summarized in several reviews [12].
In the proline‐mediated aldol reactions, the anti‐isomer was obtained predominantly, which is explained by List–Houk model (Figure 1.4). In most of the aldol reactions catalyzed by organocatalyst, the anti‐isomer is generated predominantly. The development of syn‐selective and enantioselective aldol reactions catalyzed by organocatalyst is a challenging problem. Maruoka developed a biphenyl‐based axially chiral amine with a triflamide moiety (Eq. 1.6). This catalyst is a syn‐selective catalyst and gave excellent enantioselectivity [14].
Acetaldehyde is a synthetically useful aldehyde that can act as both a nucleophile and an electrophile. Given its high reactivity, it is difficult to use acetaldehyde as a nucleophile in the aldol reaction even with a metal catalyst. Hayashi developed diarylprolinol, which is an effective catalyst with acetaldehyde as a nucleophile (Eq. 1.7) [15]. This catalyst is also effective in the other cross‐aldol reactions of two different aldehydes [16].
Figure 1.4. Transition state for the aldol reaction catalyzed by proline.
Source: Based on [13].
1.3.2. Mannich Reaction
The Mannich reaction is important for the construction of nitrogen‐containing molecules. List reported the three‐component Mannich reaction of aldehyde, ketone, and anisidine catalyzed by proline in 2000 (Eq. 1.8) [17]. Barbas reported the syn‐selective Mannich reaction of N‐PMP‐protected α‐imino ethyl glyoxylate and an aldehyde, or ketone, in 2002 (Eq. 1.9) [18]. Whereas syn‐selectivity is explained by the model shown in Figure 1.5, the anti‐selective Mannich reaction is a challenging task. Nevertheless, an axially chiral sulfonamide, developed by Maruoka, was successfully used to afford anti‐selective Mannich products [19]. In addition to simple aliphatic aldehydes, an α‐amino acetaldehyde as a nucleophile afforded an anti‐vicinal diamine derivative (Eq. 1.10).
Instead of using a bifunctional catalyst, organocatalysts without an acid moiety, such as diphenylprolinol silyl ether, are effective catalysts in the Mannich reaction to afford the anti‐product selectively with excellent enantioselectivity (Eq. 1.11) [20].