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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].

(1.6)

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].

(1.7)

Figure 1.4. Transition state for the aldol reaction catalyzed by proline.

Source: Based on [13].