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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).

(1.8)

(1.9)

(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].

Figure 1.5. Transition state of the Mannich reaction.

(1.11)