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Compared to alkylation reactions, phase‐transfer catalyzed aldol reactions have been comparatively underexplored. In 1991, Miller reported the aldol reaction of diphenyl glycine imine nucleophiles and various aldehydes with chiral cinchoninium‐based catalysts (Scheme 4.11) [51]. Unfortunately, these reactions suffered from very low enantioselectivity (3–12% ee). Over the years, improvements using cinchoninium‐based catalysts have been reported for related aldol reactions, but still suffered from moderate enantioselectivity (up to 83% ee) [52]. In 2002, Maruoka reported a highly enantioselective phase‐transfer catalyzed aldol reaction using chiral N‐spiro ammonium catalysts (up to 98% ee) [53, 54]. Mechanistic studies revealed competitive retro‐aldol reactions were occurring under first‐generation conditions, but this was solved with the use of dilute and catalytic sodium hydroxide and ammonium chloride.

Scheme 4.10. Enantioselective aza‐Michael addition of hydrazides to chalcones for the synthesis of pyrazolines.

Scheme 4.11. Enantioselective aldol reaction using glycine imines.

Source: Based on [51].

The same family of chiral N‐spiro ammonium salts was later reported by Maruoka in 2004 as selective phase‐transfer catalysts for the related Mannich reaction of a diphenyl glycine ester with a N‐PMP protected α‐imino‐ester (Scheme 4.12) [55]. A year later, Oshima and Shibasaki reported the use of a tartrate‐derived chiral bis‐ammonium catalyst as an efficient catalyst for the Mannich reactions using Boc‐protected aldimines [56].

Asymmetric phase‐transfer catalysis has also been exploited successfully for a number of other reactions involving the addition of an enolate to a carbonyl or imine electrophile. For example, the addition of α‐halo carbonyl compounds to aldehydes or ketones (Darzens reaction) to yield epoxides was first achieved using chiral phase‐transfer catalysis in 1998 by Arai and Shioiri and has since been further developed [57, 58]. Another example is the addition of cyanide nucleophiles to imine derivatives (Strecker reaction) leading to chiral α‐amino nitriles, which has been extensively studied; the first highly enantioselective phase‐transfer catalyzed version of this reaction was reported by Maruoka in 2006 [59, 60].