Aldol Reactions in Enamine Catalysis

A wide range of small organic molecules, mainly secondary amines such as proline derivatives, promote asymmetric aldol reactions through enamine catalysis [6]. List, Reymond, Gong, and others reported the first examples of peptidic catalysts for aldol reactions [7]. In their report, Reymond and coworkers [7a] developed two classes of peptides, following two different designs. In the first peptide class a primary amine is present as a side chain residue (similar to the natural type I aldolase) or as free N-terminus in the second a secondary amine or a proHne residue is present at the N-terminus of the peptide, which incorporated at least one free carboxyhc function (Figure 5.3). 

Scheme 28.2 Aldol and Mannich reactions in enamine catalysis.

It was in 2000 that Barbas and List reported their well-known proline-cat-alyzed enantioselective intermolecular aldol reaction (Scheme 1.4), as the culmination of a research which started in the 1990s with the use of aldolase antibodies as catalysts for the aldol reaction. Trying to provide a mechanistic rationale for understanding these reactions, and with the evidence of enamine intermediates participating in the reaction in hand, they developed the proline-catalyzed intermolecular aldol reaction in an attempt to mimic the enzyme s behavior. Another important landmark in this context was the introduction of the iminium catalysis concept by MacMillan, related to the enantioselective... 

Alkyl-alkyl ketones are particularly challenging in enamine-catalysis due to reactivity and regioselectivity issues. These ketones are bad donors in the direct aldol reaction because the equihbrium constants for their formation are low (Scheme 3.9)... 

Another complement to enamine catalysis is Br0nsted acid catalysis. Blanche showed that a Hg-BlNOL-derived phosphoric acid catalyzes the aldol reaction to give jy -aldols 162-165 from various ketones [175]. Gratifyingly, the method is suitable for acetophenone, fused cyclic aromatic ketones, and a,(3-unsaturated ketones, substrates that are normally challenging donors in enamine catalysis (Chart 3.22). 

Among organocatalytic aldol reactions, enamine catalysis has developed into powerful strategy for asymmetric aldol reaction. At least more than 200 publications concerned the development of the enamine-promoted aldol reaction in this decade. 

Notably, Nature uses a similar strategy in bond construction, employing Class I aldolases to participate in enamine catalysis through a nucleophilic lysine residue, promoting aldol reactions via a reactive enamine under mild ambient conditions using nonactivated, unprotected... 

Design of Enomine-Cyclization Cascade Reactions The nucleophilic Y in intermediate 6 can react with other electrophiles intermolecularly (Scheme 1.34a) or intramolecularly (Scheme 1.34b) as well as with the iminium ion. Moreover, the carbonyl group of 6 can also undergo intramolecular aldol reaction with nucleophilic X (Scheme 1.34c). These nucleophilic addition reactions after enamine catalysis induce cyclization reactions to produce versatile five- or six-membered ring structures. 

The development of enamine catalysis parallels that of iminium catalysis (Scheme 3) [24], Like iminium catalysis, the concept took a long time to mature, and also required a key discovery - the discovery of intermolecular proline-catalyzed aldol reactions by List and coworkers in 2000 [23] - to set the field in motion. The timeline of historical developments of enamine catalysis is outlined in Scheme 4. 

The delicateness of the aldol protocol has perhaps been one of the factors why enamine catalysis of the aldol reaction did not emerge nntil the 1970s. The Hajos-Parrish-Eder-Sauer-Wiechert reaction [30] (Scheme 16) was an important early example of an intramolecular enamine-catalyzed aldol reaction. However, it was not nntil 2000 when List, Barbas and Lemer demonstrated that the same reaction can also be performed in an intermolecular fashion, using proline as a simple enamine catalyst [26]. 

Over the past eight years, enantioselective enamine catalysis has expanded in scope more rapidly than perhaps any other field of asymmetric catalysis. From a handful of examples within the realm of aldol catalysis known in the beginning of 2000, the field enamine catalysis now comprises more than 50 different reactions, nearly 1000 different catalysts, and more than 1000 examples Still, major challenges remain to be solved. 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

Although attempts to catalyze bimolecular aldol condensations without resorting to enamine chemistry have not yet been successful, the Schultz group92 has prepared an antibody against the phosphinate hapten 115 that catalyzes the retro aldol reaction of 116 (kcJKm = 125 M-1 s l). The equilibrium in this case strongly disfavors the condensation product, and a histidine induced in response to the phosphinate may be involved in catalysis. Interestingly and in contrast to the previous examples, the stereoselectivity of the antibody is modest. The syn diastereomer of 116 was found to be the better substrate for the antibody by 2 1 over the anti diastereomer, but no evidence of enantioselectivity was observed. 

As discussed above, all of the cinchona-based quaternary ammonium salts used as catalysts gave only poor to moderate diastereoselectivities and enantioselectivities for direct aldol reactions. Quite recently, a highly enantioselective, catalytic, direct aldol reaction was realized by adopting the enamine catalysis approach [12], in which 9-amino-epi-cinchona alkaloids are employed as aminocatalysts [13, 14]. 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

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