Asymmetric enamine catalysis

As a catalytic concept, asymmetric enamine catalysis has been the subject of several recent reviews [8-23], In this concept review, we will focus on some of the key aspects of this mode of activation, and probe the current limitations and possible future directions of enamine catalysis. 

A range of nitrogen, phosphorus, chalcogen (O, S, Se) and halogen electrophiles react with enamines, resulting in a net a-functionalization of the carbonyl compound. In the past five years, all of these reaction variants have been subjected to asymmetric enamine catalysis, with excellent results. 

The ultimate test of any method lies in its applicability in challenging contexts, snch as total synthesis of natnral products and industrial settings. While the indnstrial applications of enamine catalysis are still mostly under development, asymmetric enamine catalysis has already been used in several instances for the synthesis of natural products. This area has been recently reviewed by Christmann [19]. 

Enamine catalysis involves a catalytically generated enamine intermediate that is formed via deprotonation of an iminium ion and that reacts with various electrophiles or undergoes pericyclic reactions. The first example of asymmetric enamine catalysis is the Hajos-Parrish-Eder-... 

As depicted in Scheme 7, the synthesis of the mosquito oviposition pheromone (-)-6-acetoxy-5-hexadecanolide (28) via an intermolecular aldol reaction represents a powerful demonstration of the high potential of asymmetric enamine catalysis (45, 46). It is noteworthy that a methodologically different successful organocatalytic approach towards 28, based on an asymmetric a-oxygenation, was reported recently (727). Reaction of aldehyde 136 with dibenzoyl peroxide (BzOOBz) and hydroqui-none (HQ) (722) in the presence of the TMS-protected prolinol catalyst (S)-138 followed by a direct allyation gave the benzoyl-protected 139 in moderate yield and good selectivity. Intermediate 139 could then be further transformed to give (—)-(57 ,65)-6-acetoxy-5-hexadecanolide (28) (Scheme 33). 

Mukherjee S, Yang JW, Hoffmann S, List B (2007) Asymmetric Enamine Catalysis. Chem Rev 107 5471... 

The classical reactions that are usually associated with asymmetric enamine catalysis are aldol and Mannich-type... 

Examples of high-pressure organocatalytic reactions published after 2002 showed that the attention of researchers has switched to other catalytic systems that are well known as being very efficient in selected reactions under classical conditions (e.g., proHne and other secondary amines as well as primary amines and thioureas). The influence of pressure on the asymmetric enamine catalysis... 

Enantioselective -Functionalization of Aldehydes and Ketones The direct and enantiosective functionalization of enolates or enolate equivalents with carbon-, nitrogen-, oxygen-, sulfur- or halogen-centered electrophiles represents a powerful transformation of chemical synthesis and of fundamental importance to modem practitioners of asymmetric molecule constmction. Independent studies from List, J0rgensen, Cordova, Hayashi, and MacMiUan have demonstrated the power of enamine catalysis, developing catalytic enantioselective reactions such as... 

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. 

Selected recent developments in the area of asymmetric organocatalysis in our laboratory have been briefly summarized. Enamine catalysis, Brpnsted acid catalysis, and iminium catalysis turn out to be powerful new strategies for organic synthesis. Using Hantzsch ester as the hydride source, highly enantioselective transfer hydrogenantion reactions have been developed. We have also developed an additional new con-... 

S.C. PanandB. List s paper spans the whole field of current organocat-alysts discussing Lewis and Brpnsted basic and acidic catalysts. Starting from the development of proline-mediated enamine catalysis— the Hajos-Parrish-Eder-Sauer-Wiechert reaction is an intramolecular transformation involving enamine catalysis—into an intermolecular process with various electrophilic reaction partners as a means to access cY-functionalized aldehydes, they discuss a straightforward classification of organocatalysts and expands on Brpnsted acid-mediated transformations, and describe the development of asymmetric counteranion-directed catalysis (ACDC). 

In 2007, Connon and McCooey developed highly efficient, asymmetric syn-selective addition reactions of enolizable carbonyl compounds to nitroolefins by adopting the enamine catalysis approach [48]. The 9-epi-amino cinchona alkaloid derivative (160,9 -epi-DHQDA) as an aminocatalyst promoted the addition ofa variety... 

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. ... 

The enamine catalysis detailed above proceeds via activation of the Mannich donor. An alternate strategy to the catalysis of the Mannich reaction is by the use of Brensted acids that activate the acceptor imine by protonation on nitrogen. Some of the most successful asymmetric variants of this process use BINOL-based phosphoric acids as catalysts. For instance Terada and coworkers used (7.144) to effect highly enantioselective addition of acetylacetone to a range of aryl aldimines ... 

With respect to the covalent activation in conjugate additions, the catalyst, usually a primary or a secondary amine, can reversibly form a chiral enamine [ 11 ] to activate the nucleophile (D, Fig. 2.2) or a chiral iminium ion [12] to activate the acceptor (E, Fig. 2.2). The detection of enamine intermediates in asymmetric oiganocatalysis has been for a long time the missing piece of evidence for the commonly accepted mechanism of enamine catalysis. This gap has been recently solved with the first detection and structnral characterization of enamine intermediates in proUne-cata-lyzed aldol reactions by real-time NMR spectroscopy [13] and the direct observation of an enamine intermediate in the crystal strnctnre of an aldolase antibody [14]. 

A wide variety of carbon nucleophiles have been successfully used in the organocatalytic asymmetric inter- and intramolecular Michael addition to different a,p-unsaturated systems. Among them, the addition of aldehydes to diverse Michael acceptors such as, a,p-unsaturated ketones, alkylidene malonates, P-nitrostyrenes, and vinyl sulfones, is one of the most studied reactions. Enamine catalysis is the most frequently employed chiral activation found in the literature. 

The term aminocatalysis has been coined [4] to designate reactions catalyzed by secondary and primary amines, taking place via enamine and iminium ion intermediates. The field of asymmetric aminocatalysis, initiated both by Hajos and Parrish [5] and by Eder, Sauer, and Wiechert [6] in 1971, has experienced a tremendous renaissance in the past decade [7], triggered by the simultaneous discovery of proline-catalyzed intermolecular aldol [8] and Mannich [9] reactions and of asymmetric Diels-Alder reactions catalyzed by chiral imidazolidinones [10]. Asymmetric enamine and iminium catalysis have been influential in creating the field of asymmetric organocatalysis [11], and probably for this reason aminocatalytic processes have been the object of the majority of mechanistic smdies in organocatalysis. 

FIGURE 2.2. Representative chiral amines with hydrogen-bond directing groups used in asymmetric enamine and iminium catalysis. 

Iminium Catalysis. Together with enamine catalysis, iminium catalysis is the most prominent activation mode in asymmetric aminocatalysis [61]. Initial work was carried out on cycloadditions [10, 62], but it was rapidly extended to... 

The first organocatalytic asymmetric Michael addition of unmodified aldehydes with nitroalkenes was reported by Barbas and co-workers [4]. In light of the concept of enamine catalysis, many chiral amines have been screened and (5)-2-(morpho-linomethyl)pyrrolidine 1 (Scheme 5.1) proved to be an effective catalyst to furnish the 7-formyl nitro products in high yields (up to 96%) with moderate enantiose-lectivity (up to 78%). Encouraged by this pioneering research on using chiral secondary... 

SCHEME 8.41. Asymmetric a-alkylation of 2-arylpropionaldehydes via hydrogen-bonding/ enamine catalysis. 

One of the first highly enantioselective examples of multicomponent cascade reactions in orgnocatalysis was developed by Enders et al. [62] in 2006. In this report they describe an asymmetric organocatalytic triple cascade reaction for the construction of tetrasubstituted cyclohexenecarbaldehydes (93) starting from from enals (15), nitroalkenes (28), and enolizable aldehydes (94) (Scheme 10.27). In this work, they did the sequential creation of three bonds by a high enantioselective combination of enamine-iminium-enamine catalysis for a triple cascade reaction. 

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