Asymmetric Organocatalysis of Aldol Reactions

Surprisingly, little follow-up work on this idea of small molecule asymmetric catalysis appeared for the next 25 years. In the late 1980s, Agami reported the asymmetric intramolecular aldol reaction of acyclic diketones with (S)-proline as the catalyst. It was not nntil the twenty-first centnry, however, when this notion of organocatalysts became fnlly exploited. List and Barbas ° pioneered enam-ines as catalysts for aldol and Mannich and related reactions. MacMillan has developed a variety of imininm-based catalysts prodncing large asymmetric indnction for Diels-Alder chemistry, Friedel-Crafts alkylations, Mnkaiyama-Michael and cyclopropanation reactions. 

Examples of amine-catalyzed aldol reactions are shown in Table 6.10. For all entries, the mole percent of amine nsed was generally 10-20 percent. While, in some cases, yields may be poor, generally the yields are qnite acceptable. 

TABLE 6.10 Examples of Amine-Catalyzed Aldo Reactions 

Theoretical chemistry has played a major role in elucidating the mechanism whereby proline and other amines catalyze the aldol reaction. Houk has reviewed the contribution of computational chemistry towards understanding the actions of organcatalysts in the aldol and other reaction. ° Before detailing the calculations and their implications, we describe some of the key experiments that provided data relevant to the mechanism. 

List ° and Barbas investigated the effect of different potential catalysts on the reaction of acetone with p-nitrobenzaldehyde (Table 6.11). The important conclusions drawn from this work are that primary and acyclic secondary amino acids do not catalyze the reaction. Cyclic secondary amino acids do catalyze the aldol reaction, the best being proline. Converting proline into either a tertiary amine (A -methylproline) or an amide destroys its catalytic behavior. It is clear that the catalyst must provide both basic and acidic sites. 

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ASYMMETRIC ORGANOCATALYSIS OF ALDOL REACTIONS 409 TABLE 6.11 Effect of Catalyst on the Direct Asymmetric Aldol Reaction"... 

Other reviews deal with aldol additions of group 1 and 2 enolates,103 direct catalytic asymmetric aldol reactions catalysed by chiral metal complexes,104 the exploitation of multi-point recognition in catalytic asymmetric aldols,105 and recent progress in asymmetric organocatalysis of aldol, Mannich, Michael, and other reactions.106... 

Allemann C, Gordillo R, Clemente FR, Cheong PH-Y, Houk KN. Theory of asymmetric organocatalysis of aldol and related reactions rationalizations and predictions. Acc. Chem. Res. 2004 37 558-569. 

Asymmetric organocatalysis of aldol and related reactions using imidazolidinones or proline as catalysts 04ACR558. 

Theory of Asymmetric Organocatalysis of Aldol and Related Reactions Rationalizations and Predictions Allemann, C. Gordillo, R. Clemente, F.R. Cheong, P.H.-Y. Houk.K.N. Acc. Chem.Res. 2004,37,558. 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

This class of catalysts covers chemocatalysts that do not contain a transition metal. The class has been known for many years, but it is relatively recently that the term organocatalyst has been used (209). A wide variety of transformations can be performed, which is currently an area of intense research (209-218). Table 5 (220-252) summarizes some key transformations in which organocatalysis can be useful. Reactions range from the asymmetric epoxidation of alkenes, which need not be conjugated to another functional group, to aldol reactions and... 

Palomo C, Oiarbide M, Garcia JM. Current progress in the asymmetric aldol addition reaction. Chem. Soc. Rev. 2004 34 3-15. Ooi T, Maruoka K. Asymmetrix organocatalysis of structurally well-defined chiral quaternary ammonium fluorides. Acc. Chem. Res. 2004 37 526-533. 

Beside the cross aldol reaction, the Mannich reaction, too, has been the object of successful efforts using organocatalysis. The use of small organic molecules such as proline, cyclohexane diamine and Cinchona alkaloid-derived catalysts has proven extraordinarily useful for the development of asymmetric Mannich reactions in traditional polar solvents such as DMSO, DMP, DMF, etc. However, very few studies have been conducted so far in non-conventional solvents. 

Routes by asymmetric organocatalysis are available to account for the occurrence of chiral molecules on earth. L-proline and L-serine yielded relatively high values of ee in aldol condensations (Cordova et al. 2005). An epimer of a distinct amino acid, for instance, proline or serine, can serve as a catalyst in aldol reactions (Cordova et al. 2005). The percentage of the catalyzing amino acid determines the ee of the reaction product. Thus, the preferred formation of D-ribose compared to that of L-ribose can be accounted for by the intrinsic property of the reaction system with an asymmetric molecule acting as biocatalyst. L-proline has exceptional properties due to its structure, Fig. 3.3. 

In our illustration of the graphical manipulations of data using reaction progress kinetic analysis, we will make use of the example of a model reaction, the intermolecnlar aldol reaction between acetone 1 and aldehyde 2 to form the aldol addition product 3, mediated by proline 4, as shown in Scheme 27.1. The demonstration by List, Lemer, and Barbas in 2000 that proline mediates intermolecular aldol reactions with a high degree of asymmetric induction heralded a revolution in the field of organocatalysis, encompassing the discovery of new catalysts and new catalytic transformations." ... 

A variety of catalytic ways of doing asymmetric aldol reactions have also been invented, but space prevents us discussing all but one. This one we highlight firstly because it illustrates the use of a supremely simple biologically derived compound to catalyse a complex reaction, and secondly because this discovery was part of the revolution in catalytic thinking which launched the field of organocatalysis in the early years of the 21st century. 

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