The Aldol and Related Reactions

The standard aldol reaction involves the addition of an enolate to a ketone or an aldehyde. However, there are related processes and this chapter includes subsections on the isocyanide aldol, nitroaldol and Morita-Baylis-Hillmami reaction. In addition there are reactions involving additions of enolates to the C=N group and a large subsection is devoted to a discussion of the catalytic asynmietric Mamiich reaction. As well as these mechanistically related processes, the carbonyl-ene reaction is also discussed here. Whilst the mechanism of the carbonyl-ene reaction is different from the aldol reaction, the synthetic result is rather similar, and perhaps fits most comfortably into this chapter. 

Significant advances in the development of a catalytic asymmetric variant of the aldol reaction have been developed recently. Both enantiomericaUy pure Lewis acids and Lewis bases have been applied to the addition of silyl enol ethers to aldehydes and ketones and highly diastereoselective and enantioselec-tive additions have been achieved. Often, the mode of diastereoselectivity can be rationalised from a consideration of the relevant open or closed transition states. 

The direct asymmetric aldol reaction has also received much recent attention. High ees have been obtained using lanthanide- or zinc-based bifunctional catalysts bearing both Lewis acidic and Lewis basic sites. The most significant recent advance in this area is the discovery that cheap, readily available organic catalysts such as L-proline are also effective. 

Some of the catalyst systems used in the asymmetric aldol reaction are also effective in related reactions. Thus, bifunctional catalysts and L-prohne-based organocatalysts have been used to good effect in the nitroaldol reaction and Mannich reaction. The latter process is also effectively catalysed by enantiomeri-cally pure Bronsted acids. Furthermore, much recent progress has been made in the development of a catalytic asymmetric Morita-Baylis-Hillman reaction using Lewis/Bronsted acid catalysts and bifunctional catalysts. 

Catalysis in Asymmetric Synthesis 2e 2009 Vittorio Caprio and Jonathan M J. Williams 

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This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

For an excellent discussion of diastereoselectivity in the aldol and related reactions see M. B. Smith, Organic Synthesis, McGraw-Hill, New York, 1994, Chapter 9, pp. 857-964. 

This chapter focuses on biocatalytic methods that have been demonstrated in the aldol and related reactions. Additionally strategies for enzyme engineering and future challenges faced in this field are addressed. 

The pKa of a typical alcohol is in the range 16-19, while that for a typical alkane is closer to 35 0. Therefore, unless the acidity of the proton on the carbon is increased dramatically, loss of water under basic conditions should not occur, the proton being lost to the base from the hydroxyl in preference to that from the carbon. Interestingly, as will be seen when the aldol and related reactions are disussed (Chapter 9), for water to be lost under basic conditions, it is sufficient to have the proton to be lost on a carbon a- to at least one carbonyl group on one side (pK, about 13-20) while also on a carbon a- to that bearing the hydroxyl group on the other, that is. 

Volume 1 of a series of texts on carbon-carbon bond formation has been advertiseda section deals, for example, with the aldol and related reactions. The importance of the aldol reaction has already been illustrated in the above-mentioned syntheses of polyethers applications of boron enolates in stereoselective aldol condensations have been discussed and exemplified by Evans et al. ... 

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