Stereoselective Aldol Reactions Using Proline Organocatalysts

Stereoselective Aldol Reactions Using Proline Organocatalysts 

The use of L-proline, amides derived from it, and related amino acids and small peptides as asymmetric organocatalysts for aldols - and indeed many other reactions mentioned elsewhere in this chapter - expanded hugely in 2006. A review deals with the direct aldol case.96 

L-Proline catalyses direct aldols of trifluoroacetaldehyde ethyl (hemi)acetals, F3C-CFl(OH)-OX (X = H, CH2CH3, CH2CF3), with ketones at room temperature to produce /Miydroxy-/9-fluoromethylated ketones with des up to 96% and ees up to 91 %.97 

Many reactions have also been carried out in water. The mechanisms of the reactions of acetone and 1,3-dihydroxyacetone using zinc-proline and related catalysts have been probed kinetically.98 The former exhibits an enamine route, whereas the latter involves rate-limiting deprotonation of the -carbon and formation of an enolate. An umbelliferyl ether of dihydroxyacetone (37) has been used as a fluorogenic probe for enolization, which may prove useful in screening of aldolases in water. 

The first asymmetric direct aldol of 1,2-diketones and ketones, to give 2-hydroxy-1,4-diketones, has been reported.100 L-Proline derivatives give high regio-, diastereo-, and enantio-selectivity in the reaction of l-arylpropane-l,2-diones with simple ketones. 

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Stereoselective Aldol Reactions Using Proline Organocatalysts... 

The synthesis of a novel Merrifield resin-supported dipeptide Pro-Ala-O-P, derived from proline and alanine, was reported by Wang and Yan with the aim of being used as an organocatalyst in asymmetric aldol reactions of ketones with aldehydes. " Indeed, this supported dipeptide was found to be an efficient catalyst to promote the asymmetric aldol reaction under neat conditions between aromatic aldehydes and cyclic ketones, generating the corresponding aldol products with moderate to high yields and diastereoselectivities of up to 80% de combined with good enantioselectivities of up to 95% ee, as shown in Scheme 2.18. Moreover, this catalyst could be used for seven times with only a minor decrease in product yields, but maintained stereoselectivities. 

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