Asymmetric aldol reactions amino acid catalysed

Small peptides - simple di- and tri-peptides with a primary amine at the N-terminus -catalyse the aqueous aldol between unmodified ketones and aldehydes with up to 86% ee.121 This is dramatically different from the corresponding amino acid-catalysed reaction, suggesting that peptide formation may have been significant in the evolution of asymmetric synthesis. Addition of a-cyclodextrin raised the ee further through the hydrophobic effect. 

In certain cases, high levels of selectivity in the asymmetric aldol reaction can be achieved in the absence of a metal salt. The amino acid proUne catalyses the aldol reaction of aldehydes or ketones (which are enolizable) with aldehydes (preferably non-enolizable or branched to disfavour enolization) to give p-hydroxy-aldehydes or ketones. For example, use of acetone (present in excess) and isobutyraldehyde gave the (3-hydroxy-ketone 81 (1.88). The reaction involves an enamine intermediate and is thought to proceed via the usual Zimmerman-Traxler chair-shaped transition state. 

In 2001 Barbas III et al. reported the amino acid-catalysed direct asymmetric aldol reaction between ketones and aldehydes. Using the benchmark condensation reaction between acetone and p-nitro-benzalde-hyde, the authors tested many different amino acids as organocatalysts, including (5 )-ot-2-methyl-proline 7a (Scheme 11.2). In this reaction however 7a proved to be much less reactive than (S)-proline (1), as well as slightly less enantioselective. Compound 7a was also found to be less efficient than 1 in the direct organocatalytic asymmetric a-oxidation of cyclohexanone with iodosobenzene, as reported by Cordova et ah in 2005 (Scheme 11.3). ... 

In the area of organocatalysis, proline has been utilised in various asymmetric reactions including direct asymmetric aldol reactions. Some such proline-catalysed aldol reactions, however, have serious limitations with respect to reactivity and selectivity. Although these problems were overcome through the development of new catalysts derived from proline, there is still an urgent need for structurally and electronically novel catalysts due to the difficulty in appropriate modification of proline. In this context, we have designed and prepared artificial amino acid catalyst (S)-l having a binaphthyl backbone as a frequently utilised chiral unit in asymmetric catalysts. ... 

The ability of amino acids to catalyse the asymmetric neogenesis of carbohydrates by sequential cross-aldol reactions was reported one year later. Cordova et al. demonstrated that O-benzylglycoaldehyde 1 could react with protected dihydrojqracetone or with itself in the presence of enantio-pure Alanine, valine or phenylalanine, leading, respectively, to 2 and 3 (Scheme 12.1). ... 

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