Aqueous intermolecular aldol reactions

Scheme 3.4 Direct aqueous intermolecular aldol reaction catalyzed by L-ttyptophan.

A combination of ytterbium (or zinc) triflate and chiral C2-symmetric prolinamide ligand leads to high enantioselectivities in direct aldol reactions under aqueous conditions (Scheme 27). The presence of 5 mol% of the catalyst affords an asymmetric intermolecular aldol reaction between umnodified ketones and aldehydes to give antiproducts with excellent enantioselectivities up to 99% ee. 

Class I aldolase-like catalysis of the intermolecular aldol reaction with amines and amino acids in aqueous solution has been studied sporadically throughout the last century. Fischer and Marschall showed in 1931 that alanine and a few primary and secondary amines in neutral, buffered aqueous solutions catalyze the self-aldolization of acetaldehyde to give aldol (11) and crotonaldehyde (12) (Scheme 4.3, Eq. (1)) [41]. In 1941 Langenbeck et al. found that secondary amino acids such as sarcosine also catalyze this reaction [42]. Independently, Westheimer et al. and other groups showed that amines, amino acids, and certain diamines catalyze the retro-aldolization of diacetone alcohol (13) and other aldols (Scheme 4.3, Eq. (2)) [43-47]. More recently Reymond et al. [48] studied the aqueous amine catalysis of cross-aldolizations of acetone with aliphatic aldehydes furnishing aldols 16 (Scheme 4.3, Eq. (3)) and obtained direct kinetic evidence for the involvement of enamine intermediates. 

Judging from these findings, the mechanism of Lewis acid catalysis in water (for example, aldol reactions of aldehydes with silyl enol ethers) can be assumed to be as follows. When metal compounds are added to water, the metals dissodate and hydration occurs immediatdy. At this stage, the intramolecular and intermolecular exchange reactions of water molecules frequently occur. If an aldehyde exists in the system, there is a chance that it will coordinate to the metal cations instead of the water molecules and the aldehyde is then activated. A silyl enol ether attacks this adivated aldehyde to produce the aldol adduct. According to this mechanism, it is expected that many Lewis acid-catalyzed reactions should be successful in aqueous solutions. Although the precise activity as Lewis acids in aqueous media cannot be predicted quantitatively... 

Tollens addition between HCOH and CH3CHO and the intermolecular aldol addition of CH3CHO have been used as reaction models to study, by quantum-mechanical methods, the importance of water in aldol-like reactions carried out in aqueous media [22]. Water accelerates the addition process because it coordinates the reactants, making the geometry of the initial complex more suitable for the reaction, and stabilizes the transition state of the reaction. Water therefore acts as a catalyst. 

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