Importance of Water or Additives

The first experiments of an organocatalysed aldol condensation between acetone and 4-nitrobenzaldehyde with aliphatic amino acids in anhydrous conditions (DMSO acetone 4 l) led to the desired adduct in very low yields ( 10%). In 2005, Amedjkouh and Cordova independently showed the importance of additional water in the reaction medium to improve the yields. The concept was based on the hypothesis that a molecule of water would participate in a proton relay in the aldolase system, and would allow for a faster hydrolysis of the intermediates. A hydrophobic amino acid might be efficient in aqueous media by strong association with hydrophobic reactants. Furthermore, water would restore the catalyst from its deactivation by condensation with the aldehyde. 

In a similar vein, bullqr silojqr derivatives of serine and threonine have been found to be hydrophobic enough to furnish the expected adducts with good enantioselectivities. In the presence of tert-butyldimethylsi-lylojy L-threonine (OTBDMS-L-Thr), the aldol reaction between cyclohexanone and benzaldehyde in water was effective with only 2 mol% of the catalyst (yield 58% ee 96%) in favour of the anti-isomer (dr 8 1). This catalyst proved to be remarkably effective with various aromatic aldehydes and the adducts were obtained in excellent yields and nearly perfect ee in water. The anti- or q n-aldol products were obtained respectively from cyclohexanone or TBDMS protected p-hydroxyaldehyde. 

The tert-butyldiphenylsilylojqr L-serine (OTBDPS-L-Ser) was a highly efficient enantioselective organocatalyst when used at a loading of 10 mol% in 

Ibrahem, Cordoba and colleagues demonstrated more recently that a hydrogen-bond donor additive could accelerate the rate of the reaction, much better than the addition of water or Bronsted acid or base. In particular, thiourea 10 used as a cocatalyst (10 mol%) with OTBDMS-L-Thr (20 mol%) led to the expected (3-hydro y ketones with configurations anti-6 or syn-7 depending on the substrate. 

The aldol reaction in the presence of an acyclic amino acid has been harnessed in total synthesis. Takabe reported the organocatalytic ot-hydro)ymethylation of a cyclic ketone in aqueous formaldehyde with L-threonine, as the key step for the formal synthesis of chiral jasmine lactone. In a similar way, the team of Chen and Chai prepared several cyclohexanone derivatives. Much more recently, a synthesis of phaitanthrin A by aldol reaction of tryptanthrin with acetone in the presence of the potassium salt of L-phenylalanine has been performed in gram-scale quantities. Numerous derivatives have been obtained with yields of up to 98% and ee of up to 99%. 

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