Propionaldehyde, self-aldol reactions

The two (i )-isomers have lower, comparable energies, suggesting these are the predominant catalytic intermediates. The computational findings are further supported by X-ray studies on model substrates by Seebach et al. [7]. Moreover, NMR spectroscopic studies by Gschwind et al. of the similar proline-catalyzed self-aldol reaction of propionaldehyde in DMSO verify the presence of an [E-s-trans]-enamine as the only observable intermediate [8]. 

At the moment the limit is reached when both components in a crossed aldol reaction are enolis-able aldehydes. One is indeed propionaldehyde 94 - a compound notorious for self-condensation - that reacts cleanly with isobutyraldehyde 89. However, it is necessary to add the propionaldehyde slowly by syringe pump. The aldol 95 is produced in very high yield considering the similarity of the two aldehydes but the most amazing aspect is the very high diastereo- and enantioselectivity.20... 

A Mannich-type condensation mechanism involving an iminium ion electrophile similar to the aminocatalytic Knoevenagel reaction has recently been proposed for the amine-catalyzed self-aldolization of propionaldehyde (Eq. (6)) [55]. Although this mechanism is not unreasonable it should be... 

Interestingly, the reaction outcome can be improved in terms of yield and enantioselectivity by applying high pressure to the reaction conditions, albeit at levels unreachable with standard to-date technical equipment. Entirely aldehyde-based versions of the proline-catalysed Mannich reaction are also possible and provide access to q n-y-amino alcohols after subsequent reduction in excellent enantioselectivities (Scheme 5.12). To avoid the favoured cross-aldol or self-Mannich side reactions of the aldehyde, propionaldehyde needed to be added slowly to the reaction mixture. 

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