Intramolecular Aldol Reaction Starting from Diketones

1 Intramolecular Aldol Reaction Starting from Diketones 

The yields of the products (+)-89a-c were moderate with 37-54% and the reaction time was somewhat long with 108 h. The opposite enantiomer can be also obtained with high enantioselectivity by use of O-acetylquinine as catalyst. In this case the (—) enantiomer of 89a was formed in 51% yield and with 86% ee. 

A reaction mechanism was proposed in which the tertiary amino group of the alkaloid organocatalyst and the carboxylic acid group form a chiral ammonium 

---

Cascade reactions triggered by the combination of chiral amines and achiral Brpnsted acid were well documented on the basis of enamine and iminium ion formation, while examples with the combination of a chiral amine catalyst and a chiral Brpnsted acid were rare, hi 2(X)7, Zhou and List reported an elegant cascade intramolecular aldol-reduction process to prepare chiral 3-substituted cyclohexyl-amines by combining achiral enamine catalysis and chiral phosphoric acid catalysis [38]. Unusually, achiral aryl primary amine was exploited as an amino catalyst to generate a transient enamine intermediate to facilitate an intramolecular aldolization-dehydration process, while chiral phosphoric acid was harnessed to accelerate the following conjugate reduction-reductive amination cascade. Starting from readily available 2,6-diketones and aryl amines, pharmaceutically relevant 3-substituted cyclohexyamine derivatives were readily produced in satisfactory yield and excellent enantioselectivity (Scheme 9.42). 

---