Three- and Four-component-domino-Knoevenagel-hetero-Diels-Alder Reaction

Three- and Four-component-domino-Knoevenagel-hetero-Diels-Alder Reaction 

reaction of thia Meldrum s acid 87 with ethyl vinyl ether 88 with different 

Generally, there is no limitation in the 1,3-dicarbonyl compound used. However, several types of these substances are not stable, such as malone dialdehydes or formyl acetic acid. In such cases, l,l,l-trichloro-4-oxo-butanone 96 is an appropriate substitute, since the trichloromethylcarbonyl moiety can easily be transformed into a carboxylic acid ester after the reaction by treatment with an alcohol and a 

The three-component domino-Knoevenagel-hetero-Diels-Alder reaction is especially fruitful if one uses aldehydes containing a protected amino function. In such cases the formed dihydropyranyl ether moiety can be used as a source of an aldehyde moiety that can undergo a condensation with the amino group after deprotection. Thus, several alkaloids such as hirsutine 108, dihydrocorynantheine 

Hirsutin 108, which belongs to the corynanthe subgroup of the indole alkaloids, was isolated from the plant Uncaria rhynchophylla MIQ and used for the preparation of the old Chinese folk medicine Kampo [32], It is of pharmacological interest since it shows a strong inhibitory effect on the influenza A virus (subtype H3N2) with an EC50 of 0.40-0.57 pg ml-1, which corresponds to a 11-20 higher bioactivity of hirsutin 108 compared to clinically used Ribavirin [33]. 

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