William James Michaely

The structure–activity relationships of the triketone class of HPPD herbicides†

The 2-benzoylcyclohexane-1,3-diones, the triketones, are a novel class of bleaching herbicides whose mode of action is the inhibition of the enzyme p-hydroxyphenylpyruvate dioxygenase. The structure–activity relationships of this chemical class are elucidated. An ortho-substituent on the aryl ring is an absolute requirement for herbicidal activity. Beyond that, the herbicidal activity of these compounds is best correlated with the overall electron deficiency of the benzoyl group induced by 2,4-disubstitution of the aryl ring, with the most electron-deficient analogs being the most active. Moreover, the degree of electron deficiency of the benzoyl group is outwardly manifested in the acidity of the molecule. The activity of these compounds is further enhanced through additional aromatic substitution in the 3-position of the aryl ring. The greater activity of these 2,3,4-trisubstituted aryl analogs over the 2,4-disubstituted aryl analogs is due to increased intrinsic activity.

Discovery of the triketone class of HPPD inhibiting herbicides and their relationship to naturally occurring β-triketones

Derivatives of naturally occurring syncarpic acids were synthesized following the observation that few plants grew under the bottle brush plant (Callistemon citrinus, a member of the Myrtaceae family) which was known to produce these compounds. The compounds were tested in herbicide screening programmes and were shown to be herbicidal to many weeds both pre and post emergent albeit at rates too high to be of commercial value. Combining this work with concurrent efforts to discover new ACCase inhibitors led to the discovery of the 2-benzoylcyclohexane-1,3-diones, a novel class of bleaching herbicides whose mode of action was subsequently found to be the inhibition of the enzyme p-hydroxyphenylpyruvate dioxygenase. The structural similarities between the naturally occurring syncarpic acids and the new inhibitors of p-hydroxyphenylpyruvate dioxygenase were apparent and an attempt was made to combine the best features of both classes resulting in the synthesis of compounds in 2-benzoyl syncarpic acid class, which to date are the most effective herbicides known in either class. These compounds had persistence in the soil, in excess of what would be desirable for a commercial herbicide. The structure activity relationships of the natural syncarpic acids and 2-benzoyl-cyclohexane-1,3-dione classes of herbicides, their relationship to each other, their physical and environmental properties and the steps leading to the discovery of Mikado® are discussed.