The last new herbicidal modes-of-action with commercial significance were introduced to the marketplace multiple decades ago. Serious weed resistance to most herbicidal classes have since emerged with widespread use. Aryl pyrrolidinone anilides represent an entirely new mode-of-action class of herbicides that interfere with de novo pyrimidine biosynthesis in plants via inhibition of dihydroorotate dehydrogenase. The chemical lead for this new herbicide class discovery was identified from highvolume sourced greenhouse screening that required structural reassignment of the hit molecule followed by an extensive synthetic optimization effort. With excellent grass weed control and pronounced safety on rice, the selected commercial development candidate has a proposed common name of tetflupyrolimet and represents the first member of the new HRAC (Herbicide Resistance Action Committee) Group 28. This paper describes the discovery path to tetflupyrolimet with an added focus on the bioisosteric modifications pursued in optimization, including replacements of the lactam core itself.
A series of six sulfonylisoxazolines, which were readily prepared via cycloaddition of benzenesulfonylcarbonitrile oxide to alkenes, were cleaved in 86-94% yield to /3-hydroxy nitriles by the action of excess 2% Na-Hg°. The stereochemistry present at the isoxazoline C-4 and C-5 positions was retained during cleavage; since nitrile oxide cycloaddition to alkenes is a stereospecific process, the overall sequence permitted high diastereoselection. Under standard conditions the sulfonylisoxazolines derived from (£)-and (Z)-stilbene gave a mixture of benzyl alcohol and phenylacetonitrile rather than /3-hydroxy nitriles; when the reactions were buffered, however, the /3-hydroxy nitriles could be obtained in 88-91% yield. The /3-hydroxy nitriles obtained from (E)-and (Z)-stilbene rapidly underwent a retro-aldol reaction in the presence of aqueous base at room temperature. The /3-hydroxy nitrile obtained from 1-methylcyclopentene was epimerized by base and, at or above 80 °C, was cleaved to 6-oxoheptanenitrile.
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