Triketone Herbicides

Selected physical chemical, toxicological, and environmental properties of sulcotrione are listed in Table 4.3.1, column 1. 

Major product names MIKADO CALLISTO Other Products (mixtures) CAMIX , CALARIS , LEXAR , LUMAX SHOW-ACE Other products mixtures) EOCUS SHOT , KUSAKONTO , SMART  

Stability in water Stable Stable Rapidly hydrolyzed 

Fish LC50 (96 h) for rainbow trout (mg L-i) 227 120 LCso(48h)for carp 10 ppm 

---

The triketones (Fig. 20), the most recent class of herbicides, were discovered in 1986 and introduced commercially (e.g. sulcotrione) in 1991. While several papers report that the triketones herbicides were derived from the plant secondary metabolite leptospermone (Fig. 20) that was isolated from the bottlebrush plant [Callistemon spp.) [Ref. 101], there is a report that suggests that the discovery may have been more serendipitous. ... 

The molecular target site of triketone herbicides is the enzyme -hydroxyphenylpyruvate dioxygenase (HPPD). Inhibition of this enzyme disrupts the biosynthesis of carotenoids and causes a bleaching (loss of chlorophyll) effect on the foliage similar to that observed with inhibitors ofphytoene desaturase (e.g. norflurazon). However, the mechanism of action of HPPD inhibitors is different. Inhibtion of HPPD stops the synthesis of homogen tisate (HGA), which is a key precursor of the 8 different tocochromanols (tocopherols and tocotrienols) and prenyl quinones. In the absence of prenylquinone plastoquinone, phytoene desaturase activity is interrupted. The bleaching of the green tissues ensues as if these compounds inhibited phytoene desaturase. 

The enzyme p-hydroxyphenylpyruvate dioxygenase is involved in the conversion of p-hydroxyphenylpyruvate into homogentisate, a key step in plastoquinone biosynthesis. Inhibition of this enzyme has an indirect effect on carotenoid biosynthesis as plastoquinone is a co-factor of the enzyme phytoene desaturase. The new maize herbicide isoxaflutole and the triketone herbicides such as sulcotrione (Figure 2.7), inhibit p-hydroxyphenylpyruvate dioxygenase and this leads to the onset of bleaching in susceptible weeds and ultimately plant death.4... 

L.G. Freitas, C.W. Gotz, M. Ruff, H.P. Singer, S.R. Muller, Quantification of the new triketone herbicides, sulcotrione and mesotrione, and other important herbicides and metabolites, at the ng/l level in surface waters using LC-MS-MS, J. Chromatogr. A, 1028(2004)277. 

Since their discovery in the early 1980s, the triketone herbicides have been extensively studied over the last two and half decades. In view of this, it may surprise the reader that only three commercial products have appeared to date. However, as has been described, other triketone products are due to appear on the market (e.g., tembotrione), and related compounds with this mode of action (see Chapter... 

Natural triketones and other natural products also inhibit The natural products tend to be competitive inhibitors of HPPD, whereas the synthetic herbicides have been optimized and bind irreversibly to the enzyme. 

Lee DL, Knudsen CG, Michaely WJ, Chin H-L, Nguyen NH, Carter CG, CromartieTH, Lake BH, Shribbs JM, Fraser T, The structure-activity relationships of the triketone class of HPPD herbicides, Pestic Sci 54 377—384, 1998. 

Inhibitors of carotenoid synthesis also lead to chlorophyll destruction by destabilizing the photosynthetic apparatus. Total carotenoid content decreased with increased (-)-usnic concentration (Fig. 1.4). Carotenoid biosynthesis can be interrupted by inhibiting the enzyme phytoene desaturase that converts phytoene to carotenes or by inhibiting the enzyme HPPD responsible for plastoquinone (required for phytoene desaturase activity) synthesis.14 Usnic acid possesses some of the structural features of the triketone HPPD inhibitors, such as sulcotrione (Fig. 1.1C).8 (-)-Usnic acid had a strong inhibitory activity on HPPD, with an apparent IC50 of 70 nM, surpassing the activity obtained with the commercial herbicide sulcotrione (Fig. 1.5). 

Leptospermone (72) is an allelochemical produced by the bottlebrush plant (Calispermon spp.).46 This compound is herbicidal, causing bleaching symptoms, and is a potent inhibitor of HPPD. The triketone-type HPPD-inhibiting herbicides such as sulcotrione (73) were developed based on the structure of... 

Evaluation of natural compounds has been a relatively small part of the herbicide discovery effort of most companies involved in pesticide discovery. In some cases, the company has put significant effort into isolation of phytotoxic compounds from various organisms as part of a bioprospecting effort. This activity has led to several commercial herbicides, including glufosinate, bialaphos, the triketones, and pelargonic acid. 

Figure 3. Effect of the p-triketone (-)-usnic acid (circles), the benzoquinone sorgoleone (triangles) and the commercial herbicide sulcotrione (squares) on the activity of p-hydroxyphenylpyruvate dioxygenase. The dotted line represents 50% inhibition of enzyme activity.

A very simple triketone has proven useful for treating the rare genetic disease tyrosinemia. The drug alternately known as nitisinone (30) or orfadin actually hears a very close relation to a pesticide. The analogue in which methylsulfonyl replaces the trifluoromethyl group, mesotrione, is an important corn herbicide. Acylation of cyclohexan-l,3-dione, shown as an enol (28) with acid chloride (29), leads in a single step to 30. ... 

With the advent of triple-quadrupole and ion-trap MS-MS systems, confirmation of identity is based on single- or midtiple-transition SRM procedures, as for instance demonstrated for sulfonyluieas [53], triketone, and various other herbicides [99]. 

Triketones with Heterocyclic Substituents. Triketones represent a well-studied, but still developing, family of herbicides. Some with pyiidyl substituents are among the most active. Much of the research in this area has been reviewed. The triketones are inhibitors of the plant enzyme 4-hydroxyphenylpymvate dioxygenase (HPPD), which plays a key role in the biosynthesis of plastoquinone and tocopherol. Compound 11.6, which is known as nicotinoyl syncarpic acid, is shown as a typical structure of this type. Its potent herbiddal activity led to synthetic work that has yielded many related stmctures in an effort to improve selectivity in the herbicidal action. 

Herbicidal activity on several weeds, such as hairy beggarsticks, black nightshade, and knotweed, was reported in 2004 for a series of 2,4,5-imidazolidine triketones, such as compound 92 [100] (Fig. 3.25). 

This chapter aims to give an insight into the discovery of the triketone class of herbicides and their continuing development. A very qualitative picture of structure-activity relationships will be discussed and currently commercialized triketones, in terms of their use, weed spectrum, crop selectivity, environmental and toxicological profiles, and manufacture will be described. This chapter also contains an overview of the major companies activities in the field in the last two decades, focusing on compounds that are likely to be brought to the market, or were putatively close to development. 

Independent of this discovery, in 1982 scientists from the same company were working on a project aimed at preparing novel Acetyl-CoA carboxylase inhibitors, based upon the typical cyclohexanedione structure known for this class. The first targeted compound (2), prepared as shown in Fig. 4.3.1, showed some herbicidal activity and they thus attempted preparation of a phenyl analogue in a similar manner. This led not to the expected product (3), but to the triketone (4). This compound was devoid of herbicidal activity, but (luckily ) in safener screens the compound showed antidotal effects in Soya for thiocarbamate herbicides. A further round of synthesis optimization was undertaken and it was found that the compound (5) with an ortho-chloro substituent showed reasonable herbicidal activity. Furthermore, they noticed that it exhibited the same unique bleaching symptomology observed for leptospermone (1, Fig. 4.3.1) [4]. Further optimiza-... 

As discussed in detail in Chapter 4.2, triketones exert their herbicidal mode of action by inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD) [6]. Triketones are not the only herbicide class that have this mode of action, and it has retrospectively been shown that apparently structurally non-related heterocyclic commercial herbicides such as isoxaflutole (7, BALANCE and MERLIN ), and the rice herbicides pyrazolate (8, SANBIRD ) and benzobicyclon (9, SHOW-ACE ) also cause these bleaching symptoms by the same mode of action. However, a common feature of these herbicides, after metabolic activation to the active metabolites (7 ) [7], (8 ) [8] and (9 ) [9] is the presence of an acidic 1,3-dicarbonyl moiety, which is also present in triketones (Fig. 4.3.2). Triketones and related her-... 

The triketones can be separated into two parts for analysis of the structure-activity relationships, namely the benzoyl and the dione moieties. Each part can be examined independently, as they appear to play distinct and different roles in the overall expression of herbicidal activity [1]. Apart from the necessity of an ortho-substituent on the phenyl ring, it was established that 2,4,- or 2,3,4-benzoic acid substitution patterns were required for optimal activity, with the 2,5-... 

They also, apparently, were very interested in triketones with a nicotinoyl acid moiety, based on the number of applications filed in this area (34, 36, and 37, Fig. 4.3.6) [42, 43]. Nissan noticed the similarity of the triketones to the pyrazole type herbicides such as pyrazolate (8), and secured intellectual property freedom in... 

BASF also explored patent free examples of triketones with novel metasubstituents, particularly acids containing heterocyclic rings at this position (e.g., 53, Fig. 4.3.9). The 4,5-dihydro-isoxazole containing pyrazole corn herbicide top-ramezone (54, IMPACT , CLIO ) [50, 51] has resulted from this work (Fig. 4.3.9). 

With regard to triketones of this structure type, Aventis (now Bayer) patented substituted 4,5-dihydro-isoxazole compounds [52] prior to BASF [53], and two compounds from Bayer (55 and 56, Fig. 4.3.9) have frequently appeared in mixture patents with safeners and other herbicides for use in corn [54]. 

Du Pont started relatively late in the triketone field, and directed their efforts toward novel fused bicyclic acids. As a result of their work in this area, they discovered the broad leaf weed cereal herbicide ketospiridox [58] (62, proposed common name. Fig. 4.3.10). Ishihara, inspired by earlier work of Hokko [59], identified some new benzoyl analogues with cyclic acetal meta-substituents (63 and 64, Fig. 4.3.11) that they claim have good pre-emergent activity in flooded rice paddy fields without damaging the rice seedlings [60]. 

Bayer have published recently - mainly after the successful merger with Aventis - a multitude of patents [61], in which they have basically explored in more detail the effect of several novel meta-substituents on the biological activity of triketones, especially those with substituted 3-alkoxyalky-2-chloro-4-alkylsulfonyl substituents in the aromatic ring. From this work, the post-emergence corn herbicide... 

Wang and collaborators prepared 52 new quinazohne-2,4-diones, containing a triketone moiety, and examined their potential as 4-hydroxyphenylpy-ruvate dioxygenase (EC 1.13.11.27, HPPD) herbicides (14JAF11786). 

Fig. 2 Inhibition of p-hydroxyphenylpymvate dioxygenase by manuka oil ( ), the j8-triketone-rich fraction ( ), and its individual jS-triketone components leptospermone ( ), flavesone (A), and grandiflorone (T). The synthetic herbicide sulcotrione (o) was added as positive control. Each data point represents the mean of two independent experiment 1 SD (N = 6) (Figure from [44]. With permission)...

Dayan, F.E. et al. (2007)p-Hydroxyphenylpyru-vate dioxygenase is a herbicidal target site for P-triketones from Leptospermum scoparium. Phytochemistry 68, 2004-2014... 

---