Precocene I and

Isolation and identification of the two natural antijuvenile hormones revealed two simple chromenes 7-methoxy-2,2-dimethyl chromene and 6,7-dimethoxy-2,2-dimethyl chromene (Figure 3). Since these compounds induced precocious metamorphosis, we called them Precocene I and II respectively. Subsequently we found that both compounds had been previously identified and synthesized ( 15, 16, 17). We developed an efficient synthesis for these compounds shown in Figure 4. 

Precocenes I and II are natural products with a simple chromene structure (7-methoxy- and 6,7-dimethoxy-2,2-dimethylchromene) which were isolated from plant sources and exhibited powerful antijuvenile hormone activities in several types of insects (1). 

Chromenes.- Continuing interest in the precocenes and their biological action has stimulated further work on their synthesis. Precocene III (82) has been synthesized from a phenol, 3-methylbut-2-enal and titanium(IV) ethoxide93 and precocenes I and II were obtained by cyclization of the relevant 3-methoxyphenol with isoprene and dehydrogenating the resultant chroman with DDQ.94 Several new positional isomers of precocenes and related compounds have been synthesized and screened for insecticidal activity in a rice crop. Chromanones [such as (83)] were reduced with LAH to the chromanol which was efficiently dehydrated with a trace of toluene-4-sulphonic acid. Under some conditions, reduction gave dimeric... 

Ageratum conyzoides L. Precocene I and II, Causes phytotoxic effects on Plant Encyclopedia... 

Precocene I and precocene II are two natural products isolated from Ageratum houstonnianum (Figure 11) (24). Studies showed these compounds possess antijuvenile hormone activity, and they are able to induce precocious metamorphosis, cause sterilization, and/or force diapause in certain insects. 

A photochemical approach to the synthesis of precocenes /, II, and III, interesting as juvenile hormome inhibitors [177,178], has been deviced starting from the phenolic esters of 3-methylcrotonic acid. This is shown in Scheme 61 for the synthesis of precocene I (235) [179] and in Scheme 62 for the synthesis of precocenes II (238) and III (239) [180]. The rate of the cyclization process leading to chromanones, like 234 or 237, has been found to depend on the stereochemistry of the double bond. Thus, ring closure is more rapid for the trans than for the cis isomer, although no clear-cut trend can be established [181],... 

Recently, the biological role of precocene I (132) and II (133) and their conversion into the epoxides has been studied. Precocene II suppresses juvenile hormone (79MI22301, 79CC920) and this has stimulated interest in synthetic analogues (80JHC1377). 

Investigations of the in vivo and in vitro metabolism of the precocenes disclosed that 3,4-dihydroxyprecocenes were the most common metabolites. The abundance of these diols suggested that precocene must have undergone epoxidation followed by hydration, leading to a constant isomer ratio of 70 30 trans cis isomers, (2,U5). Recently, it was demonstrated by incubation in vitro with Locusta migratoria corpora allata that 4- H-precocene I was metabolized stereospecifically to (-)-trans-(3R,4S) and (+)-cis-(3R,4R) diols (17). 

We chose adult female Dlploptera punctata as the test organism because the effects of precocene II on this insect have been described in detail (30) and because the CA of this insect produce exclusively JH III. Precocene II Is bioactivated by a mono-oxygenase in D. punctata CA, just as precocene I Is bioactivated in Locusta mlgratorla CA (11, 12). Indirect evidence for precocene II bioactivation to a highly reactive 3,4-epoxide Is not only provided by electron microscopy which shows extensive damage to the CA cells after in vivo or in vitro treatment (30). In addition, in vitro studies show that radio labelled precocene II is metabolized by I). punctata CA to a mixture of els- and trans-3,4-dihydrodiols which can be extracted and analyzed by HPLC (Fig. 2, HPLC conditions ether/pentane 1/1 + 0.2% 2-propanol 1.5 ml/min. 300 x 4 mm Micropak Si 5). The ratio of precocene II cis- and trans-3,4-dihydrodiols (36 64) is remarkably similar to the ratio of dihydrodiols obtained In incubations of rat liver microsomes with precocene II (16) or In incubations of L. mlgratorla CA with precocene I (11). 

A more complicated pH-rate profile is also observed for the hydrolysis reactions of benzo[a]pyrene diol epoxide epoxide 80, and is shown in Fig. 5.102 This profile shows Regions A-D that are similar to those for reaction of precocene I oxide 76 (Fig. 4), except that Region B reaches a full plateau that extends from pH 5 to 9 in water. The interpretation of this pH-rate profile is essentially the same as the interpretation of the profile for hydrolysis of precocene I oxide (Fig. 4). The pH-independent reaction of 80 in Region B (discussed in detail in Section Benzylic epoxides and arene oxides ) yields 60% tetrols in a stepwise mechanism involving a carbocation intermediate and 40% ketone from a completely separate pathway (Scheme 31). The negative inflection of the profile at pH 10-11.5 indicates that hydroxide ion reacts as a base with the intermediate carbocation to reform diol epoxide 80 and thus slow the reaction rate. There is a corresponding increase in the yield of ketone 107 at pH >11. 

The bioactivities of precocene I, 7-methoxy-2,2-dimethyl chromene, and precocene II, 6,7-dimethoxy-2,2-dimethyl chromene, are well established (Fig. (7)). These two compounds have been isolated from plants throughout the family Asteraceae [129-136, 154]. The chemical data for these compounds and references for their synthesis are compiled in Appendix IV, Tables 13 and 14. There is a wealth of information on the effects of these compounds on various insect species [42, 137]. For simplicity, we will focus on the effects of precocene II on the susceptible Hemipteran bug, Oncopeltus fasciatus. 

The high reactivity of acronycine epoxide f6n led us to speculate that this compound should be the active metabolite of acronycine in vivo and that it should be responsible for the alkylation of nucleophilic targets within the tumor cell (68). This hypothesis was in good agreement with the mode of action previously established (76) for the insecticidal chromenes precocenes I (62) and II (63 ). whose structures share a dimethylbenzopyran unit in common with acronycine (i). 

Many 2,2-dimethylchromenes (131) are oxidized (in 32—11% yield) by T1(N03)2 in MeOH to the dihydrobenzofurans (132). The naturally occurring compound precocene I (133) gave the epoxide (134) upon treatment with NBS and NaH. The epoxide is readily cleaved, and may have a role in the termination of the production of juvenile hormone in some insects. The ease with which the double-bond of the pyran is reduced in 4-aryl-2/f-chromenes varies according to whether the 4-aryl group also has a nitro-group, because the amine that is then formed increases the pH of the medium. This effect can be offset by... 

The 2H-chromene system, especially the 2,2-dimethyl-substituted derivative, is a constituent of numerous natural products, such as evodionol (12) and lapachenol (13), which occur in plants, and precocene I/ll (14), a juvenile hormone antagonist. 

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