Precocene structures

In view of the reported lability of the chromene skeleton under environmental-like conditions, i.e. acid promotes dimerization and light causes rearrangement of chromene to quinone methide (4) one of our first concerns was the chemical stabilization of the precocene structures for its potential application in field trials. 

Consequently, we anticipated that to overcome these problems it might be important to incorporate moieties in the precocene structure to alter the transport properties of the natural compounds. For this aim, we synthesized crown ether precocenes VII (11), in which C-6 and C-7 of the chromene skeleton were incorporated into a 15-crown-5 or 18-crown-6 ether ring. We also prepared several chromene derivatives VIII bearing polyoxyethylenated groups and sugar residues at the C-8 position (12). 

The negative implications for pest control by precocenes themselves are clear, but it remains to be seen whether the expansion of their spectrum of activity is limited merely by the chemical structural features of precocenes or, more problematically, by the hormonal mechanisms which control insect development. In either case the JH antagonist approach to the control of larval insect pests presents a major challenge to chemical and physiological research. 

Precocene is a compound that causes insect larvae to pupate and can also be found in some plants (Agerafwmspp.) where it may act as an insecticide. It was isolated in minute amounts and has the following spectroscopic details. Propose a structure for precocene. 

The rationale for design of proallatocidins related to chromenic structure of precocenes is discussed. Stabilization against environmental conditions and insect metabolic pathways, as well as modification of transport properties, sire some of the leads followed for the synthesis of more powerful insect growth regulators of this type. Some aspects of the chemistry of 3,4-epo-xyprecocenes are also examined. 

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). 

In searching for a relationship between antijuvenile hormone activities and epoxide chemical reactivity, we attempted to apply as a chemical probe the m-chloroperoxybenzoic-alkaline fluoride system, a reagent developed in this laboratory for preparation of acid labile epoxides (20). However, formation of hemiesters of 3,4-dihydroxy precocene, was the predominant reaction in the case of activated chro-mene structures. 

Recently, several nucleophilic reagents have been used to establish the mode of action of the metabolites of polycyclic aromatic hydrocarbons (PAH). Among them, several phosphodiesters have been examined to clarify the possibility of reaction of PAH epoxides with the phosphate groups(P-alkylation) of nucleic acids (22). In this context we have studied the reaction of 3,4-epoxyprecocene II with dibenzyl phosphate under a variety of conditions. In all cases, instead of the formation of phenol or phosphotriesters observed with PAH epoxides, we obtained predominantly dimer XI. This compound was also the main component of the mixtures obtained by reaction of the above precocene epoxide with other acid catalysts, along with dimers XII and XII. Dimer XII was formed almost exclusively by thermal treatment. The structure and configuration for compound XII has been established by spectral and X-ray diffraction analyses (23). 

It is worth of note that the formation of a dimer, with different dioxane structure, in the treatment of 3,4-dihydroxyprecocene I with p-toluensulfonic acid has been recently reported (13). Further work, to study the reactivity of precocene epoxides with selected nucleophiles, which can shed light on the mode of action of these compounds, is in progress. 

Precocenes may not provide the new approach to insect control originally expected ("4th generation" insecticides, 9) because they are not active in some major groups of agricultural pests (Lepidoptera) and because their mode of action (cytotoxicity) is not compatible with environmental concerns. Indeed, precocene II has been shown to be hepatotoxic and nephrotoxic in rats (16, 17). However, research on precocenes has led to (at least) two Important conclusions (1) compounds structurally unrelated to the JH biosynthetic pathway can reach critical sites (e.g. epoxidase) within the CA, and (2) such compounds can be catalytically processed (e.g. epoxidlzed) by enzymes of JH biosynthesis. The lax substrate specificity of methyl farnesoate epoxidase in the corpora allata and its catalytic competence might be exploited in the design of irreversible Inhibitors of JH biosynthesis (Figure 1). 

Inhibition of JH III biosynthesis In vitro. All three acetylenic compounds were significantly better Inhibitors of JH biosynthesis than precocene II under similar Incubation conditions (Fig. 4). Compound 2 was the best Inhibitor tested here, with an I50 of 16 pM, more than 25 times better than precocene II. Whether this better performance as an Inhibitor Is due to a closer structural analogy with the natural substrate of the epoxidase or whether it Is a consequence of the presumed difference In the mode of action (Irreversible Inhibition of the epoxidase for cytotoxicity of precocene epoxide eventually resulting In decreased JH biosynthetic rate for 1) Is not presently known. The Insecticide synergist (4) proved to be about 7 times better than precocene II. Its activity as an inhibitor of JH biosynthesis by D. punctata CA is similar to that of 3 and the methylenedioxyphenyl analog of JH (Ro 20-3600). 

Even small structural changes in the starting materials can result in major reactivity differences, as demonstrated by a series of diversely substituted chromanones, the sulfur analogs of the natural precocenes [19,20]. A sim-... 

More details of the discovery, biological activity, and structural elucidation of precocene are given by W. S. Bowers et a/. Science, 1976, 193, 542. 

Matolcsy et al. (1980 1981) reported that 1,2-dimethoxy-4-isopropoxy-5-vinylbenzene (77) a compound derived formally by opening the dihydropyrane ring of precocene II, possesses a precocene type anti-juvenile hormone activity. This finding indicates that compounds lacking the chromene ring structure can also be active. 

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). 

A direct procedure, partly based in earlier knowledge, giving the chrom-3-ene (2H-benzo[b]pyran) structure in one-step has been referred to earlier. In this method titanium or magnesium phenolates formed from the phenol with the metal ethoxide and removal of ethanol, are then reacted with a,p-unsaturated aldehydes or ketones in toluene solution at 110 C over 8 hours (ref. 40). In this way precocene 2 was derived from the reaction of the magnesium salt of... 

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