Cadiz Allelopathy Group (GAC), Dept. of Organic Chemistry, Faculty of Sciences University of Cadiz. Apdo. 40, 11510 – Puerto Real, Cádiz, Spain. www2.uca.es/dept/quimica_organica/ Email famacias@uca.es
Helibisabonol B is a new sesquiterpene with phytotoxic activity isolated from Helianthus annuus leaves. (±)-Helibisabonol B has been synthesized as an approach to the search for new herbicide models. Herein, we report the first total synthesis for this molecule from methylhydroquinone. The key steps of this synthesis are a Fries rearrangement, a Grignard reaction and an Arbuzov coupling reaction. The synthesis was carried out with high yield and in an easy to scale manner.
Helibisabonol B was isolated from medium polar active fractions of sunflower leaves. Now, this product has been synthesized from methylhydroquinone.
Introduction
Allelochemicals are an important potential source for new agrochemicals. Particularly, as herbicides they offer new modes of action, more specific interactions with weeds, and less environmental damage. (Vyvyan 2002; Duke 1986, 1997; Rice 1995; Macias 1995; Waller 1996). These facts make very interesting the large scale synthesis of these products in order to test them in suitable bioassays and propose them as new herbicides, antimicrobials, pesticides, and plant growth regulators models. Their interest relay in the possibility of the discovery of new target sites and modes of action, leading to the flowering of new tools for resistant and non-resistant weeds and pests. Limited and/or total synthesis procedures are usual methods for mass production of these compounds. Also, biotransformation is a very attractive production method, especially for those compounds coming from fungi and microorganisms that can be mass-produced by culture.
Helianthus annuus L. is a plant with a very high commercial interest and of their allelopathic activity in wild and agricultural ecosystems have been already reported: Helianthus rigidus exhibits autotoxicity and sunflower crop (Helianthus annuus) has a great allelopathic potential and inhibits seedling growth of several weeds, including velvet leaf, thorn apple, morning glory, and wild mustard, among others. (Leather 1987). Also, sunflower is known for its high production of secondary metabolites: we have previously described and characterized triterpenes and steroids (Macias 1997), germacranolide and guaianolide sesquiterpene lactones (Macias 1993; 1996), flavonoids (Macias 1997b), heliannuols (Macias 1993b; 1994), and the new family of spiroterpenes, the Heliespirones (Macias 1998). Recently, a new phenolic sesquiterpene with a bisabolane skeleton, Helibisabonol B, has been isolated from Helianthus annuus L. cv. Peredovick® (Macias 2002) (Fig. 1).
Figure 1. Structure of Helibisabonol B
There are no previous reports about the synthesis of helibisabonol B, but many sesquiterpenes with similar structures have been synthesized, including curcuphenol and curcudiol (Ono 1995; Fuganti 1998; Sugahara 1998). The main difference between the synthetic methods employed for these compounds is the way to link the side-chain with the aromatic moiety. Among the different alternatives, we chose the scheme shown in Figure 2, in which the new C-C bond is formed by nucleophilic addition to the aromatic ketone using a Grignard reagent.
Methods
Synthesis of Helibisabonol B
The total synthesis of Helibisabonol B needs to control the stereochemistry of the arising double bond, which has to be E. Also, adequate protective group for the aromatic hydroxyl groups are needed.
Figure 2. Retrosyntetic analysis for Helibisabonol B.
Results
According to the retrosynthetic analysis depicted in Figure 1, we use R-1 as starting material. The low yields obtained in the direct electrophilic aromatic substitution reactions enforced us to look for alternative methods to get access to the starting aromatic ketone. Thus, a Fries rearrangement (Heaney 1991) provides the desired compound (2) via the acetal derivative with quantitative yield in short time and mild conditions.
After a double sylilation with terc-butil-dimethyl-sylil chloride (Figure 3, step c), we were ready to introduce the chain by Grignard reaction (Figure 3, step d). Good yields were observed at room temperature.
A dehydration and epoxidation led to the aldehyde (7). The epoxide intermediated could not be isolated, because the acidic medium cause the authomatic rearregement towards the aldehyde. In the other hand, with an epoxidation and BF3 catalysed etherification gave the dioxolane compound (11) (Figure 4).
The more important step in the synthesis is the coupling between the previous aldehyde (7) and the dioxolane ring (11) using an Arbuzov reaction. This reaction permits to obtain the desired E double bond in two steps. Deprotection of the hydroxyl group with an acidic medium allowed the Helibisabonol B.
Figure 3. Key: a) Anhydride Acetic, py, 25 ºC, 15 h, dark; b) BF3·2H2O, 120 ºC rf., 6h; c) Cl-TBDMS, Imidazole, DMF, 25 ºC, 15h; d) CH3MgCl, THF, 25ºC, 30 min; e) KHSO4, DMF, 85ºC rf., 15 min; f) MCPBA, CH3COONa, 25 ºC, 1h; g) H+; h) (11), DMF, PPH3, 95 ºC rf., 4h; i) KH, (7), THF, 25 ºC, 21h; j) H+
Figure 4. Synthetic scheme for dioxolane ring preparation. Key: a) MCPBA, CH3COONa, 25ºC, 4 h; b) CH3COCH3, BF3.etherate, 25 ºC, 6 h
Conclusion
We have synthetized Helibisabonol B via an Arbouzov reaction with E double bond orientation in good yield.
References
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