Previous PageTable Of ContentsNext Page

First total synthesis of ()-Helibisabonol B

F.A. Macas, J.L.G. Galindo, Ascensin Torres, Rosa M. Varela, D. Marn and Jos M.G. Molinillo

Cadiz Allelopathy Group (GAC), Dept. of Organic Chemistry, Faculty of Sciences University of Cadiz. Apdo. 40, 11510 – Puerto Real, Cdiz, Spain. Email


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.

Media summary

Helibisabonol B was isolated from medium polar active fractions of sunflower leaves. Now, this product has been synthesized from methylhydroquinone.

Key Words

Allelopathy, bioactive, sunflower, Helianthus annuus, helibisabonol.


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.


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.


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 C, 15 h, dark; b) BF32H2O, 120 C rf., 6h; c) Cl-TBDMS, Imidazole, DMF, 25 C, 15h; d) CH3MgCl, THF, 25C, 30 min; e) KHSO4, DMF, 85C rf., 15 min; f) MCPBA, CH3COONa, 25 C, 1h; g) H+; h) (11), DMF, PPH3, 95 C rf., 4h; i) KH, (7), THF, 25 C, 21h; j) H+

Figure 4. Synthetic scheme for dioxolane ring preparation. Key: a) MCPBA, CH3COONa, 25C, 4 h; b) CH3COCH3, BF3.etherate, 25 C, 6 h


We have synthetized Helibisabonol B via an Arbouzov reaction with E double bond orientation in good yield.


Vyvyan JR (2002). Allelochemicals as leads for new herbicides and agrochemicals. Tetrahedron 58, 1631-1646.

Duke SO (1986). Naturally occurring chemical compounds as herbicides. Reviews of Weed Science 2, 15–44.

Duke SO, Dayan FE, Hernandez A (1997). Natural products as leads for new herbicides mode of action. In ‘The 1997 Brighton Crop Protection Conference – Weeds. Vol 2’. (Ed KE Pallett) pp. 579-586, (British Crop Protection Council: Farnham, UK).

Fuganti C and Serra S (1998). A new enantioselective route to bisabolane sesquiterpenes phenols. Synthesis of (S)-(+)-curcuphenol and (S)-(+)-curcumene. Synlett 11, 1252-1254.

Heaney H (1991). Fries Reactions. In ‘Comprehensive Organic Synthesis’. (Eds BM Trost, I Fleming,) pp. 745-747, (Pergamon: Oxford).

Leather GR (1987). Weed control using allelopathic sunflowers and herbicide. Plant Soil 98,17-23.

Macias FA, Torres A, Galindo JLG, Varela RM, Alvarez JA, Molinillo JMG (2002). Bioactive terpenoids from sunflower leaves cv. Peredovick. Phytochemistry 61, 687-692.

Macias FA, Varela RM, Torres A, Molinillo JMG (1998). Heliespirone A. The first member of a novel family of bioactive sesquiterpenes. Tetrahedron Letters 39, 427-430.

Macias FA, Molinillo JMG, Varela RM, Torres A, Galindo JCG (1997). Bioactive Compounds from the Genus Helianthus. In ‘Recent Advances in Allelopaty. A Science for the Future, Vol I’. (Eds FA Macias, JMG Molinillo, JCG Galindo, HG Cutler) pp. 121-148, (CAB Publishers: UK).

Macias FA, Molinillo JMG, Torres A, Varela RM, Castellano D (1997b). Bioactive flavonoids from Helianthus annuus cultivars. Phytochemistry 45, 683-687.

Macias FA, Torres A, Molinillo JMG, Varela RM, Castellano D (1996). Potential allelopathic sesquiterpene lactones from sunflower leaves. Phytochemistry 43, 1205-1215.

Macas FA (1995). Allelopathy in the search of Natural Herbicide models. In ‘Allelopathy: Organisms, Processes, and Applications’. (Eds Inderjit, KMM Dakshini, FA Einhellig) pp. 310-329, (ACS Symposium Series: Washington DC, USA).

Macias FA, Molinillo JMG, Varela RM, Torres A (1994). Structural Elucidation and Chemistry of a Novel Family of Bioactive Sesquiterpenes: Heliannuols. Journal of Organic Chemistry 59, 8261-8266.

Macias FA, Varela RM, Torres A, Molinillo JMG (1993). Potential allelopathic guaianolides from cultivar sunflower leaves, var. SH-222. Phytochemistry 34, 669-674.

Macias FA, Varela RM, Torres A., Molinillo JMG (1993b). Novel sesquiterpene from bioactive fractions of cultivar sunflower. Tetrahedron Letters 34, 1999-2002.

Ono M, Ogura Y, Hatogai K, Akita H (2001). Total synthesis of (S)-(+)-curcudiol, and (R)-(-)-curcuphenol. Chemical and pharmaceutical Bulletin 49, 1581-1585.

Rice EL (1995). In ‘Biological Control of Weeds and Plant Diseases: Advances in applied allelopathy’. (University of Oklahoma Press: Norman, USA).

Sugahara T and Ogasawara K (1998). A new stereocontrolled route to (+)-curcuphenol, a phenolic sesquiterpene from the marine sponge Didiscus flavus. Tetrahedron: Asymmetry 9, 2215-2217.

Waller GR and Yamasaki K (1996). ‘Saponins Used in Food and Agriculture. (Advances in Experimental Medicine and Biology)’. (Plenum Press: New York).

Previous PageTop Of PageNext Page