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Synthesis of Heliannuol D, an Allelochemical from Helianthus annuus

Subir K. Sabui and Ramnathapuram V. Venkateswaran

Department of Organic Chemistry, Indian Association for the Cultivation of Science
Jadavpur, Kolkata – 700032, India Email:


Two diverse syntheses of heliannuol D 1, an important constituent of the allelochemicals from cultivar sunflowers are described. The first involved the regioselective Baeyer-Villiger oxidation of the benzobicyclo[3.2.1]octanone 11 to furnish the lactone 12, which on hydrogenation yielded the benzoxepane carboxylate 13 in a stereocontrolled manner. Interaction of this ester with methyl magnesium iodide afforded O-methyl heliannuol D 14 , which has previously been demethylated to 1. In an alternate more effective approach, the diene ester 17 was subjected to a ring closing metathesis to provide the benzoxepine carboxylate 19 . Stereocontrolled hydrogenation followed by a Grignard reaction with methyl magnesium iodide furnished O-methyl heliannuol D 14 , in ashort number of steps and with a high overall yield.

Media summary

Two diverse methods have been developed for the synthesis of heliannuol D, an important allelopathic constituent of cultivar sunflowers, the second of which furnishes the final product in a short number of steps and with a high overall yield.

Key Words

Allelochemical, heliannuol D, benzobicyclo[3.2.1.]octanone oxidative cleavage, ring – closing metathesis


Heliannuol D 1, along with its siblings heliannuols A – C and E, 2 – 5, comprise a new group of phenolic sesquiterpenes isolated from the cultivar sunflower Helianthus annuus.(Macias et al. 1994, 1999 ). These compounds have been implicated in the allelopathic activity displayed by these plants. Due to increasing concern in recent years regarding the natural ecological balance, and to reduce further the risk posed by the use of synthetic pesticides, allelochemicals and their analogues are being looked upon as useful pest control agents that do not have hazardous side effects. In this context, heliannuols, in view of their significant bio-activity as natural herbicide models and the hitherto unknown benzo-fused six-, seven- and eight-membered cyclic ether skeletal enshrined in them have attracted wide synthetic interest. We report here two diverse approaches to the synthesis of heliannuol D.

Results and discussion

The initial approach involved the oxidative cleavage of the benzobicyclo[3.2.1.]octanone 11. It was envisaged that if the cleavage can be made regioselectively at the benzylic C – C=O bond, it will generate the desired benzoxepane ring system present in 1. The key bridged ketone 11 for this cleavage was synthesized as follows. Irradiation of a benzene solution of the chromone 6 with continuous passage of ethylene through the solution furnished a mixture of the cycloadduct 7 and the oxetanol 8 in a combined yield of 62%, with both the components in varying proportions. These could be easily separated by column chromatography. Interaction of the adduct 7 with methyl magnesium iodide produced the carbinol 9, with the methyl group coming from the exo face. On the other hand, reduction of the oxetanol 8 with lithium aluminium hydride furnished the diol 10 at a very high yield. Both 9 and 10 are suitably poised for a pinacol-pinacolone rearrangement. In the event, treatment of these carbinols with boron trifluoride etherate in benzene at room temperature caused a clean rearrangement with exclusive external bond migration to deliver the same bridged ketone 11 at a very high yield. Analytical and spectral data were fully supportive of the assigned structure ( Scheme 1 ). This bridged ketone was then subjected to a Baeyer – Villiger oxidation with m- chloro perbenzoic acid in methylene chloride containing added trifluoroacetic acid, which afforded the lactone 12 regio-selectively in 71% yield. Subsequent transformations confirmed the regio-selectivity in this oxidation.

Scheme 1

The benzylic C – O bond in 12 underwent ready hydrogenolysis when a methanolic solution was subjected to hydrogenation in the presence of palladium carbon to afford the benzoxepane carboxylate 13 in a stereocontrolled manner. Interaction of this ester with methyl magnesium iodide furnished O-methyl heliannuol D 14, spectroscopically identical with a sample reported by Vyvyan ( Vyvyan and Looper 2000) who had also carried out its demethylation to heliannuol D, thus confirming a synthesis of this allelochemical ( Scheme 2 )( Sabui and Venkateswaran 2004 ).

Scheme 2

In an alternate, expeditious approach, ring-closing metathesis was used to generate the benzoxepane core of 1. The styrenol 15 was alkylated with ethyl bromoacetate in the presence of potassium carbonate to furnish the styrene carboxylate 16 in 80% yield. A second alkylation of this ester with allyl bromide using lithium diisopropylamide as base resulted in the diene 17 at a very hight yield, properly set up for the crucial ring-closing experiment. When this diene was subjected to a ring-closing experiment with the Grubbs’ first generation catalyst ( catalyst ‘A’), it afforded only the cross metathesis product 20.

Scheme 3

However, when cyclisation was carried out using the second generation catalyst (catalyst ‘B’)( Trnka and Grubbs 2001 ), it underwent a clean cyclisation delivering the benzoxepene carboxylate 19 at a very high yield. Catalytic hydrogenation of this ester proceeded in a stereocontrolled manner furnishing the benzoxepane carboxylate 20 in near quantitative yield. Finally this was subjected to a Grignard reaction with methyl magnesium iodide to give a high yield of O-methyl heliannuol D 14, which wasidentical in all respects to our previously synthesized sample ( Scheme 3) ( Sabui and Venkateswaran 2004).


A synthesis of heliannuol D, an allelopathic constituent of cultivar sun flowers has been completed employing two distinct approaches. The second approach involving ring-closing metathesis to generate the seven-membered oxepane ring system has the overall advantage in furnishing the final product in simple reaction conditions and a short number of steps with a very high overall yield.


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