Ajoene: An Antibiotic Stable Component Found in Garlic

Reliable Method for Sythesizing Ajoene

  • Fig.1: Garlic cloves.Fig.1: Garlic cloves.
  • Fig.1: Garlic cloves.
  • Fig.2: Total synthesis of ajoene.

An efficient, robust and reliable method of making ajoene has been developed using easily available starting materials. The remarkable antibacterial properties of this compound have shown great promise and it is hoped that this breakthrough will accelerate efforts to produce ajoene in larger volumes and to better test its effectiveness as a therapeutic drug.

The use of garlic dates back many thousand years and is already mentioned in very early medical texts. Ajoene is a compound found in chopped fresh garlic (fig.1.) and the biologic effects of garlic are mainly related to this compound. Although the worldwide production of garlic is substantial and garlic extracts are being sold in several different forms, there is no efficient way to make this specific component.

As soon as garlic is chopped, several enzymes present in the damaged plant start to degrade alliin, which is one of its main organosulfur metabolites. The first degradation product is allicin, which is mainly responsible for the characteristic smell of garlic. This molecule then decomposes further into different sulfur-containing compounds. One of these is ajoene which is a main constituent of the oil extracts. It has been shown that ajoene is an effective antibacterial, antimicrobial and antifungal agent and it has also revealed promise in chemotherapy treatments for cancer [1].

The therapeutic effectiveness of ajoene is a result of the reactivity arising from its disulfide moiety, which allows reactions with molecules responsible for the chemical communication between bacteria or with the bacteria directly, preventing them from growing and spreading. In addition to these benefits, it is believed that ajoene can be used as a novel drug in fighting antibiotic resistance.

Total Synthesis of Ajoene

For the first time, this molecule has now been made by a total synthesis. A reliable method for making ajoene without the need for garlic as a starting material has been developed [2]. The synthesis starts from easily accessible compounds and ajoene is assembled in seven synthetic steps as sketched out in Scheme 1. The two bromide substituents in the starting material 1 are consecutively replaced by a selenium and a sulfur moiety to yield 2.

The triple bond attached to the sulfur atom is then transformed into a double bond through a radical sulfur addition to obtain compound 3, then the third sulfur atom bearing an allyl group is attached so that molecule 4 is synthesized (fig.2). In the final step of the synthesis, the selenium moiety is eliminated and the monosulfide is simultaneously selectively oxidized to yield ajoene as the target product. 

One of the big challenges in the synthesis of ajoene was to suppress the different side reactions which can easily occur when dealing with organosulfur compounds. These side reactions have greatly decreased the yield in an earlier biomimetic approach to ajoene, which started from allicin.[3] But initially low yields were also a problem which had to be tackled in the total synthesis. We have investigated several modifications to the reaction steps shown in Scheme 1, but an unexpected improvement was observed when scaling the synthesis from milligram to gram quantities. On a 200-gram scale, the final step yielded 56% of the product which was twice as much as when working on the milligram scale.

The ajoene product synthesized in the lab was biologically active. When testing its activity against bacteria in a bioassay, it was found that the synthetic ajoene showed similar performance than the ajoene extracted from garlic and inhibited biological communication called quorum sensing in gram-negative bacteria.
The total synthesis has now made ajoene much easier accessible and further developments in medical research will now be facilitated.

Author
Prof. Dr. Thomas Wirth 

Cardiff University
Cardiff, UK
wirth@cf.ac.uk
 

References
[1] E. Block, Garlic and Other Alliums, RSC Publishing, Cambridge (2010)
[2] F. Silva, S. S. Khokhar, D. M. Williams, R. Saunders, G. J. S. Evans, M. Graz, T. Wirth, Angew. Chem. 2018, 130, 12470-12473; DOI: 10.1002/ange.201808605; Angew. Chem. Int. Ed. 2018, 57, 12290-12293. DOI: 10.1002/anie.201808605
[3] a) E. Block, S. Ahmad, M. K. Jain, R. W. Crecely, R. Apitz-Castro, M. R. Cruz, J. Am. Chem. Soc. 1984, 106, 8295–8296; DOI: 10.1021/ja00338a049; b) E. Block, S. Ahmad, J. L. Catalfamo, M. K. Jain, R. Apitz-Castro, J. Am. Chem. Soc. 1986, 108, 7045–7055; DOI: 10.1021/ja00282a033.

Further information:

Neuroprotective Effects of Phytochemicals in Neurological Disorders
Edited by Tahira Farooqui and Akhlaq A. Farooqui
Wiley Balckwell (2017)

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