Sherburn's synthesis of (-)-Arctigenin

Origins

Arctigenin is a naturally occurring plant lignan found in certain plants of the Asteraceae family. [1] [2]

Lignans, which are a class of estrogen like compounds dubbed phytoestrogens, have been shown to have several promising anti-viral and anti-carcinogenic effects.

The lignan, Arctigenin, can be isolated from leaves of the plant Arctium lappa; more commonly known as the Burdock or Greater Burdock.

Use

Antiviral: Arctigenin is a known HIV-1 integrase and topoisomerase II inhibitor. In recent studies it has shown to inhibit both HIV protein production and reverse transcriptase activity by nearly 70% in some cases. However, conflicting reports suggest that due to its toxicity, arctigenin should not yet be used as an anti-viral treatment alone.[6] [7]

Antitumor: Arctigenin has shown promise as a potential cancer treatment in that it causes a loss of mitochondrial membrane potential and a down regulation of the anti-apoptotic protein bclxl produced by cancerous cells. [8] This loss of mitochondrial membrane potential destroys the ability of the affected cell to produce energy, and thus ceases the ability of the cell to continually replicate.

Isolation

Initially 5.4kg of plant matter was finely ground and added to 5L distilled water. This mixture was allowed to let stand for an hour at RT (even longer if necessary on ice). The mash was suction filtered adding a 20% (a.q.) lead acetate solution to the filtrate until no further precipitate is formed. After stirring the precipitate was filtered off, to which was added a 5% sodium bicarbonate solution to precipitate any excess lead. At this point the 5.4L of solution was extracted once with 600cc and three times with 400cc of ethyl acetate. The ethyl acetate extracts were combined and evaporated under reduced pressure leaving a syrupy residue with a percent yield ranging from 0.3-1.8% [2]

The original method of isolating naturally occurring arctigenin often proved difficult; with poor yields and impurities commonplace, a new method of artificial synthesis was essential for further study of these compounds.

Synthesis

• Click image for synthesis information

Synthesis of (-)-Artigenin

References

1. De Simone F, Aquino R, De Tomassi N, Mahmood N, Piacente S, Pizza C. Anti-HIV Aromatic Compounds from Higher Plants. In: Tringali C, editor. Bioactive Compounds from Natural Sources. London (UK): Taylor & Francis; 2001. 325-338 p.

2. Cavallito C J, Bailey J H, Kirchner F K. The Antibacterial Principle of Avctium minus. I. Isolation, Physical Properties and Antibacterial Action, Journal of the American Chemical Society 1945; 67: 948-950.�

3. Muhammad S, Hyoung J K, Muhammad S A, Yong S L. An update on bioactive plant lignans, Natural Product Reports 2005; 22: 696-716.��

4. Fischer J, Reynolds A J, Sharp L A, Sherburn M S. Radical Carboxyarylation Approach to Lignans. Total Synthesis of (-)-Arctigenin, (-)-Matairesinol, and Related Natural Products, Organic Letters 2004; 6 (9): 1345-1348.�

5. Mukund S P, Pingrong L, Jianguo J, Saumen H, Jian-xie C. Free-Radical-Mediated Conjugate Additions. Enantioselective Synthesis of Butyrolactone Natural Products: (-)-Enterolactone, (-)-Arctigenin, (-)-Isoarctigenin, (-)-Nephrosteranic Acid, and (-)-Roccellaric Acid, Journal of Organic Chemistry 2002; 67: 1738-1745.��

6.Eich E, Pertz H, Kaloga M, Schulz J, Fesen M, Mazumder A, Pommier Y. (-)-Arctigenin as a Lead Structure for Inhibitors of Human Immunodeficiency Virus Type-1 Integrase, Journal of Medical Chemistry 1996; 39: 86-95.

7. Charlton J L. Antiviral Activity of Lignans, Journal of Natural Products 1998; 61: 1447-1451.

8. Hausott B, Greger H, Marian B. Journal of Cancer Research and Clinical Oncology, Naturally occurring lignans efficiently induce apoptosis in colorectal tumor cells 2003; 129: 569-576.