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Table of Contents
- Historical Context
- Medicinal Uses
- Chemical Composition
- Isolation and Synthesis
The Mandrake Root, Atropa mandragora  is a plant with a long history that is plagued by myth, legend and folk lore. Behind this cloud of tall tales lies a fascinating plant which shows many medicinal uses from topical ointments to hopefully in the near future a treatment for some forms of cancer. This arises from the interesting chemical composition of the roots, which lie deep within the earth when planted and cultivated properly. Much of the "magical aura" that surrounds the Mandrake root can be attributed these chemical compounds which lie in the roots. And while it's chemical composition does have medicinal properties, if used improperly or with ill intent, the mandrake root can be fatal.
The historical and mythological references to the Mandrake and its supposed magical powers seem unending. Much of this lure stems back to the middle ages where they thought that the roots shape, which resembles a human, gave it power. The mandrake was sold in the middle ages in two forms, in small pieces of the root and whole roots. Portions of the mandrake were said to ward off evil so consequently families, soldiers and sailors bought them, when they could afford it to promote happiness. Since the price of the Mandrake root was high, stories were circulated that when you pulled a mandrake out of the ground the scream would drive you mad. Again the scream coming back to the idea that the mandrake was a human and you were wrenching it from its home. Therefore it was rumored that magicians and sorcerers alone were able to pull a mandrake [3.]
The mandrakes properties also surface in famous literature in the realm of assassinations and warfare. Legend holds that Mandrake was the plant used to poison Marcus Antonius's troops. This account, given by Plutarch speaks of the Parthian Wars. Ancient historical accounts say that the Mandrake was used in rituals to the Goddess of War in modern day Greece. As we will see, modern technology and science has disproved these tales, and that the Mandrake's supposed magical properties can be traced to a few strong toxins that are located in the root[11.]
The Atropa mandragora is one of the many forms of the mandrake root. This particular strain, the European Mandrake, belongs to the Solanaceae  family. This broad family is home to beautiful flowering plants and others more toxic, such as the Mandrake. The European Mandrake is native to southern Spain and Portugal along the Mediterranean where mild winters allow the roots to grow undisturbed and moderate amounts of water do not drench the plant and kill it. [5.] The mandrake is a relatively large plant, and while the flowers resemble those of the primrose, the roots are certainly the identifying feature of the plant. The roots, when the plant is fully grown can run three to four feet into the earth, with branches stemming from the main root [1.] Theses branches coming off the main root give it the rudimentary form of a human being, which increased the propagation of folk lore surrounding this plant.
The flowers and the leaves, when grown, can cover about eighteen to twenty four inches of the top soil sprouting many flowers and an apple like fruit [2.] The fruit is the about the same size of the apple and has a strong scent. This intriguing scent, coupled with the toxins found in the root lead the Arabs to nick name the fruit "Devil's Apple."  When more about the plant was learned, it was found that the fruit was edible cooked or eaten raw, but to avoid at all costs the dangerous roots [4.]
Close attention must be given to the mandrake root if it is growing outside of its native habitat. The cultivation of the mandrake is essentially the same as the Nightshade, Atropa belladonna. These two plants fall under the same family, but the Nightshade has a much more potent toxic count.
"In Italian, a belladonna is a beautiful lady; in English, it's a deadly poison." Ambrose Bierce 
For each of these plants, in addition to the amount of water they come in contact with, the quality of soil is crucial to their growth. When the plants are grown commercially they are usually sold for the purpose of extracting their alkaloid content from the roots; this amount is directly proportional to the quality of soil used. If the plant is growing well on its own, few people use fertilizers, but if it is struggling then the soil is usually treated with farm manure. For highest alkaloid concentrations, the plants should be grown in a dry area where they are exposed to plenty of sunlight. The Mandrake is a slow growing plant and while the seed is germinating, when the sprout comes out of the seed, it requires plenty of water. The plants alkaloid content will drop drastically in the winter months, and the harsh winters will oftentimes kill the plant. These plants, with high alkaloid contents are used for drug research for medications and potential treatment options. [11.]
As mentioned previously, the mandrake is cultivated commercially primarily for research underway for its medicinal properties. For centuries, Mediterranean cultures have used the Mandrake leaves for their cooling and therapeutic effects. Besides the fruit, which can only be consumed in small amounts, no part of the Mandrake should be consumed orally[6.] Currently, mandrake is used throughout the world as a treatment for removing warts. The compound, which will be discussed in more detail in the following section, responsible for this is podophyllotoxin [6.] An ointment is applied to the wart or desired area in no more then 3x3 inches amount and the toxin slowly kills the unwanted growth. The danger occurs when too much of the toxin is absorbed through the skin, so it should never be applied to an open lesion or cut [6.] Podophyllotoxin is used in certain drugs that are legal in the United States only in an ointment or topical cream form. Certain people are not supposed to use the ointment especially pregnant women because if too much is absorbed through the skin then the baby can be harmed. 
Podophyllum's promise in slowing and eventually killing "papillomas" or cancerous growths has lead researchers on the quest of using the mandrakes poison to kill cancerous cells. Podophyllotoxin has been tested for killing cancer but was found to be too toxic and spread to neighboring tissue that resulted in unwanted killing of cells. On rodents it proved to be too toxic with lethal doses averaging 33 mg/kg in mice and 15 mg/kg in rats [10.] Podophyllotoxin toxin is
"a potent spindle poison that blocks mitosis in metaphase...Overexposure causes neurologic, GI and hematological toxicity that occasionally results in fatalities" [10.] To reiterate, the toxin is isolated from the root alone, and the ripe fruit can be consumed only in small amounts. In current history few people have done research on how lethal or harmful the fruit actually is, but no research can be found on if the fruit is harmful. In addition to this, the main danger of the cream is if too much is applied because large amounts of absorption through the skin is a danger. Medicines with podophyllotoxin are administered through perscription only and are generally ointments.
The Chemical compound in the plant, found in the root is podophyllotoxin. The structure of podophyllotoxin, has many functional interesting groups here to note are the substituents located on the rings. Of important notice is the hydroxyl group (-OH) and the four adjacent chiral carbons. These groups will be important when the synthesis of this compound is described in more deail to come.
Podophyllotoxin or PTOX C22H22O8 has a molecular weight of 414.41 g/mol. The first recordeded isolation, which I say becasue it was known by ancient civilizations, was by Podwyssotzki in 1880 for its antitumoreffects . Podophyllotoxin's structure has been intruiging to chemists for decades, its four chiral carbons adjacent to one another, in addition to stereochemistry of the molecule bewildered chemists until the mid 1930's. During this time, it was contended whether or not there was a second hydroxyl group leading to the precense of a second degree alcohol located on the rings. In 1932 three chemists; Borshe, Niemann and Spath drew a structure to compete with Wessley and Nadler who had proposed the two hydroxyl group structure with the secondary alcohol present. Each had vehement evidence as to why theirs was correct, but the accepted IUPAC (International Union of Pure and Applied Chemistry)resulted from the work of Borshe, Niemann and Spath. Their structure, the shown above, clearly contains the one hydroxyl group. They were able to prove through various reactions that the second alcohol group was not present.
Chemists have been synthesizing podophyllotoxin since the early 1950's. Its synthesis was primarily an interest in the mid 20th century for research in medical fields. Those early steps helped paved the way to a renewed interest in PTOX's ability to firght cancer. Currently PTOX is used early in the synthesis of two anticancer medications, etopside and tenioside . The antitumor effects have long been known, and PTOX is still widely used to deter venerial warts. Because of its use current use in these drugs, a push has been made for a more commericially viable way to produce PTOX. Early systhesis strategies took more than 50 steps generally, but a new synthesis published on February 27, 2007 outlines a synthesis of only twelve steps that begins with currently commericially available substances and produces PTOX in a yield of 29 % . This new synthesis has become the template for commercial production of PTOX today. One issue with the synthesis is that it has high stereoselectivites which decrease the yield, but these negatives are not enough to outweight this cheap method of producing PTOX. It utilizes the "use of cascade addition-alkylation to ensure the key C1-C2 stereochemistry that is pivitol for the synthesis of podophyllotoxin" . The synthesis begins with 6-bromopiperonal (the commercially available product) and also uses an organocuprate and aryl lithium. This retrosynthetic analysis shows some parts of the synthesis:
Permission pending. Copyright Hongbin Zhang.
Once the structure has been synthesized, the following H1-NMR is obtained.
Permission pending. Copyright AIST. SDBS. The Link
Although it is difficult to visualize from this 100 mHz NMR, this graph actually contains 14 seperate peaks of alternating splitting . The amount of activity that appears on the H1-NMR is the result of the close vicinty of each functional and their relation with the 22 hydrogen atoms present on the structure. These interactions cause PTOX to have an increased level of activity on an H1-NMR scan. By examining each of these hydrogens and using standard rules such as the "three bonds away" and the "N+1" rule you can predict the number of peaks and the splitting of each one of the peaks which will help determine the carbon skeleton. In addition to this H1-NMR, an Infrared Spectroscopy (IR) is useful in determining the major functional groups present on the molecule. The IR viewable below
Permission pending. Copyright AIST. SDBS. The Link
The useful information which can be gathered from this IR, done on a KBr disk,
 is primarily the aromatic nature of the strucuture.
The peaks to the left of the 3000 cm-1 indicate the aromaticity of the compound. In addition to this, the strong peak in the 1750 cm-1 elucidates the presence of a C=O bond. The cluster of peaks to the right of 1500 become more and more difficult to interpret, but what is clear is the presence of C=c bonds, due to the aromatic rings, by the strong peak at 1500 cm-1.
Here is an image that I generated which shows not only the interesting stereochemistry of the molecule but also the non bonded electrons.
The structure of Podophyllotoxin was debated in the mid 1900's, the controversy centered around the four adjacent chiral carbons.
This structure viewed in 3-d looks like this
The 3-d Optimization of PTOX, Carbon is grey, Oxygen is red and Hydrogen is white.
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