Synthetic or natural: a curiosity and a reflection


This topic has been presented previously in two other blogs: In the Pipeline and Interesting Organic Chemistry and Natural Products.

The curious case of tramadol

In 1828 Friedrich Wohler was the first chemist that succeeded in synthesizing a natural product (urea) from an inorganic compound (ammonium cyanate). This event marked the beginning of the era of organic synthesis, i.e. the production of complex organic substances from simpler compounds.

Nauclea latifolia or African peach

Nauclea latifolia or African peach

Organic synthesis found its immediate use in the pigment and in the defense industries. Sulfanilamide, the first synthetic antibacterial agent, emerged from the pigment industry while 2,4-D, the first chemical herbicide, emerged from the industry of chemical / biological weapons. We could say that, indirectly, these two industries favored the development of the pharmaceutical industry and herbicides/pesticides. In the case of the pesticide industry, unfortunately, the use of organic synthesis resulted in the production of nerve gases, the most lethal chemical weapon known today.

The pharmaceutical industry benefited from numerous drug classes derived from natural product sources. The development of organic synthesis allowed the pharmaceutical industry to synthesize various natural products and their analogues, many of them with improved pharmacological properties. This is the reason why 40% of the drugs in use are structurally related to biologically active natural products.

Except in rare occasions *, the discovery of a natural product with pharmacological properties precedes its chemical synthesis. However, in September 2013, challenging what seems to be a rule, a group of French scientists led by Michel De Waard published an article stating that a fully synthetic drug commonly used was actually a natural product.


Tramadol is an equal mixture of enantiomers.

I am referring to tramadol, a synthetic analgesic widely used that was introduced in the market in 1977. At the beginning of this decade, the product was extracted and isolated from the roots of Nauclea latifolia, a tree that grows in tropical areas of Africa and that the natives of this region use as a source of traditional medicine.

This caused astonishment in the scientific community due to the serendipity associated with the discovery. Many people accepted this finding since the compound was isolated from a tree with medicinal properties (including pain relief ) and because its structure was closely related to another natural product: morphine. However, there was a group of scientists who were not convinced about the natural origin of the tramadol since the product was obtained as a mixture similar to that of the commercial tramadol (as a racemate or a mixture of equal amounts of enantiomers) and not as a single compound, or as a uneven mixture of enantiomers, as it is usually the case with natural products.

Morphine structure.

Morphine structure.

Doubts generated by the finding and its relevance, led to another group of researchers guided by Professor Mitchael Spiteller to perform additional studies. In September 2014, Spiteller’s group published an article arguing that the occurrence of tramadol in the roots of Nauclea latifolia was not because it was a natural product, but because it was an anthropogenic pollutant (i.e. generated by human activity).

The statement made by this group is based (among other things) ** in the fact that tramadol and its metabolites were found in the roots of N. latifolia and other trees in areas of Cameroon where people and animals consume this product on a daily basis. In northern Cameroon, farmers use tramadol to increase their resistance to fatigue and heat and, because of its low cost, they also use it to feed the draft animals with the drug in order to increase their performance. According to Spiteller and collaborators, tramadol and its metabolites would be excreted in the feces and urine of animals and people who, under an oppressive heat, seek relief beneath the shade trees. Conversely, this practice is not known in the southern region of the country.

CamerúnThe scientific evidence presented by Michael Spiteller served to convince the majority of the scientific community that Tramadol is indeed a synthetic analgesic and not an actual natural product. However, some natural product chemists believe that the issue is not fully resolved, including Dr. De Waar who remains convinced that tramadol is a natural product and that the differences in the results between the two studies could be because the samples taken came from different areas of Cameroon .


We live in a closed system. This means that the products generated as a result of human activity (and living beings in general) remain in the biosphere. Whenever a compound is produced in large quantities, unless it is perfectly biodegradable or entirely consumed in the process, it will eventually become part of the environment. This implies that, sooner or later, we will be in contact with a number of compounds, at an unknown frequency and with an unknown degree of exposure. Of course, this includes herbicides, pesticides and human and veterinary drugs. The case of tramadol is a clear example of how pharmaceuticals can reach high concentrations in unforeseen places .

buitresA striking example of how a drug may affect the ecosystem is what happened in India with the diclofenac in the years 2000-2003. It was found that the vultures that ate *** carcasses of animals treated with diclofenac, died within days due to kidney failure. To the diclofenac’s case we can add the well-established effect of uncontrolled use of antibiotics in the raise of bacterial resistance and the feminization of fish and amphibians due to the presence of natural and synthetic hormones **** in lakes, rivers and streams .

So far the regulators have approved drugs based on the immediate benefit they bring to the health of human beings, regardless of the environmental effects associated with their consumption. Fortunately, regulatory agencies are beginning to demand that pharmaceutical companies carry out the syntheses of their products with the least possible environmental cost. In some cases, they ask them to have a proper disposal program of the expired products and to perform a risk assessment of the potential environmental impacts associated with their use.

It is estimated that up to now we have introduced in the environment over 4000 compounds. As long as the population continues to increase and becomes more drug-dependent due to its aging, new regulations are expected to emerge that can help reduce the environmental impact of medications

*   Histidine is one case.

** The isotopic composition coincides with the synthetic drug.

*** Especially in the liver where the drug reaches high concentrations.

**** Coming mostly from birth control pills and hormone treatments.


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