Organic Chemistry in Nature

Spring 2002 

Chemistry 312 - Organic Chemistry II 
at Virginia Wesleyan College

Research Essay Project

The natural source of the organic compound is described, as well as the primary uses for the compound.  A brief explanation of its purification from its natural source and/or its laboratory synthesis is included.  Resources are listed below the compound's information.  The structures were made using the ChemSketch program from ACD Lab Software.  

Acetylcholine - Anne Provance

Acetylcholine was discovered in 1921 by an Australian scientist named Otto Lewi.  It was the first neurotransmitter discovered.  The experiment done by Lewi included two frog hearts that were electrically stimulated at different times.  The chemical he saw being emitted after the stimulation was called “Vagusstoff.”  We now call it acetylcholine.  Today Acetylcholine is used in the diagnosis and treatment of Alzheimer’s and Parkinson’s disease.  The lack of acetylcholine in the brain can clue a doctor in to the patient's disorder and treatment can soon follow.  The synthesis of acetylcholine is not too difficult.  Choline and acetyl CoA react to form acetylcholine and CoASH, which is sulfur and acetyl CoA.  It is an addition reaction.  The help of choline acetylase, an enzyme catalyst, aids the reaction.

Schwartz, Kendal.  Principles of Neural Science.  Fourth edition, Part 3:  Ch 12-16.

Cocaine - Eric Shenloogian

Cocaine was discovered thousands of years ago in South America.  The natives chewed the leaves of the plant from which cocaine is extracted.  This plant, the Erythroxylon coca bush, grows primarily in the Andean region of South America.  They chewed the leaves because it was said to relieve headaches and alleviate sickness from the mountains.  Cocaine's primary use today, is obviously as an illegal drug to receive a certain drug "high".  However, researchers are developing different ways to use cocaine in medications for illnesses.  The lab synthesis is very complicated.  It involves about a dozen steps including, deprotonation of cyclic ketones, nucleophillic addition reactions, reduction, esterification, and silylation.

Cha, J.K.  Notes -Enantioselective synthesis of unnatural (S)-(+)-cocaine.  Journal of organic chemistry.  2000.  Vol. 65, (15). 4773-4775.

Digitoxigenin - Amber Beals

Digitalis is a natural product that comes from the purple foxglove plant, or in botany it is known as Digitalis purpurea.  A Scottish doctor by the name of William Withering discovered digitalis for medical purposes in 1775 and released it for use in 1785.  Digitalis was found in a gypsy's potion and Withering isolated it and found that it helped with heart disease.  Today this is still the use of digitalis.  This drug blocks the sodium-potassium pump.  The result of this is the increase in calcium, which increases the heart muscle action.  Digitalis also helps in the treatment of Paroxysmal Supra Ventricular Trachycardia and controls the ventricular rate in atrial fibrillation and flutter.  An important thing to mention is digitalis contains three major compounds and I chose to focus on one: digitoxigenin.  The lab synthesis is done through a nine step process starting with 3b-acetoxy-5b androstan-17-one which goes through a six step process to form methyl 3b-acetoxy-14b-hydroxy-5b-etianate.  Methyl 3b-acetoxy-14b-hydroxy-5b-etianate goes through saponification, refluxing, extractions, drying, evaporation, and crystallization to form a hydroxy-acid. The hydroxy-acid is reacted with many compounds, isolated, and crystallized to form an acetoxy-acid.  The acetoxy-acid goes through a set of reactions to form  3b-14b-dehydroxy-5b-pregnan-20-one-3-acetate.  This compound is refluxed, isolated, re-acetylated, isolated again, and crystallized to form a new compound.  This compound is a dead end.  The 3b-14b-dehydroxy-5b-pregnan-20-one-3-acetate forms another compound that continues the reactions to form digitoxigenin.  Ethioxyacetylenic carbinol goes through a set of reactions that rearranges the carbinol group and forms an ab-unsaturated ester.  This ester goes through another set of reactions to form digitoxigenin.

Ephedrine - Shannon Kirby

An herbal Ephedrine extract was first discovered by Carl Linnaeus in 1753, as an extraction from the plants in the genus Ephedra (1).  These plants have been found in desert regions in central Asia and on sandy seashores in the temperate climates of both hemispheres (2).  Ephedrine is categorized as a sympathomimetic agent, which means it targets the sympathetic nervous system.  This is the division of the autonomic nervous system that stimulates such physiological processes as heartbeat and respiration (3).  It was found that ephedrine is able to help alleviate pains, as well as asthma and bronchial problems.
     More recently, ephedrine has been in the news under the name ephedra. When ephedra (ephedrine) and caffeine are combined together, they increase the heat production that takes place in the body, which causes the body to burn more fat.  Ephedra also constricts the blood vessels while speeding up the heart and nervous system, and it also helps to suppress appetite (4).   Thus, ephedra is used in many over-the-counter dietary supplements, and has been known to cause some severe adverse side effects. Such effects include hypertension (elevated blood pressure), palpitations (rapid heart rate), neuropathy (nerve damage), myopathy (muscle injury), psychosis, stroke, memory loss, heart rate irregularities, insomnia, nervousness tremors, seizures, heart attacks, and death.
     Due to such uses in society, ephedrine is now synthesized in the laboratory.  Such a process begins with a nucleophilic addition of Br- to propionaldehyde.  Its product then continues to an S_N1 substitution reaction with methanol and hydrobromic acid.  This product then reacts with a Grignard reagent and undergoes hydrolysis.  Finally, the new product reacts with methylamine and upon hydrolysis with hydrobromic acid we end up with a racemic mixture of pseudoephedrine.  This racemic base is then resolved by crystallization of the tartrates, which is the pseudoephedrine reacted with tartaric acid.  When the pseudoephedrine is reacted, it is then possible to isomerize both forms with HCl to achieve ephedrine (5).

(1)     http://www.ephedrine-ephedra.com/pages/what_is_ephedrine_1234.html, March 27, 2002.
(2)     Grieve, M. http://www.botanical.com/botanical/mgmh/e/ephedr11.html, April 11, 2002.
(3)    http://www.mhhe.com/biosci/pae/botany/botany_map/articles/article_15.html, April 24, 2002.
(4)    “Mad About Metabolife: Some call it a dieter's dream; others say it's a health hazard. But Americans can't get enough of this herbal weight-loss remedy”.  Newsweek, 1999. v134(14), p52. 
(5)    Manske and Holmes.  “Synthesis of the Ephedra Bases”.  The Alkaloids,1953. vIII, p 351 – 361.

Jojoba Oil - Matt Edwards

Jojoba, also known as Simmondsia chinenis, is a  shrub native to the Sonoran Desert of northwestern Mexico.  It is a woody evergreen shrub that reaches a height of 15 feet. It produces a seed that resembles a coffee bean.  In this seed is the jojoba oil.  Jojoba oil is chemically different from other oils because it is composed of esters (linkages of a straight chain alcohol and a fatty acid) rather than the typical triglycerides.  Oil is not even the best term for jojoba because it is actually a polyunsaturated liquid wax.  Both the alcohol and acid portions of jojoba oil have 20 or 22 carbon atoms, each of  which have one unsaturated bond.  The jojoba oil is synthesized in the plastids of the jojoba plant, and are produced in developing embryos during seed formation. The natural preparation of jojoba oil is done by pressing the jojoba seeds to extract the oil followed by filtration to assure for purity.  Jojoba is liquid at room temperature, odorless, and resistant to oxidation.  Like any ester, jojoba can be synthesized from an alcohol and an acid,  this process is commonly called esterfication.  There are many general uses for jojoba oil and  is currently used in many different industries. It can be used as a cosmetic, a cleanser, conditioner, moisturizer, a softener for the skin and hair, more recently a pesticide and has the potential to be used as an industrial lubricant.

Linoleic Acid - Natasha Safaee

(Conjugated) Linoleic Acid or octadecadienoic acid was first discovered in 1978 by Dr. Michael W. Pariza at the University of Wisconsin. Dr. Pariza was studying a piece of grilled beef that contained anti-mutagen properties when he stumbled across the compound. He did not identify the compound until 1987. Today, CLA (the mixture of conjugated geometric isomers of octadecadienoic acid) is used as a supplement in the form of a pill. The major isomer that contains the health benefits is 9(z),11(e)-octadecadienoic acid. CLA supplements are thought to help build body muscle, reduce body fat, and provide a better cellular environment. Linoleic acid is synthesized from a methyl ester by way of a Nucleophilic addition-elimination reaction.

“Linoleic Acid.” Gale Encyclopedia of Alternative Medicine. 2001.

Melatonin - Stephanie Vadasz

Melatonin has become a popular yet controversial drug in recent years.   It is a hormone that is produced in the pineal gland that regulate circadian rhythms.  It is used as a drug to alleviate the symptoms of jet lag and certain seasonal disorders, but recently many news articles and uncritical books have been written claiming it can do everything from improve sex drive and mental performance to treat cancer and extend lifespan.(1)  Many of these claims are based on flawed research, making melatonin a controversial drug.(2) 
Melatonin's systematic name is N-acetyl-5-methoxytrypamine.  Its molecular weight is 232.27 grams per mole. Melatonin was isolated from bovine pineal glands by Aaron B. Lerner in 1958.(3)  It was synthesized by reducing 5-methoxyindole-3-acetonitrile to an amine, and then acetylating the amine to form N-acetyl-5-methoxytryptamine via nucleophilic acyl substitution.(4) 

1.  Dean, W.; Morgenthaler, J.; Fowkes, S. W. ‘Cognitive Enhancement Research Institute’ http://www.ceri.com/melaton.htm, 4/16/02.
2.  Beardsley, T. ‘Melatonin Mania’ http://www.sciam.com/explorations/040196explorations.html, 4/16/02
3.  Merck Index; Budavari, S., Ed.; Merck and Co., Inc.; Rahway, N.J., 1989, Eleventh edition, p. 5695.
4.  Lerner, A.B.; Case, J.D.; Heinzelman, R.V. “Structure of Melatonin” Journal of the American Chemical Society 1959, Vol. 81, 6084.

Quinine - Jenna Kempista

Quinine is an alkaloid that is derived from the bark of the Cinchona tree and is famous for its anti-malarial properties.  It is also used as an herbal remedy for a wide variety of ailments, from anemia to the flu.  Powder made from the bark of the tree was popularized as anti-malarial remedy by the Jesuits beginning in the late 1600s.  Quinine was first isolated from the bark and recognized as its major anti-malarial component by Pierre Joseph Pelletier and Jean Bienaimé Caventou in 1820.  Woodward and Doering performed the first formal laboratory synthesis of quinine in 1944.  Recently, a stereospecific mechanism for the synthesis of quinine was discovered.  This synthesis is complicated because the quinine molecule has four stereocenters.  The starting material, 4-vinylbutyrolactone, goes through several reactions, including nucleophilic acyl substitution, substitution, a Wittig reaction, and reduction, before it is added to 6-methoxy-4-methylquinoline.  The resulting structure goes through several more reaction steps, such as oxidation, a Staudinger reaction, reduction, and nucleophilic substitution, before the final product, quinine, is formed.

1.   Taylor, Leslie ‘Quinine Bark’ http://www.rain-tree.com/quinine.htm, April 15, 2002.
2.   Balkovec, James M., Gregory R. Dake, A. Fujimoto, Emil R.Koft, Dequiang Niu, Gilbert Stork, and James R. Tata “The First Stereoselective Total Synthesis of Quinine” Journal of the American Chemical Society 2001.

Taxol - Melissa D'Avignon

Taxol was first discovered in 1967 by a research team headed by Dr. Monroe E. Wall and Dr. Mansukh C. Wani from the Research Triangle Institute. Taxol was first isolated from the Pacific Yew tree, Taxus brevifolia. Through tests on a broad range of tumors in rodents, the research team observed its antitumor activity. The discovery developed into a whole new class of chemotherapeutic agents used to treat advanced ovarian and breast cancer. It was found that the Pacific Yew tree did not contain enough Taxol to treat even one patient. This is where synthetic chemists stepped in and tried to develop a synthetic pathway in which Taxol could be synthesized in the laboratory. Today there are four possible synthetic pathways in which Taxol can be synthesized in the laboratory; they are the Holton route, the Nicolaou route, the Danishefsky route, and the Wenfer’s route. Although these routes are very complicated and sophisticated, they are prime examples of what synthetic chemists can accomplish.

Edwards, Neil www.bris.ac.uk.htm, 03/28/2002 

Tetrodotoxin - Catie Thorson

Tetrodotoxin is a neurotoxin that is found in liver, gonads, intestines, and skin of pufferfish.  The pufferfish is considered one of the most highly regarded delicacies of the world.  People risk poisoning themselves every time they eat the fish.  It was found that tetrodotoxin is ten thousand times more lethal than cyanide, and one in every sixty people that eat the fish will die of the poisoning.¹    It was discovered in 1930 by an experimental biologist at Stanford University.²   He accidentally discovered the toxin when working with lab animals.  The neurotoxin has only been synthesized in one lab by a group of Japanese scientists in 1964.  The synthesis of this compound is very lengthy.  It is over fifteen steps.  Although, most steps are done in order to add protecting groups to different potentially susceptible functional groups within the compound.  The protecting groups are then removed when that portion of the reaction is over.  There are no real uses for the compound in today's world.  It is mostly studied in order to understand the poisoning, and to try and develop a cure to the poisoning. There is some discussion into investigating the uses of the neurotoxin as anesthesia, but as of now that is all talk.

1.  'U.S. Food & Drug Administration' http://vm.cfsan.fda.gov/~mow/chap39.html, April 10, 2002.
2.  Mosher, H.S.; Fuhrman, F.A.; Buchwald, H.D.; Fischer, H.G. "Tarichatoxin - Tetrodotoxin: A Potent Neurotoxin" Science 1964. 144, pp 1100-1110.

Toluene - Jason Story

Toluene is a hydrocarbon found in petroleum and coal tar.  Toluene was discovered when petroleum distillation began.  Petroleum distillation yields very pure toluene.  Toluene is used as an organic solvent in laboratories and industry.  In addition, it is used as a starting material in the synthesis of other compounds.  An example of the usefulness of toluene is its use in synthesizing the many explosives that have been developed.  Explosives are important to a variety of industries.  The most obvious member of this group would be those organizations that produce military ordinance.  Another industry that is vital to the health of the nation is the mining industry, which uses explosives to blast through rock to find their mineral of choice.  An obvious example of a toluene-based explosive is trinitrotoluene, which is commonly known as TNT.  This explosive was and still is extremely important because it is extremely stable when it stands by itself.  In fact, the explosive is so stable that it requires a detonator in order that the substance may explode.  After examining the structure of TNT, it becomes clearer why this compound makes such a good explosive.  The toluene portion of the structure has three nitrate groups attached to it.  This mechanism makes use of sulfuric acid as well as nitric acid to form the nitronium ion, which then bonds with the aromatic ring.  With added nitrate groups comes added explosive force.  Another explosive that is produced from toluene is dinitrotoluene (DNT), which has a similar structure to TNT.  The only difference is that DNT has one less nitrate group, resulting in a lower yield explosion.

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