Total synthesis

Total synthesis

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In organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

, a total synthesis is, in principle, the complete chemical synthesis
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...

 of complex organic
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...

A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...

s from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often petrochemical
Petrochemicals are chemical products derived from petroleum. Some chemical compounds made from petroleum are also obtained from other fossil fuels, such as coal or natural gas, or renewable sources such as corn or sugar cane....

 precursors. Sometimes bulk natural products (e.g. sugars) are used as starting materials and it is assumed that these have or can be synthesised from their constituent elements. The target molecules can be natural products (biomolecules), medicinally important active ingredients, or organic compounds of theoretical interest in chemistry or biology. A new route for synthesis is developed in the course of the investigation, and the route may be the first one to be developed for the substance.


The first demonstration of organic total synthesis was Friedrich Wöhler
Friedrich Wöhler
Friedrich Wöhler was a German chemist, best known for his synthesis of urea, but also the first to isolate several chemical elements.-Biography:He was born in Eschersheim, which belonged to aau...

's synthesis of urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....

 in 1828, which demonstrated that organic molecules can be produced from inorganic precursors, and the first commercialized total synthesis was Gustaf Komppa
Gustaf Komppa
Gustaf Komppa was a Finnish chemist best known for a world-first in commercializing total synthesis, that of camphor in 1903....

's synthesis and industrial production of camphor
Camphor is a waxy, white or transparent solid with a strong, aromatic odor. It is a terpenoid with the chemical formula C10H16O. It is found in wood of the camphor laurel , a large evergreen tree found in Asia and also of Dryobalanops aromatica, a giant of the Bornean forests...

 in 1903. Early efforts focused on building chemicals which were extracted from biological sources, and using them to verify their biological activities—in this fashion, total synthesis was associated with disproving the existence of a vital force. As biology and chemistry became more sophisticated, the primary purpose for total synthesis changed, although some total synthesis continues to be a tool for biological verification, for example if a compound contains ambiguous stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....

 or to create analogs ("chemical mutations") to directly assess or improve the mechanism of biological activity.

Today, total synthesis is often justified as a playground for the development of new chemical reactions and routes, and highlights the sophistication of modern synthetic organic chemistry. Sometimes total synthesis inspires the development of novel mechanisms, catalysts, or techniques. Finally since a total synthesis project will often span a variety of reactions, it serves to prepare chemists for pursuits in process chemistry, where encyclopedic knowledge of chemical reactions and a strong and accurate sense of chemical intuition are necessary.

Formal synthesis

A formal synthesis describes not the synthesis of the desired end product but the synthesis of a compound that is already known from the literature to be a precursor to that desired end product. If it is known from the literature that B can be converted to C then a novel route from compound A to compound B is a formal proof that A can also give access to C.


Classical examples are the total syntheses of cholesterol
Cholesterol total synthesis
Cholesterol total synthesis in chemistry describes the total synthesis of the complex biomolecule cholesterol and is considered a great scientific achievement. . The research group of Robert Robinson with John Cornforth published their synthesis in 1951 and that of of Robert Burns Woodward with...

, cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...

, strychnine
Strychnine total synthesis
Strychnine total synthesis in chemistry describes the total synthesis of the complex biomolecule strychnine. The first reported method by the group of Robert Burns Woodward in 1954 is considered a classic in this research field....

, lysergic acid
Lysergic acid
Lysergic acid, also known as D-lysergic acid and -lysergic acid, is a precursor for a wide range of ergoline alkaloids that are produced by the ergot fungus and some plants. Amides of lysergic acid, lysergamides, are widely used as pharmaceuticals and as psychedelic drugs...

, reserpine
Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely...

, chlorophyll
Chlorophyll is a green pigment found in almost all plants, algae, and cyanobacteria. Its name is derived from the Greek words χλωρος, chloros and φύλλον, phyllon . Chlorophyll is an extremely important biomolecule, critical in photosynthesis, which allows plants to obtain energy from light...

, colchicine
Colchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...

, vitamin B12
Vitamin B12 total synthesis
Vitamin B12 total synthesis in chemistry describes the total synthesis of the complex biomolecule vitamin B12. A method first reported by the groups of Robert Burns Woodward and Albert Eschenmoser in 1973 is considered a classic in this research field....

 and prostaglandin F-2a
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

 by the Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...

 winner Robert Burns Woodward
Robert Burns Woodward
Robert Burns Woodward was an American organic chemist, considered by many to be the preeminent organic chemist of the twentieth century...

 between 1945 and 1976. Another classic is quinine total synthesis
Quinine total synthesis
In total synthesis, the Quinine total synthesis describes the efforts in synthesis of quinine over a 150 year period. The development of synthetic quinine is considered a milestone in organic chemistry although it has never been produced industrially as a substitute for natural occurring quinine...

 that has a history spanning 150 years. In some cases the structures of the molecules assigned by spectroscopic methods have been shown to be wrong, when synthesised.

Elias James Corey
Elias James Corey
Elias James Corey is an American organic chemist. In 1990 he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis...

 won the Nobel Prize in Chemistry
Nobel Prize in Chemistry
The Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...

 in 1990 for lifetime achievement in total synthesis and the development of retrosynthetic analysis
Retrosynthetic analysis
Retrosynthetic analysis is a technique for solving problems in the planning of organic syntheses. This is achieved by transforming a target molecule into simpler precursor structures without assumptions regarding starting materials. Each precursor material is examined using the same method. This...

. In 2005 the group of Corey published an aflatoxin total synthesis
Aflatoxin total synthesis
Aflatoxin total synthesis concerns the total synthesis of a group of organic compounds called aflatoxins. These compounds occur naturally in several fungi. As with other chemical compound targets in organic chemistry, the organic synthesis of aflatoxins serve different purposes...

 and in 2006 an oseltamivir total synthesis
Oseltamivir total synthesis
Oseltamivir total synthesis concerns the total synthesis of the antiinfluenza drug oseltamivir marketed by Hoffmann-La Roche under the trade name Tamiflu. Its commercial production starts from the biomolecule shikimic acid harvested from Chinese star anise with a limited worldwide supply...


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