Total synthesis

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A total radiosynthesis module

Total synthesis is the complete chemical synthesis of an organic molecule from simpler pieces called precursors. It usually refers to a process not involving the aid of biological processes,[1][2][3] which distinguishes it from semisynthesis. Since there are usually many steps in total synthesis, the chemist must develop a plan, called a route, or adopt one already known. There may be several different or partially different routes to the target including the choice of the substrates. To be commercially viable, syntheses must use readily obtainable, bulk quantities. Commercial synthesis often relies on petrochemical precursors. Sometimes, however, the chemist proceeds on a small scale. The target molecules can be natural products, medicinally important active ingredients, or organic compounds of theoretical interest. Often the aim is to discover new route of synthesis for a target molecule for which there already exist known routes. Sometimes no route exists and the chemist wishes find a viable route for the first time.


The discovery by Friedrich Wöhler in 1828 that an organic substance, urea, can be produced from inorganic starting materials was an important conceptual milestone in chemistry as it showed for the first time that a substance previously known only as a byproduct of life could be synthesized in the laboratory.

He obtained urea artificially by treating silver cyanate with ammonium chloride. This was a rather simple synthesis.

AgNCO + NH4Cl → (NH2)2CO + AgCl

Haller and Blanc synthesized camphor from camphoric acid. Camphoric acid, however, had an unknown structure. In 1904, Finnish chemist Gustav Komppa became the first to succeed in manufacturing synthetic camphoric acid from diethyl oxalate and 3,3-dimethylpentanoic acid. The use of these precursors provided a demonstration for the structure of camphor, which is a complicated ring. William Perkin published another synthesis a short time later. At the time camphor was a scarce and expensive natural product with a worldwide demand. Komppa realized this and began industrial production of camphor in Tainionkoski, Finland, in 1907.

The difficulties posed by the total synthesis of a complex compound often lead to the development of new chemical reactions and routes that entail 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.


The classic in synthesis is quinine total synthesis. It has a history of many partial syntheses spanning 150 years filled with disputes and frustration. The recently developed, commercially successful Stork Synthesis described at quinine total synthesis, requires 15 complicated steps and results in an impure product.

The American chemist Robert Burns Woodward was a pre-eminent figure in developing total syntheses of complex organic molecules including cholesterol, cortisone, strychnine, lysergic acid, reserpine, chlorophyll, colchicine, vitamin B12 and prostaglandin F-2a. His earlier landmark achievement was the synthesis of quinine but by a process too complicated to be useful. Another gifted chemist is Elias James Corey who won the Nobel Prize in Chemistry in 1990 for lifetime achievement in total synthesis and the development of retrosynthetic analysis.


  1. ^ K. C. Nicolaou, D. Vourloumis, N. Winssinger and P. S. Baran (2000). "The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century" (reprint). Angewandte Chemie International Edition 39 (1): 44–122. doi:10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L. PMID 10649349. 
  2. ^ Nicolaou, K. C. & Sorensen, E. J. 1996, Classics in Total Synthesis: Targets, Strategies, Methods, New York:John Wiley & Sons, ISBN 978-3-527-29231-8
  3. ^ Nicolaou, K. C. & Snyder, S. A., 2003, Classics in Total Synthesis II: More Targets, Strategies, Methods, New York:John Wiley & Sons, ISBN 978-3-527-30684-8

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