Total synthesis

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Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially available precursors. [1] [2] [3] [4] It usually refers to a process not involving the aid of biological processes, which distinguishes it from semisynthesis. 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 to find a viable route for the first time. One important purpose of total synthesis is the discovery of new chemical reactions and new chemical reagents. [5]


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. [2]

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. [2] 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.[citation needed]


A classic in total synthesis is quinine total synthesis.[2] It has a history of many partial syntheses spanning 150 years filled with disputes and frustration. 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. [2]

Oxytocin and vasopressin were isolated and their total synthesis reported in 1954,[6] work for which Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry with the citation: "for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone."[7]

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. ^ Subject Areas
  2. ^ a b c d e 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. 
  3. ^ 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
  4. ^ 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
  5. ^ Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin Era Ahlam M. Armaly , Yvonne C. DePorre , Emilia J. Groso , Paul S. Riehl , and Corinna S. Schindler Chem. Rev., Article ASAP doi:10.1021/acs.chemrev.5b00034
  6. ^ du Vigneaud V, Ressler C, Swan JM, Roberts CW, Katsoyannis PG (1954). "The Synthesis of Oxytocin". Journal of the American Chemical Society. 76 (12): 3115–3121. doi:10.1021/ja01641a004. 
  7. ^ "The Nobel Prize in Chemistry 1955". Nobel Media AB. Retrieved 17 November 2016. 

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