Total Synthesis
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Total Synthesis

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, however, 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]

Scope and definitions

The term total synthesis is less frequently but still accurately applied to the synthesis of natural polypeptides and polynucleotides. For instance, the peptide hormones oxytocin and vasopressin were isolated and their total syntheses were first reported in 1954.[6]


Although untrue from a historical perspective (see the history of the steroid, cortisone), total synthesis in the modern age has largely been an academic endeavour (in terms of manpower applied to problems). However, industrial concerns may pick up particular avenues of total synthesis efforts and expend considerable resources on particular natural product targets, especially if semi-synthesis can be applied to complex, natural product-derived drugs. Even so, there is a continuing discussion regarding the value of total synthesis as an academic enterprise, some aspects of which are summarised here.

Total synthesis projects often require a variety of reactions and so efforts to achieve complex total syntheses serve to prepare chemists for pursuits particularly in pharmaceutical discovery chemistry as well as in process chemistry. In both cases, comprehensive knowledge of chemical reactions and a strong and accurate chemical intuition are important qualifications.[]


Vitamin B12 total synthesis: Retrosynthetic analysis. Analysis of the Woodward-Eschenmoser total synthesis that was reported in two variants by these groups in 1972. The work involved more than 100 PhD trainees and postdoctoral fellows from 19 different nations. The retrosynthesis presents the disassembly of the target vitamin in a manner that makes chemical sense for its eventual forward construction. The target, Vitamin B12 (I), is envisioned being prepared by the simple addition of its tail, which had earlier been shown to be feasible. The needed precursor, cobyric acid (II), then becomes the target and constitutes the "corrin core" of the vitamin, and its preparation was envisaged to be possible via two pieces, a "western" part copses of the A and D rings (III) and an "eastern" part composed of the B and C rings (IV). The restrosynthetic analysis then envisions the starting materials required to make these two complex parts, the yet complex molecules V-VIII.

Friedrich Wöhler discovered that an organic substance, urea, could be produced from inorganic starting materials in 1828. That was an important conceptual milestone in chemistry by being the first example of a synthesis of a substance that had been known only as a byproduct of living processes.[2] Wöhler obtained urea by treating silver cyanate with ammonium chloride, a simple, one-step synthesis:

AgNCO + NH4Cl -> (NH2)2CO + AgCl

Camphor was a scarce and expensive natural product with a worldwide demand.[when?][according to whom?] Haller and Blanc synthesized it from camphor acid;[when?][2] however, the precursor, camphoric acid, had an unknown structure. When Finnish chemist Gustav Komppa synthesized camphoric acid from diethyl oxalate and 3,3-dimethylpentanoic acid in 1904, the structure of the precursors allowed contemporary chemists to infer the complicated ring structure of camphor. Shortly thereafter,[when?]William Perkin published another synthesis of camphor.[relevant? ] The work on the total chemical synthesis of camphor allowed Komppa to begin industrial production of the compound, in Tainionkoski, Finland, in 1907.

The American chemist Robert Burns Woodward was a pre-eminent figure in developing total syntheses of complex organic molecules, some of his targets being cholesterol, cortisone, strychnine, lysergic acid, reserpine, chlorophyll, colchicine, vitamin B12, and prostaglandin F-2a.[2]

Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry for the total synthesis of the natural polypeptide oxytocin and vasopressin, which reported in 1954 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 for the development of retrosynthetic analysis.


One classic in total synthesis is quinine total synthesis, which, before its total synthesis by Robert Burns Woodward and William von Eggers Doering in 1944,[8] had a history of many partial syntheses that spanned 150 years and included disputes and frustration.[2]


  1. ^ "Archived copy". Archived from the original on 2014-12-20. Retrieved .CS1 maint: archived copy as title (link)
  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 2016.
  8. ^ Remembering Organic Chemistry Legend Robert Burns Woodward, "C&EN", 4/10/2017

External links

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