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. Syntheses may sometimes conclude at a precursor with further known synthetic pathways to a target molecule, in which case it is known as a formal synthesis. Total synthesis target molecules can be natural products, medicinally-important active ingredients, known intermediates, or molecules of theoretical interest. Total synthesis targets can also be organometallic or inorganic,[5][6] though these are rarely encountered. Total synthesis projects often requires a wide diversity of reactions and reagents, and subsequently requires broad chemical knowledge and training to be successful.

Often, the aim is to discover a new route of synthesis for a target molecule for which there already exist known routes. Sometimes, however, no route exists and chemists wish to find a viable route for the first time. Total synthesis is particularly important for the discovery of new chemical reactions and new chemical reagents, as well as establishing synthetic routes for medicinally important compounds.[7]

Scope and definitions[edit]

There are numerous classes of natural products for which total synthesis is applied to. These include (but are not limited to): terpenes, alkaloids, polyketides and polyethers.[8] Total synthesis targets are sometimes referred to by their organismal origin such as plant, marine, and fungal. The term total synthesis is less frequently but still accurately applied to the synthesis of natural polypeptides and polynucleotides. The peptide hormones oxytocin and vasopressin were isolated and their total syntheses first reported in 1954.[9] It is not uncommon for natural product targets to feature multiple structural components of several natural product classes.


Although untrue from a historical perspective (see the history of the steroid, cortisone), total synthesis in the modern age has largely been an academic endeavor (in terms of manpower applied to problems). Industrial chemical needs often differ from academic focuses. Typically, commercial entities 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, for decades[10] there has been a continuing discussion regarding the value of total synthesis as an academic enterprise.[11][12][13] While there are some outliers, the general opinions are that total synthesis has changed in recent decades, will continue to change, and will remain an integral part of chemical research.[14][15][16] Within these changes, there has been increasing focus on improving the practicality and marketability of total synthesis methods. The Phil S. Baran group at Scripps, a notable pioneer of practical synthesis have endeavored to create scaleable and high efficiency syntheses that would have more immediate uses outside of academia.[17][18]


Vitamin B12 total synthesis: Retrosynthetic 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 countries. 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 composed 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 VVIII.

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?] Haller and Blanc synthesized it from camphor acid;[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."[19]

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,[20] 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 2015-08-22.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. ^ Schaak, Raymond (22 April 2013). "Emerging Strategies for the Total Synthesis of Inorganic Nanostructures". Angewandte Chemie International Edition. 52 (24): 6154–6178. doi:10.1002/anie.201207240. Retrieved 15 July 2021.
  6. ^ Woodward, R. B. (1963). "Versuche zur Synthese des Vitamins B12". Angewandte Chemie. 75 (18): 871–872. doi:10.1002/ange.19630751827.
  7. ^ 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
  8. ^ Springob, Karin (1 June 2009). Plant-derived Natural Products. Springer. pp. 3–50. ISBN 978-0-387-85498-4. Retrieved 24 June 2021.
  9. ^ 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.
  10. ^ Heathcock, Clayton (1996). Chemical Synthesis Gnosis to Prognosis. Springer. pp. 223–243. ISBN 978-94-009-0255-8. Retrieved 24 June 2021.
  11. ^ Nicolaou, K. C. (1 April 2019). "Total Synthesis Endeavors and Their Contributions to Science and Society: A Personal Account". Chinese Chemical Society. 1 (1): 3–37. doi:10.31635/ccschem.019.20190006. Retrieved 24 June 2021.
  12. ^ Nicolaou, K.C. (22 April 2020). "Perspectives from nearly five decades of total synthesis of natural products and their analogues for biology and medicine". Natural Product Reports. 37: 1404–1435. doi:10.1039/D0NP00003E. Retrieved 24 June 2021.
  13. ^ Qualmann, Kate. "Excellence in Industrial Organic Synthesis: Celebrating the Past, Looking to the Future". ACS Axial. ACS Axial. Retrieved 24 June 2021.
  14. ^ Baran, Phil (11 April 2018). "Natural Product Total Synthesis: As Exciting as Ever and Here To Stay". Journal of the American Chemical Society. 140 (18): 4751–4755. doi:10.1021/jacs.8b02266. Retrieved 24 June 2021.
  15. ^ Hudlicky, Tomas (31 December 2018). "Benefits of Unconventional Methods in the Total Synthesis of Natural Products". ACS Omega. 3 (12): 17326–17340. doi:10.1021/acsomega.8b02994. PMC 6312638. Retrieved 24 June 2021.
  16. ^ Derek, Lowe. "How Healthy is Total Synthesis". In The Pipeline (AAAS). The American Association for the Advancement of Science. Retrieved 24 June 2021.
  17. ^ "Phil Baran Research". Phil Baran Research Lab. Scripps Institute. Retrieved 24 June 2021.
  18. ^ Hayashi, Yujiro (21 October 2020). "Time Economy in Total Synthesis". Journal of Organic Chemistry. 86: 1–23. doi:10.1021/acs.joc.0c01581. Retrieved 24 June 2021.
  19. ^ "The Nobel Prize in Chemistry 1955". Nobel Media AB. Retrieved 17 November 2016.
  20. ^ Remembering Organic Chemistry Legend Robert Burns Woodward, "C&EN", 4/10/2017

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