Total synthesis

There are numerous classes of natural products for which total synthesis is applied to. These include (but are not limited to): terpenes, alkaloids,{{cite journal | last1 = Eichberg | first1 = Michael J. | last2 = Dorta | first2 = Rosa L. | last3 = Grotjahn | first3 = Douglas B. | last4 = Lamottke | first4 = Kai | last5 = Schmidt | first5 = Martin | last6 = Vollhardt | first6 = K. Peter C. | year = 2001 | title = Approaches to the Synthesis of (±)-Strychnine via the Cobalt-Mediated [2 + 2 + 2] Cycloaddition: Rapid Assembly of a Classic Framework | journal = J. Am. Chem. Soc. | volume = 123 | issue = 38| pages = 9324–9337 | doi = 10.1021/ja016333t | pmid = 11562215 | bibcode = 2001JAChS.123.9324E }} polyketides.{{citation|author=Michael Müller, Kai Lamottke, Erich Löw, Eva Magor-Veenstra, Wolfgang Steglich |date=2001 |issue=15 |pages=2483-2489. https://doi.org/10.1039/B003053H |periodical=Journal of the Chemical Society, Perkin Transactions 1 |title=Stereoselective total syntheses of atrochrysone, torosachrysone and related 3, 4-dihydroanthracen-1 (2 H)-ones|doi=10.1039/B003053H }}{{citation|author=Guido François, Tania Steenackers, Laurent Aké Assi, Wolfgang Steglich, Kai Lamottke, Jörg Holenz, Gerhard Bringmann |date=1999 |issue=7 |pages=582–588 https://doi.org/10.1007/s004360050598 |periodical=Parasitology Research |pmid=10382608 |title=Vismione H and structurally related anthranoid compounds of natural and synthetic origin as promising drugs against the human malaria parasite Plasmodium falciparum: structure-activity relationships |volume=85|doi=10.1007/s004360050598 }} and polyethers.{{cite book | vauthors = Springob K |title=Plant-derived Natural Products |date=1 June 2009 |publisher=Springer |isbn=978-0-387-85498-4 |pages=3–50 |doi=10.1007/978-0-387-85498-4_1 |url=https://link.springer.com/chapter/10.1007/978-0-387-85498-4_1 |access-date=24 June 2021}} 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.{{cite journal|title = The Synthesis of Oxytocin| vauthors = du Vigneaud V, Ressler C, Swan JM, Roberts CW, Katsoyannis PG |journal = Journal of the American Chemical Society|volume = 76|issue = 12|pages = 3115–3121|year = 1954|doi = 10.1021/ja01641a004| bibcode = 1954JAChS..76.3115D }} It is not uncommon for natural product targets to feature multiple structural components of several natural product classes.

Although untrue from an 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{{cite book | vauthors = Heathcock C |title=Chemical Synthesis Gnosis to Prognosis |chapter=As We Head into the 21st Century, is there Still Value in Total Synthesis of Natural Products as a Research Endeavor? |date=1996 |publisher=Springer |isbn=978-94-009-0255-8 |pages=223–243 |doi=10.1007/978-94-009-0255-8_9 |chapter-url=https://link.springer.com/chapter/10.1007/978-94-009-0255-8_9 |access-date=24 June 2021}} there has been a continuing discussion regarding the value of total synthesis as an academic enterprise.{{cite journal | vauthors = Nicolaou KC |title=Total Synthesis Endeavors and Their Contributions to Science and Society: A Personal Account |journal= CCS Chemistry |date=1 April 2019 |volume=1 |issue=1 |pages=3–37 |doi=10.31635/ccschem.019.20190006 |doi-access=free}}{{cite journal | vauthors = Nicolaou KC, Rigol S | title = Perspectives from nearly five decades of total synthesis of natural products and their analogues for biology and medicine | journal = Natural Product Reports | volume = 37 | issue = 11 | pages = 1404–1435 | date = November 2020 | pmid = 32319494 | pmc = 7578074 | doi = 10.1039/D0NP00003E }}{{cite web | vauthors = Qualmann K |title=Excellence in Industrial Organic Synthesis: Celebrating the Past, Looking to the Future |url=https://axial.acs.org/2019/08/15/excellence-in-industrial-organic-synthesis-celebrating-the-past-looking-to-the-future/ |website=ACS Axial |date=15 August 2019 |access-date=24 June 2021}} 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.{{cite journal | vauthors = Baran PS | title = Natural Product Total Synthesis: As Exciting as Ever and Here To Stay | journal = Journal of the American Chemical Society | volume = 140 | issue = 14 | pages = 4751–4755 | date = April 2018 | pmid = 29635919 | doi = 10.1021/jacs.8b02266 | doi-access = free | bibcode = 2018JAChS.140.4751B }}{{cite journal | vauthors = Hudlicky T | title = Benefits of Unconventional Methods in the Total Synthesis of Natural Products | journal = ACS Omega | volume = 3 | issue = 12 | pages = 17326–17340 | date = December 2018 | pmid = 30613812 | pmc = 6312638 | doi = 10.1021/acsomega.8b02994 }}{{cite web | vauthors = Derek L |title=How Healthy is Total Synthesis |url=https://www.science.org/content/blog-post/healthy-field-total-synthesis |website=In The Pipeline (AAAS) |publisher=The American Association for the Advancement of Science |access-date=24 June 2021}} 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 scalable and high efficiency syntheses that would have more immediate uses outside of academia.{{cite web |title=Phil Baran Research |url=https://baranlab.org/research/ |website=Phil Baran Research Lab |publisher=Scripps Institute |access-date=24 June 2021}}{{cite journal | vauthors = Hayashi Y | title = Time Economy in Total Synthesis | journal = The Journal of Organic Chemistry | volume = 86 | issue = 1 | pages = 1–23 | date = January 2021 | pmid = 33085885 | doi = 10.1021/acs.joc.0c01581 | s2cid = 224825988 }}

{{expert needed|chemistry|section|reason=The provided examples are poor, narrow in scope, and incomplete. This section would greatly benefit from a rewrite and expansion by experts in the field|date=June 2021}}

File:VitaminB12 retrosynthesis.svg: 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 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. 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|date=March 2017}} Haller and Blanc synthesized it from camphor acid; 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|date=March 2017}} William Perkin published another synthesis of camphor.{{relevance inline|date=March 2017}} 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.

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."{{cite web|title = The Nobel Prize in Chemistry 1955|website = Nobelprize.org|url = http://nobelprize.org/nobel_prizes/chemistry/laureates/1955/index.html|access-date = 17 November 2016|publisher = Nobel Media AB}}

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.

• Quinine total synthesis{{cite journal | vauthors = Halford B | date = 10 April 2017 | volume = 95 | issue = 15 | url = https://cen.acs.org/articles/95/i15/Remembering-organic-chemistry-legend-Robert-Burns-Woodward.html | title = Remembering Organic Chemistry Legend Robert Burns Woodward | journal = C&EN }} First synthesized by Robert Burns Woodward and William von Eggers Doering in 1944, this achievement was significant due to quinine's importance as an antimalarial drug.
• Strychnine total synthesis First synthesized by Robert Burns Woodward in 1954, this synthesis was a landmark achievement due to the molecule's structural complexity.
• Morphine: First synthesized by Marshall D. Gates in 1952, with subsequent more efficient syntheses developed by other chemists, including Toshiaki Fukuyama in 2017.
• Cholesterol total synthesis{{cite journal | vauthors = Mulheirn G | title = Robinson, Woodward and the synthesis of cholesterol. | journal = Endeavour | date = September 2000 | volume = 24 | issue = 3 | pages = 107–110 | doi = 10.1016/S0160-9327(00)01310-7 }} Synthesized by Robert Burns Woodward in 1951, this was a significant achievement in steroid synthesis.
• Cortisone: Another notable steroid synthesis by Robert Burns Woodward in 1951.
• Lysergic acid: Synthesized by Robert Burns Woodward in 1954, this was an important precursor to LSD.
• Reserpine: Completed by Robert Burns Woodward in 1956, this synthesis was notable for its complexity and the molecule's importance as an antihypertensive drug.
• Chlorophyll: Synthesized by Robert Burns Woodward in 1960, this achievement was significant due to chlorophyll's crucial role in photosynthesis.
• Colchicine: Another notable synthesis by Robert Burns Woodward, completed in 1963.
• Prostaglandin F-2a: Synthesized by E.J. Corey in 1969, this was an important achievement in the synthesis of prostaglandins.
• Vitamin B₁₂ total synthesis{{cite book | vauthors = Rao RB |date=2016 |title=Logic of Organic Synthesis |publisher=LibreTexts |url= https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Logic_of_Organic_Synthesis_(Rao)/13%3A_Synthesis_of_Vitamin_B }} Completed by Robert Burns Woodward and his team in 1972, this synthesis is considered one of the most complex ever achieved, involving over 100 steps.
• Paclitaxel (Taxol) total synthesis: First synthesized by Robert A. Holton in 1994, and later by K. C. Nicolaou in 1995, this anticancer drug's synthesis was a major breakthrough in medicinal chemistry.
• Brefeldin A: Synthesized by S. Raghavan in 2017, this complex macrolide has potential as an anticancer agent.
• Ryanodine: Synthesized by Sarah E. Reisman in 2017, this complex diterpenoid has important biological activity.

{{reflist|refs=

{{cite journal | vauthors = Nicolaou KC, Vourloumis D, Winssinger N, Baran PS | title = The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century | journal = Angewandte Chemie | volume = 39 | issue = 1 | pages = 44–122 | date = January 2000 | pmid = 10649349 | doi = 10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L | author-link = K. C. Nicolaou }}

{{cite book | vauthors = Nicolaou KC, Sorensen EJ |title=Classics in total synthesis. 1: Targets, strategies, methods v|date=2008 |publisher=VCH |location=Weinheim |isbn=978-3-527-29231-8 |edition=5th}}

{{cite book | vauthors = Nicolaou KC, Sorensen EJ |title=Classics in total synthesis. 2: More Targets, strategies, methods |date=2003 |publisher=VCH |location=Weinheim |isbn=978-3-527-30684-8}}

{{cite journal | vauthors = Armaly AM, DePorre YC, Groso EJ, Riehl PS, Schindler CS | title = Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin Era | journal = Chemical Reviews | volume = 115 | issue = 17 | pages = 9232–76 | date = September 2015 | pmid = 26176418 | doi = 10.1021/acs.chemrev.5b00034 }}

{{cite web |url=http://www.nature.com/subjects/total-synthesis |title= Definition: Total synthesis | publisher = Nature Publishing Group |access-date=2015-08-22 |url-status=dead |archive-url=https://web.archive.org/web/20141220143334/http://www.nature.com/subjects/total-synthesis |archive-date=2014-12-20 }}

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• [http://www.synarchive.com The Organic Synthesis Archive]
• [https://www.organic-chemistry.org/Highlights/totalsynthesis.shtm Total Synthesis Highlights]
• [http://www.totallysynthetic.com/ Total Synthesis News]
• [http://www.chem.wisc.edu/areas/reich/syntheses/syntheses.htm Total syntheses schemes with reaction and reagent indices]
• [http://www.biocis.u-psud.fr/spip.php?article332 Group Meeting Problems in Organic Chemistry] {{Webarchive|url=https://web.archive.org/web/20120426005137/http://www.biocis.u-psud.fr/spip.php?article332 |date=2012-04-26 }}

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Category:Organic synthesis