Editing Total synthesis

{{Short description|Complete chemical synthesis of a complex molecule}}
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'''Total synthesis''', a specialized area within [[organic chemistry]], focuses on constructing complex organic compounds, especially those found in nature, using laboratory methods.<ref name=nature /><ref name=Nicolaou1 /><ref name=Nicolaou2 /><ref name=Nicolaou3 /> It often involves synthesizing [[natural product]]s from basic, commercially available starting materials. Total synthesis targets can also be [[organometallic]] or [[inorganic]].<ref name="Inorganic synth">{{cite journal | vauthors = Buck MR, Schaak RE | title = Emerging Strategies for the Total Synthesis of Inorganic Nanostructures | journal = Angewandte Chemie | volume = 52 | issue = 24 | pages = 6154–6178 | date = June 2013 | pmid = 23610005 | doi = 10.1002/anie.201207240 }}</ref><ref name=RBW1963>{{cite journal|doi=10.1002/ange.19630751827|title=Versuche zur Synthese des Vitamins B<sub>12</sub>|journal=Angewandte Chemie|volume=75|issue=18|pages=871–872|date=1963| vauthors = Woodward RB |bibcode=1963AngCh..75..871W|author-link1=Robert Burns Woodward}}</ref> While total synthesis aims for complete construction from simple starting materials, modifying or partially synthesizing these compounds is known as [[semisynthesis]].

Natural product synthesis serves as a critical tool across various scientific fields. In organic chemistry, it tests new synthetic methods, validating and advancing innovative approaches. In medicinal chemistry, natural product synthesis is essential for creating bioactive compounds, driving progress in drug discovery and therapeutic development.<ref>{{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 }}</ref> Similarly, in [[chemical biology]], it provides research tools for studying biological systems and processes.<ref>{{citation|author=Stéphane Helleboid, Christian Haug, Kai Lamottke, Yijun Zhou, Jianbing Wei, Sébastien Daix, Linda Cambula, Géraldine Rigou, Dean W. Hum, Robert Walczak |date=2014 |doi=10.1177/1087057113497095 |issue=3 |pages=399–406 |periodical=SLAS Discovery |pmid=23896689 |title=The Identification of Naturally Occurring Neoruscogenin as a Bioavailable, Potent, and High-Affinity Agonist of the Nuclear Receptor RORα (NR1F1) |volume=19|doi-access=free }}<!-- auto-translated from German by Module:CS1 translator --></ref> Additionally, synthesis aids natural product research by helping confirm and elucidate the structures of newly isolated compounds.<ref name=Lamottke>{{citation|author=Michael Müller, Kai Lamottke, Erich Löw, Eva Magor-Veenstra, Wolfgang Steglich |date=2000 |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 }}<!-- auto-translated from German by Module:CS1 translator --></ref><ref>{{citation|author=Michael Müller, Kai Lamottke, Wolfgang Steglich, Stefan Busemann, Matthias Reichert, Gerhard Bringmann, Peter Spiteller |date=2004 |pages=4850–4855 |doi=10.1002/ejoc.200400518 |periodical=European Journal of Organic Chemistry |title=Biosynthesis and Stereochemistry of Phlegmacin-Type Fungal Pigments|issue=23 }}</ref>

The field of natural product synthesis has progressed remarkably since the early 19th century, with improvements in synthetic techniques, analytical methods, and an evolving understanding of chemical reactivity.<ref name=armaly /> Today, modern synthetic approaches often combine traditional organic methods, biocatalysis, and chemoenzymatic strategies to achieve efficient and complex syntheses, broadening the scope and applicability of synthetic processes.

Key components of natural product synthesis include [[retrosynthetic analysis]], which involves planning synthetic routes by working backward from the target molecule to design the most effective construction pathway. Stereochemical control is crucial to ensure the correct three-dimensional arrangement of atoms, critical for the molecule's functionality. Reaction optimization enhances yield, selectivity, and efficiency, making synthetic steps more practical. Finally, scale-up considerations allow researchers to adapt lab-scale syntheses for larger production, expanding the accessibility of synthesized products. This evolving field continues to fuel advancements in drug development, materials science, and our understanding of the diversity in natural compounds.<ref name="Fay_2023">{{cite journal | vauthors = Fay N, Kouklovsky C, de la Torre A | title = Natural Product Synthesis: The Endless Quest for Unreachable Perfection | journal = ACS Organic & Inorganic Au | volume = 3 | issue = 6 | pages = 350–363 | date = December 2023 | pmid = 38075446 | doi = 10.1021/acsorginorgau.3c00040 | pmc = 10704578 }}</ref>

==Scope and definitions==
There are numerous classes of natural products for which total synthesis is applied to. These include (but are not limited to): [[terpenes]], [[alkaloids]],<ref>{{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 }}</ref> [[polyketides]].<ref>{{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 }}<!-- auto-translated from German by Module:CS1 translator --></ref><ref>{{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 }}<!-- auto-translated from German by Module:CS1 translator --></ref> and [[polyethers]].<ref name="Natural Products">{{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}}</ref> Total synthesis targets are sometimes referred to by their organismal origin such as plant, marine, and fungal.<ref name=Lamottke/> The term total synthesis is less frequently but still accurately applied to the synthesis of natural [[polypeptide]]s and [[polynucleotide]]s. The peptide hormones [[oxytocin]] and [[vasopressin]] were isolated and their total syntheses first reported in 1954.<ref>{{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 }}</ref> It is not uncommon for natural product targets to feature multiple structural components of several natural product classes.

==Aims==
Although untrue from an historical perspective (see the [[Cortisone#History|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<ref>{{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}}</ref> there has been a continuing discussion regarding the value of total synthesis as an academic enterprise.<ref name="Nicolaou prospective">{{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}}</ref><ref>{{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 }}</ref><ref>{{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}}</ref> 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.<ref name="Baran - Here to stay">{{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 }}</ref><ref>{{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 }}</ref><ref name="In the Pipeline (1)">{{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}}</ref> 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 Research Institute|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.<ref name="Baran">{{cite web |title=Phil Baran Research |url=https://baranlab.org/research/ |website=Phil Baran Research Lab |publisher=Scripps Institute |access-date=24 June 2021}}</ref><ref name="JOC Time economy">{{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 }}</ref>

==History==
{{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|thumb|right|300px|'''[[Vitamin B12 total synthesis|Vitamin B<sub>12</sub> 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 B<sub>12</sub> ('''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 synthesis|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.<ref name=Nicolaou1 /> Wöhler obtained [[urea]] by treating [[silver cyanate]] with [[ammonium chloride]], a simple, one-step synthesis:
: AgNCO + NH<sub>4</sub>Cl → (NH<sub>2</sub>)<sub>2</sub>CO + 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;<ref name=Nicolaou1 /> 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 total synthesis|cholesterol]], [[cortisone]], [[strychnine total synthesis|strychnine]], [[lysergic acid]], [[reserpine]], [[chlorophyll]], [[colchicine]], [[Vitamin B12 total synthesis|vitamin B<sub>12</sub>]], and [[prostaglandin|prostaglandin F-2a]].<ref name=Nicolaou1 />

[[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."<ref>{{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]]}}</ref>

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]].

==List of notable total syntheses==

* [[Quinine total synthesis]]<ref>{{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 }}</ref><ref name=Nicolaou1 /> 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 total synthesis|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]]<ref>{{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 }}</ref> 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|Vitamin B<sub>12</sub> total synthesis]]<ref>{{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 }}</ref> 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 total synthesis|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.

== References ==
{{reflist|refs=

<ref name=Nicolaou1>{{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 }}</ref>

<ref name=Nicolaou2>{{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}}</ref>

<ref name=Nicolaou3>{{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}}</ref>

<ref name=armaly>{{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 }}</ref>

<ref name=nature>{{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 }}</ref>

}}

== External links ==
* [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:Total synthesis| ]]
[[Category:Organic synthesis]]