Synthesis of morphine-like alkaloids in

chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, structure, proper ...

describes the

total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes i ...

of the natural

morphinan Morphinan is the prototype chemical structure of a large chemical class of psychoactive drugs, consisting of opiate analgesics, cough suppressants, and dissociative hallucinogens, among others. Structure Morphinan has a phenanthrene core struct ...

class of alkaloids that includes

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically ...

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

oripavine Oripavine is an opioid and the major metabolite of thebaine. It is the parent compound from which a series of semi-synthetic opioids are derived, which includes the compounds etorphine and buprenorphine. Although its analgesic potency is compara ...

, and

thebaine Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, '' Thēbai'' (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically similar ...

and the closely related

semisynthetic Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with ...

analogs

methorphan Methorphan comes in two isomeric forms, each with differing pharmacology and effects: * Dextromethorphan - An over-the-counter cough suppressant, as well as dissociative hallucinogen. * Levomethorphan - A potent opioid analgesic that was neve ...

buprenorphine Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal ...

hydromorphone Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is an opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by mou ...

hydrocodone Hydrocodone, also known as dihydrocodeinone, is an opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe eno ...

isocodeine Isocodeine is an opioid research chemical related to codeine. It is an epimer of codeine that can be prepared from codeine via a Mitsunobu reaction. Dozens of derivatives and analogs of isocodeine and the related compound isomorphine have bee ...

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been foun ...

, nalbuphine, oxymorphone,

oxycodone Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a strong, semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and a commonly ...

, and

naloxone Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin withi ...

. The structure of morphine is not particularly complex, however the electrostatic polarization of adjacent bonded atoms does not alternate uniformly throughout the structure. This "dissonant connectivity" makes bond formation more difficult and therefore significantly complicates any synthetic strategy that is applied to this family of molecules. The first morphine total synthesis, devised by

Marshall D. Gates, Jr. Marshall D. Gates Jr. (1915–2003) was an American chemist, holding the position of C.F. Houghton Professor of Chemistry at the University of Rochester. He was an organic chemist whose research was in the field of natural product synthesis. He i ...

in 1952 remains a widely used example of total synthesis. This synthesis took a total of 31 steps and proceeded in 0.06% overall yield. The

synthesis of Kenner C. Rice is one of the most efficient and proceeds in 30% overall yield in 14 steps. At 9 steps, the Barriault route is the shortest to date, but contains a number of low-yielding steps and is racemic. Several other syntheses were reported, notably by the research groups of

Evans Evans may refer to: People *Evans (surname) * List of people with surname Evans Places United States *Evans Island, an island of Alaska * Evans, Colorado *Evans, Georgia *Evans County, Georgia *Evans, New York *Evans Mills, New York *Evans Cit ...

, Fuchs, Parker, Overman, Mulzer- Trauner, White, Taber, Trost, Fukuyama, Guillou,

Stork Storks are large, long-legged, long-necked wading birds with long, stout bills. They belong to the family called Ciconiidae, and make up the order Ciconiiformes . Ciconiiformes previously included a number of other families, such as herons an ...

, Magnus, Smith, and Barriault.

Gates synthesis

Gates' total synthesis of morphine provided a proof of the structure of morphine proposed by

Robinson Robinson may refer to: People and names * Robinson (name) Fictional characters * Robinson Crusoe, the main character, and title of a novel by Daniel Defoe, published in 1719 Geography * Robinson projection, a map projection used since the 1960 ...

in 1925. This synthesis of morphine features one of the first examples of the Diels-Alder reaction in the context of total synthesis. Gates synthesis

Rice synthesis

The Rice synthesis follows a

biomimetic Biomimetics or biomimicry is the emulation of the models, systems, and elements of nature for the purpose of solving complex human problems. The terms "biomimetics" and "biomimicry" are derived from grc, βίος (''bios''), life, and μίμησ ...

route and is the most efficient reported to date. A key step is the Grewe cyclization that is analogous to the cyclization of reticuline that occurs in morphine biosynthesis. Kenner Rice morphine synthesis

References

External links

Morphine Total Syntheses @ SynArchive.com
* {{cite web , url = http://www.scs.illinois.edu/denmark/presentations/2006/gm-2006-01n31.pdf , title = Synthesis of Morphine Alkaloids , author = Wilson T , year = 2006 , work = Professor Scott E. Denmark Research Group Presentations , publisher = University of Illinois at Urbana-Champaign , url-status = dead , archive-url = https://web.archive.org/web/20130228131105/http://www.scs.illinois.edu/denmark/presentations/2006/gm-2006-01n31.pdf , archive-date = 2013-02-28 Natural opium alkaloids Total synthesis