Synthesis and opioid receptor activity of furansubstituted salvinorin a analogues andrew p. Claviceps purpurea, a fungus effecting barley, rye, and morning glory plants ergotamine migraines jakubczyk, d cheng, j. There have been several total synthesis approaches to salvinorin a, and these will be detailed within this chapter. How to start a total synthesis from the wielandmiescher ketone. Construction of the tricyclic salvinorin core is predicated on the. The absolute stereochemistry of salvinorin a has been determined by a number of methods 2, 4. N hn n nme h hn o nh h n n o h o o oh me bn h dostinex cabergoline parkinsons disease o o nhet nme2. Chemistry and biology of hallucinogens princeton university. In contrast, salvinorin a is a potent and selective kor agonist but is structurally dissimilar to other kor ligands, such as u69,593 and norbni.
Enantioselective access to key intermediates for salvinorin a. Commercially available leaves were extracted as previously described 1, 2, and 17 and afforded salvinorin a. Pdf extraction and analytical study of salvinorin a from. To date, salvinorin a has not been found in any other salvia species analysed. The visions seen with salvinorin a seem particularly real and convincing. A concise total synthesis of the neoclerodane diterpene salvinorin a from 3furaldehyde is reported using two highly diastereoselective intramolecular diels alder reactions imda as the key transformations. Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin a. A 2mg quantity of salvinorin a was dissolved in 1 ml anhydrous ethyl alcohol then sprayed on the inner surfaces of the mouth using an aspirator. Quite often people accept these visions as reality and forget they are under the influence of a psychedelic substance. Laboratory study has shown that salvinorin a is found in both salvia divinorum leaf extracts and the powdered leaves, but not in related species, such as kitchen sage salvia officinalis. Total synthesis of the neoclerodane diterpene salvinorin a.
Synthesis and in vitro pharmacological studies of new c2 modified salvinorin a analogues, bioorg med chem lett 15. The most extensively studied among t hese compounds are salvinorin a and salvinorin b. Salvinorin a is the active principle in the leaves of the psychotropic mint salvia divinorum. Synthesis of fenfluramine, with an immense amount of novel amphetamine synthesis reactions sodium percarbonate dakin reaction. Citations are publications that use tocris products. Of the approximately 11 million known chemical compounds, about 10 million are organic. Wagner 2019 sara coulup phd, synthesis and evaluation of a metabolically stabilized analog and conjugates of pironetin advisor. It is made from salvinorin b, which is most conveniently made. Salvinorin a 1, a psychoactive neoclerodane diterpenoid from the mexican sage s. Salvinorin a sala is a plant metabolite that agonizes the human kappaopioid receptor. Chemical total syntheses of salvinorin a have recently been completed but they are too complex to be used for the production of the substance. How to start a total synthesis from the wielandmiescher. Salvinorin a 1 is natural hallucinogen that binds the human opioid receptor. Salvia divinorum has several known constituents, but salvinorin a is typically known as the active component 14, and is selective for kappa1opioid receptors 1,17.
A concise total synthesis of the neoclerodane diterpene salvinorin a from 3 furaldehyde is reported using two highly diastereoselective. Sigmaaldrich offers a number of salvinorin a products. Salvia divinorum is a member of the sage family, most familiarly illustrated by common or garden sage, salvia officinalis, used in sage and onion stuffing, for example. Dielsalder reaction of 9b with methyl acrylate in aqueous media. The whisper of the goddess by salvinorin published on 201705t. Total synthesis of the hallucinogenic neoclerodane. Dec 12, 2016 salvinorin a 1 is natural hallucinogen that binds the human. Ed had moved to eli lilly after his postdoc and they hired woodward as a consultant. In order to gain selectivity of action on opioid receptors 15, and 16, semi synthetic. This title includes a number of open access chapters. It is a very common mistake to attribute the total synthesis to woodward because he was such a great chemist so everyone just assumes he did it. Salvinorin a from wikipedia, the free encyclopedia jump to navigation jump to search. A longstanding problem for the total synthesis of salvinorin a and its analogs is the molecules propensity to epimerize, or switch chirality at a particular stereogenic center, according to. As widely used in the total synthesis, the wielandmiescher ketone is treated at the beginning of total synthesis, and protocols for treating the wielandmiescher ketone are worthy to be addressed.
Aug, 2010 there have been several total synthesis approaches to salvinorin a, and these will be detailed within this chapter. Synthetic simplification of hallucinogen pays off chemical. During grad school, tori strong worked on the total synthesis of the psychotropic molecule salvinorin a. The best part of the book is an astonishing collection of beautifully written trip reports on salviasalvinorin and combinations with acid, 2cb, mushrooms, dmt, etc.
The logic of chemical synthesis the title of this threepart volume derives from a key theme of the bookthe logic underlying the rational analysis of complex. Salvia divinorum salvia the salvia divinorum research. Evans territory, with a catalytic enantioselective orthoester alkylation using an interesting nickel complex. Most of the lipids in the leaf other than chlorophyll are not very soluble in ice cold acetone. A total asymmetric synthesis of salvinorin a, which relies on a transannular michael reaction cascade to construct the ring system, was achieved as a 4. Salvinorin a is not water soluble so injection was not attempted. Many other terpenoids have been isolated from salvia divinorum, including classes named divinatorins and salvinicins. Its effects are considered unpleasant by many people. Mazatec shamans used salvia divinorum to induce visionary states for divinatory rituals. Salvinorin a analogs as probes in opioid pharmacology. The first jacs total synthesis ive seen in a while, this is a nice piece of work by the legend that is dave evans. But salvia divinorum contains an entheogen, salvinorin a, a psychoactive stimulant that brings on mystical experiences. Or with high affinity and high selectivity over mu and deltaopioid receptors. Tsuji allylation set the c9 quaternary center and a late.
The furyl lactone moiety in salvinorin a is identical to that observed in the molluscicide ricciocarpina20 and has been found necessary for the insect antifeedant properties of bac. It has a longer duration of action of around 23 hours, compared to less than 30 minutes for salvinorin a, and has increased affinity and potency at the. Salvinorin a is a structurally unique hallucinogen and kor ligand. Salvinorin a is the most potent naturally occurring psychedelic known, and in many ways the most enigmatic.
Total synthesis of salvinorin a 1, a neoclerodane diterpenoid having the most potent hallucinogenic activity and a selective. Salvinorin b methoxymethyl ether 2omethoxymethylsalvinorin b is a semisynthetic analogue of the natural product salvinorin a used in scientific research. Standard protecting groups create potent and selective kappa opioids. Its leaves contain the extremely potent salvinorin a. A concise total synthesis of the neoclerodane diterpene salvinorin a from 3furaldehyde is reported using two highly diastereoselective intramolecular dielsalder reactions. Effects were measured through semistructured interview and administration of the peak experience profile. Secondgeneration synthesis of salvinorin a sciencedirect. The robinson annulation of 2methyl1,3cyclohexanedione with methyl vinyl ketone is able to afford the wielandmiescher ketone. Total synthesis of the neoclerodane diterpene salvinorin a via an.
Studies toward the total synthesis of solomonamide b, 247th national meeting of the american chemical society dallas, texas. Now, hes starting a clothing line called i h8 me 2 that combines scientific concepts. A new mexican psychotropic drug from the mint family. A concise total synthesis of the neoclerodane diterpene salvinorin a from 3furaldehyde is reported using two highly diastereoselective.
Preparation of neoclerodane diterpenes as probes for the opioid. A pentacyclic furanosteroid containing trisubstituted furan ring was synthesized via a multistep sequence in acceptable total yield. Total synthesis of salvinorin a 1, a densely functionalized neoclerodane diterpenoid, having the most potent hallucinogenic activity and a selective. Salvinorin a molecule of the month july 2014 htmlonly. Salvinorin a is the main active psychoactive molecule within salvia divinorum, a mexican plant which has a long history of use as an entheogen by indigenous mazatec shamans. First total synthesis of the neoclerodane diterpenoid salvinorin f. Most modifications have focused on the manipulation of the acetate at c2 and the furan ring. Total synthesis of salvinorin a by evans organic chemistry portal. Salvia divinorum is an extraordinary herb used in shamanism, divination, healing, meditation, and the exploration of consciousness. Wielandmiescher ketone, total synthesis, structural modification, screening chiral organocatalysts, bioactive molecules, novel protocols. While salvinorin a, lsd, and psilocin are all hallucinogens, the latter two act through serotonin 5ht 2a receptors. As widely used in the total synthesis, the wielandmiescher ketone is treated at the beginning of total synthesis, and protocols for treating the wielandmiescher ketone are worthy to. Total synthesis highlights organic chemistry portal.
The nagorny synthesis of cannogenol and cannogenol3o. A total synthesis has been developed that parlays the. It has a history of buccal use as a divinatory psychedelic, and has been widely available since the mid 1990s primarily as a smoked herb. Synthesis of salvinorin a 341 many labdane and clerodane diterpenes possess similar structures to salvinorin a but differ vastly in bioactivity. The key tricylic intermediate 3a, for the total synthesis of the c20nor analogue of salvinorin a, was prepared in seven steps from 3furaldehyde. May 22, 2018 a concise total synthesis of the neoclerodane diterpene salvinorin a from 3furaldehyde is reported using two highly diastereoselective intramolecular dielsalder reactions imda as the key transformations. A synthesis of salvinorin a containing 3substituted furan ring was reported. Chemistry and biology of hallucinogens ergot alkaloids isolation. The purpose of these sacraments is to purify, and to open the road. The first total synthesis of lysergic acid was not by r. Salvinorin a extraction and purification salvia divinorum. Total synthesis of the hallucinogenic neoclerodane diterpenoid.
Organic chemists are currently working to produce better polymers with specific prope. Synthesis of salvinorin a analogues as opioid receptor probes. Synthesis of deuterium labeled salvinorin a, hive novel. This book presents a range of research on important topics in the field.
Asymmetric synthesis of salvinorin a, a potent k opioid. Salvinorin b alkoxymethyl ethers, bioorg med chem 16. Salvinorin a journeys conclusions bibliography appendix a. A novel synthesis of huperzine a via tandem intramolecular azaprins cyclizationcyclobutane fragmentation. Rather than begin a lengthy total synthesis of salvinorin a, we initially focused on extracting salvinorin a from the dried leaves of s. It is structurally distinct from other naturally occurring hallucinogens such as dmt, psilocin and mescaline because it contains no nitrogen atoms, making it a terpenoid and not an alkaloid as is the norm. Salvinorin a supplier cas 83729015 divinorin a tocris. Our alumni college of pharmacy university of minnesota. Georgharrison west phd, selfassembling phosphoramidate pronucleotides. Prisinzano, department of chemistry and department of medicinal chemistry, school of pharmacy, the university of kansas, lawrence, kansas 66045, united states. Braida et al 2009 potential anxiolytic and antidepressantlike effects of salvinorin a, the main active ingredient of salvia divinorum, in rodents. Dec 14, 2014 the first total synthesis of lysergic acid was not by r.
Salvinorin a 1 is natural hallucinogen that binds the human. Also, salvinorin a is present on leaf surface and not inside cells, so it is easily removed without powdering leaves. Ester and lactone moieties required for salvinorin synthesis were introduced. Salvia divinorum cultivation introduction salvinorin a is the primary psychoactive component of salvia divinorum.
A total synthesis has been developed that parlays the stereochemistry of l. Its therapeutic potential has stimulated extensive semisynthetic studies and total synthesis campaigns. Additionally, research efforts have concentrated on structure modification of the salvinorin a scaffold through semisynthetic methods. The role of imda in the total synthesis of naturally occurring products has been. Siebert has reported on a number of themes which are frequently experienced with salvinorin a. Recent applications of intramolecular dielsalder reaction in total. Many who use salvinorin a spend the peak of their journey lying down or reclining, apparently engrossed in an internal world. At the onset of the experience there is often a complete separation of consciousness from the body and personality. Salvinorin a is very soluble in acetone, even when the acetone is at 0f. There is a light somewhere by salvinorin published on 20170808t11. Salvinorin a is a pharmacologically interesting compound.
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