Tutin is a poisonous plant derivative found in New Zealand tutu plants (several species in the genus Coriaria). It acts as a potent antagonist of the glycine receptor, and has powerful convulsant effects. It is used in scientific research into the glycine receptor. It is sometimes associated with outbreaks of toxic honey poisoning when bees feed on honeydew exudate from the sap-sucking passion vine hopper (Scolypopa australis) insect, when the vine hoppers have been feeding on the sap of tutu bushes. Toxic honey is a rare event and is more likely to occur when comb honey is eaten directly from a hive that has been harvesting honeydew from passionvine hoppers feeding on tutu plants.
History Tutin was first discovered as a honey contaminant in the late 19th century. Missionaries from overseas introduced the western honey bee (Apis mellifera) to New Zealand in 1839. A few decades later, people eating the local honey would suffer from symptoms like vomiting, headaches and confusion. At this point the neurotoxin was studied, and in the early 1900s its toxic effects were fully characterised. The toxin was known to come from the tutu plant. However, neither the nectar nor the pollen of the tutu plant contain this toxin, the two parts the honey bees ingest. Eventually it was found that the passion vine hopper (Scolypopa australis), a pest insect, extracts sap from young shoots of the tutu plant and releases secretions, honeydew, that contain the tutin toxin. Honeybees will consume honeydew as a supplementary food source, thereby contaminating the honey they produce with this toxin. Further outbreaks of tutin poisoning would periodically appear from that point onwards. As late as 2008 a family had to be hospitalized due to severe symptoms caused by homegrown honey with tutin contaminations.
Structure and chemical properties Tutin is a polyoxygenanted polycyclic sesquiterpene convulsant neurotoxin. Tutin is one of a series of chemically and pharmacologically similar compounds of which picrotoxinin and coriamyrtin have been mostly studied. Conroy proposed the structure for picrotoxinin, which was confirmed by X-ray crystallographic studies and also determined the absolute configuration of the molecule. Karyone and Okuda proposed the tutin structure based on the pictrotoxinin structure and chemical degradation studies. The structure of tutin including absolute stereochemistry was confirmed by X-ray crystal analysis together with chemical and chiroptical means. Tutin has a highly strained skeleton, including two epoxide rings and a lactone, which is susceptible to various rearrangements. Tutin has a characteristic intensely bitter taste. Tutin is very soluble in acetone, but dissolves moderately in chloroform and is insoluble in carbon disulfide or benzene. Addition of strong sulfuric acid to a few drops of a saturated aqueous solution of tutin results in a blood-red coloration.
Isolation from nature In 1901, tutin was first isolated by Easterfield and Aston and identified as the convulsive poison present in the New Zealand species of Coriaria (‘’tutu’’ or ‘’toitoi’’ in Maori). Easterfield and Aston used 1.5 kilograms of seeds and 11 kilograms of the air-dried Coriaria thymifolia plant (without roots) from Dunedin at the time of flowering in January. The seeds were pulverised and exhausted by carbon disulfide removing a green drying oil. The plant was put through a chaff cutter and boiled with water. The mixture was treated with a large volume of ethanol. The ethanol precipitated inorganic salts, ellagic acid and a large amount of black matter. After distilling, the residue was extracted with diethyl ether. The crystals were recrystallized several times from water, which resulted in separating of the substance in characteristic needle forms and recrystallization from ethanol in oblique ended prisms. The final product contained the characteristic highly poisonous non-nitrogenous glucoside tutin as colourless crystals melting at 204–205 °C (399–401 °F).
Chemical synthesis of (+)-tutin In 1989, Wakamatsu and coworkers reported in details the first total synthesis of (+)-tutin in a stereocontrolled manner. (+)-Tutin can be synthesized in a nine-step reaction process. First, a (-)-bromo alcohol was protected by silylation. After this step, conversion of the allylic bromide moiety into the allylic alcohol was achieved by the Corey's conditions. Next, the hydroxyl moiety was introduced at C-2, regio- and stereoselectively of the intramolecular reaction was due to the use of the C-14 hydroxyl function to gain the desired cyclic ether. Thereafter, the ethereal bond was cleaved providing the allylic bromide. Subsequently, the silyl protection group was removed by using tetra-n-butylammonium fluoride in THF. The intramolecular SN2 reaction at the allylic bromide moiety led to the formation of the epoxy olefin. Then, the epoxy olefin was converted into the bisepoxide in three-steps, first alkaline hydrolysis to give the alcohol, second esterification to form 2,2,2-trichloroethyl carbonate and as last epoxidation. Thereafter, the bisepoxide was oxidized with ruthenium(VII)oxide affording 2,2,2-trichloroethoxycarbonyl α-bromotutin. The final part of the synthesis of (+)-tutin is a reduction with zinc and ammoniumchloride.
Chemical reactions Acylation of the secondary alcohol 2-OH and double acetylation at both the 2-OH and C6-OH of tutin has been reported. In the New Zealand toxin honey two main structures of tutin conjugates were found; 2-(β-D-glucopyranosyl)-tutin and 2-[6’-(α-D-glucopyranosyl)-β-D-glucopyranosyl]-Tutin. Chemical synthesis of 2-(β-D-glucopyranosyl)-tutin could be achieved via the β-O-glycosylation reaction between tutin and an activated sugar donor. Multiple methods of O-glycosylation have been published about the synthesis of complex glycosides with anomeric β-stereoselectivity.
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