Absinthin is a naturally produced triterpene lactone from the plant ''

Artemisia absinthium ''Artemisia absinthium'' (wormwood, grand wormwood, absinthe, absinthium, absinthe wormwood, mugwort, wermout, wermud, wormit, wormod) is a species of ''Artemisia'', native to temperate regions of Eurasia and North Africa, and widely naturalized ...

'' ( Wormwood). It constitutes one of the most bitter chemical agents responsible for

absinthe Absinthe (, ) is an anise-flavoured spirit derived from several plants, including the flowers and leaves of ''Artemisia absinthium'' ("grand wormwood"), together with green anise, sweet fennel, and other medicinal and culinary herbs. Historical ...

's distinct taste. The compound shows

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

and has shown promise as an anti-inflammatory agent, and should not to be confused with

thujone Thujone () is a ketone and a monoterpene that occurs predominantly in two diastereomeric (epimeric) forms: (−)-α-thujone and (+)-β-thujone. Though it is best known as a chemical compound in the spirit absinthe, it is unlikely to be responsib ...

, a neurotoxin also found in ''

''.

Chemical Structure

Absinthin's (1) complex structure is classified as a sesquiterpene lactone, meaning it belongs to a large category of natural products chemically derived from 5-carbon "building blocks" (3) derived from

isoprene Isoprene, or 2-methyl-1,3-butadiene, is a common volatile organic compound with the formula CH2=C(CH3)−CH=CH2. In its pure form it is a colorless volatile liquid. Isoprene is an unsaturated hydrocarbon. It is produced by many plants and animals ...

(4). The complete structure consists of two identical monomers (2) that are attached via a suspected naturally occurring Diels Alder reaction occurring at the alkenes on the 5-membered ring of the

guaianolide In organic chemistry, a guaianolide is a type of sesquiterpene lactone consisting of a gamma-lactone and either a cyclopentane or cyclopentene, both fused to a central cycloheptane or cycloheptene structure. There are two subclasses, structural ...

. :

Total synthesis

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 ...

of (+)-Absinthin was conducted in 2004 by Zhang, et al. The final yield reported for the synthesis was 18.6% over a course of 10 steps originating from

Santonin Santonin is a drug which was widely used in the past as an anthelminthic. It is an organic compound consisting of colorless flat prisms, turning slightly yellow from the action of light and soluble in alcohol, chloroform and boiling water. Acc ...

(1), a commercially available reagent. The basis of the synthesis was the ring expansion of the original 6-membered carbon ring to the 7-membered ring, engendering the formation of the guaianolide monomer (2) scaffold, followed by Diels Alder coupling (3) and final stereochemical modifications resulting in (+)-Absinthin (4).

Biosynthesis

The full biosynthesis of Absinthin in ''

'' has not been elucidated, but a great portion of it can be inferred from the natural product precursors required to access Absinthin. While terpenoids like Absinthin can be said to consist of

"units,"

by itself is too stable and does not react directly. Rather, the isoprene units are transferred and reacted as diphosphates. As the nomenclature for terpenes suggests, the first Absinthin precursor farnesyl diphosphate contains 15 carbons, or 3 isoprene units. Diphosphate departure (1) generates a carbo-cation within the synthase, which can then be attacked by a carbon-carbon double bond at the opposing end of the molecule (2). The first stable intermediate in the biosynthesis pathway in Artemisia is likely Germacrene A which has been previously identified in plant sesquiterpene pathways as a precursor to guaianolides. From there, hydroxylation (3) occurs, followed by oxidation (4) to an aldehyde directly followed by further hydroxylation (5) and formation of a carboxyl group. It is important to note the disappearance of the terminal carbon-carbon double bond after (4), as the reduction of this bond in the final product differentiates the Absinthin monomer from other Germacrene A downstream products. This reduction does not necessarily occur at step (4), but may occur further downstream. With the carboxyl and hydroxyl group in position, the guaiano-lactone formation via dehydration (7) can occur, as proposed for a general guaianolide pathway. Formation of the Absinthin sesquiterpene guaianolide monomer from hydroxylation and double bond rearrangement (8,9) is then postulated to directly precede dimerization to Absinthin via a naturally occurring Diels-Alder reaction 0 which is likely facilitated by the associated synthase even though the reaction itself can occur in good yields spontaneously, albeit slower than typical natural product biosynthesis. While no synthases specific to ''

'' have been sufficiently isolated to recreate this particular sesquiterpene formation in vitro, the general reaction scheme presented here portrays a likely scenario for Absinthin biosynthesis through the use of terpene intermediates utilized in the biosynthesis of Germacrene A, another sesquiterpene lactone. Enzymatic analogs from terpene biosynthesis which help rationalize the above proposed numbered biosynthetic steps are as follows: # Farnesyl diphosphate departure via a generic sesquiterpene synthase # Ring closure via a generic sesquiterpene synthase (as for #1) # Hydroxylation of terminal allylic carbon via Germacrene A hydroxylase, a cytochrome P450 enzyme. # Oxidation of alcohol to aldol, via -germacrene A hydroxylase. # Hydroxylation of alcohol to carboxyl group, via Germacrene A hydroxylase. #

NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...

-mediated hydroxylation of allylic carbon via a postulated hydroxylation to precede lactone ring closure # Lactone formation/ring closure # Hydroxylation at carbon-carbon tertiary double bond. # Additional 5-membered ring formation/cyclization # Diels-Alder coupling via an unidentified enzyme in ''Artemisia absinthium''.

References

External links

*{{Commonscatinline Total synthesis Triterpenes Cyclopentanes Bitter compounds Sesquiterpene lactones Tertiary alcohols Absinthe Heterocyclic compounds with 6 rings