Santonin structure

The photorearrangement of a dienone was noted<4) as early as 1830 in a study of the sesquiterpene a-santonin (1). However, the structure and stereochemistry of the various photoproducts were not conclusively established until 1965.(6) Upon irradiation in neutral media, a-santonin (1) undergoes rapid rearrangement to the cyclopropyl ketone, lumisantonin (2). However, if the irradiation is not terminated after a short period of time the lumisantonin itself rearranges into a linearly conjugated dienone (3). The dienone (3) can be isolated from the photolysis of either (1) or (2) in benzene or ether. In nucleophilic solvents (alcohol or water) the dienone (3) is also photo-chemically active and is further converted into an ester or an acid (photo-santonic acid) (4). 

It is in this area of dienone photochemistry that the effect of structure on reactivities of excited states seems to be especially complex. For example, Kropp has shown that the presence of the 4-methyl group in santonin is responsible for preferential formation of the fused 5,7 ring system in photosantonic lactone.403 An analogous cross-conjugated dienone with a 2-methyl substituent yields only a spiro compound in acidic media,404 while a dienone with neither 2- nor 4-substituents yields mixtures of the two types of products.409... 

A second and more recent example, the photochemical rearrangement of 4,4-diphenylcyclohexadienone (VIII), was provided by the present author and co-workers (4, 5,14). This compound (VIII) when photolyzed in aqueous dioxane with light of wavelength above 310 mp. was found (4, 5) to afford the bicyclic ketone IX, 2,3-diphenylphenol (X) and an acid whose structure was shown (14) to correspond to XI. Additionally, 3,4-diphenylphenol (XII) was shown (14) to be a minor by-product. Strikingly and reminiscent of the dependence of product distribution on solvent in santonin photolysis, it was found (14) that approximately equal quantities of 3,4-diphenylphenol and 2,3-diphenylphenol (X) were formed when the photolysis was run in 50% aqueous acetic acid. [Control experiments (14) demonstrated that neither 4,4-diphenylcyclohexadienone nor bicyclic ketone IX were reactive in the dark under the aqueous dioxane or aqueous acetic acid reaction conditions, in the presence or absence of acid XI.] Furthermore, the bicyclic ketone IX has been demonstrated to afford 2,3-diphenylphenol (X) and the photoacid XI on photolysis in aqueous dioxane, and consequently this ketone may be formulated as a reaction intermediate in the formation of X and XI from 4,4-diphenylcyclohexadienone (VIII) (4, 5, 14). 

The structure of chlorosantonin (491) obtained from santonin 4,5-epoxide with hydrogen chloride gas has been solved by X-ray analysis. Undoubtedly the most remarkable sesquiterpenoid rearrangement is that observed when the dried sodio salt of (492) is heated to reflux in excess phosphorus oxychloride. The rearrangement product in question was isolated by removal of the excess POCI3, followed by neutralization with concentrated aqueous ammonia. The resultant ether extract was treated with hot 15% sodium hydroxide and the product mixture was distilled and purified by column chromatography. One of the products (about 3% yield) has been identified by X-ray analysis as (493), but as yet no mechanism has been suggested... 

Reisch J, Henkel G, Topaloglu Y, Simon G. Crystal structure of santonin contribution to the lattice controlled photodimerization. Pharmazie 1988 43 15-17. 

For those who are familiar with natural products chemistry it will be easy to recognize in structure I the main features of a-Santonin (III). This was a heavily investigated compound during the 1950s and 1960s, especially its photochemistry. The particular functionality that attracted so much attention is the cross-conjugated enone moiety. It is this function in fact that warranted the construction of the starting compound I by way of a double Michael-type addition of hydroxylamine. ... 

Earlier work by Matsuura et al. reported that there was a difference in the photochemical behaviour of santonin dependent on whether the reactions were carried out in the liquid or solid phase. - More recent work has demonstrated that the dienones (273) and (274) do not exhibit this difference in behaviour. Irradiation of these compounds yields the same products (275) and (276) respectively whether the reactions are in solution or in the crystal. The authors - suggest that this similarity in behaviour is due to loose crystal lattice structures. The solid state irradiation of the dienone (277) results in the formation of the normal products for such systems, namely the corresponding photoketone, photophenol, and lumiketone. The ratio of these three products was sensitive to temperature. In solution no temperature dependence was detected. Interestingly when the dienone is irradiated in the solid with wavelengths > 400 nm a quantitative yield of the lumiketone is obtained. ... 

In the l960s, Kropp showed that fused bicyclic dienones structurally related to santonin could potentially serve as synthetically useful precursors to either spirocyclic skeletons or hydroazulenones. One of these cases, 91, was successfully used by Marshall and Johnson as the starting point in an elegant synthesis of the spirocyclic sesquiterpene )6-vetivone (Scheme 23). More recently, a variety of bicyclic cyclohexadienones have been studied by Caine and coworkers. For example, bicyclic dienone 92 could be photochemically rearranged to the oxygenated bicyclo[4.3.0]nonenone system 93, along with other rearrangement products, via acetic acid solvolysis of the cyclopropyl ketone intermediate. ... 

The structure of a-santonin chlorohydrin (639) has been revised as a result of an X-ray analysis.285 Further irradiation of photosantonin (640) produces neophotosantonin (641)286 by a [1,5] antarafacial sigmatropic hydrogen migration. 

Santonin (la,b), an effective drug for treating intestinal roundwormS/ was first isolated from unexpanded flower heads of Artemesia plants (Levant Wormseed) grown in Russian and Chinese Turkestan and the Southern Ural region. The structure of this compound was established by Clemo et al. [2,3] and Ruzicka and Steiner [4]. Santonin exists in two forms, a-santonin and p-santonin, the stereochemistry of which has been worked out by several workers [5-7]. 

Irradiation of 2,5-cyclohexadienone with visible light >400 nm) results in quantitative formation of two isomeric lumiketones 1 0 and 21 solid state 1 0 and 21 are formed with comparable yields, whereas in solution the isomer 1 0 is the major product. Failure for crystalline to photorearrange into a 2,4-cyclopentadienone structure, like a- santonin ( ) does in the solid state (eq 4), is attributed to insufficient compactness of the crystal packing of (28). 

The structure of the acetylenic norsesquiterpene chamaecynenol (274) has been derived by X-ray analysis. The stereochemistry of the C-4 hydroxy-group in the naturally-occurring hydroxyisochamaecynone (275) has been established as a by total synthesis. Both epimers were synthesised from the known acetylenic ketone (276) (obtained from a-santonin) in a five-step process. From a study... 

Further research on terpenoid plant growth regulators has shown that cross-conjugated dienones such as zerumbone (288), epoxyzerumbone (289), and santonin (290) display root-promoting activity whereas related compounds (291)—(293) devoid of this structural feature do not. Molecular mechanics... 

Artemisin. 3a,5,5a,9b-Tetrahydro-4-hydroxy-3,5a, 9.trimethylnaphlho[l, 2-bffu ran-2,8(3H,4H l-dione 6a,8ct-dihydroxy-3-oxoeudesma-l,4-dien-12-oie acid 12,6-lactone 8-hydroxysantonin. C jH S04 mol wt 262.29, C 68.68%, H 6.92%, O 24.40%. From the closed, unexpanded flower heads of several Artemisia spp, especially Artemisia maritima L., and A. clna Berg., Compositae ( wormseed ). Found in the mother liquors from the extraction of santonin. Isoln E. Merck, Merck s Jahresber. 1894, 3 Chem. Zentr. 1895, I, 436. Structure Sumi. J. Am. Chem. Soc. 80, 4869 (1958) Cocker, McMurry, Tetrahedron 8, l8l (1960). Stereochemistry Bolt et of., J. Chem. Soc 1963, 5235. Synthesis of (+) -artemisin Nakazaki, Naemura, Tetrahedron Letters 1966, 2615. 

The C n.m.r. spectra of santonin (259) and some of its derivatives indicate that the data obtained can be used to determine the stereochemistry of the lactone fusion and the configuration of the methyl group at C-ll. Further work on the chemistry of santonin, santonene, and related compounds has been reported and pyrosantonin has been shown to have structure (260). Pyrolysis of santonin also produces a smaller amount of 1-nordesmotroposantonin (261). Reaction of santonin (259) with nonacarbonyldi-iron at 40 °C produces the two... 

ABSTRACT This article reviews the literature published in the last decade dealing with the transformation of a-santonin into bioactive or potentially bioactive sesquiterpenes. A number of syntheses starting from 8a-hydroxysantonin (artemisin) have also been included. Special emphasis has been placed on synthesized products that show biological activity. Major advances in this field include the application of new reagents and methodologies for the structural modification of the santonin skeleton and functionality, and its transformation into other sesquiterpenes, especially sesquiterpene lactones. 

Introduction An overview of the structure and biological activity of the starting material santonin. 

Miscellaneous In this section, a number of structural modifications of santonin that do not lead to natural products, but that may be of synthetic interest, are described. 

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