Transformation of santonin

Synthesis of 6,12-sesquiterpenolides This section describes the synthesis of sesquiterpenes bearing a lactone moiety between C(6) and C(12). The transformation of the A-ring in santonin to give eudesmanolides, guaianolides, and elemanolides, as well as the modification of the lactone ring is described. Some microbiological transformations of santonin and its derivatives are also described. 

Transformation of santonin (1) into guaianolides has been carried out by two different methods, namely photochemical rearrangement of the dienone system present in the A ring of santonin, and solvolytic rearrangement of a proper 1-sulfonate derivative. 

In this section we will focus on the transformation of santonin (1) and artemisin (2) into sesquiterpenes that do not bear a lactone moiety. Most of these syntheses required the transformation of the 6,12-lactone ring into an isopropyl chain or one of its derivatives. 

We have also reported [60] the transformation of santonin (1) into two natural 8-oxo-j3-cyperone derivatives 420 and 423 (Scheme 49) whose antibiotic activity had been reported previously. Trienone 291 (see... 

A particularly intriguing rearrangement is the Type-A transformation of 2,5-cyclohexadienones, a reaction typified by the photochemical conversion of Santonin (1) to... 

There are probably no photochemical transformations which are more intriguing to the organic chemist than the deep-seated skeletal rearrangements of dienones (7-11). An interesting and thoroughly studied example is that of the dienone santonin (III), whose complex transformations are outlined in Chart I. Lumisantonin (8, 9) (IV) results from the irradiation of santonin in dioxane. Isophotosantonic lactone (8) (V) is formed on photolysis of santonin instead in aqueous acetic... 

Remote functionalization of the angular methyl group in santonin derivatives has also been accomplished using the Barton reaction. For example a key step in the previously reported synthesis of the norsesquiterpenoid rishitin (450) from tetrahydro-a-santonin (443) involves photochemical transformation of the nitrite ester (447) to the oxime (448) (c/. Scheme 46). Rishitin (450) is a well known antifungal phytoalexin produced by diseased potato tubers and recent studies... 

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. 

Artemisin (2) is an 8-hydroxy-functionalized eudesmanolide that is isolated from Artemisia maritima and is closely related to santonin, and is a compound that has been successfully used by our group in several syntheses of sesquiterpenolides functionalized at C(8) or C(9). For example, artemisin (2) has been transformed into the cytotoxic compounds artapshin (147) and dihydro-8a-hydroxybalchanin (148) [28] in a synthetic sequence (Scheme 19) in which the transformation of the A ring was achieved in a similar way to that described previously in the synthesis of dihydrosantamarin (see Scheme 8). 

Attylic oxidation. r-Butyl chromate was found superior to selenium dioxide or CrOa -Pya for oxidation of the trienone (1) to (2). This reaction was used in a transformation of a-santonin (4) into yomogin (5), ... 

The first synthesis, that of Corey, Ohno, Vatakencherry, and Mitra (27), is schematically shown in Chart 1. The key-feature in the synthesis is the internal Michael addition (7 -> 8), which had precedence in the reported (25) conversion of santonin (10) into santonic acid (11) under the influence of hot aqueous potassium hydroxide. However, in the present case Michael cyclization proved quite difficult and was finally achieved in a yield of 10—20%, by prolonged exposure of (7) to triethylamine in ethylene glycol at 225°. After methylation of the resulting diketone (8), the less hindered carbonyl function was removed as shown to yield (i)-longicamphenilone (9) which could be readily transformed into ( )-... 

Hashimoto, T Y. Noma. C. Murakami, M. Tanaka, and Y. Asakawa, 2000b. Microbial transformation of a-santonin derivatives and nootkatone. Proceedings of 44th TEAC, pp. 157 159. 

Fig. 4.3 Two molecules of santonin occupy two different sites in the crystals of santonin. Upon irradiation, one of them is more reactive (MR) and the other one much less (LR). The transformation is topotactic (that is guided by the crystal lattice) and, up to 30 % conversion, occurs in a crystal to crystal way. The arrangement of the two molecules before and after irradiation is indicated by filled (0 %) and light bonds (30 % conversion). Reprinted with permission Ifom [18]. Copyright 2007 American Chemical Society...

The protection of carboxylic acids as their phenacyl esters has been described regeneration is effected with great facility at room temperature by zinc in glacial or dilute aqueous acetic acid. Of notable applicability is the formation of y-hydroxyesters from y-lactones, an otherwise indirect transformation an example is the obtention of the ester (13) from the sodium salt of santonin (12). This protection can be extended to phenols. 

The irradiation of santonin in the solid state leads mainly to cyclopentadienone 129, which spontaneously dimerizes to give compound 130 as well as small amounts of other dimers and lumisantonin (120) (Scheme 22). The formation of 129 can be understood in terms of the migration of a hydrogen atom from Cl in the zwitterionic intermediate 128 (path b). The selective transformation of 119 into 130, which predominates over lumisantonin formation (path a), is interpreted by considering that path b requires less atomic movement in the geometry of santonin and, therefore, is preferred in the solid state. 

In the course of an ingenious scheme designed to gain access into the santonin series, Abe and co-workera noted the following lactone-gencnitiiig transformation (Eq. 57), a very useful one in this particular instance. 

The known derivative of a-santonin (480) has been transformed into the three lactones (481)—(483) which, in turn, have been converted into arglanine (484), vulgarin (485), and C-4-epivulgarin (486) respectively. In a related study the ketone (487) has served as a synthetic precursor for douglanine (488) and ludovicins A (489) and B (490) (Scheme 62). ... 

Application of this mechanism to the Santonin photochemistry leads to the correct Lumisantonin skeleton. We are then left with the matter of stereochemistry. However, writing the Santonin mechanism in three dimensions but with the same electronic transformations, we arrive specifically at the experimental stereochemistry of Lumisantonin as depicted in Scheme 1.3. ... 

Santonin (1) and other related compounds have been used many times as test substrates for new reactions and methodologies. In this last section we will present some modifications of these compounds that involve a reduced number of synthetic steps. These transformations do not lead, in principle, to natural products, although they may be eventually used for this purpose. 

Furthermore, santonin has been readily transformed into 8-oxyfunctionalized trienones 96a and 96b, which after photochemical rearrangement and lactonization provided a convenient method for the preparation of, among others, the 8,12-guaianohdes 8-ept-pseudoivalin (141), (-i-)-zedolactone A (142), and podoandin (143) (Scheme 24). ... 

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