The Santonin Rearrangement

Treatment of santonin (7.30) with aqueous base also gives a rather unexpected product. Initially, the strained lactone ring is hydrolysed. A series of keto-enol tautomerisations then allows the ene-one-ol system of santonin to rearrange to a dione. Deprotonation of this dione gives an anion, (7.40), which undergoes an internal Michael reaction to give the acid (7.41). 

The most surprising of all of santonin s reactions is the formation of lumisantonin (7.31) upon irradiation. The mechanism of this reaction is not at all obvious and it was the subject of much research by some of the greatest minds of twentieth-century organic chemistry including Sir Derek Barton and Paul de Mayo. The following description of the mechanism is based on that of Zimmermann and Schuster.7 7 In order to 

Protonation of the carbonyl oxygen of (7.45) and simultaneous attack at the rear face of the P-carbon atom (with inversion as in an SN2 reaction) by the nucleophile allows a reaction, reminiscent of the Michael 

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Complex rearrangements such as the santonin rearrangement are best followed through using molecular models. 

Zimmerman has shown that the rearrangement of 4,4-diphenyl-cyclohexadienone, 33, can proceed by an excited triplet.406 Acetophenone acts as a photosensitizer for the reaction, but dilute naphthalene is an inefficient quencher of the unsensitized reaction. As observed for santonin, rearrangement apparently is fast enough to compete favorably with diffusion-controlled quenching. 

Skeletal rearrangements similar to the santonin-lumisantonin rearrangement have also been reported for some 2-cyclohexenones, such as A4-cholesten-3-one413 and 4,4-dimethylcyclohexenone.414... 

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). 

Formula 46) in the irradiation of the dienone (Formula 56) has also been shown to involve Formula 45 as an intermediate (35). The difference in the nature of the photochemical rearrangements of prednisone acetate (Formula 47) and santonin (Formula 28) appears to be associated with the absence of a 4-methyl group in prednisone acetate (see Secs. IIA,4 and IIA,7). 

The overall yield of this synthesis was poor and so the same authors devised a new sequence starting from compound 206, obtained from santonin in 10 steps in 23% overall yield (Scheme 27). Solvolysis of 206 gave, in 75% yield, a 2 1 3 mixture of guaianolides 207, 208 and 209, which possess tetra-, tri-, and di-substituted double bonds, respectively. It is likely that the solvolytic rearrangement of206 proceeded via 210, since... 

A early partial synthesis of the guaianolide nucleus was based on photochemical rearrangement of a-santonin (44) to give isophotosantonic lactone (45) [17] (Scheme 98.5). The stereochemistry of this reaction is remarkable. Irradiation of the santonin isomer, in which the C6-06 bond is 3 disposed gives the C6-06, C7-C11 cis isomer of 45 [18]. 

Kropp, P.J., Photochemical rearrangements of cross-conjugated cyclohexadienones. V. A model for the santonin series, /. Org. Chem., 29, 3110,1964. 

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). 

In acidic solution the rearrangement of a-santonin to lumisantonin and then ultimately to photosantonic acid is not as efficient as rearrangement to the hydroxy ketone, isophotosantonic lactone (5), shown on page 308. Fisch and Richards(6) found that the photorearrangements of a-santonin could be sensitized with benzophenone or Michler s ketone. Moreover, if the irradiation of a-santonin (3660 A) is carried out in piperylene as solvent, the photoreaction is completely quenched. This suggests that the rearrangements proceed via triplet states. 

The rearrangement of cross-conjugated cyclohexadienones to bicyclo[3.1.0]-hex-3-en-2-ones was one of the first photochemical reactions to be thoroughly studied for mechanistic and synthetic purposes 344). The examples outlined below are the conversion of the lactone a-santonin to lumisantonin 345) (3.29)... 

The observed quenching effects suggest that the excitation energy of the reactive triplet may be close to the 71 kcal Zimmerman estimated from the phosphorescence spectrum of 35. On the other hand, lumi-santonin, also an enone, must have a relatively low-energy reactive triplet, since its rearrangement is sensitized by Michler s ketone.401 From a Stern-Volmer plot of the effect of naphthalene on the quantum yield for photorearrangement of 35, kjkr was measured to equal 7000.416 Thus if naphthalene quenches triplet 35 at the diffusion-con-... 

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... 

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... 

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