Santonins

Dihydrocostunolide was synthesized from santonin as SM goal by a sequence in which the photochemical cleavage of a 6,6-fusion bond was a key step. 

Sxample There have been various attempts to generate optical activity without the investment of some optically active reagent. The most notorious is the alleged synthesis of optically active santonin (17) from in-... 

In aqueous acid cross-conjugated cyclohexadienones are principally photoconverted to one or more hydroxy ketones. In the case of a-santonin (1), isophotosantonic lactone (5) is formed in about 50% yield. A series of papers by Kropp and co-workers has aided in understanding this reaction/32-39-411 They have shown that the presence of a 4-methyl group (steroid numbering) results in the preferential formation of the 5-7 fused ring system (isophoto-... 

Show that the stereochemistry of lumisantonin and isophotosantonic lactone formed from a-santonin are consistent with the mechanisms presented in this chapter. 

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 discovery45 that santonin is converted by enneacarbonyldiiron in a thermal process into products that are akin to those from uncatalyzed photolysis has encouraged further work in this area. 

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)... 

This reduction of epoxy ketones has been used to prepare a number of santan-olides from the diepoxide (1) of a-santonin.2 Thus reduction of 1 is accompanied by dehydration of the intermediate tertiary alcohol to give dehydroisoerivanin (2) in 80% yield. 

Sanseveria cylindriea, 11 297 Santalex, 24 498 Santanaite, 6 471t SANTO a-Santonin, 24 549-550 Santonin rearrangement, 24 550... 

Of the multitude of ID 13C NMR experiments that can be performed, the two most common experiments are a simple broadband proton-decoupled 13C reference spectrum, and a distortionless enhancement polarization transfer (DEPT) sequence of experiments [29]. The latter, through addition and subtraction of data subsets, allows the presentation of the data as a series of edited experiments containing only methine, methylene and methyl resonances as separate subspectra. Quaternary carbons are excluded in the DEPT experiment and can only be observed in the 13C reference spectrum or by using another editing sequence such as APT [30]. The individual DEPT subspectra for CH, CH2 and CH3 resonances of santonin (4) are presented in Fig. 10.9. 

Fig. 10.9. Multiplicity edited DEPT traces for the methine, methylene and methyl resonances of santonin (4). Quaternary carbons are excluded in the DEPT experiment and must be observed in the 13C reference spectrum or through the use of another multiplicity editing experiment such as APT.

Fig. 10.13. 2D J-resolved NMR spectrum of santonin (4). The data were acquired using the pulse sequence shown in Fig. 10.12. Chemical shifts are sorted along the F2 axis with heteronuclear coupling constant information displayed orthogonally in F . Coupling constants are scaled as J/2, since they evolve only during the second half of the evolution period, t /2. 13C signals are amplitude modulated during the evolution period as opposed to being phase modulated as in other 13C-detected heteronuclear shift correlation experiments.

In an interesting reaction, -santonin was reduced with lithium in liquid ammonia so that the lactone was hydrogenolyzed to an add and one of the double bonds conjugated with the carbonyl was reduced. The other double bond as well as the keto group did not undergo reduction [1091]. 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

Herbs rich in colchicine Artemisia species rich in santonin... 

Similarly, the tricyclic trans-fused lactone 16 has been diastereoselectively methylated by the same method to give 17 in 97% yield15. The stereochemistry of the methylation was proved by converting 17 into /3-santonin (R = CH3 R1 = H). of known configuration. Protonation of the enolate derived from 17 is again completely diastereoselective and furnished the epimeric lactone 18 in 80% yield, which was converted into a-santonin (R = H R1 = CH3). 

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