Santonin, reduction

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. 

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]. 

Deoxygenation. Greene has applied Kabalka s method for reduction of an enone (6, 98 7, 54) to the tosylhydrazone of a cross-conjugated ketone, 6-epi-a-santonin (2). Unexpectedly only one olefin (3) was obtained in 50% yield. This product was converted into the diene 4 by allylic oxidation, reduction to an allylic alcohol, and dehydration. The product was converted into (—)-dictyolene (5) by a method developed previously. ... 

Linearly conjugated dienones may be completely reduced to saturated alcohols using excess lithium in liquid ammonia. In variously substituted dienones, the less-substituted double bond is often selectively reduced under these conditions. For example, treatment of a steroidal 14,16-dien-20-one with lithium in liquid ammonia (with or without 1-propanol) leads mainly to reduction of the 16,17 double bond (Scheme 13), - and the less-substituted double bond of cross-conjugated steroidal dienones, - - - - santonin, or related substrates is selectively reduced under these conditions (Scheme 13). ° ... 

The dihydroxy-ketal (240), previously prepared from ( —)-santonin, has been used to synthesize a number of related sesquiterpenoids. Thus the diacetate of (240) was converted in six steps into (241), which was then treated with iso-propenyl acetate-sulphuric acid the derived enol-acetate was cleaved to the triol (242) by ozonolysis and lithium aluminium hydride reduction. The triol (242) was then converted into the di-iodo acetate (243) in a number of steps and thence to shyobunone (244) by dehydroiodination, reduction, and oxidation. Thermolysis of shyobunone at 160—180 °C gave preisocalamendiol (245) in about 30% yield. More recently, Iguchi et al. have shown that preisocalamendiol (245) can be cyclized to isocalamendiol (246) in aqueous acetic acid no trace of calamendiol (247) was found. A number of other interesting acid-catalysed cyclizations have been observed in this area, e.g. the formation of (248 R = OH) and (248 R = OAc) from (249) and the formation of (250) from (251). Finally, e-cadinene (252) has been obtained from (253), the lithium aluminium hydride product of preisocalamendiol (245). 

Saligenin, 719 Sandmeyer reaction, 1098 Santonin, 19, 608 (—)-j8-Santonin, 995 Sarcosine methyl ester, 1160 Sarett reagent, 145-146 Schiff bases, 139, 273, 318, 428, 430, 746, 788, 885 reduction, 1230 Schiemann reaction, 394,1140 Scopoletin, 790 ScylUtol, 1209 Sebacamide, 1265 Sebadc acid, 584, 1265 Sebadl, 159... 

Scheme 4 Compound (45) prepared from a-santonin (41), on reduction afforded alcohol (46), which was converted to derivative (48) by standard organic reaction. Irradiation of (48) in benzene at room temperature followed by reflux in tetrahydrofuran and 2-propanol, produced 15-oxime derivative (49). Its conversion to nitrile (50) was achieved by treatmente with acetic anhydryde in pyridine. Dehydration of (50) followed by decyanation, yielded compound (52). Its acetonide derivative (53), was converted to compound (54), whose convertsion to rishitin (40), was achieved by heating with 0.5% PPA in ethanol...

Scheme 9 Santonin (41) was converted to the derivative (99), whose conversion to alcohol (100) by metal hydride reduction and Mitsunobu reaction. Diol (102), prepared from (100), on acid catalysed cyclization and followed by subjection to Mitsunobu reaction, gave (104), which was converted to ketone (106), whose transformation to homoallylic alcohol (108), was achieved by standard organic reactions. Phenylselenylation afforded (110), which was finally converted to phytuberin.

Watanabe and Yoshikoshi have converted dihydro-a-santonin (213) into dihydronovanin (216 R = a-Me), the reduction product of novanin (216 R = =CH,), by a route which is not dissimilar to that used by Corey and Hortmann in the synthesis of dihydrocostunolide. Enol acetylation of (213) with isopropenyl acetate gave the diene (214) which, on photolysis and treatment with potassium hydroxide, yielded the dienone (215). Reduction of (215) with sodium borohydride and subsequent acetylation afforded (216 R = a-Me). 

Successful application of the Mitsonobu epimerization procedure to an eudesmanic alcohol 44 to bring about inversion of configuration at C(l) is the crucial step in the Harapanhalli synthesis of erivanin (50) from santonin (Scheme 7) [16]. Reduction of enone 43, prepared from santonin in 10 steps, with sodium borohydride furnished the )8-alcohol 44 as the sole product. This product results from the approach of the hydride anion from the less hindered Of-face of the molecule. The chemical modification of the C(3)-C(4) double bond to give a 3a-hydroxy-A4-i4 rnoiety was accomplished via the epoxide 46 and its rearrangement in a basic medium. Epoxidation of 44 with MCPA yielded only one product without any directing effect exerted by the homoallylic alcohol. Treatment of 46 with lithium diisopropylamide (EDA) afforded l-e/>/-erivanin (47). For the synthesis of erivanin (50), epimerization at C(l) prior to the A -modification sequence was required. Attempts to epimerize this carbon atom in 44 by acetolysis of the tosyl derivative 45 were unsuccessful as they led to eliminated product 13 (Scheme 3). 

A short-step synthesis of l-oxoeudesma-2,4-dien-l l)3i/-12,6a-olide (65), a sesquiterpene lactone isolated from Artemisia herba-alba, has been devised by Kawamata and coworkers [19]. The synthesis (Scheme 9) involved the reduction of santonin to compounds 36a and 36b and their oxidation with pyridinium chlorochromate (PCC) in CH2CI2 to give 9% of the rearranged product 65 and 30% of santonin. This procedure... 

The same authors have developed an alternative metiiod for the synthesis of 6)8-eudesmanolides from santonin (Scheme 15) [26]. The epimerization process at C(6) consisted of the LiAlH4 reduction of the trans-6oc- actone moiety in compound 122, followed by selective protection of the hydroxyl groups at C(3) and C(12), oxidation of C(6) to give compound 128, and stereoselective reduction of the carbonyl group by attack with sodium borohydride from the less hindered a-side. Re-lactonization was achieved by oxidation, after prior deprotection of the C(12)-hydroxyl group, with RuH2(Ph3P)4 or tetra- -propylammonium... 

Pioneering work in the synthesis of 8,12-eudesmanolides from santonin was carried out by Yamakawa and coworkers [47], These authors reported an allylic oxidation, with Cr(VI)-based oxidants, of methyl 3-oxoeudesm-1,4,6-trienoate (291) to give the corresponding 8-oxo-compound 294. Compound 291 was prepared from santonin (1) in a multi-step synthesis in 20% overall yield. Subsequent allylic oxidation of 291 with chromium reagents proceeded in low yield and the 8-oxo-compound (294) obtained in this way presented further difficulties when reduction of the carbonyl group at C(8) into a hydroxyl group was attempted. 

In recent years two procedures for the reductive cleavage of the C(6)-0 bond in santonin (1) and related sesquiterpene y-enone lactones that do not require prior epimerization at C(6) have appeared in the literature. 

In the second method, developed in our laboratory [65], reduction was achieved by treatment of the y-enone lactones with Zn in acetic acid assisted by ultrasound. The reaction proceeded extremely quickly and in good yields when the C(6)-0 bond was axial, as is the case in 105, 298, and 449. More interestingly, the reaction also took place with the most common trans-lactones in which the C(6)-0 bond is equatorial, as in 5, 149-151,155, and 171. However, with santonin (1) a complex reaction mixture was obtained. Although the yield of this method was somewhat lower in comparison with the aforementioned method, it was simpler and safer from the experimental point of view. 

Matsushima, A., M. E.F. Hegazy, G. Kuwata, Y. Sato, M. Otsuka, and T. Hirata, 2004. Biotransformation of enones using plant cultured cells—The reduction of a santonin. Proceedings of 48th TEAC, pp. 396-398. 

Artemisia maritima is a drug that was widely used in the past as anthelmintic and was later removed based on its severe side effects. Its biosynthesis is based on the methylene reduction of costunolide (23) and its proton activation and cyclization of germacrane core to provide eudesmyl cation (14). Sequential oxidative steps at C-1 and C-3 positions, followed by elimination of water, complete the route to a-santonin [19]. 

Sesquiterpene lactones with an eudesmane-6a-olide structure are abundant in nature and the biotransformations of some of them, such as a-santonin 87, have been extensively investigated [94]. Beside reduction products, using A. niger MEL 5024, several monohy-droxylated metabolites at positions C-8, C-11, and C-13 have recently been isolated [119], while a Pseudomonas strain (ATCC 43388), incubated with a-santonin in the presence of an ATPase inhibitor, accumulated a 4,5-dihydroxylated metabolite (88) [120]. 

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