Santonin synthesis

Blay G, Bargues V, Cardona L et al (2000) Stereoselective synthesis of 7,ll-guaien-8,12-olides from Santonin. Synthesis of Podoandin and (+)-Zedolactone A. J Org Chem 65 6703-6707... 

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-... 

Synthesis of terpenoid compounds from tricyclic y-lactone a-santonin 93T4761. 

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. ... 

Corey and Hortmann achieved the synthesis of dihydrocostunolide (6) from santonin (1) by a process indicated in outline in the formulation. For the dehydro-bromination of (2) to (3) the method of Joly proved much superior (yield 80-90%) to... 

A full report on the preparation of the photo-adduct (590) from methylcyclo-butene and (—)-piperitone and its thermal conversion into the various shyobunones (591) and related sesquiterpenoids has appeared.267 Another synthesis of the cytotoxic compound (+)-deoxyvernolepin (592) Starting from a-santonin has been recorded.268... 

Although a number of natural products have enjoyed wide usage in the treatment of various helminth diseases of man and domestic animals prior to 1960, with the advent of more effective and safer synthetic anthelmintics most of them were eventually abandoned and are now of historical value only [52]. For example, santonin was included in 25th edition of the United States Dispensary (1955), but was removed from the U.S. Medical Compendium of National Formulary (1960). Similarly, aspidium oleoresin was included in the U.S. Pharmacopeia of 1960 and the full clinical usage of this drug was available in the U.S. Dispensary only until 1973 [1]. This makes the description of SAR and synthesis of most of the anthelmintic natural products less meaningful and is, therefore, not discussed in the present text. However, the SAR profile of avermectins and milbemycins is discussed, of which the former have in recent years been used extensively in the treatment of onchocerciasis and lymphatic filariasis in humans [20]. 

The synthesis of a- and P-santonins (la,b) has been described by Abe and coworkers [89]. The key intermediate for preparing santonins utilizes eusantonin (38) which is obtained by condensing 3-keto-4,9-dimethyl-l,2,3,7,8,9-hexahydro-naphthalene (37) with diethyl methylmalonate. The two different routes to arrive at a-and P-santonins are given in scheme 1. 

A stereocontrolled total synthesis of a-santonin (la) and the less stable P-san-tonin (lb) has been developed by Marshall and Wuts [90] which is outlined in scheme 2. 

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... 

Modification of the synthetic strategy previously used " in the synthesis of ( )-occidentalol (c/. Vol. 8, p. 103) has resulted in a new synthesis of a-santonin (418) and its less stable /S-epimer (419) (Scheme 36). An extension of previous... 

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... 

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. 

Masamune and collaborators have accomplished26 a total synthesis or rishitin (40) from a-santonin and this is described in Scheme 4. 

---