Trioxane lactone

In the laboratory of G.A. Posner, semisynthetic antimalarial trioxanes in the artemisinin family were prepared via an efficient Friedel-Crafts alkylation using a pyranosyi fluoride derived from the natural trioxane lactone artemisinin. The alkylating agent, pyranosyi fluoride, was prepared from the lactone in two steps reduction to the lactol followed by treatment with diethylaminosulfur trifluoride. The highly chemoselective alkylation was promoted by BF3-OEt2 and several electron-rich aromatic and heteroaromatic compounds were alkylated in moderate to high yield using this method. 

The 1,2,4-trioxane lactone structural unit that is part of artemisinin (9) has been synthesized by the laser irradiation of benzoquinone (170) and dihydro-4,4-dimethyl-2/7-pyran-2-one (179) under oxygen (Equation (24)) <88JOC4986>. Two regioisomeric c -fused trioxanes, (180) and (181), and the /rans-fused isomer (182) are obtained besides the pair of less and more hindered oxetanes in a ratio of 9 18 28 17 28 and yields of ca. 65%. 

Antimalarial drug artemisinine, sesquiterpenic 8-lactone with 1,2,5-trioxane (endoperoxide) fragment 98CSR273. 

Using various derivatives of artemisinic acid, the methodology onthned in Scheme 184 was extended to the synthesis of a nnmber of modified artemisinin-type tetracychc trioxanes. For example, the syntheses of 6,9-desdimethylartemisinin 586a , A-fi-hydroxyartemisinin , and C9-alkylated artemisinin analognes were reported . In some cases it is possible to avoid the lactonization step while preserving the ester fnnctionality and interrnpting the cychzation of aldehyde-peroxyhemiacetals of type 652, at the step of formation of tricyclic 5-hydroxy-1,2,4-trioxane . ... 

Some of the more important monomers whose ring opening polymerisations have been induced by stable cation salts include, 1,4-epoxides, notably tetra-hydrofuran (20,112,113), 1,2-epoxides (114), 1,3-episulphides (thietans) (33,53), 1,2-episulphides (thiiranes) (53), azetidines (115,116), aziridines (117), the cyclic formals, 1,3-dioxolan (23,54, 118-120), and 1,3-dioxepan (118,119), trioxane (121,122) and more recently lactones (123). Aldehydes (124) may also be included since these molecules can be regarded as the smallest possible oxygen hetero-... 

Long and his co-workers (Long, Dunkle, and McDevit, 75) have used the acidity function to decide whether or not a water molecule is present in the activated complex in the acid-catalyzed hydrolysis of 7-butyro-lactone. They found no correlation with Ho and therefore conclude that the water molecule is present in the activated complex. This is in contrast to their findings for the hydrolysis of /S-propiolactone. Paul (76) has studied the decomposition of trioxane in mixtures of perchloric acid and sodium perchlorate at constant perchlorate concentration (6 M) and found good correlation with the acidity function as determined by Harbottle (77). 

Adam, W., Kliem, U., Peters, E. M., Peters, K., Von Schnering, H. G. Preparative vis-laser photochemistry. Qinghaosu-type 1,2,4-trioxanes by molecular oxygen trapping of Patemo-Buchi triplet 1,4-diradicals derived from the bicyclic enol lactones D1,6- and D1,10-2-oxabicyclo[4.4.0]decen-2-one and p-benzoquinone. J. Prakt. Chem. 1988, 330, 391-405. 

Artemisinin and its antimalarial derivatives belong to the chemical class of unusual 1,2,4-trioxanes. Artemisinin is poorly soluble in water and decomposes in other protic solvents, probably by opening of the lactone ring. It is soluble in most aprotic solvents and is unaffected by them at temperatures up to 150 °C and shows a remarkable thermal stability. This section will focus on biological and pharmaceutical aspects synthetic routes to improve antimalarial activity and to synthesize artemisinin derivatives with differ-... 

A variation on this model has recently been proposed by Kelly et al. who suggested that the hydroxy group of the Criegee intermediate could not be immobilized in such a mechanism, and that unreasonable steric constraints would be imposed for many of the substrates transformed reported for these enzymes. A new tautomer of the the flavin hydroperoxide was proposed as part of an alternative scheme (lower cycle, Fig. 16.5-16) in which an intermediate trioxane decomposes to yield the lactone and flavin hydrate. 

The treatment of (9) with potassium carbonate in aqueous methanol at 25 °C unravels the lactone and trioxane rings. The first formed hydroperoxide (70) then reacts further to furnish the peroxide (71) and the epoxide (72) in 20% yield (Scheme 6) <86T4437>. 

From a prediction of the comparative molecular field analysis (CoMFA) trioxanes, four 8a,9-seco artemisinin analogs (50 1-4) which have no lactone were prepared and tested [42]. Their relative activity between predicted and actual activity were very similar and they were three to ten times more active than artemisinin. 

Antimalarial activity of 4,5-secoartemisinins (51 1-4) which consisted of 1,2,4-trioxane with a lactone has been reported [53]. (-)-5-Nor-4,5-secoartemisinin (51 2, Rj = CH3> R2= H, R3= CH3) was as effective as artemisinin against the D-6 clone. The same analogs which were prepared by using the prediction in CoMFA analysis showed that the differences of activity were small between the predicted and actual values [41]. 

Artemisinin (44) is a structurally complex cadinane sesquiterpene lactone bearing an endoperoxide group embedded in a 1,2,4-trioxane ring. With its unique juxtaposition of peracetal, acetal and lactone functionalities, it has very much to interest organic chemists. Totally synthetic routes to artemisinin have been developed [64], but their complexity suggests that they will very unlikely supplant the natural extract as drug source. 

The isomeric p-lactone 60 bearing two trifluoromethyl groups at a-carbon was obtained by cycloaddition of bis(trifluoromethyl)ketene (61) to formaldehyde generated from trioxane (Scheme 2.28). " ... 

Kerr and McCullough have reported the novel formation of the lactone (229), in fair yield, by the thermolysis of the trioxane (230). The reaction presumably proceeds via the diradical intermediate (231) (Scheme 23) <85CC590>. 

In fact, the importance of the cationic photopolymerization lies beyond epoxides (39). Many oxygen-containing compounds, e.g., vinyl ethers, tetra-hydrofuran, oxetane, lactones, trioxane, and some unsaturated compounds (Fig. 3) can be polymerized by the same mechanism to form adhesives or coating materials. Crivello (43) reviews the scope of cationic photopolymerization, providing us with a perspective on this promising process. 

Because of their free electron pairs or electron shell vacancies heteroatoms are particularly susceptible to attack by catalyst. Since heteroatom-containing groups react both by polycondensation and polyaddition mechanisms, they are especially readily catalyzed. The polymerization of rings with heteroatoms (lactams, lactones, trioxane, etc.) can also be easily initiated. On the same basis, however, deactivation of the chain can also occur frequently in these substances therefore, only low degrees of polymerization can be obtained. On the other hand, the activation of cycloalkanes in polymerization reactions proceeds with difficulty. The following discussion will therefore concentrate on the polymerization of rings and monomers with multiple bonds. 

---