1,3,5-Trioxanes

A review of the chemistry and biological activity of artemisinin and related compounds has been published 07THC(9)1 . 

Several novel 3,5-bridged 1,2,4-trioxanes have been prepared from tetrahydroftirans 07T10189 and the synthesis of 6-arylvinyl and 6-adamantylvinyl 1,2,4-trioxanes has been reported 07JMC521 . 

Thermolysis of dispiro-l,2,4-trioxane 66 affords the macrocyclic ketolactone 67. P-Scission of the cyclohexane ring is accelerated by the a-methoxy in accord with DFT calculations 07OL5569 . 

Developments in artemisinin chemistry include the application of Heck coupling of lOP-allyldeoxoartemisinin to aryl iodides 05TL4243 and a Ru-catalysed self crossmetathesis reaction of artemisinin allylio ethers and alcohols which produces artemisinin dimers with high E/Z selectivity and without affecting the endoperoxide bridge 05OL5219 . 

The search for antimalarials based on, but of simpler structure than, artemisinin continues. The photooxygenation of allylio alcohols generates P-hydroxyhydroperoxides and these react with alioyolio ketones including adamantanone 05BMC595 and cyclohexane- 

The fast In-catalysed cyclotrimerisation of aldehydes affords excellent yields of 1,3,5-trioxanes 05SC2801 . 

6-disilylated-3-vinyl-l,2-dithiins 38, obtained by the self-dimerisation of silylated allenes, undergo a Lewis aeid-promoted rearrangement to the bicyclic endodisulfide 05TL4711 . Tethered bilayer lipid membranes have been obtained using 4-hydroxy-l,2-dithianes as the anchor for coupling reactions with the lipid 05AJC738 . 

The base-promoted decomposition of 4-substituted l,3-dithiane-5-tosyUiydrazones 39 results in the formation of dithiins the regioselectivity is ca. 9 1 in favour of the 2,6-drhydro isomer. The reaction formed part of a synthesis of a-lipoic acid 05SL1129 . 

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Most ozonolysis reaction products are postulated to form by the reaction of the 1,3-zwitterion with the extmded carbonyl compound in a 1,3-dipolar cycloaddition reaction to produce stable 1,2,4-trioxanes (ozonides) (17) as shown with itself (dimerization) to form cycHc diperoxides (4) or with protic solvents, such as alcohols, carboxyUc acids, etc, to form a-substituted alkyl hydroperoxides. The latter can form other peroxidic products, depending on reactants, reaction conditions, and solvent. 

Cyclic 1,2,4-trioxanes (18 and 19) have been obtained from the photosensitized oxidation of fiirans (10,44,163). These compounds are... 

Trioxane 210 has been used as a model system by Gu and coworkers to study the antimalarial drug artemisinin 211 (Scheme 137) [97CPL234, 99JST103]. It is the boat/twist form rather than the chair conformer of 210 that describes the subunit in 211. Moreover, geometric parameters and vibrational frequencies can only reliably be computed at the DFT level and by post-Hartree-Fock methods. B3-LYP/6-31G calculations on the conformers of 3,3,6,6-tetramethyl-1,2,4,5-tetroxane show that the chair conformer is stabilized with respect to the twisted conformer by about -2.8 kcal/mol [00JST85]. No corresponding boat conformer was found. 

The mechanism of oxetane formation is similar to the one discussed for cyclobutane formation in chapter 4.3.3. The 1,4-diradicals can be efficiently trapped with molecular oxygen. The resulting 1,2,4-trioxanes are interesting synthetic intermediates (4.81) 495>. 

Studies on the mode of activity of the antimalarials related to artemisinin have centred on simpler 1,2,4-trioxanes, 1,2,4,5-tetraoxanes and bicyclic endoperoxides <00H(52)1345 00JCS(P1)1265 00JMC2753 00TL3145>. The chemical and electro-chemical reduction of artemisinin has been reported <00JCS(P1)4279>. 

The thermolysis of a variety of 1,2,4-trioxanes in methanol has been followed by mass spectrometry and provided evidence of the corresponding products. A smdy of the thermal decomposition of 3,6-diphenyl-1,2,4,5-tetroxane in toluene and methanol revealed a significant solvent effect that supported a homolytic stepwise mechanism instead of a concerted process. ... 

O Neill PM, Rawe SL, Borsmik K, Miller A, Storr RC, Ward SA, Bray PG Davies J, Ho Oh C, Posner GH. (2005) Enantiomeric 1,2,4-trioxanes display equivalent in vitro antimalarial activity versus Plasmodium falciparum... 

Posner GH, Oh CH, Webster HK, Ager ALJr, Rossan RN. (1994) New antimalarial tricyclic 1,2,4-trioxanes evaluation in mice and monkeys. Am J Prop Med Hyg 50 522-526... 

Artemisinin, a tetracyclic 1,2,4-trioxane isolated from Artemisia annua L., is currently recommended as a first-line agent against Plasmodium falciparum malaria. Artemisinin and its synthetic derivatives have also been shown to be promising prototypes for the development of new antiproliferative agents. This chapter presents the recent advances on the analytic methods for extraction and quantification of artemisinin from A. annua plants as well as the biological properties of this natural product. 

Recently, Jones et al. described the synthesis and antiproliferative activities of a series of C-12 carba artemisinin 1,2,4-trioxane-acridine hybrids 93-96 Fig. 7). HL-60 and HT-29 were more sensitive to hybrid 95 while the growth of MCF7 cancer cells and highly metastatic human breast cancer (MDA-MB-231) cells were dramatically affected by hybrids 95 and 93, respectively. Among all artemisinin 1,2,4-trioxane-acrimide hybrids evaluated, compound 92 was the least active against cancer cells. ... 

Also for 1,2,4-trioxane, from MM3 calculations, a structure close to a chair with the protons and substituents in axial and equatorial positions, respectively, was suggested [92JCS(CC)1689]. The substituted derivatives 63 (Scheme 25) have substituents R [Me, iPr, CH2HgBr, CH(HgBr)Me] in an equatorial position (all in agreement with standard conformational principles), and only in 64-66 were axial methyl substituents reported, based on NOE measurements and 7c-h coupling constants [92JCS(CC)1689]. 

The first ring expansion of a 1,2,4-trioxolane to a 1,2,4-trioxane was observed with (47) where the orientation of the peroxide group was crucial in assisting the triflate to leave (Equation (2)). A 1,2-peroxide shift then follows with loss of silicon giving the methylene substituted 1,2,4-trioxane (48) as the product <91JA8168>. The equatorial triflate does not undergo rearrangement. 

Section II covers the synthesis of the cyclic peroxides with medium ring size from 5 to 7. Section HI covers the synthesis of 1,2,4-trioxanes. Classification in sub-sections and sub-sub-sections is done according to the type of reaction by which the cyclic peroxide system is formed. Syntheses of dioxirans, 1,2-dioxetanes, trioxolanes (ozonides), tetrox-anes, and macrocyclic peroxides are not discussed in this review. 

AUylic alcohols constitute an alternative valuable source for the preparation of S-hydroperoxyalcohols suitable for peroxyacetalization to 1,2,4-trioxanes. A number of 3-alkyl-substituted allyl alcohols undergo a highly regio- and stereoselective ene-reaction with singlet oxygen to generate the corresponding /l-hydroperoxyalcohols. ... 

For example, such a photooxygenation of alcohols 569 lead to unsaturated alcohol-hydroperoxides 570, which react with ketones and aldehydes to give 1,2,4-trioxanes 571 characterized by a-styryl-substituents at the 6-position (Scheme Geraniol... 

Trioxanes were prepared through the intramolecular oxymercuration of various allylic peroxyhemiacetals and peroxyhemiketals . For example, 1,2,4-trioxanes... 

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 . ... 

Treatment of compound 222, containing a 1,2,4-trioxane ring fused to a cyclopentene ring, with O2 leads to formation of a hydroperoxide (223) with ene displacement, as shown in equation 76. The structure of 223 was determined by single-crystal XRD analysis. A contact of the hydroperoxy group with the endocyclic ether O atom of a neighboring molecule (287.4 pm) points to weak H-bonding. ... 

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