1.2- Dioxepans

A high level of activity continues in connection with the synthesis of antimalarial artemisinin analogues and congeners, in which the 1,2-dioxepane moiety is embedded. Recent examples include the syntheses of various 10-substituted deoxoartemisinins of type 123 (eg. R1 = Cl COMe) from dihydroartemisinin acetate, and of type 124 (eg. R2 = a-OH, R3 = Me), from Grignard reagent addition to 10-(2-oxoethyl)deoxoartemisinin . 

Reactivity of (Nonartemisinin) Nonconjugated 1,2-Dioxepanes, 1,2-Oxathiepanes, and 1,2-Dithiepanes... 

The peroxide 0-0 bond is relatively weak therefore, reactions at another site of a molecule, which bears a peroxide function, are carefully controlled. The tolerance of the peroxy 0-0 bond to a number of metal hydrides including 1,2-dioxepane derivatives was studied (Equations 10-12). For example, 58 was examined with the targeted reduction site being an ester group. The peroxide bond survived these reduction conditions <2005JOC4240>. 

Synthesis of 1,2-dioxepane derivatives can be achieved through mainly four methods, three of which have the potential 0-0 bond already in one reactant, namely ozone, oxygen gas, or a hydroperoxide moiety. The fourth method involves the linking of two oxygen atoms to form a 1,2-dioxepine bond. 

Ozonolysis of a substituted ene function (as part of acyclic or cyclic structure) has been used extensively in the preparation of 1,2-dioxepane derivatives. A classic example of this reaction was the ozonolysis of ene 64 to yield artemisinin 1 in 35% yield (Equation 13) <1992JA974, 1997BML2357, 2002JME4321, 1996JME4149, 1996JME2900>. 

Ozonolysis of 1-methylcyclopentene in the presence of formaldehyde, acetyl chloride of benzoyl cyanide gave 1,2-dioxepane (trioxane) 66 (Equation 14). 

Similarly, the ozonolysis of acenaphthylene 67, under the above conditions, led to 1,2-dioxepane (trioxane) 68 (Equation 15) <2000EJ0335>. 

The conversion of a-(2,2,2-trifluoroethoxy)-a -hydroperoxide ether 69 to 1,2-dioxepane (trioxane) 70 bears resemblance to the above-cited reactions (Equation 16) <1998J(P1)3059>. 

Another interesting ozonolysis reaction is summarized by the conversion of 2-(2 -cyanoethyl)-l-(benzyloxymethyl-ene)cyclohexane 76 into 1,2-dioxepane (trioxane) 77 the experimental section cites a 92% yield (Equation 18) <2002JME3824, 2000BMC1361>. 

Dioxepane derivatives were made by the photolytic addition of an ene or 1,3-diene. Recently, an ene hydro-peroxylation-[4+2] cycloaddition with 02 of 78, followed by selective reduction, led to the formation of a mixture (1 1.5) of 1,2-dioxepanes 79 and 80, respectively (Equation 19). 

The reactions illustrated in Equations (22)—(26) the general utility of photooxygenation in the formation of 1,2-dioxepane derivatives. 

One report made use of the hydroperoxide moiety to prepare 1,2-dioxepanes in moderate to low yields (Equations 27 and 28) <1998J(P1)3053>. 

The antimalarial, artemisinin, which has an embedded 1,2-dioxepane moiety within its structure, together with a range of related synthetic peroxides, is treated in a detailed review by Jefford [01MI1803] structure-activity and mode of action considerations are also reviewed. 

The monocyclic saturated peroxides 196 have been prepared by the treatment of the respective hydroperoxides with lead tetraacetate (Scheme 94) <1981S633>. Another general approach to the 1,2-dioxepan ring system involves the ozonolysis of appropriate precursors with a double bond e.g., the ozonolysis of cyclopentene gives 1,2-dioxepan (trioxane) 197 . 

Dioxepane, the basic structure of 1,2-dioxepine, is actually a cyclic peroxide therefore, often appearing in the literature as an intermediary structure for further conversion. 

Introduction of a triflate group (trifluoromethanesulfonate) in the synthesis facilitates a convenient synthesis of the 1,2-dioxepane ring, according to the reaction sequence, as follows alkylation of the alkyltriflate with bis(trialkyltin)peroxide yields an oxonium intermediate. Expulsion of a... 

Unsaturated hydroperoxides (3) underwent cyclization when treated with mercuric nitrate or trifluoroacetate to give the )S-mercurated cyclic peroxides, which were isolated by HPLC as the alkyl mercuric bromides in ca. 40% yields, which were then reduced with borohydride to afford the cyclic peroxide, 1,2-dioxepane (4) (Scheme 2) <78JA7li6,78JOC4048>. 

Pentyl-hydroperoxide was prepared from the corresponding alcohol by oxidation with 50% H2O2 in the presence of 85% H3PO4 at 60°C for 6 h to give the hydroperoxide in 48% yield, which was then treated with Pb(OAc)4 in pentane under reflux for 18-45 h to generate 1,2-dioxepane (5) in 10-14% yield (Equation (1)) <81S633>. 

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