1.3.5- Trioxepanes

In connection with studies on anthnalarial compounds, simpler mimics of artemisinin based on substituted 1,2,4-trioxepanes were examined. Examples include the 1,2,4-trioxepanes 152, 153 and 154, with the seven-membered ring being made by acid catalysed condensation of the appropriate ketone with the hydroxy hydroperoxide 151. Unfortunately the 1,2,5-trioxepanes were not active as antimalarials in vitro (up to 1000 nM) probably due to their resistance to Fe(II)-mediated degradation <06BMCL6124>. 

Aerobic Co(II) catalysed hydroperoxysiiyiation of allylic alcohols provides silyl peroxides that can be condensed with ketones to produce 1,2,4-trioxanes or 1,2,4-trioxepanes by a simple one-pot procedure (Scheme 35A). A recent improvement in the use of Co(acac)2 is the use of Co(thd)2 (thd = bis (2,2,6,6-tetramethyl-3,5-heptanedionato)). This more reactive catalyst allows cyclic allylic alcohols to be oxygenated and the resulting peroxysilyl alcohol can be transformed to spiro trioxanes, some of which have potent in vitro antimalarial activity (Scheme 35B). For example, compound 87 expresses activity around 20 nM (artemisinin = 10 nM). 

More recently, Nojima utilized the DBPO-TBHP procedure for making 1,2,4-trioxanes and trioxepanes from unsaturated hydroperoxy acetals (cf. Scheme 46) [82], The preparation of 1,2,4-trioxepanes is especially noteworthy since seven-membered cyclic peroxides have not been previously obtained by such pathways. 

Terminally unsaturated hydroperoxyacetals are cyclised to 1,2,4-trioxanes in moderate yields on treatment with N-halogenosuccinimides. When a non-terminal double bond is present, mixtures of the trioxane and a 1,2,4-trioxepane result <97JCS(P1)5>. Similar... 

The next structural study of polydioxolans of DP ranging from 7 to 70 by Plesch and Westermann [6] confirmed the regular structure of the polymer. It was also shown that when a polydioxolan was formed and then depolymerised in solution by perchloric acid, the only product was monomer. This is apparently in conflict with the findings of Miki, Higashimura, and Okamura [7] who reported that a reaction mixture, in which dioxolan had been polymerised for 3 hours at 35 °C by BF3-Et20, contained 1,3,5-trioxepan, 1,4-dioxane, trioxane, and other compounds. Most probably the difference is at least partly due to the long reaction time and the use of boronfluoride, which is well known to produce more side-reactions than protonic acids. 

For instance, Jaacks and Boehlke [16] reported that for 1 with perchloric acid in methylene dichloride at 30 °C, water caused the formation of 1,3,5-trioxepane, mol for mol, and... 

Other cyclic acetals that have been studied are 1,3,5-trioxane, 1,3,5-trioxepane, 1,3,6,9-tetraoxacycloundecane, and 1,3,5,7-tetroxocane (also referred to as 1,3,5,7-tetroxane) [Kawakami and Yamashita, 1979 Munoz-Escalona, 1978 Schulz et al., 1984 Szwarc and Perrin, 1979]. Polymerization of bicyclic acetals has been of interest for synthesizing polysaccharides [Good and Schuerch, 1985 Hirasawa et al., 1988 Okada, 1991 Okada et al., 1989 Sumitomo and Okada, 1984]. 

Polymerization of 1,3,5-trioxepane involves more complicated propagation-depropagation equilibria. The initially formed oxycarbocation XX loses formaldehyde to yield oxycarbocation XXI, which in turn loses 1,3-dioxolane to regenerate XX ... 

No information on 1,3,5-trioxepins and 1,3,5-trithiepins as well as on oxadithiepins and dioxathiepins appeared in CHEC(1984) or CHEC-II(1996). The monocyclic disubstituted 1,3,5-trioxepane was synthesized by multicomponent cyclocondensation (Section 13.16.9.5). The most common approach to various fused and bridged trioxepanes,... 

More complex reaction mixtures containing also trioxolanes 196, trioxepanes 197, and (with longer chains) a trioxocane were formed from cyclohexane-based unsaturated hydroperoxy acetals 195 (Equation 14) <1997JOC4949>. 

The formation of cyclic oligomers in the polymerization of tetrahydrofuran has not been observed (23). In the case of 1,3-dioxolane small amounts of oligomers going from dimer to nonamer have been isolated (24). Under the influence of borontrifluo-ride etherate in methylene chloride at 35 °C small amounts of 1,3,5-trioxepane are formed (25). Miki, Higashimura and Okamura (25) ascribed the formation of this substance to a backbiting reaction in the polymerization of dioxolane ... 

Tetraoxonane 113 underwent a ring contraction to afford 1,3,5-trioxepane 114, which is also observed as the main by-product of the tetraoxonane synthesis (Equation 2) <1998CC1809, 2001TL271> (Chapter 13.16). 

The first synthesis of 3-sila-l,2,4-trioxepane 208 was achieved by a two-step procedure involving initial ozonolysis of undecen-4-ol followed by bissilylation with BuSiSiOTf) , in the presence of imidazole (Equation 39). Compound 208 was separated by flash chromatography in 45% yield. Alkylation of 208 with alkyltrimethylsilane in the presence of SnCU gave alkylated silatrioxepane 209 in 5% yield <2005T4657>. 

Dihydro-3//-2,4-benzodioxepin, 472 7,7-Dimethyl-l,2,4-trioxepane, 472 3,3-Dialkyl-6-(l-phenylvinyl)-l,2,4-trioxane, 473... 

TEA, CuCl, NaH, DMSO, 10% aq. HCl/THF, 10% NaOH/MeOH, TsOH/MeOH, f-BuOK/THF, Pt/H2, FiAlH4. This group is not stable to BuFi. A 1,3-dioxolane can be cleaved in the presence of the trioxepane group. ... 

New investigations into the kinetics of monomeric formaldehyde copolymerization were subsequently conducted. In papers63,64 a degradation kinetics method for the analysis of polyacetal microstructure is proposed in paper6 5 is outlined a pyrolitie method based on a chromatographic determination of 1,3,5-trioxepane at the junctions of oxymethylene and dioxolane blocks. 

Fig. 9. Kinetic curves of the reagents conversion in liquid-phase cationic copolymerization of formaldehyde with 1,3-dioxolane. 1) 1,3 dioxolane consumption 2) 1,3,5-trioxepane yield 3) yield of ethylene oxide units in copolymer 4) yield of soluble polymer...

The process of formaldehyde copolymerization with dioxolane is characterized by the formation of a number of by-products with a dynamic equilibrium established among them60. To the previously found trioxepane and trioxane was later added a soluble copolymer whose composition is similar to that of polytrioxepane58 (Fig. 9). 

An interesting system related to those discussed previously was investigated by Schulz et al.200, namely a cationic polymerization of trioxepane. This monomer may be treated as a cyclic co-polymer of ethylene oxide (E) and two molecules of formaldehyde (M)... 

Its cationic polymerization yields a living polymer terminated by -0=CH2 group, whereas the energetically improbable -OCH2CH2+ group is never formed. Electrophilic attack of the -0=CH2 on oxygens of trioxepane yields two kinds of terminal sequences, either... 

Since the two modes of addition are equally probable, the resulting polymer has a random structure with hetero-diads such as MEMEMM and EMMMEM as well as homodiads, viz. EMMEMM and MEMMEM. Its degradation may yield other monomers than trioxepane. The latter results from the reactions... 

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