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The 3-(hydroxymethyl)-3,4,4-trimethyl-1,2-dioxetane (HTMD) highly efficiently damages DNA compared to the merely alkyl-substituted derivative 3,3,4,4-tetramethyl-1,2-dioxetane (TMD). To elucidate this difference in oxidative reactivity, two additional hydroxymethyl-substituted 1,2-dioxetanes, namely cis/trans-3-(hydroxymethyl)-3,4-dimethyl-4-(phenylmethyl)- (1α/1β) and 3-(hydroxymethyl)-4,4-dimethyl-3-(phenylmethyl)-1,2-dioxetane (2), were investigated in regard to their photochemical and photobiological properties. The high genotoxic effects of the hydroxymethyl-substituted 1,2-dioxetanes, which are reflected in the significant formation of single-strand breaks in plasmid pBR 322 DNA and the efficient oxidation of guanine in calf thymus DNA and the nucleoside 2'-deoxyguanosine (dGuo), are for the first time understood in terms of radical chemistry. The reactivity order of the dioxetanes 1α/1β > HTMD > 2 ≫ TMD to damage DNA parallels the propensity of these dioxetanes to generate radicals. These reactive species are formed in the thermolysis of the dioxetanes through α cleavage of the intermediary triplet-excited α-hydroxy- and α-phenyl-substituted carbonyl products. The presence of radicals was confirmed by spin-trapping experiments with 5,5-dimethyl-1-pyrroline N-oxide and by laser-flash photolysis. These carbon-centered radicals are efficiently scavenged by molecular oxygen to produce peroxyl radicals, which are proposed as the active DNA-damaging species in the thermal decomposition of the hydroxymethyl-substituted 1,2-dioxetanes HTMD, 1α/1β, and 2.

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In view of their ability to serve as an efficient source of excited carbonyl products, I ,2-dioxetanes have been the subject of intensive investigation for almost twenty years." J However, aside from unimolecular fragmentations in excited carbonyl compounds, only little was hitherto known about the chemical transformations of these strained peroxides. One of the first reactions of 1,2-dioxetanes with heteroatomic nucleophiles to be reported was their deoxygenation by phosphanes.r21 Biphylic insertion into the peroxide bond first yields a pentacovalent intermediate, which, after thermal elimination of phosphane oxide affords the epoxide. Also the reaction of dioxetanes with sulfidesr3] generates epoxides, whereas lithium aluminum h~dride,[~I t h i~l s [~l and biologically relevant reductants,16] such as ascorbic acid or NADH, reduce 1,2-dioxetanes to 1,Zdiols. Moreover, although reactions of cyclic acyl peroxides['] with x-nucleophiles, e.g. olefins, are quite common, such transformations do not appear to be known in the case of dioxetanes. In this communication we report the cycloaddition of 3,3-disubstituted 1,2-dioxetanes 1 with electron-rich olefins 2 to afford unusual products, whose structure depend on the type of olefin and solvent employed (Scheme 1, Table 1). The dioxetane 1 a was synthesized as described in the literature.[*] The previously unknown halogen-substituted derivatives 1 b and lc['I were prepared from the corresponding p-bromohydroperoxides according to the usual Kopecky method.l4] The reaction of dioxetane l c with tetraethoxyethene 2a and 1 ,4-dioxene 2 b, electron-rich olefins without allylic hydrogen, afforded the dioxane derivatives 3 in good yields; cleavage of the dioxetane into carbonyl fragments occurred only to a small extent (Table l), and deoxygenation to epoxides was not observed. The moisture-sensitive orthoester product 3a (m.p. 47-48 "C) showed characteristic singlets at 6 = 108.8 and 109.4 in the I3C-NMR spectrum (CDCI,, 63 MHz) for the orthoester carbon atoms. The cycloadduct 3b formed from dioxetane 1 c and 1 ,Cdioxene 2 b, was established as its cis isomer (coupling between the acetal protons: J = 1.6 Hz) and was isolated as the diastereomeric mixture (52:48). In contrast, reaction of the 2,3-dimethylbenzo-l,4-dioxene 2c with dioxetane l c furnished the ene product 4a as the main product (two diastereomers, 59:41), together with appreciable amounts of a-bromoacetophenone as cleavage product from dioxetane 1 c (Table 1). Epoxides or cycloadducts 3 were not observed. In a similar way, 1,2-dimethylcyclopentene 2d and 2,3-dimethyl-2-butene 2e gave with dioxetane l c the corresponding ene products, namely the pmethylene-fY-hydroxy ethers 4 b, c; two diasteromers (77 : 23) were found for the ene product derived from olefin 2d. No cycloadducts 3 were detected, but cleavage into carbonyl products and deoxygenation of the dioxetane 1 c leading to 2-bromomethyl-2-phenyloxirane, together with the corresponding oxygen transfer products 1,2-dimethyl-I ,2-epoxycyclopentane 5 a[' l a ] a...

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