The singlet oxygen reactions of sterically crowded allylic alcohols result in the preferential formation of γ‐hydroperoxy alcohols with regioselectivities up to 98:2. The kinetic cis effect still prevails in the first, rate‐determining step of this two‐step non‐intermediate ene mechanism (kE‐5/kZ‐5=1.9). The primary allylic alcohol 3 showed no regioselectivity at all, increasing the steric demands at the α carbon and directing the singlet oxygen addition towards the γ carbon up to 98:2 regioselectivity. DFT calculations rationalized these results and show the decisive role of the symmetry‐breaking bifurcation following the early transition states. The use of the products as substrates for the synthesis of five‐ and seven‐membered ring peroxides, namely 4‐methylene‐1,2‐dioxolanes and 6‐methylene‐1,2,4‐trioxepanes, by rare earth metal complexes as Lewis acids is also demonstrated.

The singlet oxygen reactivities and regioselectivities of the model compounds 1b-d were compared with those of the geminal (gem) selectivity model ethyl tiglate (1a). The kinetic cis effect is k(E)/k(Z) = 5.2 for the tiglate/angelate system 1a/1a' without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes 1e-g. A vinylogous gem effect was observed for the γ,δ-dimethylated and α,γ,δ-trimethylated substrates 1h and 1i, respectively. The corresponding phenylated substrates 1j-l showed similar mode selectivity, as monomethylated 1j exhibited exclusively [4 + 2] reactivity while the tandem products 12 and 14 were isolated from the di- and trimethylated substrates 1k and 1l, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes 19 and 20 in an ene-diene transmissive cycloaddition sequence. These products were reduced to give alcohols (16, 17, and 18) or furans (24 and 25), respectively, or treated with titanium(IV) alkoxides to give the epoxy alcohols 26 and 27. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete.

The synthesis of 4-styryl-substituted 2,3,8-trioxabicyclo[3.3.1]nonanes, peroxides with the core structure of the bioactive 1,2,4-trioxane ring, was conducted by a multistep route starting from the aryl methyl ketones 1a–1c. Condensation and reduction/oxidation delivered enals 4a–4c that were coupled with ethyl acetate and reduced to the 1,3-diol substrates 6a–6c. Highly diastereoselective photooxygenation delivered the hydroperoxides 7a–7c and subsequent PPTS (pyridinium-p-toluenesulfonic acid)-catalyzed peroxyacetalization with alkyl triorthoacetates gave the cyclic peroxides 8a–8e. These compounds in general show only moderate antimalarial activities. In order to extend the repertoire of cyclic peroxide structure, we aimed for the synthesis of spiro-perorthocarbonates from orthoester condensation of β-hydroxy hydroperoxide 9 but could only realize the monocyclic perorthocarbonate 10. That the central peroxide moiety is the key structural motif in anticancer active GST (glutathione S-transferase)-inhibitors was elucidated by the synthesis of a 1,3-dioxane 15—with a similar substitution pattern as the pharmacologically active peroxide 11—via a singlet oxygen ene route from the homoallylic alcohol 12.

The primary chemical reactions of singlet molecular oxygen with polyunsaturated carotenoids are the focus of this research report. Model compounds that exhibit electronic properties and substituent pattern similar to natural carotenes, xanthophylls or apocarotenoids, respectively, were investigated with regard to photooxygenation reactivity. For dienes and trienes as substrates, high tandem reactivity was observed and hydroperoxy-endoperoxides were isolated as the secondary products of singlet oxygen reaction. The electronic gem-effect on the regioselectivity of the ene reaction is conserved also in vinylogous positions and thus appears to originate from a radical-stabilizing effect. In an attempt to combine different peroxide groups derived from natural products as a tool for new pharmaceutically active products, a dyade synthesis of an artemisinine-safranol with subsequent singlet oxygen addition was realized.

Tandem singlet oxygen reactions photocatalyzed by meso-tetraphenylporphyrin were performed with substrates designed for primary a-gemselectivity or high vinylogous gem-selectivity. The 1,3,5-triene ester 1 was designed as a model compound for the natural compound crocin and resulted in a highly regioselective singlet oxygen ene reaction with e-hydrogen activation (93:7 ene vs. [4 + 2] cycloaddition). The initially formed hydroperoxide 2a adds another singlet oxygen molecule in a slower reaction step to furnish the endoperoxide 3a. From the hydroperoxide stage, oxygen transfer gives the epoxide 4, reduction leads to the allylic alcohol 2b and subsequent photooxygenation (to 3b) followed by reduction results in the furan derivative 5. The allylic alcohol could also be reacted with other dienophiles as shown for the PTAD adduct 6. From the 1,4-diene 7, a gem-regioselective singlet oxygen ene reaction generates a mixture of the hydroperoxides 8a and 9a. Product 8a adds another singlet oxygen molecule to give the endoperoxide 10a. Catalyst activity was demonstrated by analysis of the changes in the electronic absorption properties.