Synthetic Approaches to Mono- and Bicyclic Perortho-Esters with a Central 1,2,4-Trioxane Ring as the Privileged Lead Structure in Antimalarial and Antitumor-Active Peroxides and Clarification of the Peroxide Relevance

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

Strong Asymmetry in the Perepoxide Bifurcation Mechanism: The Large-Group Effect in the Singlet Oxygen Ene Reaction with Allylic Alcohols

The singlet oxygen reactions of sterically crowded allylic alcohols result in the preferential formation of g-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 (k(E-5)/k(Z-5)=1.9). The primary allylic alcohol 3 showed no regioselectivity at all, increasing the steric demands at the a carbon and directing the singlet oxygen addition towards the gamma 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

Singlet oxygen and natural substrates: functional polyunsaturated models for the photooxidative degradation of carotenoids

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

ChemInform Abstract: Singlet Oxygen and Natural Substrates: Functional Polyunsaturated Models for the Photooxidative Degradation of Carotenoids

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

Stereoselective Synthesis of Proline- Derived Dipeptide Scaffolds ( ProM-3 and ProM-7) Rigidified in a PPII Helix Conformation

Following a peptide coupling/metathesis-based strategy, the two diastereomeric scaffolds ProM-3 and ProM-7 were stereoselectively synthesized (as 9-fluorenylmethoxycarbonyl derivatives), and their configuration was unambiguously proven by means of X-ray crystallography. The required dehydroisoleucine building blocks were prepared by applying the enantioselective Kazmaier-Claisen rearrangement. The target compounds represent dipeptide analogs rigidified in a PPII helix conformation, which are of interest for the development of new proteomimetics that selectively bind to protein domains specialized in the recognition of ligands adopting a PPII helix secondary structure

Studies towards the synthetic applicability of biocatalytic allylic oxidations with the lyophilisate of Pleurotus sapidus

The edible fungus Pleurotus sapidus (PSA) is a particularly interesting biocatalytic system for allylic oxidation and has a remarkably broad substrate range from terpenoids to fatty acids. The oxidations are most likely catalyzed by a lipoxygenase and involve the formation of peroxides via radical intermediates in the first rate-limiting step. We provide herein a rationalization of the observed regioselectivity of these conversions by means of computational determination of bond dissociation enthalpies of a set of tailor-made spirocyclic terpenoids. It was found that only strongly activated allylic positions (BDH298 of <80 kcal/mol) with neighboring heteroatoms or with activating alkyl groups are oxidized to the corresponding unsaturated lactones or enones, respectively. With the synthesis and purification of allylic hydroperoxide intermediates, we have been able to characterize the putative direct precursors of enones in PSA oxidations. Our results suggest a two-step oxidation mechanism involving hydroperoxide intermediates which are rapidly converted to the observed enones by an enzymatic reaction. (C) 2015 Elsevier B.V. All rights reserved

Ene-Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The Vinylogous Gem Effect and Its Use for Polyoxyfunctionalization of Dienes

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 gamma,delta-dimethylated and alpha,gamma,delta-trimethylated substrates 1h and 1i, respectively. The corresponding phenylated substrates 1j-1 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

Ene–Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The <i>Vinylogous Gem Effect</i> and Its Use for Polyoxyfunctionalization of Dienes

The singlet oxygen reactivities and regioselectivities of the model compounds <b>1b</b>–<b>d</b> were compared with those of the geminal (gem) selectivity model ethyl tiglate (<b>1a</b>). The kinetic cis effect is <i>k</i>_<i>E</i>/<i>k</i>_<i>Z</i> = 5.2 for the tiglate/angelate system <b>1a</b>/<b>1a′</b> 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 <b>1e</b>–<b>g</b>. A vinylogous gem effect was observed for the γ,δ-dimethylated and α,γ,δ-trimethylated substrates <b>1h</b> and <b>1i</b>, respectively. The corresponding phenylated substrates <b>1j</b>–<b>l</b> showed similar mode selectivity, as monomethylated <b>1j</b> exhibited exclusively [4 + 2] reactivity while the tandem products <b>12</b> and <b>14</b> were isolated from the di- and trimethylated substrates <b>1k</b> and <b>1l</b>, 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 <b>19</b> and <b>20</b> in an ene–diene transmissive cycloaddition sequence. These products were reduced to give alcohols (<b>16</b>, <b>17</b>, and <b>18</b>) or furans (<b>24</b> and <b>25</b>), respectively, or treated with titanium­(IV) alkoxides to give the epoxy alcohols <b>26</b> and <b>27</b>. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete