title: 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.
abstract: 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 ketones1a-1c. Condensation and reduction/oxidation delivered enals4a-4cthat were coupled with ethyl acetate and reduced to the 1,3-diol substrates6a-6c. Highly diastereoselective photooxygenation delivered the hydroperoxides7a-7cand subsequent PPTS (pyridinium-p-toluenesulfonic acid)-catalyzed peroxyacetalization with alkyl triorthoacetates gave the cyclic peroxides8a-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 hydroperoxide9but could only realize the monocyclic perorthocarbonate10. 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-dioxane15-with a similar substitution pattern as the pharmacologically active peroxide11-via a singlet oxygen ene route from the homoallylic alcohol12.
authors.affiliation: Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany. griesbeck@uni-koeln.de.
authors.forename: Axel G
authors.initials: AG
authors.lastname: Griesbeck
authors.affiliation: Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany. marialisa.braeutigam@googlemail.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Bräutigam
authors.affiliation: Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany. m.kleczka@uni-koeln.de.
authors.forename: Margarethe
authors.initials: M
authors.lastname: Kleczka
authors.affiliation: Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany. angela@raabe.com.
authors.forename: Angela
authors.initials: A
authors.lastname: Raabe
mesh_terms: D000085:Acetates / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis*; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D037621:Artemisinins / Q000138:chemical synthesis*; D001557:Benzenesulfonates / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D004952:Esters / Q000138:chemical synthesis*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006588:Hexanones / Q000737:chemistry; D010084:Oxidation-Reduction; D010545:Peroxides / Q000138:chemical synthesis*; D026082:Singlet Oxygen / Q000737:chemistry; D013141:Spiro Compounds / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: C503429:1,2,4-trioxane; D000085:Acetates; D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D001557:Benzenesulfonates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004952:Esters; D006571:Heterocyclic Compounds; D006588:Hexanones; D010545:Peroxides; D013141:Spiro Compounds; D026082:Singlet Oxygen; C007650:ethyl acetate
keywords: 1,2,4-trioxane; artemisinin; hydroperoxides; orthoester; peroxides; singlet oxygen