Peroxide Dyads from Natural Artemisinin and Synthetic Perorthoesters and Endoperoxides

Abstract

P e r o x i d e D y a d s f r o m N a t u r a l A r t e m i s i n i nAbstract: The hydroxyethyl-substituted bicyclic perorthoesters are building blocks for the coupling with artesunic acid. Peroxides were synthesized in a three-step process from unsaturated aldol adducts by singlet oxygenation and subsequent acid-catalyzed peroxyacetalization. Coupling to artesunic acid by the Mitsonobu method furnised the trioxane dyad in moderate yields. Late introduction of an endoperoxide bridge was achieved from the dehydroartemisininsorbinol adduct via photooxygenation.Artemisinin A is a remarkable lead structure for an expanding family of cyclic peroxides that have been prepared and investigated as antimalarials in recent years. 1 The basic pharmacophor is a 1,2,4-trioxane in A, but also others structures such as trioxolanes (sec-ozonides) or 1,2,4,5-tetroxanes have been identified as highly active motifs. 2 It is evident that the peroxide group in these compounds is correlated with molecular activation by the hemoglobin iron in the red blood cell. The intoxication of the malaria plasmodium parasite is either a consequence of subsequent protein-radical interactions or of the inhibition of the hemozoin aggregation and the production of toxic-free iron(III)protoporphyrin. 3 Figure 1The antimalarial artemisinin A and the 1,2,4-trioxane containing 2,3,8,9-tetraoxobicyclo[3.3.1]nonane skeleton BWe were the first to describe the synthesis of a new family of perorthoesters with the 1,2,4-trioxane substructure: the 2,3,8,9-tetraoxabicyclo[3.3.1]nonanes B (Figure 1). 4 This approach takes use of the well-established photooxygenation of allylic alcohols to give b-hydroperoxy alcohols 5 and subsequent peroxyacetalization to 1,2,4-trioxanes. 6 The bicyclic peroxides B were synthesized from allylic alcohols with an additional bishomoallylic hydroxy group.Following the recently published remarkably enhanced activity effects obtained for dimeric dehydrartemisinin adducts, 7 we became interested in coupling of the new trioxane derivatives to the natural artemisinin skeleton thus producing dyades of natural and unnatural peroxide A-B motifs. In order to couple B, an additional functional group was necessary, and we decided to use a third hydroxy group for esterification with artesunic acid. The allylic alcohol function was installed by aldol addition of the acetoacetate dienolate with 3-methylcrotonaldehyde (Scheme 1). 8 Subsequent reduction of the central carbonyl group was achieved by two stereodivergent ways: syn reduction was performed by methyl dimethylborinate chelation and borohydride reaction with excellent diastereoselectivity to give syn-2, 9 anti-2 was obtained by directed hydride addition with triacetoxyborate as chirality and hydride-transfer reagent. 10 Scheme 1 Synthesis of 1,3-diols 2 from ethyl acetoacetate. Reagents and conditions: a) double deprotonation with LDA (2.5 equiv) in THF at -78°C; b) aldol addition with 3-methyl crotonaldehyde (1.2 equiv) at -78°C. Reduction of the aldol adduct 1: c) Et 2 BOMe, NaBH 4 , THF,...

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

“…At the same time, however, reports appeared that describe the appearance of malaria-producing plasmodium species resistant against artemisinin and artemisinin-derivatives [53,54]. Three approaches currently try to deal with this fatal trend: a) artemisinin combination therapy (ACT, with other non-peroxidic antimalarial drugs) [55], b) new peroxidic substances following the structural prototype [56,57], c) dyade concepts [58] involving structure combinations of two artemisinin monomers [59], artemisinin and quinolines [60], or artemisinin derivatives with synthetic 1,2,4-trioxane structures [61,62]. In this context, also the natural endoperoxide ascaridole was described as one potential dyade partner molecule [63].…”

Singlet oxygen addition to cyclo-1,3-hexadienes from natural sources and from organocatalytic enal dimerization

“…10,11 Three approaches are currently under investigation to deal with this fatal trend: a) artemisinin combination therapy (ACT, with other non-peroxidic antimalarial drugs), 12 b) new peroxidic substances following the structural prototype, 13,14 c) dyade concepts 15 involving structure combinations of two artemisinin monomers, 16 artemisinin and quinolines, 17 or artemisinin derivatives with synthetic 1,2,4-trioxane structures. 18,19 In this context, ascaridole was also described as one potential dyade partner molecule. 20 To explore new structural motifs, we envisaged other natural occuring terpenoids with pre-endoperoxide structures.…”

Spirofused and Annulated 1,2,4‐Trioxepane‐, 1,2,4‐Trioxocane‐, and 1,2,4‐Trioxonane‐Cyclohexadienones: Cyclic Peroxides with Unusual Ring Conformation Dynamics

“…[12] Furthermore,d yads (in addition to hybrids and dimeric structures) [13] composed of natural artemisinin derivatives and synthetic trioxanes were generated. [14] To expand these compound families,w es ynthesized as eries of ester-substituted 1,2,4-trioxanes (e.g., 2), which were found to be remarkably strong glutathione transferase (GST) inhibitors. [15] The(homo)allylic alcohol/singlet oxygen approach to allylic hydroperoxides that was used for these processes limits the reaction to 1,2,4-trioxanes [12] and seven-membered analogues such as compound 3.…”