Photooxygenation in polymer matrices: En route to highly active antimalarial peroxides

Abstract

Photooxygenation involving the first excited singlet state of molecular oxygen is a versatile method for the generation of a multitude of oxy-functionalized target molecules often with high regio- and stereoselectivities. The efficiency of singlet-oxygen reactions is largely dependent on the nonradiative deactivation paths, mainly induced by the solvent and the substrate intrinsically. The intrinsic (physical) quenching properties as well as the selectivity-determining factors of the (chemical) quenching can be modified by adjusting the microenvironment of the reactive substrate. Tetraarylporphyrins or protoporphyrin IX were embedded in polystyrene (PS) beads and in polymer films or covalently linked into PS during emulsion polymerization. These polymer matrices are suitable for a broad variety of (solvent-free) photooxygenation reactions. One specific example discussed in detail is the ene reaction of singlet oxygen with chiral allylic alcohols yielding unsaturated β-hydroperoxy alcohols in (threo) diastereoselectivities, which depended on the polarity and hydrogen-bonding capacity of the polymer matrix. These products were applied for the synthesis of mono- and spirobicyclic 1,2,4-trioxanes, molecules that showed moderate to high antimalarial properties. Subsequent structure optimization resulted in in vitro activities that surpassed that of the naturally occurring sesquiterpene-peroxide artemisinin.

Stereoselectivity in Ene Reactions with 1O2: Matrix Effects in Polymer Supports, Photo‐oxygenation of Organic Salts and Asymmetric Synthesis

“…In the extreme case of CCl 4 , the syn isomer dominated at approximately 92%; in methanol, the synlanti ratio drops to 2:1. In our hands, different polymers resulted in characteristic stereoisomer composition of the allylic hydroperoxides ( 5 ): Low diastereoselectivities were observed for polar polymers like polyhydroxybutyrate (PHB), polylactic acid (PLA) or in cellulose acetate films (55). In the current investigation, we have monitored the diastereoselectivity of the ene reaction of 4 in polystyrene beads as a function of the initial concentration of the substrate and its degree of conversion.…”

Diastereoselective schenck ene reaction of singlet oxygen with chiral allylic alcohols; access to enantiomerically enriched 1,2,4-trioxanes

“…[18][19][20][21][22] The diastereoselectivity of singlet oxygen photooxygenation of chiral allylic alcohols in non-polar solvents yields threo-b-hydroperoxy alcohols as the major product. [19][20][21][22][23][24][25][26][27] The hydroxy-directed regio and diastereoselective photooxygenation of chiral alcohols, to yield allylic hydroperoxides, was first discovered by Adam et al 26 Griesbeck et al utilised this diastereoselective photooxygenation to synthesise racemic threo-b-hydroperoxy alcohols that were in turn used to synthesise diastereomerically pure racemic chiral 1,2,4-trioxanes similar to trioxanes 1-8. [12][13][14]20,28 Dye-sensitised photooxygenation of achiral allylic alcohols has been used by Chandan Singh to obtain b-hydroperoxy alcohols, which were then used to synthesise 1,2,4-trioxanes.…”

“…[19][20][21][22][23][24][25][26][27] The hydroxy-directed regio and diastereoselective photooxygenation of chiral alcohols, to yield allylic hydroperoxides, was first discovered by Adam et al 26 Griesbeck et al utilised this diastereoselective photooxygenation to synthesise racemic threo-b-hydroperoxy alcohols that were in turn used to synthesise diastereomerically pure racemic chiral 1,2,4-trioxanes similar to trioxanes 1-8. [12][13][14]20,28 Dye-sensitised photooxygenation of achiral allylic alcohols has been used by Chandan Singh to obtain b-hydroperoxy alcohols, which were then used to synthesise 1,2,4-trioxanes. 29 To our knowledge no one has ever reported the synthesis of enantiomerically enriched chiral 1,2,4-trioxanes 1-8 described in Figure 2.…”

“…19,27 Diastereoselectivities (threo/erythro) were in the range of 91:9 to 92:8, which were similar to the previously reported data for similar alcohols. 12,19,20,22,[24][25][26][27] It was difficult to separate the major diastereomers of b-hydroperoxy alcohols 12-14, so they were used in the next step after purification by liquid chromatography (EtOAc/n-Hex).…”

Peroxide Dyads from Natural Artemisinin and Synthetic Perorthoesters and Endoperoxides

“…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.…”