Design and Synthesis of Endoperoxide Antimalarial Prodrug Models

O’Neill, Paul M.; Stocks, Paul A.; Pugh, Matthew D.; Araújo, Nuna; Korshin, É. E.; Bickley, Jamie F.; Ward, Stephen A.; Bray, Patrick G.; Pasini, Erica M.; Davies, Jill; Verissimo, Edite; Bachi, Mario D.

doi:10.1002/anie.200453859

Cited by 56 publications

(30 citation statements)

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“…Our present results reveal another novel mode of reactivity initiated by ET that could have implications not only on understanding the reduction mechanism of naturally occurring endoperoxides, but could also be useful in the design and synthesis of antimalarial prodrug models. [41] Experimental Section Materials: N,N-Dimethylformamide (DMF) was distilled over CaH 2 under a nitrogen atmosphere at reduced pressure. Tetraethylammonium perchlorate (TEAP) from Fluka was recrystallized three times from ethanol and stored under vacuum.…”

Section: Resultsmentioning

confidence: 99%

A Radical‐Anion Chain Mechanism Initiated by Dissociative Electron Transfer to a Bicyclic Endoperoxide: Insight into the Fragmentation Chemistry of Neutral Biradicals and Distonic Radical Anions

Magri

Workentin

2008

Chemistry A European J

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The electron-transfer (ET) reduction of two diphenyl-substituted bicyclic endoperoxides was studied in N,N-dimethylformamide by heterogeneous electrochemical techniques. The study provides insight into the structural parameters that affect the reduction mechanism of the O-O bond and dictate the reactivity of distonic radical anions, in addition to evaluating previously unknown thermochemical parameters. Notably, the standard reduction potentials and the bond dissociation energies (BDEs) were evaluated to be -0.55+/-0.15 V and 20+/-3 kcal mol(-1), respectively, the last representing some of the lowest BDEs ever reported. The endoperoxides react by concerted dissociative electron transfer (DET) reduction of the O-O bond yielding a distonic radical-anion intermediate. The reduction of 1,4-diphenyl-2,3-dioxabicyclo[2.2.2]oct-5-ene (1) results in the quantitative formation of 1,4-diphenylcyclohex-2-ene-cis-1,4-diol by an overall two-electron mechanism. In contrast, ET to 1,4-diphenyl-2,3-dioxabicyclo[2.2.2]octane (2) yields 1,4-diphenylcyclohexane-cis-1,4-diol as the major product; however, in competition with the second ET from the electrode, the distonic radical anion undergoes a beta-scission fragmentation yielding 1,4-diphenyl-1,4-butanedione radical anion and ethylene in a mechanism involving less than one electron. These observations are rationalized by an unprecedented catalytic radical-anion chain mechanism, the first ever reported for a bicyclic endoperoxide. The product ratios and the efficiency of the catalytic mechanism are dependent on the electrode potential and the concentration of weak non-nucleophilic acid. A thermochemical cycle for calculating the driving force for beta-scission fragmentation is presented, and provides insight into why the fragmentation chemistry of distonic radical anions is different from analogous neutral biradicals.

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Section: Resultsmentioning

confidence: 99%

A Radical‐Anion Chain Mechanism Initiated by Dissociative Electron Transfer to a Bicyclic Endoperoxide: Insight into the Fragmentation Chemistry of Neutral Biradicals and Distonic Radical Anions

Magri

Workentin

2008

Chemistry A European J

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“…The The O'Neill group employed the TOCO reaction for the synthesis of 2,3-dioxabicyclo[3.3.1]nonanes 69 (Scheme 35). 81 Hydroxyperoxide 70 generated from the TOCO reaction were reacted with cyclohexanone to afford 1,2,4-trioxanes 71. 82 They also employed this reaction in the synthesis of other 1,2,4-trioxepanes derivatives.…”

Section: A N U S C R I P Tmentioning

confidence: 99%

Recent advances in sulfur- and phosphorous-centered radical reactions for the formation of S–C and P–C bonds

et al. 2015

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“…The TOCO reaction of (R)-limonene (233) to give β-sulfanyl endoperoxides 234-239 is more effective when mediated by aromatic thiols than when mediated by aliphatic thiols (Scheme 54) 206 . Substitution of the methyl group of limonene 233 by the phenyl group as in 240 results in acceleration of the TOCO reaction and in a remarkable increase in yield of the corresponding bicyclic peroxide (72% for 241 as compared with 55% for 234) 207 . Cyclic peroxides like 228a,b and 234a,b served as intermediate compounds for the synthesis of potent antimalarial endoperoxides like 242a, 243a and 243b (Chart 2) 208 -210 .…”

Section: Thiyl and Selenyl Radical-mediated Domino Reactions Of Dienementioning

confidence: 99%

Synthesis of Cyclic Peroxides

Korshin

Bachi

2009

Patai's Chemistry of Functional Groups

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Design and Synthesis of Endoperoxide Antimalarial Prodrug Models

Cited by 56 publications

References 56 publications

A Radical‐Anion Chain Mechanism Initiated by Dissociative Electron Transfer to a Bicyclic Endoperoxide: Insight into the Fragmentation Chemistry of Neutral Biradicals and Distonic Radical Anions

A Radical‐Anion Chain Mechanism Initiated by Dissociative Electron Transfer to a Bicyclic Endoperoxide: Insight into the Fragmentation Chemistry of Neutral Biradicals and Distonic Radical Anions

Recent advances in sulfur- and phosphorous-centered radical reactions for the formation of S–C and P–C bonds

Synthesis of Cyclic Peroxides

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