Thomas D. Avery

Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

ABSTRACT Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.

Synthesis and Chemistry of 2,3-Dioxabicyclo[2.2.2]octane-5,6-diols

1,4-Disubstituted 2,3-dioxabicyclo[2.2.2]oct-5-enes were dihydroxylated with osmium tetroxide to yield diols anti to the peroxide linkage in a highly selective manner. Reduction of the peroxide bond furnished cyclohexane-1,2,3,4-tetraols with toxocarol relative stereochemistry in excellent yield. This new methodology was employed to synthesize the natural product (1S,2R,3S,4R,5R)-2-methyl-5-(propan-2-yl)cyclohexane-1,2,3,4-tetrol (1) in a short sequence from (R)-alpha-phellandrene. Moreover, during the study of the chemistry of 2,3-dioxabicyclo[2.2.2]octane-5,6-diols a hitherto unknown rearrangement was discovered which has wide applicability for the synthesis of 1,4-dicarbonyls, including optically enriched synthons. A broad range of mechanistic investigations applicable to this rearrangement are also reported.

A Concise Route to β-Cyclopropyl Amino Acids Utilizing 1,2-Dioxines and Stabilized Phosphonate Nucleophiles

1,2-Dioxines react with glycine-derived phosphonate nucleophiles via a multistep cascade reaction to give beta-cyclopropyl amino acid derivatives in good yield with excellent control of the cyclopropane stereocentres. The cyclopropyl ketones were oxidized to the corresponding carboxylic esters using Baeyer-Villiger conditions. Standard deprotection protocols produced a series of known beta-cyclopropyl amino acids that are selective and potent agonists or antagonists of the metabotropic glutamate receptors in excellent yields.

The first total synthesis of natural grenadamide

A concise, high yielding route to the naturally occurring enantiomer of grenadamide utilizing a 3,6-disubstituted 1,2-dioxine starting material is presented. The route allows for ease in synthesizing grenadamide derivatives varying at cyclopropyl carbons 2 and 3, with access to both enantiomers. Evidence for phosphorus-assisted deprotonation of 1,2-dioxines is also discussed.

Carbenoid insertion into the peroxide bond vs the olefin bond of cyclic peroxides.

Herein we report examples of the insertion of a carbenoid into a peroxide linkage. This study reveals that intramolecular insertion of carbenes into the peroxide linkage of 3,6-dihydro-1,2-dioxines is preferred over olefin insertion. The initial scope of the reaction and mechanistic considerations, have been probed. This methodology also generates unusual bicyclic hemiacetals (2) and tricyclic peroxides (3).

Crystal structure of tert-butyl 2-(2-benzoyl-3-phenylcyclopropyl)acetate, C22H24O3

C22H24O3, orthorhombic, P2\2\2\ (No . 19), a = 5 . 8 6 2 3 ( 4 ) Ä, b = 8 . 5 8 3 5 ( 4 ) A, c = 3 5 . 8 6 4 ( 2 ) A, V= 1804 .6 A 3 , Ζ = 4 , Rgl(F) = 0 .041 , wRK(<F) = 0 . 0 3 6 , T= 173 K.

Exploitation of ylide steric bulk to alter cyclopropanation outcome during the reaction of 1,2-dioxines and stabilised phosphorus ylides

A new approach for the synthesis of diastereomerically pure cyclopropanes from 1,2-dioxines and sterically bulky stabilised phosphorus ylides is presented.

New synthetic methodology utilising 1,2-dioxines and stabilised phosphorus ylides: a highly diastereoselective cyclopropanation reaction

A new method is described for the synthesis of diastereomerically pure cyclopropanes from substituted 1,2-dioxines 1a–c and stabilised phosphorus ylides 2a–e.