Charles Jefford

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ABSTRACT Submission of racemic, cis-fused cyclopenteno-1,2,4-trioxanes (1 and 1-ent) to catalytic amounts of K2OsO4 and (DHQD)2PHAL and 1.2 equivalents of N-methylmorpholine N-oxide in aqueous acetone at 20°C (hybrid AD-mix-β) for 2 h gave the (-)-enantiomer, 1-ent (ee 95%) in 30% yield. The same reaction, but with (DHQ)2PHAL, (hybrid AD-mix-α) afforded the (+)-enantiomer, 1 (ee 95%) in 25% yield after 2.7 h reaction. Similar, efficient kinetic resolution of the racemic di-p-fluoro analogues (2 and 2-ent) was also achieved with the same reagents.

The activities of artemisinin (QHS) and a number of its semi-synthetic analogues, as well as Fenozan B07 (B07), a synthetic 1,2,4-trioxane, and arteflene (ATF), a synthetic surrogate of yingzhaosu, were compared in mice infected with drug-sensitive Plasmodium berghei or chloroquine-resistant P. yoelii ssp. NS. The studies were stimulated by the observation that B07, in certain aqueous preparations, appears to be equipotent by the subcutaneous (sc) or oral (po) routes in the rodent model but not in a simian model. In the rodent model, B07 was found to undergo rapid alteration (with a half-life of <24h) in an aqueous stock solution prepared using dimethyl sulphoxide (DMSO) to pre-dissolve the drug. Therefore, for all later experiments with aqueous preparations, the test material was newly formulated each day. In a carboxymethylcellulose formulation used as a 'standard suspending vehicle' (SSV), B07 and dihydroartemisinin (DIHYD) were found to be, respectively, one sixth and one 10th as active po as when the drugs were pre-dissolved in DMSO and then diluted with water. ATF in DMSO given po was less than one 20th as active as when used sc in the rodent model, and this drug in SSV was almost inactive po. The relatively low oral activity of these three compounds (especially DIHYD and ATF) may be attributable to extensive first-pass metabolism in the mouse. Oral beta-artemether (AM) and beta-arteether (AE) were highly active when used in SSV. ATF has been found to have low activity in simian models and clinical trials because of its poor absolute bio-availability. In in-vivo studies of the blood schizontocidal action of anti-malarials, in rodent malaria models, the data collected on the structure-activity relationships (SAR) of the drugs must be viewed critically when selecting specific compounds from a chemical series for further development. A study of the influence of drug formulation on the activity of other, novel antimalarials is crucial to the evaluation of the drugs, and merits high priority.

... Printed in Great Britain. Q 1994 IUPAC Concise enantiospecific syntheses of a-h yd roxy-a-am ino acids and i ndo I iz id i nes of natural origin Charles W. Jefford, Zhi-Hui Lu, Jian Bo Wan& ... Cheni. Soc. 105, 5470 (1983); PA Grieco, YS Hon and A. Perez-Medrano, .I. Am. Cheni. ...

A selective, heterogeneous oxidation using a mixture of potassium permanganate and cupric sulfate: (3aS,7aR)-hexahydro-(3S,6R)-dimethyl-2(3H)-benzofuranone reactant: 31 g (0.20 mol) of isopulegolintermediate: (−)-(1R,3R,4S,8R)-p-menthane-3,9-diolproduct: 3aS,7aR-hexahydro-3S,6R-dimethyl-2(3H)-benzofuranonereactant: 31 g (0.20 mol) of isopulegolintermediate: (−)-(1R,3R,4S,8R)-p-menthane-3,9-diolproduct: 3aS,7aR-hexahydro-3S,6R-dimethyl-2(3H)-benzofuranoneKeywords:annulation, heterocyclic-[5];cyclization, condensation;hydroboration;oxidation, CC  CH2-CH2oh;oxidation, CH2OH  CO2H;potassium permanganate-copper sulfate, preparation;tetrahydrofuranannulation, heterocyclic-[5];cyclization, condensation;hydroboration;oxidation, CC  CH2-CH2oh;oxidation, CH2OH  CO2H;potassium permanganate-copper sulfate, preparation;tetrahydrofuran

Thephotochemical reaction of [3(3)](1,3,5)cyclophane 2, which is a photoprecursor for the formation of propella[3(3)]prismane 18, was studied using a sterilizing lamp (254 nm). Upon photolysis in dry and wet CH2Cl2 or MeOH in the presence of 2 mol/L aqueous HCl solution, the cyclophane 2 afforded novel cage compounds comprised of new skeletons, tetracyclo[6.3.1.0.(2,7)0(4,11)]dodeca-5,9-diene 43, hexacyclo[6.4.0.0.(2,6)0.(4,11)0.(5,10)0(9,12)]dodecane 44, and pentacyclo[6.4.0.0.(2,6)0.(4,11)0(5,10)]dodecane 45. All of these products were confirmed by the X-ray structural analyses. A possible mechanism for the formation of these photoproducts via the hexaprismane derivative 18 is proposed. The photophysical properties in the excited state of the [3n]cyclophanes ([3n]CP, n = 2-6) were investigated by measuring the emission spectra and determining the quantum yields and lifetimes of the fluorescence. All [3n]CPs show excimeric fluorescence without a monomeric one. The lifetime of the excimer fluorescence becomes gradually longer with the increasing number of the trimethylene bridges. The [3n]CPs also shows excimeric phosphorescence spectra without vibrational structures for n = 2, 4, and 5, while phosphorescence is absent for n = 3 and 6. With an increase in symmetry of the benzene skeleton in the [3(3)]- and [3(6)]CPs, the probability of the radiation (phosphorescence) process from the lowest triplet state may drastically decrease.