Masatomo Nojima

Synthesis, crystal structure and anti-malarial activity of novel spiro-1,2,4,5-tetraoxacycloalkanes

(Cycloalkylidene)bishydroperoxides 3 react with 1,n-dihaloalkanes (n = 3–6) in the presence of CsOHH 2 O in DMF affording the corresponding spiro-1,2,4,5-tetraoxacycloalkanes 4 in moderate yields. Compound 4ba exhibits significant antimalarial activity in vitro against P. falciparum .

Synthesis of novel macrocyclic peroxides by bis(sym-collidine)iodine (I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides and unsaturated alcohols

Bis(sym-collidine)iodine (I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides, prepared by a variety of different methods, afforded the corresponding 10- to 20-membered macrocyclic peroxides having two or three peroxide units located within one ring in moderate yields. By analogy, cyclization of unsaturated alcohols having one or two peroxide bond in the chain afforded the corresponding cyclic ethers. The efficiency of the latter reactions were found to be a function of the structure of the alcohols.

SYNTHESIS, CRYSTAL STRUCTURE AND ANTIMALARIAL ACTIVITY OF NOVEL 1,2,5,6-TETRAOXACYCLOALKANES FROM 2,3-DIHYDROPEROXY-2-PHENYLNORBORNANE

Abstract Photooxygenation of 2-phenylnorbornene 1 in the presence of 30% aqueous hydrogen peroxide in acetonitrile afforded the labile 1,2-bis-hydroperoxide 3 which could be cycloalkylated to provide the tricyclic peroxides 5 , albeit in low yield, on treatment with silver oxide and a 1,ω-diiodoalkane. Trimethylsilylation of 3 , followed by TMSOTf-catalyzed cyclocondensation with carbonyl compounds led to the formation of the tricyclic peroxides 8 containing a 1,2,4,5-tetroxepane structure. The structures of two novel tricyclic peroxides 5a and 8a were unambiguously determined by the X-ray crystallographic analysis.

Determination of absolute configuration of trans-2-arylcyclohexanols using remarkable aryl-induced 1H NMR shifts in diastereomeric derivatives

Abstract A facile determination of the absolute configuration of trans-2-arylcyclohexanols was achieved. It takes advantage of the observations of the remarkable aryl-induced 1H NMR shifts that seems to be ascribable to the discrimination of the diastereo-environment between intermediary optically active diastereomers by intramolecular CH/π interaction.

1,2,4,5-Tetraoxacycloalkanes: Synthesis and Antimalarial Activity

In this short review the methods of preparation of novel 1,2,4,5-tetraoxacycloalkanes and the related peroxides are summarized, with the emphasis on the usefulness of 1,1-bishydroperoxides as the precursor. Also, their antimalarial activities in vitro and in vivo are discussed.

Yingzhaosu A analogues: synthesis by the ozonolysis of unsaturated hydroperoxides, structural analysis and determination of anti-malarial activity

Abstract Ozone-mediated cyclization of a series of unsaturated hydroperoxides 7, prepared from dienes 2, afforded the corresponding yingzhaosu A analogues 9 in moderate to high yield. X-Ray crystallographic analysis of two yingzhaosu A analogues, endo-9f and 13, showed that the 2,3-dioxabicyclo[3.3.1]nonane system adopts a chair–boat arrangement. Subsequent treatment of endoperoxides 9 with Ag2O/MeI afforded the expected methyldioxy-substituted cyclic peroxides 14, several of which showed notable anti-malarial activity against P. falciparum in vitro.

Synthetic methods for unsymmetrically-substituted 1,2,4,5-tetroxanes and of 1,2,4,5,7-pentoxocanes

Ozonolysis of vinyl ethers 1a–c in the presence of hydrogen peroxide in diethyl ether gave the corresponding 1,1-bis(hydroperoxide)s 2a–c. Subsequent trimethylsilylation, followed by the TMSOTf-catalyzed cyclocondensation with carbonyl compounds gave the unsymmetrically-substituted 1,2,4,5-tetroxanes 5–14. Similarly, the 1,2,4,5,7-pentoxocanes 18, 19 were prepared by the reaction of an α,α′-bis(trimethylsilylperoxy) ether 17 and carbonyl compounds. The tetroxane 14 showed notable antimalarial activity in vitro and in vivo.

Regio- and stereo-selective formation of 2-siloxy-2-alkoxyoxetanes in the photoreaction of cyclic ketene silyl acetals with 2-naphthaldehyde and their transformation to aldol-type adducts

Abstract Regio- and stereo-selective formation of bicyclo 2-siloxy-2-alkoxyoxetanes 7, 13, 14 was achieved by the proper choice of the solvent and the silyl group in the photoreaction of the cyclic ketene silyl acetals 6, 11, 12 with 2-naphthaldehyde 2 , and their transformation to the aldol-type adducts 9, 15, 16 was easily accomplished under the neutral conditions.

The synthesis and crystal structure analysis of novel macrocyclic peroxides

Abstract Bis(syn-collidine)iodine(I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides afforded the corresponding 11- to 16-membered macrocyclic peroxides having three peroxide units located within one ring. The crystal structures of three novel macrocyclic triperoxides were unambiguously determined by X-ray analysis.

Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, N-89 and N-251.

The endoperoxide artemisinin is a current first-line antimalarial and a critical component of the artemisinin-based combination therapies (ACT) recommended by WHO for treatment of Plasmodium falciparum, the deadliest of malaria parasites. However, recent emergence of the artemisinin-resistant P. falciparum urged us to develop new antimalarial drugs. We have shown that synthetic endoperoxides N-89 and its hydroxyl derivative N-251 had high antimalarial activities both in vivo and in vitro. However, the mechanisms including the cellular targets of the endoperoxide antimalarials are not well understood. Thus, in this study, we employed chemical proteomics to survey potential molecular targets of endoperoxides by evaluating P. falciparum proteins capable to associate with endoperoxide structure (N-346, a carboxyamino derivative of N-89). We also analyzed the protein expression profiles of malaria parasites treated with N-89 or N-251 to explore possible changes associated with the drug action. From these experiments, we found that P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC) had high affinity to the endoperoxide structure (N-346) and was decreased by treatment with N-89 or N-251. PfERC is a member of CREC protein family, a potential disease marker and also a potential target for therapeutic intervention. We propose that the PfERC is a strong candidate of the endoperoxide antimalarials target.