13858-85-0

Usage

Synthesis Reference(s)

The Journal of Organic Chemistry, 22, p. 1024, 1957 DOI: 10.1021/jo01360a007

InChI:InChI=1/C7H13NO/c1-9-8-7-5-3-2-4-6-7/h2-6H2,1H3

Upstream product

• 67-62-9 O-Methylhydroxylamin 
• 108-94-1 cyclohexanone 
• 100-64-1 cyclohexanone-oxime 
• 77-78-1 dimethyl sulfate 
• 1122-60-7 1-nitrocyclohexane 
• 74-88-4 methyl iodide 
• 105532-86-3 N,O-bis(trimethylsilyl)-N-methoxycarbamate 
• 67-56-1 methanol 
• 14371-10-9 (E)-3-phenylpropenal 
• 19731-71-6 cyclohexanone-O-(phenylmethyl)oxime 
• 420-37-1 trimethoxonium tetrafluoroborate 
• 2181-42-2 trimethylsulphonium iodide 
• 593-56-6 N-methoxylamine hydrochloride 

Downstream Products

• 105-60-2 caprolactam 
• 193805-51-5 3-Methyl-3-phenyl-1,2,4-trioxaspiro[5.4]decane 
• 1443469-77-9 C₉H₁₂F₃NO₂ 
• 1443469-88-2 2,2,2-trifluoro-N-[1-(4-methoxyphenyl)cyclohexyl]acetamide 
• 67-62-9 O-Methylhydroxylamin 
• 19731-71-6 cyclohexanone-O-(phenylmethyl)oxime 
• 134023-73-7 2-(1-Methoxyamino-cyclohexyl)-propan-2-ol 
• 108-94-1 cyclohexanone 
• 4278-87-9 dicyclohexylidenehydrazine 
• 502-42-1 cycloheptanone 

Relevant academic research and scientific papers

Activity-based protein profiling reveals that secondary-carbon-centered radicals of synthetic 1,2,4-trioxolanes are predominately responsible for modification of protein targets in malaria parasites

Endoperoxide-containing antimalarials, such as artemisinin and the synthetic trioxolane OZ439, are prodrugs activated by heme to generate primary and secondary carbon-centered radicals. We employed activity-based protein profiling (ABPP) to show that the

A click chemistry-based proteomic approach reveals that 1,2,4-trioxolane and artemisinin antimalarials share a common protein alkylation profile

In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based protein-profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi-quantitatively, suggesting a common mechanism of action that raises concerns about potential cross-resistance liabilities. Clickable 1,2,4-trioxolane activity-based protein-profiling probes (ABPPs) were designed to retain antimalarial activity and alkylate the molecular targets of the blood stage of Plasmodium falciparum in situ. Comparison of the 1,2,4-trioxolane protein alkylation signature with the corresponding artemisinin ABPPs indicates that both drug classes target key proteins in the glycolytic, hemoglobin degradation, antioxidant defence and protein synthesis pathways.

Titanium-Mediated Synthesis of Spirocyclic NH-Azetidines from Oxime Ethers

The TiIV-mediated synthesis of spirocyclic NH-azetidines from oxime ethers using either an alkyl Grignard reagent or terminal olefin ligand exchange coupling partner is described. Through a proposed Kulinkovich-type mechanism, a titanacyclopropane intermediate forms and serves as a 1,2-aliphatic dianion equivalent, inserting into the 1,2-dielectrophilc oxime ether to ultimately give rise to the desired N-heterocyclic four-membered ring. This transformation proceeds in moderate yield to furnish previously unreported and structurally diverse NH-azetidines in a single step.

Alkyloximes and imines via silyl carbamates

The reactions between different N,O-bis-trimethylsilyl-carbamates and oxo compounds were studied. The N,O-bis-trimethylsilyl-N-methoxy-carbamate converts ketones to the corresponding O-methyl oximes. The product is usually a mixture of syn and anti isomers. If the carbonyl compound bears a hydroxyl group, the oxime formation and the O-silylation take place simultaneously. In the case of -haloketones, the undesired substitution of halogen was not observed. The reactions between N,O-bis-trimethylsilyl-N-methyl-carbamate and oxo compounds resulted in the corresponding imines, although the yield are moderate in some cases. Analoguos reaction of ferrocenylated oxo derivatives gave similar results.

Rationale design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics

The semisynthetic artemisinin derivatives such as artesunate and artemether, along with the fully synthetic endoperoxide antimalarials (e.g., OZ277, Nature 2004, 430, 900-904), are believed to mediate their antimalarial effects by iron-induced formation of carbon-centered radicals capable of alkylating heme and/or protein. Here, we describe the design and synthesis of a series of biotinylated endoperoxide probe molecules for use in proteomic studies. The target molecules include derivatives of the artemisinin and OZ families, and we demonstrate that these conjugates express nanomolar in vitro activity versus cultured strains of Plasmodium falciparum. We also describe the synthesis of chemically cleavable linked conjugates designed to enable mild elution of labeled proteins during target protein identification.

Dual molecules containing peroxy derivative, the synthesis and therapeutic applications thereof

The invention relates to dual molecule compounds containing a peroxide derivative, to processes for the synthesis of such compounds, to pharmaceutical compositions comprising such compounds, and to methods of treatment and prevention of malaria comprising

Scandium(III) catalysis of transimination reactions. Independent and constitutionally coupled reversible processes

Sc(OTf)3 efficiently catalyzes the self-sufficient transimination reaction between various types of C=N bonds in organic solvents, with turnover frequencies up to 3600 h-1 and rate accelerations up to 6 × 105. The mechanism of the crossover reaction in mixtures of amines and imines is studied, comparing parallel individual reactions with coupled equilibria. The intrinsic kinetic parameters for isolated reactions cannot simply be added up when several components are mixed, and the behavior of the system agrees with the presence of a unique mediator that constitutes the core of a network of competing reactions. In mixed systems, every single amine or imine competes for the same central hub, in accordance with their binding affinity for the catalyst metal ion center. More generally, the study extends the basic principles of constitutional dynamic chemistry to interconnected chemical transformations and provides a step toward dynamic systems of increasing complexity.

Spiro and dispiro 1,2,4-trioxolane antimalarials

A means and method for treating malaria using a spiro or dispiro 1,2,4-trioxolane is described. The preferred 1,2,4-trioxolanes include a spiroadamantane group on one side of the trioxolane group, and a spirocyclohexyl or spiropiperidyl ring on the other side of the trioxolane group, whereby the spirocyclohexyl ring is preferably functionalized or substituted at the 4-position or a spiropiperidyl ring that is functionalized or substituted at the nitrogen atom. In comparison to artemisinin semisynthetic derivatives, the compounds of this invention are structurally simple, easy to synthesize, non-toxic, and potent against malarial parasites.

Axial/equatorial populations in α-hetero-substituted cyclohexanone oximes and O-methyl oximes

Axial equatorial populations were determined for (E)-2-X-cyclohexanone oximes and O-methyl oxime ethers in chloroform by the Eliel method [X = F, Cl, Br, OCH3, N(CH3)2, SCH3]. A novel approach is presented, whic

Electroorganic Chemistry. 144. Electroreductive Coupling of Ketones with O-Methyl Oximes, N,N-Dimethylhydrazones, amd Nitrones. A Convenient Route to Synthesis of β-Amino Alcohol

The intermolecular coupling of a variety of ketones with some types of O-methyl oximes took place when a mixture of both components was electrochemically reduced in i-PrOH with an Sn cathode.The product, β-methoxyamino alcohol was easily converted to β-amino alcohol by simple reduction.A chiral ligand effective for the enantioselective addition of diethylzinc to an aldehyde was easily obtained from the product formed by the electroreductive coupling of (-)-menthone with O-methylacetaldoxime.The intermolecular coupling of a ketone with a N,N-dimethylhydrazone or nitrone was also promoted by the electroreduction.Furthermore, the electroreductive coupling of a carbonyl group with an intramolecular O-methyl oxime moiety gave the corresponding cyclized product stereoselectively.