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Synthesis of 2-(4-chlorophenyl)-2-(4-chloro-3-thiophenol)-1,1-dichloroethene (3-SH-DDE) via Newman-Kwart rearrangement - A precursor for synthesis of radiolabeled and unlabeled alkylsulfonyl-DDEs
Stockholm University, Faculty of Science, Department of Environmental Chemistry.
Stockholm University, Faculty of Science, Department of Environmental Chemistry.
Stockholm University, Faculty of Science, Department of Environmental Chemistry.
(English)Manuscript (Other academic)
Abstract [en]

For the first time, a pathway for synthesis of 2-(4-chlorophenyl)-2-(4-chloro-3-thiophenol)-1,1-dichloroethene (3-SH-DDE), is presented. The compound is of particular interest as a precursor for synthesis of alkylsulfonyl-DDE containing different alkyl groups to discover structural activity relationships, and to promote synthesis of radiolabeled methylsulfonyl-DDE. 2-Chloro-5-methylphenol was first methylated and further oxidized to the corresponding benzoic acid. The acid was reduced to the corresponding aldehyde (4-chloro-3-methoxy benzaldehyde) via 4-chloro-3-methoxy-benzene methanol. A lead/aluminium bimetal system was used to carry out the reductive addition of tetrachloromethane to 4-chloro-3-methoxy benzaldehyde to obtain 2,2,2-trichloro-1-(4-chloro-3-methoxyphenyl)ethanol, the desired starting material to synthesize the DDT-analogue (2-(4-chlorophenyl)-2-(4-chloro-3-methoxy-phenyl)-1,1,1-trichloroethane). Elimination of hydrochloric acid and removal of the methyl group led to the 3-OH-DDE. The Newman-Kwart rearrangement was applied to convert 3-OH-DDE to 3-SH-DDE via the dimethylcarbamothioate derivative. 3-SH-DDE is then used as a precursor for the radiolabel synthesis. The overall yield to acquire 3-SH-DDE after 11 steps was 3%. The step with the lowest yield was the DDT-analog synthesis with a yield of 30%. All other step had a yield of >50%. 3-SH-DDE was methylated with 14C-labeled iodomethane and oxidized by hydrogen peroxide to obtain 3-[14C]MeSO2-DDE in an overall yield of 30%.

Keyword [en]
NKR, DDT, 14C
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
URN: urn:nbn:se:su:diva-26965OAI: oai:DiVA.org:su-26965DiVA: diva2:212128
Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Toxicologically important DDT metabolites: Synthesis, enantioselective analysis and kinetics
Open this publication in new window or tab >>Toxicologically important DDT metabolites: Synthesis, enantioselective analysis and kinetics
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

DDT was extensively and globally used as a pesticide in agriculture and for malaria vector control from the 1940’s until the 1970’s. Due to its heavy use, DDT became ubiquitously distributed throughout the environment. DDT and several DDT metabolites are persistent organic pollutants. Two DDT metabolites, 3-MeSO2-DDE and o,p’-DDD have been proved to be tissue specific toxicants in the adrenal cortex. They are bioactivated to reactive intermediates which bind covalently to the adrenal cortex causing cell death. Due to its tissue specific toxicity o,p’-DDD has been used as a chemotherapy drug for adrenal cancer in humans. The efficacy and potency is however low and o,p’-DDD treatment is associated with serious side effects. 3-MeSO2-DDE has been suggested as a potential alternative therapeutic agent.

A key aim of this thesis has been to improve the understanding of the kinetics of the two adrenocorticolytic compounds o,p’-DDD, its two enantiomers and 3-MeSO2-DDE. To meet this objective chemical synthesis and enantioselective analysis were required. Furthermore, in vitro toxicity of o,p’-DDD enantiomers and diastereomers were performed.

An 11 step synthesis of 3-SH-DDE has been developed to promote both labelled and unlabelled synthesis of 3-alkylsulfonyl-DDE. Toxicokinetic studies showed that 3-MeSO2-DDE and o,p’-DDD were accumulated in tissues and retained in adipose tissue in minipigs. 3-MeSO2-DDE however had a twice as long biological t1/2 and a considerably lower Vd compared to o,p’-DDD. Suckling offspring were more exposed to 3-MeSO2-DDE than their mothers who were given 3-MeSO2-DDE orally. Interindividual differences in enantiomer kinetics in minipigs were observed suggesting polymorphism among the minipigs. Preparative isolation of the o,p’-DDD enantiomers is presented allowing determination of the absolute structures of the o,p’-DDD enantiomers by X-ray. The pure enantiomer of o,p’-DDD showed significant differences in toxicity in human adrenocortical cells.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Chemistry, Stockholm Univerisity , 2009. 55 p.
Keyword
o, p'-DDD, 3-Methylsulfonyl-DDE, adrenocorticolytic compounds, chiral
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
urn:nbn:se:su:diva-26952 (URN)978-91-7155-829-9 (ISBN)
Public defence
2009-05-29, Magnélisalen, Svante Arrhenius väg 12 A, Stockholm, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2009-05-08 Created: 2009-04-21 Last updated: 2009-04-23Bibliographically approved

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