Stereoselective Synthesis of the Urinary Metabolite N-Acetyl-S-(3,4-dihydroxybutyl)cysteine

Abstract

On exposure to the potential carcinogen 1,3-butadiene, the major urinary metabolite in humans is N-acetyl-S-(3,4-dihydroxybutyl)cysteine. A novel, stereoselective synthesis of this cysteine-butadiene metabolite has been developed that is suitable for the production of either diastereomer for use in occupational exposure analysis. L-cysteine and 4-bromo-1-butene are coupled via an S N 2 reaction to give the core structure. A Sharpless asymmetric dihydroxylation using the DHQD ligand provided the terminal 1,2-diol with the 3-hydroxyl group in the R configuration.Keywords: 1,3-butadiene, urinary metabolite, stereoselective synthesis, dihydroxylationThe volatile compound 1,3-butadiene used in the manufacture of rubber has been shown to cause cancer in mice and rats and has been labelled a probable carcinogen to humans. [1,2] Although environmental levels of this compound are low, workers in butadiene manufacturing plants and rubber factories can be exposed to high levels of this compound. [3] The metabolism of 1,3-butadiene in mice and rats has been the subject of many studies with the first step being an epoxidation with Cytochrome P450 dependent enzymes and then a variety of metabolites are produced depending on the activity of the epoxide hydrolases and the glutathione transferases. [4,5,6] The first metabolites to be identified were the cysteine derivatives MI and MII. [7] Subsequently the regio and stereoisomers of MII have been separated and identified [8] and the metabolites have been shown to arise predominantly from the R-butadiene monoxide. [4] The MII metabolites are the major urinary metabolite in rats and mice, but * Address correspondence to Lynne Pilcher, Department of Chemistry, University of Pretoria, Pretoria, 0002South Africa. Tel: +27 12 420-5384. E-mail: lynne.pilcher@up.ac.za cysteinethe MI metabolite proved to be the major metabolite in monkeys. [7] A more recent study of the metabolites from low level exposure (1-20 ppm) of rats and mice to 1,3-butadiene by inhalation,showed that MI and new metabolites MIII were the dominant urinary metabolites in these animals at concentrations encountered in occupational exposure situations. [6] A thorough investigation byAlbertini monitoring the urine of humans working in the production or the polymerisation of butadiene showed that MI is the major urinary metabolite in humans [3] and as such it represents a useful biomarker for monitoring the occupational exposure of factory workers to the potential carcinogen.[ To support the structural characterisation of the urinary metabolites, synthetic standards of the cysteine derivatives have been prepared. Sabourin first reported the synthesis of MI from acetyl cysteine and acetoxy methyl vinyl ketone as a mixture of diastereomers. [7] where the butadiene component was prepared from commercially available 2-butyne-1,4-diol.[10] The four MII metabolites were first cysteine -3 -prepared by Elfarra from acetyl cysteine and butadiene monoxide in a single reaction. The four regio/stereoisomers and a fifth ...

NonvolatileS-Alk(en)ylthio-l-cysteine Derivatives in Fresh Onion (Allium cepa L. Cultivar)

“…To confirm our hypothesis, we prepared authentic samples as described previously in the literature without improvements in the procedure; our goal was to make the purest references possible. The S -methyl, S -propyl, and S -allyl cysteine derivatives 9 , 10 , and 12 were prepared from cysteine 13 in aqueous sodium hydroxide solution containing ethanol by addition of the corresponding alk(en)yl bromides. , All compounds were purified by ion exchange chromatography, and the purities were checked by NMR and compared with published data. − Oxidations to prepare 1 , 2 , and 4 were performed with H 2 O 2 , as described for the first time by Stoll and Seebeck in 1949, and the spectroscopic data were in agreement with more modern publications. , Isoalliin 3 was obtained after isomerization of S -allyl- l -cysteine 12 with potassium tert -butoxide in dimethyl sulfoxide to prepare ( E / Z )- 11 , which was then oxidized with H 2 O 2 to give a mixture of R / S / E ; R / S / Z ; R / R / E ; R / R / Z 3 . − The preparation of S -alk(en)ylthio l -cysteines 5 – 8 was more challenging. The first preparation described by Cavallito et al started with the reaction of thiosulfinates with cysteine, and 8 was obtained and fully characterized. ,, Recently, Zhang et al prepared mixed disulfides from dithiophosphoric acids with good yields (70–80%), but they were unable to make compound 7 .…”

“…19À21 Oxidations to prepare 1, 2, and 4 were performed with H 2 O 2 , as described for the first time by Stoll and Seebeck in 1949, 22 and the spectroscopic data were in agreement with more modern publications. 21,23 Isoalliin 3 was obtained after isomerization of S-allyl-L-cysteine 12 with potassium tert-butoxide in dimethyl sulfoxide to prepare (E/Z)-11, which was then oxidized with H 2 O 2 to give a mixture of R/S/E; R/S/Z; R/R/E; R/R/Z 3. 20À22 The preparation of S-alk(en)ylthioLcysteines 5À8 was more challenging.…”