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Syntheses of D‐Labelled Oxidative Metabolites of Acrylamide and Acrylonitrile for the Quantification of Their Toxicities in Humans
Author(s) -
Belov Vladimir N.,
Korneev Sergei M.,
Angerer Jürgen,
de Meijere Armin
Publication year - 2008
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200800291
Subject(s) - chemistry , acrylonitrile , acrylamide , medicinal chemistry , trifluoroacetic anhydride , nucleophile , trifluoroacetic acid , pyridine , organic chemistry , catalysis , copolymer , polymer
Syntheses of the labelled oxidative metabolites of acrylamide and acrylonitrile – reference compounds for the evaluation of human exposure to important toxicants – are reported. For that, L ‐cystine tert ‐butyl ester was acetylated and the product reductively cleaved to L ‐cysteine tert ‐butyl ester, which reacted with carbamoyl[D 3 ]oxirane (obtained from [D 3 ]acrylonitrile and 30 % aq. H 2 O 2 at pH = 7.0–7.5) and afforded a separable mixture of tert ‐butyl N ‐acetyl‐ S ‐(2‐hydroxy‐2‐carbamoyl[D 3 ]ethyl)cysteinate and tert ‐butyl N ‐acetyl‐ S ‐(1‐carbamoyl‐2‐hydroxy[D 3 ]ethyl)cysteinate (ca. 9:1). Removal of the tert ‐butyl group in these intermediates with aq. HCl gave the final deuterated internal standards with carbamoyl residues. Protection of the secondary hydroxy group in the major intermediate with t BuMe 2 SiCl/imidazole in DMF followed by dehydration of the carbamoyl group (trifluoroacetic anhydride/pyridine in CH 2 Cl 2 ) and stepwise removal of the tert ‐butyl and t BuMe 2 Si protecting groups (TFA, Et 3 SiH,CH 2 Cl 2 ; aq. HF in MeCN) yielded N ‐acetyl‐ S ‐(2‐cyano‐2‐hydroxy[D 3 ]ethyl)cysteine. Monoprotection of [D 4 ]ethylene glycol with t BuMe 2 SiCl and NaH in THF, oxidation to t BuMe 2 SiOCD 2 CDO, conversion to t BuMe 2 SiOCD 2 CD(OH)CN and t BuMe 2 SiOCD 2 CD(OTs)CN followed by nucleophilic substitution of the tosyloxy group with N ‐acetyl‐ L ‐cysteine (MeOD, Et 3 N) and deprotection with 4 M HCl in dioxane resulted in N ‐acetyl‐ S ‐(1‐cyano‐2‐hydroxy[D 3 ]ethyl)cysteine. All transformations (except the last but one) gave the respective products in good yields.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)