Studies on the synthesis of trans-dihydrodiols of polycyclic aromatic thiaarenes as potential proximate carcinogenic metabolites: first synthesis of trans-10,11-dihydroxy-10,11-dihydroacenaphtho[1, 2-b]benzo[d]thiophene and 6,7-dihydroxy-6,7-dihydronaphtho[1, 2-b]thiophene.
Polyaromatic thiophene compounds are found to occur concomitantly with numerous coal-derived products and shale oils and are suspected mutagens and/or carcinogens. The first synthesis of the two title compounds 9 and 16 has been achieved in five or four steps starting from 8,9-dihydroacenaphtho[1,2-b]benzo[d]thiophene (1) and 7-methoxynaphtho[1,2-b]thiophene (12), respectively. Compound 1 was converted to the cis-diol (11) (via treatment with OsO(4)/pyridine) or to trans-diol (3) [via Prevost reaction (PhCOOAg/I(2)) followed by hydrolysis] in 95-98% yield, respectively. Subsequent dehydration (PTS/benzene) of the diol followed by aromatization of the resulting ketone (5) produced the phenolic compound 6 in 97% yield. Oxidation of the phenol with phenyl iododiacetate followed by hydrolysis of the o-quinone monoketal 7 gave the o-quinone (8) in 86% yield. Stereoselective reduction of 8 with NaBH(4)/EtOH under oxygen afforded trans-10,11-dihydroxy-10,11-dihydroacenaphtho[1,2-b]benzo[d]thi oph ene(9) (orange yellow solid) in 55% yield. Compound 16 was obtained as a colorless solid, through the stereoselective reduction of the o-quinone 15 (with NaBH(4)), which in turn was prepared from 12 following the protocol of functional group transformation of methoxy --> phenol --> o-quinone monoketal --> o-quinone, as used in the previous case. The yields for all the steps are very good. The mutagenicity assay of compound 9 and 16 as well as their parent thiaarenes have been performed. The results showed that 9 may not be the proximate carcinogen of acenaphtho[1,2-b]benzo[d]thiophene, while it is likely that compound 16 is one of the possible proximate carcinogens for naphtho[1,2-b]thiophene.
Ray
J K
JK
Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India. jkray@chem.iitkgp.ernet.in
Gupta
S
S
Kar
G K
GK
Roy
B C
BC
Lin
J M
JM
Amin
S
S
D000818:Animals; D002273:Carcinogens / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D009152:Mutagenicity Tests; D009153:Mutagens / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D012486:Salmonella typhimurium; D013876:Thiophenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
C418732:10,11-dihydroxy-10,11-dihydroacenaphtho(1,2-b)benzo(d)thiophene; C418733:6,7-dihydroxy-6,7-dihydronaphtho(1,2-b)thiophene; D002273:Carcinogens; D006575:Heterocyclic Compounds, 3-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; D009153:Mutagens; D013876:Thiophenes