Fluorinated alcohol mediated displacement of the C10 acetoxy group of benzo[a]pyrene-7,8,9,10-tetrahydrotetraol tetraacetates: a new route to diol epoxide-deoxyguanosine adducts.
We describe a novel trifluoroethanol (TFE) or hexafluoropropan-2-ol (HFP) mediated substitution reaction of the bay-region C10 acetoxy group in four stereoisomeric 7,8,9,10-tetraacetoxy-7,8,9,10-tetrahydrobenzo[a]pyrenes (tetraol tetraacetates, two pairs of cis and trans isomers at the 9,10 positions) by the exocyclic N2-amino group of O6-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine (3). The tetraacetates are derived from cis and trans hydrolysis of (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P DE-1) and of (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P DE-2) at C-10 followed by acetylation. Excellent yields and high regioselectivity were observed. Similar cis/trans product ratios were observed for each set of cis and trans tetraol tetraacetates derived from DE-1 ( approximately 75/25) and from DE-2 (approximately 67/33) in HFP. This strongly suggests that the substitution proceeds via an SN1 mechanism involving a carbocation intermediate that is common to the cis and trans tetraacetates. Since it is likely that the cis and trans products from 3 arise from different conformations of the carbocation, its lifetime must be sufficiently long to permit conformational equilibration before its capture by the purine nucleophile. The corresponding reaction of (+/-)-9alpha-bromo-7beta,8alpha,10beta-triacetoxy-7,8,9,10-tetrahydrobenzo[a]pyrene with 3 in HFP was highly regio- and stereoselective and gave exclusively trans 10beta-adducts. This newly developed substitution reaction provides an attractive alternative synthetic strategy for the preparation of polycyclic hydrocarbon adducted oligonucleotide building blocks.
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland 20892, USA.
Haruhiko
H
Yagi
Donald M
DM
Jerina
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000737:chemistry*; D018736:DNA Adducts / Q000138:chemical synthesis* / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D006868:Hydrolysis; D008968:Molecular Conformation; D017646:Organosilicon Compounds / Q000737:chemistry*; D020005:Propanols / Q000737:chemistry*; D013237:Stereoisomerism; D014270:Trifluoroethanol / Q000737:chemistry*; D006845:Hydrocarbons, Fluorinated
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D018736:DNA Adducts; D003849:Deoxyguanosine; D017646:Organosilicon Compounds; D020005:Propanols; D014270:Trifluoroethanol; C527459:O(6)-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated