title: Fluorinated alcohol mediated control over cis vs trans opening of benzo[a]pyrene-7,8-diol 9,10-epoxides at C-10 by the exocyclic amino groups of O6-allyl protected deoxyguanosine and of deoxyadenosine.
abstract: A detailed study was carried out on the stereoselective control of cis- vs trans-opening of (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene {B[a]P DE-1 (1)} and (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene {B[a]P DE-2 (2)} at C-10 by the exocyclic amino groups of protected purine nucleosides in the fluorinated alcohols trifluoroethanol (TFE), hexafluoropropan-2-ol (HFP), and perfluoro-tert-butanol (PFTB). Addition of the 2-amino group of O6-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine (3) and of the 6-amino group of 3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyadenosine (4) occurs at C-10 of the epoxides. The observed cis:trans ratio for the reaction of DE-1 (1) in the presence of 5 equiv of 3 over the range of 10-250 equiv of fluorinated alcohol varied from 53:47 to 87:13 for TFE, 60:40 to 92:8 for HFP, and 52:48 to 73:27 for PFTB. The corresponding ratios for DE-2 (2) varied from 22:78 to 72:28 for HFP under the same set of conditions. In contrast, the corresponding ratios for DE-2 (2) remained unchanged ( approximately 40:60) for TFE and for PFTB over the range of 25-250 molar equiv. Unlike the addition of the dGuo reactant 3, the corresponding addition of the dAdo reactant (4) to the DEs (1 or 2) in over 25 molar equiv of TFE occurred highly stereoselectively to afford only cis adducts for both DEs. A highly efficient HPLC separation of dGuo adduct diastereomers derived from DE-2 (2) was developed using acetone as a modifier in CH2Cl2 or in n-hexane. Through the use of varying molar ratios of the different fluorinated alcohols described above and the newly developed HPLC separation method, the four possible phosphoramidites (cis/trans, R/S) of the B[a]P DE-2 N2-dGuo adducts can be prepared in an efficient fashion on gram scale for use in oligonucleotide synthesis.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health/DHHS, Bethesda, MD 20892, USA.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yagi
authors.forename: Donald M
authors.initials: DM
authors.lastname: Jerina
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D001564:Benzo(a)pyrene / Q000737:chemistry*; D002625:Chemistry, Organic / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D003839:Deoxyadenosines / Q000737:chemistry*; D003849:Deoxyguanosine / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry*; D005466:Fluorocarbons / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008956:Models, Chemical; D009841:Oligonucleotides / Q000737:chemistry; D020005:Propanols / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D014270:Trifluoroethanol / Q000737:chemistry; D020002:tert-Butyl Alcohol / Q000031:analogs & derivatives / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated
chemical_list: D000438:Alcohols; D001564:Benzo(a)pyrene; D003839:Deoxyadenosines; D003849:Deoxyguanosine; D005461:Fluorine; D005466:Fluorocarbons; D009841:Oligonucleotides; D020005:Propanols; D012997:Solvents; D014270:Trifluoroethanol; D020002:tert-Butyl Alcohol; C521478:perfluoro-tert-butyl alcohol; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated