Synthesis and absolute configuration of cis- and trans-opened cyclopenta[cd]pyrene 3,4-oxide N2-deoxyguanosine adducts: conversion to phosphoramidites for oligonucleotide synthesis.
Fluorinated alcohols such as trifluoroethanol (TFE) or hexafluoropropan-2-ol (HFP) catalyze addition of the N2-amino group of O6-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine (3) to cyclopenta[cd]pyrene 3,4-oxide (CPPO). The reaction occurs via a carbocation intermediate at C-3 such that cis- and trans-opened dGuo adducts are formed in a combined yield of approximately 37% together with the 4-ketone and a cis-opened solvent adduct. Fluorinated alcohol-mediated regioselective substitution at C-3 of the CPP cis- (11) and trans-3,4-dihydrodiol diacetates (15) with the N2-amino group of 3 proceeded smoothly to give the O6-allyl di-(tert-butyldimethylsilyl) cis- and trans-opened dGuo-adduct acetates (8a,b and 9a,b) in 75-85% yields. The cis-opened adducts predominated (56-70%) from both 11 and 15. Interestingly, trans-3-acetoxy-4-bromo-3,4-dihydro-CPP and 3 in TFE or HFP gave a mixture of 8a,b and 9a,b in 75-85% yield with cis:trans adduct ratios similar to those observed for 11 and 15. This observation is consistent with initial formation of a cyclic acetoxonium intermediate followed by formation of the same carbocation as that derived from 11 or 15. Absolute configurations of 8a,b and 9a,b were assigned by using enantiomerically pure (+)-trans-[3S.4S]-dihydrodiol as the starting material, which afforded a single cis-[3R,4S]-dGuo adduct and a single trans-[3S,4S]-dGuo adduct. The optically active trans-3,4-dihydrodiols were obtained by HPLC separation of their bis-(-)-menthoxyacetates. Their absolute configuration was determined by several empirical methods in addition to application of the exciton chirality CD method to their bis-(p-N,N-dimethylamino)benzoates. Removal of all blocking groups from the protected cis- and trans-opened dGuo adducts (8a,b and 9a,b) in three steps (overall yields of >70%) gave the free dGuo adducts, which are useful markers for DNA-binding studies. Adducts 8a,b and 9a,b were also converted to the appropriately protected phosphoramidites in three steps (overall yields of 72-81%).
Yagi
Haruhiko
H
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, DHHS, Bethesda, Maryland 20892, USA.
Frank
Heinrich
H
Seidel
Albrecht
A
Jerina
Donald M
DM
D000085:Acetates / Q000737:chemistry; D000438:Alcohols / Q000737:chemistry; D002942:Circular Dichroism; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D008968:Molecular Conformation; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011721:Pyrenes / Q000138:chemical synthesis* / Q000737:chemistry
D000085:Acetates; D000438:Alcohols; D009841:Oligonucleotides; D009943:Organophosphorus Compounds; D011721:Pyrenes; C023963:bromohydrins; C434331:phosphoramidite; D006151:Guanosine; C016328:cyclopenta(c,d)pyrene