Scheme 1
Figure 2. C8- and N2-deoxyguanosine AIA adducts.
of 2-aminofluorene (AF) and its N-acetyl analogue have been
prepared, and their structures and mutagenic effects are well
studied.3 Recently, PhIP (9) has been site-specifically
incorporated into oligonucleotides.4 These oligonucleotides
were prepared by a biomimetic approach in which N-acetoxy-
PhIP was reacted with oligonucleotides containing a single
guanosine; Johnson has previously commented on the
drawbacks to this synthetic appraoch.3c Overall, the mutage-
nicity of the C8-PhIP adduct was similar to that of the
corresponding AF adduct; however, the mutagenic frequency
of PhIP was up to nine times higher depending on sequence.
A computational study of an IQ adduct has been recently
reported and suggests some structural differences from the
corresponding AF adduct.5 We report here the synthesis of
the C8-2′-deoxyguanosine adduct of the food mutagen IQ
(2). The synthesis features a Buchwald-Hartwig6 palladium-
catalyzed N-arylation of a suitably protected 8-bromo-2′-
deoxyguanosine derivative with IQ as the key reaction.
The Buchwald-Hartwig reaction has been used recently
for the preparation of nucleoside-carcinogen adducts by
Lakshman7 and later Johnson,8a for the preparation of N6-
2′-deoxyadensosine derivatives. Hopkins and Sigurdsson9 and
Johnson4b-d synthesized N2-dG-N2-dG and N2-dG-N6-dA
nitrous acid cross-links as well as other N2-dG aryl deriva-
tives via an N-arylation reaction. It is worth noting that
Johnson’s N-arylation approach involved coupling of the
exocyclic amino groups of a suitably protected dA and dG
derivative with bromoarenes, while Lakshman and Hopkins
and Sigurdsson employed the corresponding bromopurine
with arylamines. To our knowledge, the synthesis of C8-dG
adducts of arylamine using a palladium-catalyzed N-arylation
reaction has not yet been reported.
Buchwald and others have reported the N-arylation of
amides.10 Thus, conventional amide protecting groups for
N2 of dG would be unsatisfactory. Initially, we employed a
dimethyl formamidine group which is commonly used for
N2-dG protection (Scheme 1). The O6-position was protected
as a benzyl ether. Attempted palladium-catalyzed N-arylation
of 13 with model substrate 14 gave only transfer of the N2-
protecting group to the amino group of 14. No N-arylation
of the C8-position was observed. The transfer of the
formamidine group to other amines has been previously
reported.11
We next examined the tetramethyldisilylazacyclopentane
(STABASE) group, a base-stable protecting group for
primary amines developed by Magnus.12 The substrate for
the N-arylation reaction (17) was readily prepared from
8-bromo-2′-deoxyguanosine according to Scheme 2. Buch-
wald-Hartwig reaction of 17 with model amine 14 under
the conditions shown in Scheme 1 gave the desired product
in 32% yield. We found that the prolonged reaction time
led to decomposition of 17. Other mild bases such Cs2CO3
or K3PO4 gave lower yields. The optimal conditions for the
desired reaction involved increasing the catalyst loading to
10 mol % and using lithium hexamethyldisilazide as the base
(Scheme 2). Under these conditions a 68% yield of the
desired product (18) could be obtained in just 20 min. These
conditions were also satisfactory for the coupling of IQ (2)
with 17 to give 19 in 68% yield (Scheme 3). Treatment of
(3) (a) Zhou, Y.; Romano, L. J. Biochemistry 1993, 32, 14043. (b)
Shibutani, S.; Gentles, R. G.; Iden, C. R.; Johnson, F. J. Am. Chem. Soc.
1990, 112, 5667. (c) Johnson, F.; Huang, C.-Y.; Yu, P.-L. EnViron. Healh
Perspect. 1994, 102 Supp. 6, 143. (d) Patel, D. J.; Mao, B.; Gu, Z.; Hingerty,
B. E.; Gorin, A.; Basu, A. K.; Broyde, S. Chem. Res. Toxicol. 1998, 11,
391.
(4) Shibutani, S.; Fernandes, A.; Suzuki, N.; Zhou, L.; Johnson, F.;
Grollman, A. P. J. Biol. Chem. 1999, 274, 27433.
(5) Wu, X.; Shapiro, R.; Broyde, S. Chem. Res. Toxicol. 1999, 12, 895.
(6) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31,
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(8) (a) De Riccardis, F.; Bonala, R. R.; Johnson, F. J. Am. Chem. Soc.
1999, 121, 10453. (b) Bonala, R. R.; Yu, P.-L.; Johnson, F. Tetrahedron
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