Synthesis of two 8-[(anthraquinone-2-yl)-linked]-2′-deoxyadenosine 3′-benzyl hydrogen phosphates for studies of photoinduced hole transport in DNA

Article abstract of DOI:10.1081/NCN-200051894

The challenge in working with anthraquinone-2′-deoxyadenosine (AQ-dA) conjugates is that they are insoluble in water and only sparingly soluble in most organic solvents. However, water-soluble AQ-dA conjugates with short linkers are required for study of

Full text of DOI:10.1081/NCN-200051894

Nucleosides, Nucleotides, and Nucleic Acids, 24 (2):85–110, (2005)
Copyright D 2005 Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200051894
SYNTHESIS OF TWO 8-[(ANTHRAQUINONE-2-YL)-LINKED]-2’-
DEOXYADENOSINE 3’-BENZYL HYDROGEN PHOSPHATES FOR
STUDIES OF PHOTOINDUCED HOLE TRANSPORT IN DNA
5
Reham A. I. Abou-Elkhair and Thomas L. Netzel
Department of Chemistry,
Georgia State University, Atlanta, Georgia, USA
5
The challenge in working with anthraquinone-2’-deoxyadenosine (AQ-dA) conjugates is that they are
insoluble in water and only sparingly soluble in most organic solvents. However, water-soluble AQ-dA
conjugates with short linkers are required for study of their electrochemical and intramolecular electron
transfer properties in this solvent prior to their use in laser kinetics investigations of photoinduced hole
(cation) transport in DNA. This article first describes the synthesis of a water-soluble, ethynyl-linked
AQ-dA conjugate, 8-[(anthraquinone-2-yl)ethynyl]-2’-deoxyadenosine 3’-benzyl hydrogen phosphate,
based on initial formation of a 5’-O-(4,4’-dimethoxytrityl) (5’-O-DMTr) intermediate. Because
intended H2 over Pd/C reduction of the ethynyl linker in 5’-O-DMTr --protected 2’-deoxyadenosines
cleaves the DMTr protecting group and precipitates multiple side products, this work also describes the
synthesis of an ethylenyl-linked AQ-dA conjugate, 8-[2-(anthraquinone-2-yl)ethyl]-2’-deoxyadenosine
3’-benzyl hydrogen phosphate, starting with a 5’-O-tert-butyldiphenylsilyl protecting group.
Keywords Photoinduced Electron Transfer, Modified DNA, Modified Nucleoside,
Anthraquinone-modified 2’-Deoxyadenosine, 2-Ethynylanthraquinone, Anthraquinone-2’-
Deoxyadenosine Phosphate
INTRODUCTION
The DNA double helix presents a unique medium for electron transfer (ET)
due to the p-stacked array of its aromatic heterocyclic base pairs. Several
approaches have been developed to study ET in DNA.[1--23] In most of these
approaches, either photoexcitation or ionizing irradiation is employed to inject a
hole (cation radical) or an excess electron (anion radical) into the DNA base stack
depending, respectively, upon whether a DNA base is initially oxidized or
reduced.[24,25] Long-range ET is then monitored, generally indirectly, by detecting
effects due to the oxidation or reduction of a nucleobase remote from the injection
site.[26--33] In these experiments yields of the detected oxidized or reduced bases or
Received 22 September 2004, accepted 8 November 2004.
Address correspondence to Thomas L. Netzel, Department of Chemistry, Georgia State University, P. O.
Box 4098, Atlanta, GA 30302-4098, USA; E-mail: tnetzel@gsu.ed
85
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R. A. I. Abou-Elkhair and T. L. Netzel
FIGURE 1 Structures of four AQ-dA conjugates: the 3’-benzyl phosphate nucleotides 1 and 2 are soluble in
both water and MeOH, while the nucleosides 1a and 2a are insoluble in water but sparingly soluble in MeOH.
their chemical products are low (ꢀ 5 Â 10À3).[34--38] Our approach is to develop
modified nucleosides that will permit direct study of the short- and long-range
dynamics of charge transport in modified DNA duplexes using real-time transient
absorbance (TA) spectroscopy. Key to reaching this goal is the construction of
DNA containing covalently modified nucleosides that can yield long-lived charge-
separated (CS) products upon photoexcitation. CS products can be comprised of
SCHEME 1 Reagents and conditions: (a) DMTrCl, 4-DMAP, TEA, Py, rt, 4 h; (b) i. (BnO)2PN(iPr)2, Me-
tetrazol, THF, rt, 1 h; ii. m-CPBA in CH2Cl2, À78°C, 15 min; (c) Pd(Ph3P)4, CuI, TEA, DMF, 65°C, 6 h; (d) 30%
DCA in CH2Cl2, rt, 30 min; (e) DABCO, 1,4-dioxane, reflux, 2 h.

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
87
either holes or excess electrons on DNA bases depending on the nature of the
conjugate group joined to a particular base.
From a hole transfer perspective, conjugates between electron-deficient
derivatives of anthraquinone (AQ) and 2’-deoxyadenosine (dA) are interesting as
sources of holes in DNA.[12,13,15,16,39--47] In AQ-dA conjugates, photoexcited AQ is
expected to be the electron acceptor, and adenine is expected to be the electron
donor; thus photoexcitation of such conjugates is expected to form the AQ.À/dA.+
CS product. Separating AQ.À from its associated hole in the AQ.À/dA.+
photoproduct by allowing the initial dA.+ hole to hop to a nearby G should
prolong the lifetime of the resulting AQ.À/dA/dG.+ secondary charge-separated
(SCS) product. Key questions concern how efficiently can SCS products be
produced and how long can they be made to live. Our goal here is to synthesize the
water-soluble AQ-dA 3’-phosphates, 1 and 2 (see Figure 1) so that their
electrochemistry and intramolecular ET photochemistry can be studied in water.
If they can be shown to undergo reductive quenching of their p,p* excited states to
form AQ.À/dA.+ photoproducts in water, it will then be desirable to transform
them into the corresponding phosphoramidite reagents for incorporation into DNA
oligomers for studies of hole transport in DNA.
SCHEME 2 Reagents and conditions: (a) TBDPSCl, Im, Py, rt, 3h; (b) Pd(Ph3P)4, CuI, TEA, DMF, 65°C, 6 h;
(c) 10% Pd/C, H2, 40 psi, EtOAc/MeOH, rt, 24 h; (d) i. (BnO)2PN(iPr)2, Me-tetrazol, THF, rt, 1 h; ii. m-CPBA in
CH2Cl2, À78°C, 15 min; (e) NH4F, MeOH/THF, 60°C, 6 h; (f) 10% Pd/C, H2, 40--45 psi, EtOAc/MeOH, rt, 31 h.

88
R. A. I. Abou-Elkhair and T. L. Netzel
SCHEME 3 Reagents and conditions: (a) i. HCl, NaNO2, THF/H2O, 0°C; ii. KI, 0°C, 75 min; (b) Pd(Ph3P)2Cl2,
CuI, Et3N, THF, TMSA, rt, 10 min; (c) KF, THF/MeOH, rt, 1 h.
Synthesis of the 3’-phosphate AQ-dA conjugates 1 and 2 appears appealing for
study of the chemistry of water-soluble AQ-dA conjugates because the phosphate
group is attached to the sugar and, therefore, is not likely to affect the redox
potentials of either the AQ or dA subunits. From the perspective of substitution of 1
and 2 into DNA duplexes, the rigid ethynyl linker in 1 appears advantageous over
the more flexible ethylenyl linker in 2 because it will likely permit fewer
nonbonded interactions between the anthraquinonyl group and neighboring DNA
bases. However, at this point the electrochemistry and ET photochemistry of
neither compound is known in water and both need to be made and studied. The
challenge in working with AQ-dA conjugates is that in general they are insoluble in
water and only sparingly soluble in most organic solvents. Thus the goal of
producing moderate amounts of the 3’-phosphates 1 and 2 requires development
of protecting group strategies to increase the solubility of synthetic intermediates.
Since the 4,4’-dimethoxytrityl (DMTr) group is commonly used to make
phosphoramidite reagents for use on automated solid-phase DNA synthesizers,
we begin this work with a description of the synthesis of the ethynyl-linked AQ-dA
3’-phosphate conjugate 1 based on initial formation of a 5’-O-DMTr intermediate as
shown in Scheme 1. Unfortunately, attempted reduction of the ethynyl linker in 5’-
O-DMTr--protected 2’-deoxyadenosines with H2 over Pd/C cleaves the DMTr
protecting group and precipitates multiple side products. Thus this work also
describes in Scheme 2 a synthetic strategy based on initial 5’-O-tert-butyldiphe-
nylsilyl (5’-O-TBDPS) protection of 8-bromo-2’-deoxyadenosine to make the
ethylenyl-linked AQ-dA conjugate 2. Finally, useful syntheses of two substituted
anthraquinones are described in Scheme 3.
RESULTS AND DISCUSSION
Synthesis of an Ethynyl-Linked AQ-dA Conjugate, 1
The water-insoluble AQ-dA nucleosides 1a and 2a were made on a 100-mg
scale without protecting groups, but with silica gel column purification difficulties.

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
89
However, their extremely poor solubility in organic solvents precluded phosphor-
ylating them directly with POCl3 in trimethyl phosphate[48--50] or b-cyanoethyl
phosphate.[51] To allow chemical transformations of AQ-dA intermediates in
organic solvents, 8-bromo-2’-deoxyadenosine must first be protected at the 5’-O
position to ensure that its AQ-adducts remain soluble. With this in mind, we
attempted to use (BnO)2POCl and tert-BuMgCl to produce a 5’-O--protected 3’-
phosphate. Unfortunately, this modified version of a reported reaction[52] did not
succeed. Either phosphite triester[53,54] or phosphoramidite coupling[55--58] followed
by oxidation also appeared reasonable as alternate ways of producing our desired 5’-
O-protected 3’-phosphates of AQ-dA. We chose the latter procedure since dibenzyl
N,N-diisopropylphosphoramidite was commercially available, whereas tribenzyl
phosphite was not.
The synthetic strategy to form 1 described in Scheme 1 was developed
based on trial phosphorylation reactions of 2’-deoxyadenosine rather than the
more expensive 8-bromo-2’-deoxy adenosine reagent. The goal of these trial
reactions was threefold: 1) to test phosphoramidite chemistry without N6
protection, 2) to determine the stability of phosphate protection toward DMTr
deprotection, and 3) to establish the stability of both the N-glycosidic bond and
the phosphate group itself toward the conditions needed to produce the 2’-
deoxyadenosine 3’-benzyl phosphate products in Scheme 1. While unprotected
ethynyl and ethylenyl AQ-dA conjugates are only sparingly soluble in most
solvents, all three 3’-dibenzyl phosphates in Scheme 1 were readily soluble in a
variety of standard organic solvents. However, purification of 7 was sometimes a
problem, as will be discussed.
Synthesis of 5’-O-Dimethoxytrityl-8-bromo-2’-deoxyadenosine
3’-Dibenzyl Phosphate (5) from 2’-Deoxyadenosine
Treatment of 2’-deoxyadenosine with Br2 in a 1 M solution of acetate buffer at
pH 4.0 produced 3 in 79% yield. Adjusting the pH to 4.0 rather than 5.0[59] or 5.4[60]
and using a buffer concentration of 1 M was essential to dissolve the starting
materials. Additionally, pure 3 was obtained by extracting it from the buffer with
chloroform (CHCl3);[61] extraction was aided by CHCl3 mixing with the large
1
amount of acetic acid required to drop the pH of the buffer to 4.0. H and 13C
NMR data for 3 were identical to those previously published, and the product was
used without further purification.[61] Alternately, separation of 3 from the buffer was
also done by precipitation following neutralization with sodium hydroxide.[62]
However, in this case recrystallization from boiling water was required to separate a
trace amount of unreacted 2’-deoxyadenosine. The yield for this latter product
collection method was only 50%.
5’-O-Dimethoxytrityl-8-bromo-2’-deoxyadenosine (4) was prepared in 72% yield
by tritylation of 3 using DMTrCl, TEA, and 4-DMAP (as a catalyst) in pyridine.[63]
A solution of DMTrCl in pyridine was added drop-wise at 0°C. This procedure was
intended to increase the selectivity of tritylation at 5’-OH. Phosphorylation of 4 by
coupling with (BnO)2PN(iPr)2 followed by oxidation produced 5 as shown in

90
R. A. I. Abou-Elkhair and T. L. Netzel
Scheme 1. Based on our trial phosphorylation of 2’-deoxyadenosine, we avoided
using less than 1.5 equivalents of (BnO)2PN(iPr)2 in order to react 4 completely,
and hoped that any N6-phosphorylated side product would be easily removed by
silica gel chromatography as in the trial chemistry. However, the amount of this side
product, as shown by TLC, was larger than the amount seen previously when
phosphorylating 5’-O-DMTr-2’-deoxyadenosine. Worse, complete separation of the
3’,N6-bis(dibenzyl phosphate) side product from the 3’-dibenzyl phosphate 5
required biotage chromatography. Therefore, to eliminate N6-phosphorylation, it
was worth re-optimizing the number of equivalents of (BnO)2PN(iPr)2 used. Some
published procedures used lower equivalents of similar phosphoramidite reagents
but an excess of the required base.[64,65] Based on this reasoning, 2.2 equivalents of
Me-tetrazol were used with 1.2 equivalents of (BnO)2PN(iPr)2, keeping all other
conditions unchanged. This modified procedure yielded a single spot of 5 on TLC
with complete consumption of 4.
Coupling Anthraquinone to 5 Followed by Two
Deprotections to Yield 1
5’-O-Dimethoxytrityl-8-[(anthraquinone-2-yl)ethynyl]-2’-deoxyadenosine 3’-
dibenzyl phosphate (7) was synthesized by Pd(0) catalyzed cross-coupling of 5
and 6. Monitoring the progress of this reaction by TLC was not possible because
both the starting material 5 and the product 7 had the same Rf in most commonly
used eluting solvent mixtures. The time of the reaction was suggested by
comparison with similar Pd(0)-catalyzed cross-coupling reactions in the literature
(2.5--6 h).[65--67] Complete consumption of 5 by reaction with 6 was essential to
obtain 7 pure after silica gel chromatography; purity of 7 was checked by 1H NMR.
Frequently, however, 5 reacted incompletely even with 30% excess of 6.
Unfortunately, increasing the reaction time still left a trace amount of unreacted
5. Because unreacted 5 and 7 underwent the same kinds of reactions in Scheme 1,
proceeding to the next step also yielded products with the same Rf values as 5 and
7. Thus, obtaining 8 pure was also a problem unless all of 5 reacted when forming
7. However, obtaining 1 pure was not a problem as HPLC separated it cleanly
from all other reaction products.
The DMTr group of 7 in Scheme 1 was cleaved by stirring with 40 equivalents
of 30% DCA in dichloromethane (CH2Cl2) at room temperature for 30 min. (Lower
concentrations or equivalents of the acid caused incomplete detritylation of trial
compound 5’-O-DMTr-2’-deoxyadenosine 3’-dibenzyl phosphate.) After silica gel
chromatographic purification, 8-[(anthraquinone-2-yl)ethynyl]-2’-deoxyadenosine 3’-
dibenzyl phosphate (8) was obtained in 76% yield. No depurination of 8 was
observed during the acidic cleavage of DMTr.
Mono-deprotection of the dibenzyl phosphate group in 8 to produce 1 was
achieved by treatment with 2.7 equivalents of DABCO under anhydrous con-
ditions in refluxing 1,4-dioxane. During purification of 1 by preparative HPLC
eluting with MeCN/water, the Bn-quaternarized DABCO counter-cation was

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
91
1
replaced by hydrogen as judged by H NMR. Hydrogenolysis was not used
for benzyl deprotection, as this would have also reduced the alkynyl linker.
Additionally, benzyl deprotection of trial 2’-adenosine 3’-dibenzyl phosphate with
5 equivalents of TMSBr in anhydrous CH2Cl2 followed by quenching with 1 M
aqueous ammonium bicarbonate[68] produced a mixture of unidentified products
as judged by 1H NMR. Thus this benzyl deprotection method was not used either.
Note also that 2.7 equivalents of DABCO produced only monobenzyl deprotected
1 without evidence of any dibenzyl deprotected product.
Synthesis of an Ethylenyl Linked AQ-dA Conjugate, 2
The initial strategy to synthesize 2 was based on using Pd/C catalyzed
hydrogenation of 8 both to reduce the ethynyl linker and also to remove the
benzyl groups on the 3’-phosphate.[69] Unfortunately, this strategy was not
successful due to precipitation of the reactant following benzyl cleavage prior to
complete reduction of the triple bond. (In our experience, unprotected ethynyl-
linked AQ-dA conjugates had poorer solubility in most organic solvents than the
corresponding ethylenyl-linked conjugates.) Therefore, we decided to reduce the
triple bond independently from 3’-dibenzyl phosphate deprotection. Additionally,
since protected phosphates were more stable and easier to handle than
unprotected ones, we also decided to form a 3’-dibenzyl--protected phosphate
intermediate immediately after reduction of the ethynyl linker. The last step in
our synthesis of the water-soluble AQ-dA nucleotide 2 (as shown in Scheme 2)
was a second hydrogenation to monobenzyl-deprotect the 3’-dibenzyl phosphate
intermediate 13.
To improve the solubility of AQ-dA intermediates prior to hydrogenation of
the alkynyl linker, we tried to use DMTrCl to protect the 5’-OH of 3 before
coupling it to 6 (2-ethynylanthraquinone). Accordingly, we reacted 5’-O-DMTr--
protected 4 (see Scheme 1) with 6 using Pd(0) catalyzed cross-coupling
chemistry. However, hydrogenation of the resulting product, 5’-O-DMTr-8-
[anthraquinone-2-yl]ethynyl-2’-deoxyadenosine, using 10% Pd/C and H2 (40 psi) at
room temperature for 24 h, cleaved the DMTr group and precipitated multiple
side products as determined by TLC. This was surprising, because DMTr
protection of 5’-OH on 2’-deoxyuridine was stable to the same hydrogenation
conditions.[70,71] Perhaps the 5’-O DMTr group in 2’-deoxypurine nucleosides
was more labile than in 2’-deoxypyrimidine nucleosides.[72] However, it was also
true that trityl groups on other compounds were cleaved by hydrogenation
under similar conditions.[73] Clearly, a different 5’-OH protecting group was
needed to solubilize intermediates during our synthesis of 2. We selected the
tert-butyldiphenylsilyl (TBDPS) group because it could selectively protect 5’-OH
in 2’-deoxyribonucleosides,[74--77] and it could be cleaved under mild conditions
using NH4F in MeOH.[78] Finally, our second water-soluble AQ-dA target
compound 2 was successfully prepared as described in Scheme 2 following
initial 5’-OH protection of 3 with TBDPSCl.

92
R. A. I. Abou-Elkhair and T. L. Netzel
Synthesis of 5’-O-tert-Butyldiphenylsilyl-8-[2-(anthraquinone-2-
yl)ethyl]-2’-deoxyadenosine (11)
Compound 11 was synthesized in three steps starting with 3 as described in
Scheme 2. Treatment of 3 with TBDPSCl and imidazol (1 equivalent each) in dry
pyridine produced 9 in 91% yield. Because of disilylation of 3, this yield decreased
significantly when excess equivalents of TBDPSCl were used. Importantly for future
work, both the purity and yield of 5’-O-TBDPS--protected 9 were better than those
of 5’-O-DMTr--protected 4 (see Scheme 1).
5’-O-tert-Butyldiphenylsilyl-8-[(anthraquinone-2-yl)ethynyl]-2’-deoxyadenosine
(10) was synthesized in 90% yield via Pd(0)-catalyzed cross-coupling between
9 and 6 under the same conditions described in Scheme 1. Unfortunately, 10
was frequently still mixed with a trace amount of unreacted 9 after
chromatographic purification. This was the case because nucleosides 9 and 10
had nearly the same Rf in most commonly used eluting solvent mixtures. A
similar problem was encountered previously when synthesizing 1 also starting
with 3; in fact, both 8-bromo-2’-deoxyadenosine nucleosides 9 and 4 protected,
respectively, with TBDPS and DMTr groups had the same Rf values. Again using
30% excess of 6, and increased reaction time did not completely eliminate 9. The
latter contaminant was easily eliminated, however, after ethynyl reduction during
purification of 11.
5’-O-tert-Butyldiphenylsilyl-8-[2-(anthraquinone-2-yl)ethyl]-2’-deoxyadenosine
(11) was produced in 86% yield by hydrogenation of 10 using Pd/C and H2 in
MeOH/ethyl acetate (EtOAc) (3:2). The yellow color of 11 was less intense than
that of 10 and it was more soluble in organic solvents. Importantly, 11 had a
more polar Rf value on TLC than 10. Since unreacted 9 from the Pd(0)-cat-
alyzed cross-coupling step did not undergo hydrogenation, traces of 9 were easily
separated from 11 using Biotage silica gel chromatography. Importantly for the
synthesis of 2, the 5’-O-TBDPS group in 10 was stable with respect to hy-
drogenation, and thus the ethylenyl-linked product 11 remained soluble in
MeOH/EtOAc solution.
Phosphorylation of 11 and Two Subsequent
Deprotections to Form 2
5’-O-tert-Butyldiphenylsilyl-8-[2-(anthraquinone-2-yl)ethyl]-2’-deoxyadenosine 3’-
dibenzyl phosphate (12) was prepared by phosphorylation of 11 using 1.2
equivalents of (BnO)2PN(iPr)2 and 2.2 equivalents of Me-tetrazol in THF, followed
by oxidation with m-CPBA. Phosphorylation of the ethylenyl-linked AQ-dA
conjugate 11 showed five product spots in addition to a minor amount of un-
reacted 11 on TLC compared to a single spot found earlier when phosphorylating
4. The major TLC spot corresponded to 12, while the side products were not
identified. Nevertheless, silica gel column chromatography easily purified 12 in
82% yield.

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
93
The desilylated product 8-[2-(anthraquinone-2-yl)ethyl]-2’-deoxyadenosine 3’-
dibenzyl phosphate (13) was produced in 88% yield by treatment of 12 with excess
NH4F in THF/MeOH. The amount of added NH4F was not fully soluble in the
reaction solvent. Nevertheless, the product was purified via silica gel chromatog-
raphy without prior separation of NH4F by filtration or water workup. Finally, the
monobenzyl-deprotected product 2 was formed from the 3’-dibenzyl phosphate
intermediate 13 by catalytic hydrogenation using Pd/C and H2 in MeOH/EtOAc
(8:1). Although Pd/C hydrogenolysis has been reported many times to cleave both
benzyls on a phosphate group,[53--55,57,69,79] hydrogenolysis of 13 produced only
monobenzyl deprotection. Analytical reverse-phase HPLC of the crude product
mixture showed 71% yield of 2. Due to an error in sample handling, however,
purification by preparative reverse-phase HPLC gave 2 in only 22% yield.
Syntheses of Two Substituted Anthraquinones:
2-Iodoanthraquinone (15) and 2-Ethynylanthraquinone (6)
Early steps in the syntheses of both 1 and 2 involve Pd(0)-catalyzed cross-
coupling between a 5’-O--protected 2’-deoxyadenosine (5 or 9) and 2-ethynylan-
thraquinone (6). Compound 6 in turn is prepared in two steps beginning with 15
as shown in Scheme 3. In the first step, Pd(Ph3P)2Cl2 catalyzed cross-coupling of
trimethylsilylacetylene (TMSA) with 15 gives 2-(trimethylsilylethynyl)anthraqui-
none (16); then the terminal alkyne of 16 is deprotected with KF to give 6.
Although 2-chloroanthraquinone is commercially available, its Pd(0)-catalyzed
cross-coupling reaction is likely to occur less readily than those for either 2-bromo
or 2-iodoanthraquinone. Also, direct bromination of commercially available
anthraquinone yields a mixture of polybromoanthraquinones that is difficult to
separate.[80] Other reported syntheses of 2-bromoanthraquinone either have low
yields[81] or require harsh conditions.[82] For these reasons, as well as the fact that
iodide is a better leaving group than bromide, 15 appears to be a good precursor
for forming 6.
Synthesis of 2-Iodoanthraquinone (15)
To form 15, 2-aminoanthraquinone (14) was diazotized with nitrous acid that
was prepared in situ from HCl and NaNO2 and then substituted with iodide in a
manner similar to the Sandmeyer reaction. TLC of the product mixture, however,
showed a less polar, minor product very close to 15. Thus, although 15 was
difficult to purify by silica gel column chromatography, three separations using 30%
CH2Cl2 in hexane as the mobile phase produced 3.4 g of 15 in 75% yield.
Synthesis of 2-Ethynylanthraquinone (6)
Following a general procedure for Pd-catalyzed cross-coupling between an aryl
halide and trimethylsilylacetylene (TMSA),[83] 15 was readily converted to 16 via
cross-coupling with TMSA using dichlorobis(triphenylphosphine)palladium(II)

94
R. A. I. Abou-Elkhair and T. L. Netzel
[Pd(Ph3P)2Cl2] as the catalyst. This reaction was complete within 10 min in
tetrahydrofuran (THF) at room temperature. However, the above difficulty in
purifying 15 made using commercially available 2-chloroanthraquinone to
produce 16 attractive. Unfortunately, both of our attempts to do so by substituting
2-chloroanthraquinone for 15 (a) under the same reaction conditions and (b) by
heating the reaction mixture at 60°C for 24 h failed. Thus, at present, the best route
for producing 6 appears to be via precursors 14 and 15.
All of the anthraquinones in Scheme 3 had low solubility in organic solvents.
For example, 26 mL of THF/MeOH (1:1 v:v) along with 30 min of stirring were
required to dissolve 200 mg of 16 for deprotection by potassium fluoride to
produce 6, and it was harder to dissolve 6 than 16 in CH2Cl2, CHCl3, THF,
MeOH, or EtOAc. Additionally, the low solubility of 6 made difficult purification
of its crude reaction mixture by silica gel chromatography. Thus the crude product
was purified initially by extraction and recrystallization. However, TLC analysis of
the precipitated crystals showed very faint spots with higher polarity than 6, and 1H
NMR of the crystals showed extra proton resonances. Complete purification of 100
mg of 6 required silica gel chromatography on a 20-cm long  5-cm dia. column,
an impractical procedure for large quantities of 6. Late in our work, we found that
light below 370 nm degraded 6. In particular, 6 changed its color from pale
yellow to brown soon after silica gel purification when exposed to fluorescent
laboratory light.
EXPERIMENTAL
Materials and General Synthetic Methods
2’-Deoxyadenosine monohydrate was purchased from TCI America as white a
powder. TMSA obtained from GFS Chemicals was used after vacuum transfer
from CaH2. DMTrCl and Br2 were obtained from Alfa-Aesar. Ten percent Pd on
activated carbon catalyst (Pd/C) and Pd(Ph3P)2Cl2 was obtained from Strem
Chemicals and used as received. 2-Amino-anthraquinone was purchased from
Aldrich as a brown powder (93% pure) and was used as received. Other remaining
reagents used were purchased from Aldrich or VWR. 2-Ethynylanthraquinone (6)
was synthesized as described in Scheme 3. Pd(Ph3P)4 was prepared according to the
literature[84] and stored between uses in our glove box’s freezer at À20°C.
Anhydrous DMF was purchased from Aldrich and stored in our Vacuum
Atmospheres M040-2 glove box that was pressurized with nitrogen boil-off gas from
a liquid nitrogen tank. All starting materials for anhydrous reactions were dried
prior to use on a vacuum line (1--4 Â 10À4 torr) for at least 12 h. Two to three co-
evaporation cycles were also used for drying compounds as indicated below.
Solvents for synthesis were dried and redistilled in continuous circulation
distillation apparati: THF was dried with benzophenone /Na0 and stored over
activated molecular sieves in our glove box. Pyridine was always freshly distilled

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
95
over CaH2 before use. Water was deionized by a Millipore (Milli-Q Plus) ultrapure
water system (18.0 MO). All manipulations of DMTrCl, TBDPSCl, Pd(Ph3P)4,
Pd(Ph3P)2Cl2, and (BnO)2PN(iPr)2 were performed in our glove box. Most of the
reactions were monitored with glass-backed TLC Plates precoated with silica gel 60
F254 (EMD Chemicals). TLC was run using 5--7% MeOH in CH2Cl2 as the eluent.
HPLC-grade solvents were used for chromatographic purifications. Flash column
chromatography was carried out on either a Biotage Flash-40k system using
˚
prepackaged KP-Silk cartridges or on Whatmank flash silica (60 A pore, 230--400
mesh) that was packed in glass columns and pressurized with boil-off nitrogen.
NMR Spectra were recorded at GSU on three spectrometers, a Varian Unity + 300,
a Varian Unity Inova 500, and a Brucker Avance 400, using either CDCl3 or
1
DMSO-d6 as solvents. Chemical shifts for H NMR in these solvents were
referenced, respectively, relative to tetramethylsilane (0.00 ppm) and DMSO (2.49
ppm). 31P NMR spectra were recorded using orthophosphoric acid (85%) as an
external standard in a capillary tube inside of the NMR tube. Low-resolution (LR)
MS were obtained at GSU: for substituted anthraquinones EI (electron impact) MS
were recorded in positive ion mode on a Shimadzu 5050A MSD single quadrupole
spectrometer with one amu resolution; for substituted 2’-deoxyadenosines ESI
(electrospray ionization), MS were recorded in either positive or negative ion
modes on a Waters Micromass Q-TOFTM with 50 ppm error.
8-Bromo-2’-deoxyadenosine, 3. 2’-Deoxyadenosine monohydrate (6 g,
22.28 mmol) was dissolved in 800 mL of 1 M acetate buffer at pH 4.0 (prepared by
adding glacial acetic acid to 700 mL of 1 M sodium acetate and adjusting the pH).
Br2 (2.3 mL, 44.43 mmol, 2 equiv.) was added, and the reaction mixture was stirred
at room temperature for 4 h in the dark. The reaction was quenched by gradual
addition of a saturated aqueous solution of NaHSO3 until the red color of Br2
disappeared. The product was extracted by shaking with CHCl3 (8 Â 500 mL) in a
separatory funnel; the combined extracts were dried over anhydrous MgSO4 and
evaporated to yield a solution of the product in acetic acid. Co-evaporation with
toluene (2 Â 200 mL) provided 3 as a pale yellow powder that was used without
further purification (5.96 g, 79% yield). 1H and 13C NMR spectra for 3 were identical
to ones published in the literature.[61]
5’-O-Dimethoxytrityl-8-bromo-2’-deoxyadenosine, 4. Com-
pound 3 (640 mg, 1.94 mmol) was dried 3 times by co-evaporation with dry
pyridine and suspended in dry pyridine (5 mL). To the suspension was added
TEA (0.37 mL, 2.72 mmol, 1.4 equiv.) and 4-DMAP (13 mg, 0.1 mmol, 0.05
equiv.) in our glove box. The mixture was next removed from our glove box, and
DMTrCl (789 mg, 2.33 mmol, 1.2 equiv.) was dissolved in dry pyridine and added
drop-wise at 0°C to the reaction mixture with 3 under a nitrogen atmosphere using
a cannula. The orange reaction mixture was stirred at room temperature under a
nitrogen atmosphere for 4 h, after which time the mixture was homogeneous and

96
R. A. I. Abou-Elkhair and T. L. Netzel
TLC showed complete consumption of 3. The reaction was quenched with a
saturated aqueous solution of NaHCO3, and the solvent was evaporated. The
residue was dissolved in CH2Cl2 (50 mL) and water (20 mL); the organic layer was
separated, washed with water (2 Â 20 mL), and dried over MgSO4. The crude
product was purified by silica gel chromatography on a column that had been pre-
equilibrated with 1% TEA in CH2Cl2 and eluted with MeOH/CH2Cl2 (0:100--3:97).
Evaporation of the eluting solvent afforded 4 as pale yellow foam (940 mg, 72%
1
yield). The H NMR spectrum given here is very similar to ones previously
reported in CD2Cl2[66] and CDCl3.[65] 1H NMR (300 MHz, CDCl3): d (ppm) 2.31--
2.4 (1H, m, H2’), 3.39 (2H, d, J = 5.7 Hz, H5’, H5’’), 3.51--3.60 (1H, m, H2’’), 3.77
[6H, s, OCH3 (DMTr)], 4.12 (1H, dd, J = 5.7 and 10.2 Hz, H4’), 4.95 (1H, dd,
J = 4.8 and 10.2 Hz, H3’), 5.78 (2H, br s, NH2), 6.4 (1H, t, J = 6.7 Hz, H1’), 7.66 [4H,
dd, J = 4.2 and 8.7 Hz, OPh-meta (DMTr)], 7.16--7.28 [7H, m, OPh-ortho (DMTr,
4H) and Ph-meta and para (DMTr, 3H)], 7.37 [2H, d, J = 7.5 Hz, Ph-ortho (DMTr)],
and 8.06 [1H, s, H2 (dA)].
5’-O-Dimethoxytrityl-8-bromo-2’-deoxyadenosine 3’-dibenzyl
phosphate, 5. To 4 (440 mg, 0.70 mmol), previously dried 2 times by co-
evaporation with anhydrous THF, was added Me-tetrazole (130 mg, 1.54 mmol, 2.2
equiv.) and anhydrous THF (5 mL) in our glove box. The mixture was removed
from our glove box and cooled to 0°C using an ice-water bath, and (BnO)2PN(iPr)2
(0.28 mL, 0.84 mmol, 1.2 equiv.) was added drop-wise under nitrogen with a
syringe. The reaction mixture was stirred under a nitrogen atmosphere for 10
minutes at 0°C; then it was warmed to room temperature, and the reaction progress
was monitored by TLC. A white precipitate began to form after 20 min, and TLC
showed complete consumption of 4 after a total reaction time of 1.5 h. The
suspension obtained was cooled to À78°C using a dry ice--acetone bath, and a
solution of m-CPBA (250 mg) in CH2Cl2 (5 mL) was added gradually to the chilled
mixture. After 15 minutes of stirring at À78°C, the mixture became homogeneous,
and TLC showed conversion of an intermediate spot to a more polar one. The
mixture was next warmed to room temperature, and saturated aqueous NaHCO3
was added. More CH2Cl2 (30 mL) and water (15 mL) were added; the organic layer
was separated, washed with water, dried with anhydrous MgSO4, and evaporated
to dryness. The syrup obtained was purified using silica gel chromatography on a
Biotage column that had been pre-equilibrated with 1% TEA and eluted with
MeOH/CHCl3 (0:100--3:97). Evaporation of the eluting solvent afforded 5 as white
1
foam (469 mg, 75% yield). H NMR (500 MHz, CDCl3): d (ppm) 2.39 (1H, ddd,
J = 2, 6.5 and 13.5 Hz, H2’), 3.30 (1H, dd, J = 5.5 and 10 Hz, H5’) , 3.39 (1H, dd,
J = 6.5 and 10 Hz, H5’’), 3.75--3.81 [7H, m, H2’’ and OCH3 (DMTr)], 4.33--4.35 [1H,
m, H4’), 5.05 (4H, m, CH2 (Bn)], 5.35--5.37 (1H, m, H3’), 5.65 (2H, br s, NH2), 6.4
(1H, t, J = 7 Hz, H1’), 6.72 [4H, dd, J = 7 and 9 Hz, OPh-meta (DMTr)], 7.16--7.25
[7H, m, OPh-ortho (DMTr, 4H) and Ph-meta and para (DMTr, 3H)], 7.31 [10 H, s,
Ph (Bn)], 7.36 [2H, d, J = 6.5 Hz, Ph-ortho (DMTr)], and 7.94 [1H, s, H2 (dA)]. 13
C

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
97
NMR (75 MHz, CDCl3): d (ppm) 43.26 (C2’), 55.15 [OCH3 (DMTr)], 62.93 (C5’),
69.55 [d, JC -- P = 5.7, CH2 (Bn)], 84.68, 86.19 , 88.75 [C1’, C4’, and CAr3 (DMTr)],
112.94, 120.41 [OPh-meta (DMTr), and C5 (dA)], 126.67 [C8 (dA)], 127.66, 128,
128.11, 128.62, 130, 135.56, 135.81, 144.61 [Ar (DMTr and Bn)], 150.82 [C4 (dA)],
152.49 [C2 (dA)], 154.07 [C6 (dA)], and 158.35 [OPh-C4 (DMTr)]. 31P NMR (121
MHz, CDCl3): d (ppm) À1.19. Low-resolution ESI MS m/z (M + H)+: calc’d.
892.21, found 892.18.
5’-O-dimethoxytrityl-8-[(anthraquinone-2-yl)ethynyl]-2’-deox-
yadenosine 3’-dibenzyl phosphate, 7. To 5 (410 mg, 0.46 mmol) was
added in our glove box Pd(Ph3P)4 (24 mg, 0.02 mmol, 0.05 equiv.), CuI (9 mg, 0.05
mmol, 0.1 equiv.), TEA (0.13 mL, 0.92 mmol, 2 equiv.), compound 6 (130 mg, 0.56
mmol, 1.3 equiv.), and anhydrous DMF (5 mL). The mixture was removed from
our glove box and stirred under a nitrogen atmosphere for 6 h at 65°C in an oil
bath, after which time DMF was removed under reduced pressure. The residue was
dissolved in CH2Cl2 and filtered over celite to remove insoluble materials. After
evaporation of solvent, the crude product was applied to a silica gel column that
had been pre-equilibrated with 1% TEA in CHCl3 and eluted with MeOH/CHCl3
(0:100--3:97). Evaporation of the eluting solvent afforded 6 as a yellow foam (469
mg, 57% yield). 1H NMR (300 MHz, CDCl3): d (ppm) 2.53 (1H, ddd, J = 2.7, 6.6 and
14.1 Hz, H2’), 3.36--3.49 (2H, m, H5’ and H5’’), 3.66--3.75 [7H, m, H2’’ and OCH3
(DMTr)], 4.39--4.43 (1H, m, H4’), 5.06 [4H, d, JH--P = 8.4 Hz, CH2 (Bn)], 5.39--5.43
(1H, m, H3’), 5.73 (2H, br s, NH2), 6.57 (1H, t, J = 6.9 Hz, H1’), 6.71 [4H, dd, J = 4.2
and 8.7 Hz, OPh-meta (DMT)], 7.15--7.39 [19H, m, OPh-ortho (DMT, 4H), Ph
(DMT, 5H), and Ph (Bn, 10H)], 7.82--7.85 [2H, m, H6 (AQ) and H7 (AQ)], 7.94
[1H, dd, J = 1.5 and 8.1 Hz, H3 (AQ)], 8.04 [1H, s, H2 (dA)], 8.30--8.36 [3H, m, H4
(AQ), H5 (AQ) and H8 (AQ)], and 8.53 [1H, d, J = 1.5 Hz, H1 (AQ)].
8-[(Anthraquinone-2-yl)ethynyl]-2’-deoxyadenosine 3’-diben-
zyl phosphate, 8. Compound 7 (250 mg, 0.24 mmol) was dissolved in a
30% DCA in CH2Cl2 mixture (7.5 mL), and the resulting red solution was stirred at
room temperature for 30 min. (Note that many times it was convenient to perform
this detritylation step directly on the crude product 7 without silica gel purification.)
The reaction was quenched by addition of saturated aqueous NaHCO3 until the
red color of the DMTr cation disappeared. More CH2Cl2 (25 mL) and water (10
mL) were added, and the organic layer was separated, washed with water, dried
with anhydrous MgSO4, and evaporated to dryness. The syrup obtained was
purified using flash silica gel chromatography on a biotage column with MeOH/
CHCl3 (0:100--3:97) as the eluting system to yield yellow foam after evaporating the
eluting solvent. This foam was dissolved in a minimum amount of CH2Cl2 and
precipitated by adding hexane. Evaporation of CH2Cl2/hexane from the
1
precipitate afforded 8 as a bright yellow solid (135 mg, 76% yield). H NMR
(300 MHz, CDCl3): d (ppm) 2.46 (1H, dd, J = 5.7 and 14.1 Hz, H2’), 3.08--3.15 (1H,

98
R. A. I. Abou-Elkhair and T. L. Netzel
m, H2’’), 3.37--3.65 (1H, m, 5) 3.86--3.91 (1H, m, H5’’), 4.33 (1H, s, H4’), 5.04--5.18
[4H, m, CH2 (Bn)], 5.20--5.24 (1H, m, H3’), 6.17 (2H, br s, NH2), 6.56--6.62 (2H, m,
H1’ and OH5’), 7.29--7.37 [10H, m, Ph (Bn)], 7.72--7.83 [2H, m, H6 (AQ) and H7
(AQ)], 7.92 [1H, d, J = 8.1 Hz, H3 (AQ)], 8.23--8.26 [3H, m, H2 (dA), H5 (AQ) and
1
H8 (AQ)], 8.32 [1H, d, J = 8.1 Hz, H4 (AQ)], and 8.56 [1H, s, H1 (AQ)]. H NMR
(500 MHz, CDCl3 + D2O): d (ppm) 2.45 (1H, dd, J = 5 and 14 Hz, H2’), 3--3.14 (1H,
m, H2’’), 3.59 (1H, d, J = 12.5 Hz, H5’) 3.87 (1H, d, J = 12.5 Hz, H5’’), 4.33 (1H, s, H4’),
5.05--5.16 [4H, m, CH2 (Bn)], 5.21--5.23 (1H, m, H3’), 6.59 (1H, dd, J = 5 and 9 Hz,
H1’), 7.31--7.38 [10H, m, Ph (Bn)], 7.76--7.82 [2H, m, H6 (AQ) and H7 (AQ)], 7.93
[1H, d, J = 8 Hz, H3 (AQ)], 8.23--8.25 [3H, m, H2 (dA), H5 (AQ) and H8 (AQ)], 8.32
[1H, d, J = 8 Hz, H4 (AQ)], and 8.56 [1H, s, H1 (AQ)]. 31P NMR (121 MHz, CDCl3):
d (ppm) À1.55. 13C NMR (100 MHz, CDCl3): d (ppm) 38.67 (C2’), 63.10 (C5’), 69.79
[d, JP--C = 6, CH2 (Bn)], 80.05 (d, JP--C = 6, C3’), 80.86 [dA-C (ethynyl)], 87.19, 88.04
(C1’ and C4’), 94.48 [AQ-C (ethynyl)], 120.85 [C5 (dA)], 126.11 [C8 (dA)], 127.40,
127.60, 128.19, 128.71, 128.87, 131.08 [AQ and Ph (Bn)], 132.05, 133.25, 133.40,
133.54, 133.63 (AQ), 134.44 [d, JP--C = 3.1, Ph-C1 (Bn)], 135.50, 136.78 [AQ and Ph
(Bn)], 148.40 (AQ), 152.20 [C4 (dA)], 153.36 [C2 (dA)], 155.67 [C6 (dA)], 181.89
(CO), and 182.15 (CO). Low-resolution ESI MS m/z (M + H)+: calc’d 742.21, found
742.18.
8-[(Anthraquinone-2-yl)ethynyl]-2’-deoxyadenosine 3’-benzyl
hydrogen phosphate, 1. Compound 8 (59 mg, 0.08 mmol) was dissolved
in anhydrous 1,4-dioxane (8 mL) by heating to 60°C. DABCO (24 mg, 0.22 mmol,
2.7 equiv.) was added to this solution in our glove box, and the homogeneous
mixture was refluxed on the bench top for 2 h under a nitrogen atmosphere. The
solvent was evaporated, and the crude product was separated by analytical HPLC
to give ca. 95% yield of 1. The crude product was then purified by preparative
HPLC using a Varian Microsorb C-18 reverse-phase column (250 mm  41.4 mm
dia.). The column was eluted with a flow rate of 40 mL/min, and the fractions were
monitored by UV detection at 260 nm. The mobile phase consisted of a
programmed gradient of solution A (70% MeCN in water) and solution B (water):
from 0% A/100% B to 50% A/50% B over 15 min; then to 100% A/0% B over 5 min,
and finally at 100% A/0% B for another 10 min. Evaporation of the eluent was
facilitated by co-evaporation with MeOH to afford 1 as yellow plates (30 mg, 58%
yield). 1H NMR (500 MHz, DMSO-d6): d (ppm) 2.52--2.56 (1H, m, H2’), 3.08--3.14
(1H, m, H2’’), 3.35 (1H, br s, OH5’), 3.52--3.54 (1H, m, H5’), 3.64--3.66 (1H, m, H5’’),
4.14 (1H, s, H4’), 4.80 [2H, d, JH--P = 5.5 Hz, CH2 (Bn)], 5.03 (1H, s, H3’), 6.55 (1H,
t, J = 7 Hz, H1’), 7.17 [1H, t, J = 7.5 Hz, Ph-para (Bn)], 7.24 [2H, t, J = 7.5, Ph-meta
(Bn)], 7.33 [2H, d, J = 7.5 Hz, Ph-ortho (Bn)], 7.68 (2H, br s, NH2), 7.94 [2H, dd,
J = 5.5 and 3.5 Hz, H6 (AQ) and H7 (AQ)], 8.13 [1H, s, H2 (dA)], 8.17 [1H, d, J = 8
Hz, H3 (AQ)], 8.20--8.22 [3H, m, H4 (AQ), H5 (AQ) and H8 (AQ)], and 8.32 [1H, s,
H1 (AQ)]. 1H NMR (500 MHz, DMSO-d6 + D2O): d (ppm) 2.52--2.56 (1H, m, H2’),
3.11 (1H, s, H2’’), 3.50--3.53 (1H, m, H5’), 3.65--3.67 (1H, m, H5’’), 4.15 (1H, s, H4’),

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
99
4.79 [2H, s, CH2 (Bn)], 5.0 (1H, s, H3’), 6.55 (1H, s, H1’), 7.18 [1H, d, J = 6 Hz, Ph-
para (Bn)], 7.24 [2H, t, J = 6, Ph-meta (Bn)], 7.32 [2H, d, J = 6 Hz, Ph-ortho (Bn)],
7.94 [2H, d, J = 2.5 Hz, H6 (AQ) and H7 (AQ)], 8.11 [1H, s, H2 (dA)], 8.14 [1H, d,
J = 8.5 Hz, H3 (dA)], 8.19--8.21 [3H, m, H4 (AQ), H5 (AQ) and H8 (AQ)], and 8.30
[1H, s, H1 (AQ)]. 13C NMR (125 MHz, DMSO-d6): d (ppm) 45.22(C2’), 62.38 (C5’),
66.07 [d, JC--P = 4.6 Hz, CH2 (Bn)], 75.31 (d, J = 20 Hz, C3’), 82.22 [dA-C
(ethynyl)], 84.92, 86.96 (C1’ and C4’), 92.73 [AQ-C (ethynyl)], 119.85 [C5 (dA)],
125.57 [C8 (dA)], 126.87, 127.07, 127.30, 128.07, 129.65, 132.07 [AQ and Ph (Bn)],
132.83, 132.97, 133.05, 133.16, 136.96, 134.75 (AQ) 139.28 [d, JC--P = 8.3, Ph-C1
(Bn)], 148.48 [C4 (dA)], 153.75 [C2 (dA)], 156.16 [C6 (dA)], 181.55 (CO), and 181.66
(CO). 31P NMR (202 MHz, DMSO-d6): d (ppm) À0.35. Low resolution ESI MS m/z
(M--H)À: calc’d 650.14, found 650.11.
5’-O-tert-butyldiphenylsilyl-8-bromo-2’-deoxyadenosine,
9. Compound 3 (5 g, 15 mmol) was dried two times by co-evaporation with
anhydrous pyridine and then suspended in anhydrous pyridine (40 mL); imidazol
(1.02 g, 15 mmol, 1 equiv.) was added to this suspension in our glove box. The
mixture was removed from the glove box and cooled to 0°C using an ice-water
bath. TBDPSCl (4.09 mL, 15.7 mmol, 1.05 equiv.) was added drop-wise (over
27 min) under nitrogen with a syringe. The pale yellow reaction mixture was
warmed to room temperature, at which time the mixture became homogeneous.
Stirring continued at room temperature under a nitrogen atmosphere, and the
reaction progress was monitored with TLC. The starting materials were completely
consumed after a total reaction time of 3 h. The reaction was quenched with MeOH
(5 mL), and the solvent was evaporated. The residue was dissolved in EtOAc (500
mL) and washed with water (2 Â 200 mL); the organic phase was dried over
MgSO4. The crude product was purified on a silica gel column that was eluted with
MeOH/CH2Cl2 (0:100--3:97). Evaporation of the eluting solvent afforded 9 as white
1
foam (7.755 g, 91% yield). H NMR (300 MHz, CDCl3): d (ppm) 1.02 [9H, s, t-Bu
(TBDPS)] 2.3--2.41 (2H, m, H2’ and OH3’), 3.53--3.62 (1H, m, H2’’), 3.84 (1H, dd,
J = 8.1 and 10.2 Hz, H5’), 3.98 (1H, dd, J = 7.5 and 10.2 Hz, H5’’), 4.04--4.1 (1H, m,
H4’), 4.99--5.08 (1H, m, H3’), 5.6 (2H, br s, NH2), 6.38 (1H, dd, J = 6.3 and 7.2 Hz,
H1’), 7.29--7.43 [6H, m, Ph-ortho and para (TBDPS)], 7.62 [4H, dt, J = 1.5 and 8.1 Hz,
Ph-meta (TBDPS)], and 8.09 [1H, s, H2 (dA)]. 13C NMR (75 MHz, CDCl3): d (ppm)
19 [CMe3 (TBDPS)], 26.67 [CH3 (TBDPS)], 36.37 (C2’), 63.68 (C5’), 72.09 (C3’),
86.04, 87.05 (C4’ and C1’), 120.15 [C5 (dA)], 127.51 [Ph-meta (TBDPS)], 127.66 [C8
(dA)], 129.63 [Ph-para (TBDPS)], 133 [Ph-C1 (TBDPS)], 135.38 [Ph-ortho (TBDPS)],
150.55 [C4 (dA)], 152.38 [C2 (dA)], and 154.28 [C6 (dA)]. Low-resolution ESI MS
m/z (M + H)+: Calc’d 568.14, found 568.13.
5’-O-tert-Butyldiphenylsilyl-8-[(anthraquinone-2-yl)ethynyl]-
2’-deoxyadenosine, 10. To 9 (1.914 g, 3.37 mmol) was added in our glove
box Pd(Ph3P)4 (194 mg, 0.17 mmol, 0.05 equiv.), CuI (65 mg, 0.34 mmol, 0.1

100
R. A. I. Abou-Elkhair and T. L. Netzel
equiv.), TEA (0.94 mL, 6.7 mmol, 2 equiv.), compound 6 (1.016 g, 4.38 mmol, 1.3
equiv.), and anhydrous DMF (29 mL). The mixture was removed from our glove
box and stirred under a nitrogen atmosphere in the dark for 6 h at 65°C in an oil
bath. DMF was removed under reduced pressure, and the residue was dissolved in
10% MeOH in CH2Cl2; insoluble materials were removed by filtration over celite.
After evaporation the crude product was purified with two silica gel columns using
MeOH/CH2Cl2 (0:100--3:97) as the eluting system to yield yellow foam after
evaporation of the eluting solvent. This foam was dissolved in a minimum amount of
CH2Cl2 and precipitated by adding hexane. Evaporation of CH2Cl2/hexane from
1
the precipitate afforded 10 as a bright yellow solid (2.19 g, 90%). H NMR
(300 MHz, CDCl3): d (ppm) 1.03 [9H, s, t-Bu (TBDPS)] 2.45--2.53 (1H, m, H2’), 2.63
(1H, d, J = 3 Hz, OH3’), 3.5--3.59 (1H, m, H2’’), 3.89 (1H, dd, J = 5.1 and 10.2 Hz,
H5’), 4.03 (1H, dd, J = 7.8 and 10.2 Hz, H5’’), 4.13--4.19 (1H, m, H4’), 5--5.08 (1H, m,
H3’), 5.96 (2H, br s, NH2), 6.32 (1H, t, J = 6.9 Hz, H1’), 7.29--7.42 [6H, m, Ph-ortho
and para (TBDPS)], 7.63 [4H, t, J = 6.6 Hz, Ph-meta (TBDPS)], 7.79 [2H, t, J = 3.6,
H6 (AQ) and H7 (AQ)], 7.88 [1H, d, J = 8.1 Hz, H3 (AQ)], 8.12 [1H, s, H2 (dA)],
8.25 [1H, d, J = 8.1 Hz, H4 (AQ)], 8.27--8.32 [2H, m, H5 (AQ) and H8 (AQ)], and
8.48 [1H, s, H1 (AQ)]. 13C NMR (100 MHz, CDCl3): d (ppm) 19.17 [CMe3
(TBDPS)], 26.80 [CH3 (TBDPS)], 37.02 (C2’), 64.12 (C5’), 73.05 (C3’), 81.78 [dA-C
(ethynyl)], 85.19, 87.02 (C4’ and C1’), 93.74 [AQ-C (ethynyl)], 120.01 [C5 (dA)],
126.32 [C8 (dA)], 127.30, 127.67 (Ph-meta (TBDPS), and AQ), 129.74 [Ph-para
(TBDPS)], 130.80 (AQ), 133.10, 133.30, 134.02, 134.27, 134.32 (Ph-C1 (TBDPS) and
AQ), 135.48 [Ph-ortho (TBDPS)], 136.47(AQ), 149.12 [C4 (dA)], 153.69 [C2 (dA)],
155.24 [C6 (dA)], 181.89 (CO), and 182.06 (CO). Low-resolution ESI MS m/z
(M + H)+: Calc’d 720.26, found 720.25.
5’-O-tert-Butyldiphenylsilyl-8-[2-(anthraquinone-2-yl)ethyl]-2’-
deoxyadenosine, 11. Compound 10 (940 mg, 1.3 mmol) was dissolved in
EtOAc (60 mL) by slight heating while stirring; MeOH (90 mL) was then added to
the solution. The resulting solution was transferred to a hydrogenation vessel
containing 10% Pd/C (500 mg) that had been activated by stirring under H2 (40 psi)
in MeOH (20 mL) for 30 min at room temperature. The vessel was next charged
with H2 gas and then degassed using an aspirator in a cycle that was repeated 5--6
times. The vessel was finally charged with hydrogen gas at 40 psi and stirred at
room temperature for 24 h, by which time TLC showed complete conversion of an
initial spot to a more polar spot. The Pd/C catalyst was then removed by filtration
over celite, and adsorbed nucleoside residue was extracted from the catalyst by
washing with boiling 10% MeOH in CHCl3. The crude product was applied to a
silica gel column and eluted with MeOH/CH2Cl2 (0:100--3:97). Evaporation of the
1
eluting solvent afforded 11 as a pale yellow foam (810 mg, 86% yield). H NMR
(300 MHz, CDCl3): d (ppm) 0.98 [9H, s, t-Bu (TBDPS)], 2.28 (1H, ddd, J = 3.9, 6.9
and 13.2 Hz, H2’), 3.03 (1H, br s, OH3’), 3.19--3.4 (4H, m, ethylene), 3.58--3.68 (1H,
m, H2’’), 3.8 (1H, dd, J = 4.8 and 10.5 Hz, H5’), 3.96 (1H, dd, J = 6.9 and 10.5 Hz,

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
101
H5’’), 4.05--4.1 (1H, m, H4’), 4.92--4.98 (1H, m, H3’), 5.67 (2H, br s, NH2), 6.25 (1H, t,
J = 6.9 Hz, H1’), 7.26--7.38 [6H, m, Ph-ortho and para (TBDPS)], 7.52--7.66 [5H, m,
Ph-meta (TBDPS) and H3 (AQ)], 7.79 [2H, t, J = 4.5 Hz, H6 (AQ) and H7 (AQ)],
8.09 [1H, s, H2 (dA)], 8.16 [1H, d, J = 7.8 Hz, H4 (AQ)], 8.2 [1H, d, J = 1.8 Hz, H1
(AQ)], and 8.24--8.3 [2H, m, H5 (AQ) and H8 (AQ)]. 13C NMR (125 MHz, CDCl3):
d (ppm) 19.17 [CMe3 (TBDPS)], 26.79 [CH3 (TBDPS)], 29.16 [dA-CH2 (ethyl)],
33.35 [AQ-CH2 (ethyl)], 36.86 (C2’), 64.02 (C5’), 72.69 (C3’), 84.18, 86.76 (C4’ and
C1’), 118.96 [C5 (dA)], 127.17 [C8 (dA)], 127.65 [Ph-meta (TBDPS)], 129.73 [Ph-para
(TBDPS)], 131 (AQ), 133.2, 133.52, 133.63 (Ph-C1 (TBDPS) and AQ), 135.49 [Ph-
ortho (TBDPS)], 147.52 (AQ), 150.84 [C4 (dA)], 151.92 [C2 (dA)], 154.62 [C6 (dA)],
182.75 (CO), and 183.14 (CO). Low-resolution ESI MS m/z (M + H)+: Calc’d
724.30, found 724.25.
5’-O-tert-butyldiphenylsilyl-8-[2-(anthraquinone-2-yl)ethyl]-2’-
deoxyadenosine 3’-dibenzyl phosphate, 12. To 11 (750 mg, 1.036
mmol), previously dried two times by co-evaporation with anhydrous THF, was
added Me-tetrazole (193 mg, 2.28 mmol, 2.2 equiv.) and anhydrous THF (7 mL) in
our glove box. The mixture was removed from our glove box and cooled to 0°C
using an ice-water bath, and (BnO)2PN(iPr)2 (0.41 mL, 1.24 mmol, 1.2 equiv.) was
added drop-wise under nitrogen with a syringe. The reaction mixture was stirred
under a nitrogen atmosphere for 10 minutes at 0°C and then allowed to warm to
room temperature with continued stirring for a total reaction time of 1 h. A white
precipitate began to form after 20 min of stirring, and TLC showed formation of a
spot that was less polar than the starting material. This new TLC spot did not
increase with additional stirring. The suspension was cooled to À78°C using a dry
ice--acetone bath, and a solution of m-CPBA (375 mg) in CH2Cl2 (7 mL) was added
gradually to the chilled mixture. After 15 minutes of stirring at À78°C, the mixture
became homogeneous, and TLC showed conversion of an initial spot to a more
polar one. The mixture was next warmed to room temperature, and saturated
aqueous NaHCO3 (8 mL) was added. More CH2Cl2 (50 mL) and water (20 mL)
were then added. Finally, the organic layer was separated, washed with water, dried
with anhydrous MgSO4, and evaporated to dryness. The syrup obtained was
purified on silica gel column (16 cm  2.5 cm dia.) that was eluted with MeOH/
CHCl3 (0:100--3:97). Evaporation of the eluting solvent afforded 12 as pale yellow
1
foam (833 mg, 82% yield). H NMR (300 MHz, CDCl3): d (ppm) 0.99 [9H, s, t-Bu
(TBDPS)], 2.4 (1H, ddd, J = 2.1, 6 and 13.8 Hz, H2’), 3.18--3.37 (4H, m, ethylene),
3.70 (1H, dd, J = 5.4 and 11.1 Hz, H5’), 3.82--3.90 (1H, m, H2’’), 3.96 (1H, dd,
J = 6.6 and 11.1 Hz, H5’’), 4.23--4.28 (1H, m, H4’), 5--5.12 [4H, m, CH2 (Bn)], 5.35--
5.39 (1H, m, H3’), 5.54 (2H, br s, NH2), 6.4 (1H, dd, J = 6 and 7.8 Hz, H1’), 7.23--7.4
[16H, m, Ph-ortho and para (TBDPS, 6H) and Ph (Bn, 10H)], 7.54--7.59 [4H, m, Ph-
meta (TBDPS)], 7.62 [1H, dd, J = 1.8 and 8.1 Hz, H3 (AQ)], 7.76--7.82 [2H, m, H6
(AQ) and H7 (AQ)], 7.98 [1H, s, H2 (dA)], 8.21 [1H, d, J = 8.1 Hz, H4 (AQ)], 8.2
[1H, d, J = 1.8 Hz, H1 (AQ)], and 8.23--8.32 [2H, m, H5 (AQ) and H8 (AQ)].

102
R. A. I. Abou-Elkhair and T. L. Netzel
13C NMR (125 MHz, CDCl3): d (ppm) 19.13 [CMe3 (TBDPS)], 26.69 [CH3
(TBDPS)], 29.05 [dA-CH2 (ethyl)], 33.07 [AQ-CH2 (ethyl)], 34.68 (C2’), 63.04 (C5’),
69.31--69.68 [m, CH2 (Bn)], 78.66 (C3’), 84.18, 86.76 (C4’ and C1’), 118.85 [C5 (dA)],
127.13 [C8 (dA)], 127.58 [Ph-meta (TBDPS)], 128.02, 128.6 [Ph (Bn)], 129.68 [Ph-para
(TBDPS)], 131.88 (AQ), 132.95 [d, JP --C = 6.1, Ph-C1 (Bn)], 133.43, 133.44, 133.52
(Ph-C1 (TBDPS) and AQ), 134.04, 134.3 [Ph (Bn)], 135.48 [Ph-ortho (TBDPS)],
147.42 (AQ), 150.86 [C4 (dA)], 151.80 [C2 (dA)], 154.48 [C6 (dA)], 182.82 (CO), and
183.16 (CO). 31P NMR (121 MHz, CDCl3): d (ppm) À1.19. Low-resolution ESI MS
m/z (M + H)+: Calc’d 984.36, found 984.31.
8-[2-(Anthraquinone-2-yl)ethyl]-2’-deoxyadenosine 3’-dibenzyl
phosphate, 13. Compound 12 (375 mg, 0.38 mmol) was dissolved in THF
(1.5 mL) by stirring at 60°C for 1 min, and then MeOH (10 mL) was added. To this
solution was added NH4F (162 mg, 4.38, 11.5 equiv.), and the reaction mixture was
stirred at 60°C for 6 h, by which time TLC showed nearly complete consumption of
the starting material. The solvent was reduced in volume, and the residue was
adsorbed on silica gel. The adsorbed residue was applied to flash silica gel on a
biotage column that was eluted with MeOH/CHCl3 (0:100--5:95). Evaporation of
the eluting solvent yielded pale yellow foam. This foam was dissolved in a
minimum amount of CH2Cl2 and precipitated by adding hexane. Evaporation of
CH2Cl2/hexane from the precipitate afforded 13 as pale yellow powder (250 mg,
88% yield). 1H NMR (300 MHz, CDCl3): d (ppm) 2.22 (1H, dd, J = 5.4 and 14.1 Hz,
H2’), 3.02--3.38 (5H, m, ethylene, and H2’’), 3.55 (1H, d, J = 12.9 Hz, H5’), 3.8 (1H,
d, J = 12.9 Hz, H5’’), 4.21 (1H, s, H4’), 5.0--5.17 (5H, m, CH2 (Bn), and H3’), 5.77
(2H, br s, NH2), 6.13 (1H, dd, J = 5.1 and 9.9 Hz, H1’), 6.73 (1H, br s, OH5’), 7.31--
7.38 [10H, m, Ph (Bn)], 7.65 [1H, dd, J = 1.5 and 7.8 Hz, H3 (AQ)], 7.78--7.82 [2H,
m, H6 (AQ) and H7 (AQ)], 8.22--8.33 [5H, m, H2 (dA), H4 (AQ), H1 (AQ), H5
(AQ), and H8 (AQ)]. 13C NMR (125 MHz, CDCl3): d (ppm) 29.01 [dA-CH2
(ethyl)], 33.01 [AQ-CH2 (ethyl)], 38.16 (C2’), 63.01 (C5’), 69.71 [d, JP--C = 1, CH2
(Bn)], 80.21 (C3’), 85.67, 87.60 (C1’ and C4’), 119.38 [C5 (dA)], 127.22 [C8 (dA)],
127.83, 128.20, 128.7, 128.83 [AQ and Ph (Bn)], 132.05 (AQ), 133.45 [d, JP--C = 3.1,
Ph-C1 (Bn)], 133.63 (AQ), 134.09, 134.20, 134.32, 135.41, 135.46 [AQ and Ph (Bn)],
147.01, 149.78 (AQ), 150.62 [C4 (dA)], 151.75 [C2 (dA)], 155.08 [C6 (dA)], 182.82
(CO), and 183.17 (CO). 31P NMR (162 MHz, CDCl3): d (ppm) À1.23. Low-
resolution ESI MS m/z (M + H)+: Calc’d 746.24, found 746.24.
8-[2-(Anthraquinone-2-yl)ethyl]-2’-deoxyadenosine 3’-benzyl
hydrogen phosphate, 2. Compound 13 (210 mg, 0.28 mmol) was
dissolved in a mixture of EtOAc (10 mL) and MeOH (80 mL). The resulting
solution was transferred to a hydrogenation vessel containing 10% Pd/C (30 mg) that
had been activated by stirring under H2 (40 psi) in MeOH (20 mL) for 30 min at
room temperature. The vessel was next charged with H2 gas and then degassed
using an aspirator in a cycle that was repeated 5--6 times. The vessel was finally

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
103
charged with hydrogen gas at 40 psi and stirred at room temperature for 24 h, at
which time TLC showed that some 13 was still present. More 10%Pd/C (20 mg) was
added, and the hydrogenation vessel was recharged with H2 as described above.
The mixture was stirred at room temperature for an additional 7 h under H2 gas (45
psi), by which time TLC showed complete consumption of 13. The Pd/C catalyst
was then removed by filtration over celite, and adsorbed nucleotide residue was
extracted from the catalyst by washing with boiling MeOH. The crude product was
then purified by preparative HPLC using a Varian Microsorb C-18 reverse-phase
column (250 mm  41.4 mm dia.). The column was eluted with a flow rate of
40 mL/min, and the fractions were monitored with UV detection at 260 nm. The
mobile phase consisted of a programmed gradient of solution A (70% MeCN in
water) and solution B (water): from 0% A/100% B to 50% A/50% B over 15 min, then
to 100% A/0% B over 5 min, and finally at 100%A/0% B for another 10 min.
Evaporation of the eluent was facilitated by co-evaporation with MeOH and
1
afforded 2 as yellow plates (30 mg, 22% yield). H NMR (500 MHz, DMSO-d6): d
(ppm) 2.33 (1H, ddd, J = 3.5, 6.5, and 13 Hz, H2’), 2.98--3.04 (1H, m, H2’’), 3.25--3.4
(4H, m, ethylene), 3.45--3.49 (1H, m, H5’), 3.5--3.58 (1H, m, H5’’), 4.01 (1H, d, J = 3
Hz, H4’), 4.71 [2H, d, JH--P = 5 Hz, CH2 (Bn)], 4.87--4.96 (1H, m, H3’), 6.12 (1H, br
d, J = 7 Hz, OH5’), 6.28 (1H, t, J = 7 Hz, H1’), 7.15 (2H, br s, NH2), 7.18 [1H, t,
J = 7.5 Hz, Ph-para (Bn)], 7.25 [2H, t, J = 7.5, Ph-meta (Bn)], 7.33 [2H, d, J = 7.5 Hz,
Ph-ortho (Bn)], 7.87 [1H, d, J = 8 Hz, H3 (AQ)], 7.91--7.93 [2H, m, H6 (AQ) and H7
(AQ)], 8.05 [1H, s, H2 (dA)], 8.12--8.14 [2H, m, H1 (AQ) and H4 (AQ)], and 8.18--
1
8.22 [2H, m, H5 (AQ) and H8 (AQ)]. H NMR (500 MHz, DMSO-d6+ D2O): d
(ppm) 2.3--2.38 (1H, m, H2’), 2.98--3.04 (1H, m, H2’’), 3.25--3.4 (4H, m, ethylene),
3.52--3.6 (2H, m, H5’ and H5’’), 4.05 (1H, s, H4’), 4.71 [2H, d, JH--P = 5 Hz, CH2
(Bn)], 4.86 (1H, s, H3’), 6.27 (1H, t, J = 7 Hz, H1’), 7.18 [1H, t, J = 7.5 Hz, Ph-para
(Bn)], 7.25 [2H, t, J = 7.5, Ph-meta (Bn)], 7.32 [2H, d, J = 7.5 Hz, Ph-ortho (Bn)], 7.87
[1H, d, J = 8 Hz, H3 (AQ)], 7.91 [2H, s, H6 (AQ) and H7 (AQ)], 8.04 [1H, s, H2
(dA)], 8.1--8.13 [2H, m, H1 (AQ) and H4 (AQ)], and 8.19 [2H, m, H5 (AQ) and H8
(AQ)]. 13C NMR (125 MHz, DMSO-d6): d (ppm) 28.34 [dA-CH2 (ethyl)], 32.72
[AQ-CH2 (ethyl)], 37.15 (C2’), 62.42 (C5’), 65.96 [d, JC--P = 1 Hz, CH2 (Bn)], 75.4 (d,
J = 20.3 Hz, C3’), 84.16 (C4’), 86.79 (C1’), 118.18 [C5 (dA)], 126.71 [C8 (dA)], 127.03,
128.05, 131.28 [AQ and Ph (Bn)], 132.98, 133, 134.52, 134.92 (AQ), 139.5 [d,
JC--P = 7.4, Ph-C1 (Bn)], 148.15, 149.79 (AQ), 150.82 [C4 (dA)], 151.63 [C2 (dA)],
155.49 [C6 (dA)], 182.22 (CO), and 182.53 (CO). 31P NMR (202 MHz, DMSO-d6): d
(ppm) 0.77. Low-resolution ESI MS m/z (M--H)À: Calc’d 654.18, found 654.20.
2-Iodoanthraquinone, 15. To a suspension of 14 (3.06 g, 0.137 mol) in
THF (21 mL) was added HCl (28 mL) and water (7 mL). The mixture was stirred at
40°C for 24 h to give a thick, rosey beige suspension. This suspension was cooled to
0°C using an ice-water bath, and a solution of NaNO2 (1.90 g, 0.027 mol, 2 equiv.)
in H2O (6.5 mL) was added drop-wise with a syringe. A solution of KI (5.69 g, 0.034
mol, 2.5 equiv.) in H2O (12.5 mL) was added gradually to the reaction mixture

104
R. A. I. Abou-Elkhair and T. L. Netzel
while stirring at 0°C. The reaction mixture was then stirred for an additional 15 min
at 0°C, for 30 min at room temperature, and finally for 30 min at 60°C. THF was
evaporated from the mixture, and the residue was filtered. The precipitate was
collected and washed first with water and then with a saturated solution of aqueous
Na2CO3. The residue was dissolved in CHCl3 (54 mL), and the solution was shaken
with an aqueous solution of Na2S2O3. The CHCl3 layer was separated, dried with
anhydrous MgSO4, and evaporated to dryness. Three consecutive silica gel columns
eluted with CH2Cl2/hexane (10:90--30:70) afforded 15 as yellow powder (3.42 g,
1
75% yield). H NMR (300 MHz, CDCl3): d (ppm) 7.83 (2H, m, H7), 8.01 (1H, d,
J = 8.4, H4), 8.16 (1H, dd, J=8.4, 1.5, H3), 8.30--8.33, (2H, m, H5, and H8), and 8.66
(1H, s, H1). 13C NMR (75 MHz, CDCl3): d (ppm) 127.30, 128.6, 132.5, 133, 133.27,
134, 134.34, 136.23, 143.06, 181.87, and 182.58. Low-resolution EI MS m/z (M+): 334.
2-(Trimethylsilanylethynyl)anthraquinone, 16. Pd(Ph3P)2Cl2
(24 mg, 0.03 mmol, 0.05 equiv.), CuI (13.1 mg, 0.07 mmol, 0.1 equiv.), TEA
(0.19 mL, 1.38 mmol, 2 equiv.), and 15 (229.8 mg, 0.69 mmol) were combined and
stirred in dry THF (4.6 mL) under a nitrogen atmosphere until dissolved; then
TMSA (0.23 mL, 2.064 mmol, 3 equiv.) was added. After 10 minutes of stirring at
room temperature, TLC (CH2Cl2/hexanes, 1:1 v:v) showed complete consumption
of 15. The solvent was evaporated in vacuo, and the crude material was purified by
flash silica gel chromatography (CH2Cl2/hexanes, 0:100--20:80 v:v) to give 16 as
1
pale yellow solid (210 mg, 96% yield). H NMR (300 MHz, CDCl3): d (ppm) 0.3
(9H, s, 3 Â CH3), 7.84--7.77 (3H, m, H4, H6, and H7), 8.234 (1H, dd, J = 8.1, 0.3,
H3), 8.319--8.268 (2H, m, H5, and H8), and 8.35 (1H, dd, J = 1.5, 0.3, H1). 13C
NMR (75 MHz, CDCl3): d (ppm) À0.27, 100.11, 103.14, 126.21, 127.26, 127.29,
129.30, 130.62, 132.44, 133.26, 133.33, 133.45, 134.17, 134.26, 136.80, 182.43, and
182.47. Low-resolution EI MS m/z (M+): 304.
2-Ethynylanthraquinone, 6. To a solution of 16 (200 mg, 0.657
mmol) in THF/MeOH (1:1 v:v, 26 mL) was added potassium fluoride (57.26 mg,
0.985 mmol, 1.5 equiv.) at room temperature. After 1 h the solvent was evaporated;
the product was extracted with CHCl3, shaken with charcoal, and recrystallized
from CHCl3 to afford 6 as brown solid (150 mg, 99% yield). NMR spectra were run
1
on a pale yellow, silica gel purified portion of this product. H NMR (300 MHz,
CDCl3): d (ppm) 3.37 (1H, s, ꢁ C--H), 7.82 (2H, dd, J = 5.7, 3.3, H6, H7), 7.67 (1H,
dd, J = 8.1, 1.8, H3), 8.34--8.27 (3H, m, H4, H5, H8), and 8.41 (1H, d, J = 1.5, H1).
13C NMR (75 MHz, CDCl3): d (ppm) 81.88, 127.33, 130.85, 134.3, 134.36, 137.1,
and 182.42. EI MS m/z (M+): 232.
CONCLUSIONS
Working with 6 as described in Schemes 1 and 2 to make, respectively, the 3’-
benzyl phosphates 1 and 2 imposes synthetic constrains due to the photo-instability

Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
105
of 6 and the poor solubility of anthraquinonyl intermediates. Nevertheless, careful
control of reaction conditions, including avoiding short wavelength light when using
6, allows synthesis of 1 and 2 and their precursors on a few-gram scale. Based on
our experience with the chemistry in Schemes 1--3, a common modification to
Schemes 1 and 2 appears worth investigating in the future as a means of possibly
making the 3’-phosphate conjugates 1 and 2 and related AQ-dA nucleosides with
less effort and in larger quantities. This alternate chemistry would switch the order
of the alkynylation steps in each scheme. Schemes 1 and 2 alkynylate 2-
iodoanthraquinone (15) with TMSA first and then Pd cross-couple the resulting 6
with the 5’-protected 8-bromo-2’-deoxyadenosines, respectively, 5 and 9. An
interesting modification of these two schemes would alkynylate their 5’-protected 8-
bromo-2’-deoxyadenosines with TMSA first and then Pd cross-couple the resulting
5’-protected 8-ethynyl-2’-deoxyadenosines with 15. One clear advantage of such a
switched reaction order would be that use of photochemically unstable 6 would be
avoided. A second and also important advantage would be that 5’-protected 8-
ethynyl-2’-deoxyadenosine intermediates would replace the 5’-protected 8-bromo-2’-
deoxyadenosines 5 and 9. Thus, in these two cases the vexing coincidence of Rf
values for intermediates 5 and 7 and 9 and 10 would also be eliminated. In short,
the work presented here provides a sound basis for synthesizing the 3’-benzyl
phosphates 1 and 2 for investigation of their electrochemical reduction and
photoinduced intramolecular ET properties in water. Lacking the solubilizing effect
of the 3’-benzyl phosphate group, the nucleosides 1a and 2a are insoluble in water,
and thus these physical chemical experiments cannot be done on them. Finally,
future synthesis of AQ-dA--substituted DNA oligomers based on standard solid-
phase synthetic protocols appears achievable based either on the chemistry of
Schemes 1--3 themselves or on variations of Schemes 1 and 2 that use a switched
order of alkynylation.
LIST OF ABBREVIATIONS
(BnO)2PN(iPr)2 Dibenzyl N,N-diisopropylphosphoramidite
(BnO)2POCl
(EtO)2POCl
4-DMAP
AQ
Dibenzyl phosphorochloridate
Diethyl phosphorochloridate
4-(Dimethylamino)pyridine
Anthraquinone
AQ. À
AQ*
Anthraquinone anion radical
3
Lowest energy (p,p*) state of anthraquinone
AQSÀ
CS
dA
2-Anthraquinone sulfonic acid sodium salt
Charge separated
2’-Deoxyadenosine
m-CPBA
DABCO
DCA
meta-Chloroperbenzoic acid
1,4-Diazabicyclo[2,2,2]octane
Dichloroacetic acid

106
R. A. I. Abou-Elkhair and T. L. Netzel
DMF
DMTrCl
ET
N,N-Dimethylformamide
4,4’-Dimethoxytrityl chloride
Electron transfer
EtOAc
HPLC
Im
Ethyl acetate
High-performance liquid chromatography
Imidazole
MeCN
MeOH
Me-tetrazol
Pd
Acetonitrile
Methanol
5-Methyl-1H-tetrazol
Palladium
Pd/C
Palladium on activated carbon catalyst
Tetrakis(triphenylphosphine) palladium(0)
Dichlorobis(triphenylphoshine) palladium(II)
Pyridine
Pd(Ph3P)4
Pd(Ph3P)2Cl2
Py
rt
SCS
TA
TBDPSCl
TEA
Room temperature
Secondary charge-separated
Transient absorbance
tert-Butyldiphenylsilyl chloride
Triethylamine
tert-BuMgCl
TFA
THF
tert-Butylmagnesium chloride
Trifluoroacetic acid
Tetrahydrofuran
TLC
Thin-layer chromatography
Trimethylsilylacetylene
Trimethylsilyl bromide
Trimythylsilyl chloride
TMSA
TMSBr
TMSCl
ACKNOWLEDGMENTS
We thank Jerry Rose of the Southern Research Institute, Birmingham, AL for
helpful discussions on the synthesis of 8-bromo-2’-deoxyadenosine; Dr. Steve
Patterson of Pharmasset Inc., Tucker, Georgia for HPLC purification of compounds
1 and 2; and Dr. Siming Wang of GSU for MS analyses. We also thank the
donors of The Petroleum Research Fund, administered by the ACS, for support of
this research.
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Synthesis of Two 8-[(AQ-2-yl)-linked]-dA 3’-Benzyl Hydrogen Phosphates
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